anticoagulation in diagnostic and interventional procedure and monitoring and antiplatelet drugs
DESCRIPTION
seminar on anticoagulationTRANSCRIPT
Anticoagulation in Anticoagulation in Diagnostic and Diagnostic and
Interventional Procedure Interventional Procedure and Monitoring and and Monitoring and Antiplatelet DrugsAntiplatelet Drugs
Moderator Prof RV PhadkeModerator Prof RV Phadke Presenter Dr Deb K BoruahPresenter Dr Deb K Boruah 2626thth November rsquo09 November rsquo09
The Blood Clotting MechanismThe Blood Clotting MechanismThe three mechanisms of Blood Clotting areThe three mechanisms of Blood Clotting are Vascular SpasmVascular Spasm - The smooth muscle in blood vessel - The smooth muscle in blood vessel
walls contracts immediately the blood vessel is walls contracts immediately the blood vessel is broken This response reduces blood loss for some broken This response reduces blood loss for some time while the other hemostatic mechanisms become time while the other hemostatic mechanisms become activeactive
Platelet Plug FormationPlatelet Plug Formation - When blood platelets - When blood platelets encounter a damaged blood vessel they form a encounter a damaged blood vessel they form a platelet plugplatelet plug to help to close the gap in the broken to help to close the gap in the broken blood vessel (The key stages of this process are blood vessel (The key stages of this process are called called platelet adhesionplatelet adhesion platelet release platelet release reactionreaction and and platelet aggregationplatelet aggregation))
Blood Clotting Blood Clotting (Coagulation)(Coagulation) - - Blood normally remains in its liquid state while Blood normally remains in its liquid state while
it is within the blood vessels but when it leaves it is within the blood vessels but when it leaves them the blood may thicken and form a gel them the blood may thicken and form a gel (coagulation) (coagulation)
Blood clotting (technically Blood clotting (technically blood blood coagulationcoagulation) is the process by which (liquid) ) is the process by which (liquid) blood is transformed into a solid stateblood is transformed into a solid state
bull Interventional procedures
Virchowrsquos Triad
Mechanism of blood Mechanism of blood coagulationcoagulation
HemostasisHemostasis involves a sequence of interactions of coagulation involves a sequence of interactions of coagulation
factor interactions in two pathways called the factor interactions in two pathways called the intrinsic and extrinsic coagulation cascades intrinsic and extrinsic coagulation cascades
The final common pathway involves the The final common pathway involves the transformation of prothrombin to thrombin by factor transformation of prothrombin to thrombin by factor Xa Xa
Thrombin (factor IIa) then serves to catalyze the Thrombin (factor IIa) then serves to catalyze the activation of fibrinogen to fibrin in addition to its role activation of fibrinogen to fibrin in addition to its role in feedback activation of several other clotting factorsin feedback activation of several other clotting factors
UFH LMWH and fondaparinux( saccharides) all UFH LMWH and fondaparinux( saccharides) all exert their anticoagulant effect in a similar fashion by exert their anticoagulant effect in a similar fashion by binding to and activating antithrombinbinding to and activating antithrombin that then that then neutralizes selected coagulation factorsneutralizes selected coagulation factors
Stages of blood coagulationStages of blood coagulation Formation of Formation of ProthrombinaseProthrombinase
Prothrombinase can be formed in two ways depending of which of Prothrombinase can be formed in two ways depending of which of two systems or pathways apply two systems or pathways apply
Intrinsic SystemIntrinsic System This is initiated by liquid blood making contact with a foreign This is initiated by liquid blood making contact with a foreign
surface ie something that is not part of the body surface ie something that is not part of the body Extrinsic SystemExtrinsic System
This is initiated by liquid blood making contact with damaged This is initiated by liquid blood making contact with damaged tissuetissue
Both the intrinsic and the extrinsic systems involve interactions Both the intrinsic and the extrinsic systems involve interactions between between coagulation factorscoagulation factors
2 2 ProthrombinProthrombin converted into the enzyme converted into the enzyme ThrombinThrombinProthrombinase (formed in stage 1) converts prothrombin which is Prothrombinase (formed in stage 1) converts prothrombin which is a plasma protein that is formed in the liver into the enzyme a plasma protein that is formed in the liver into the enzyme thrombinthrombin
3 3 FibrinogenFibrinogen (soluble) converted to (soluble) converted to FibrinFibrin (insoluble) (insoluble)In turn thrombin converts fibrinogen into fibrin Fibrin is insoluble In turn thrombin converts fibrinogen into fibrin Fibrin is insoluble and forms the threads that bind the clotand forms the threads that bind the clot
BLOOD COAGULATION
A sequence of reactions that are present in an inactive state in bloodKey is the conversion of the plasma protein fibrinogen to fibrin Intrinsic pathway Extrinsic pathway(activated by exposure of (activated by substances blood to damaged tissue) released from damaged tissue)
Active factors X and V
Prothrombin Thrombin
Fibrinogen Fibrin Fibrin mesh
inhibited by warfarin
inhibited by heparin
Rationale for anticoagulant Rationale for anticoagulant therapytherapy
PHARMACOLOGICAL PHARMACOLOGICAL AGENTSAGENTS
Pharmacologic AgentsPharmacologic Agents
AnticoagulantsAnticoagulants
Fibrinolytics (Agents for pharmacological Fibrinolytics (Agents for pharmacological recanalization)recanalization)
Anti platelet drugsAnti platelet drugs
Thrombin inhibitorThrombin inhibitor
ANTICOAGULANTSANTICOAGULANTS
Heparin and Low Molecular Weight Heparins Heparin and Low Molecular Weight Heparins ((eg enoxaparin dalteparin)eg enoxaparin dalteparin)
Oral anticoagulantsOral anticoagulants Coumarin Derivatves Coumarin Derivatves eg Warfarin eg Warfarin
AcenocoumarolAcenocoumarol Indandione Derivatves Indandione Derivatves eg Phenindione eg Phenindione
AnisindioneAnisindione
ThrombolyticsThrombolytics
Plasminogen activators
Fibrinolytics
Anti Platelet DrugsAnti Platelet DrugsDrug Mechanism UsesDrug Mechanism UsesAspirinAspirin Permanently inhibits Permanently inhibits
COX-1 and COX-2COX-1 and COX-2CADCAD
Stroke-TIAsStroke-TIAs
NSAIDsNSAIDs Reversibly inhibits Reversibly inhibits COX-1COX-1
LimitedLimited
DipyridamoleDipyridamole Inhibits PDE Inhibits PDE increases cAMPincreases cAMP
TIAsTIAs
ThenopyridinesThenopyridines
(Ticlopidine(Ticlopidine
Clopidegrel)Clopidegrel)
Inhibits ADP Inhibits ADP
PlatAg PlatAg
TIAsStrokeTIAsStroke
CAD PVDCAD PVD
Abciximab (ReoPro)Abciximab (ReoPro)
Eptifibatide Eptifibatide (Integrilin)(Integrilin)
TirofibaTirofibann
GP IIBIIIA InhibitorsGP IIBIIIA Inhibitors
Stroke- TIAs Stroke- TIAs
Maintainance of patency Maintainance of patency of vascular of vascular grafts catheters shunts bypassesgrafts catheters shunts bypasses
Arterial thromboembolic diseaseArterial thromboembolic diseasebull Transient ischemic attacksTransient ischemic attacksbull Stroke in evolutionStroke in evolution
Ischemic events occurs in Ischemic events occurs in 1313 of of conventional neuroangiographic conventional neuroangiographic procedures without Endovascular surgeryprocedures without Endovascular surgery
Indications for Antithrombotic Therapy in Indications for Antithrombotic Therapy in Diagnostics and Interventional ProceduresDiagnostics and Interventional Procedures
WHY TO MONITOR ANTICOAGULANT THERAPYWHY TO MONITOR ANTICOAGULANT THERAPY
Narrow therapeutic rangeNarrow therapeutic range
Can increase risk of bleedingCan increase risk of bleeding
Coagulation TestingCoagulation Testing
Monitoring therapyMonitoring therapy
Intrinsic Pathway
Extrinsic Pathway
Common Pathway
CLOT
Heparin Coumadin
Monitor with
ACT aPTT
Monitor with PTINR
Thrombolytics
Monitor with TT Fibrinogen
Monitoring of Monitoring of Anti platelet drugsAnti platelet drugs
Bleeding timeBleeding time
Optical aggregometryOptical aggregometry
Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay
HeparinHeparin
Heterogeneous 3000-30000 dalton in Heterogeneous 3000-30000 dalton in molecular weight molecular weight
Average=15000 d (~45monosaccharide Average=15000 d (~45monosaccharide chains)chains)
About About 13 of dose binds to AT III and forms 13 of dose binds to AT III and forms the AT IIIHeparinClotting Factor Complexthe AT IIIHeparinClotting Factor Complex
Complex binds to clotting factors of the Complex binds to clotting factors of the intrinsic and common pathway (Xa IIa IXa intrinsic and common pathway (Xa IIa IXa XIa XIIa XIIIa) and inactivates themXIa XIIa XIIIa) and inactivates them
Anticoagulant of choice in pregnancy (not Anticoagulant of choice in pregnancy (not crosses placenta)crosses placenta)
Heparin and Low molecular weight heparinsHeparin and Low molecular weight heparins
Structure and sequence
O
OH
OH
O
COO
O
O
CH2OH
NHSO3
OH
_
_
O
O
CH2OSO3
NHSO3
OH
_
_
O
OH
OH
O
COOO
O
CH2OSO3
NHSO3
OH
_
_
O
OSO3
OHO
COOO
O
CH2OSO3
NHCOCH3
OH
_
_ _
_
_
O
OH
OH
O
COO
1
23
4
5
6
-D-glucosamine -L-iduronic acid -D-glucuronic acid
O
O
CH2OH
NH2
OH 12
3
4
5
6
O
OH
OHO
COO_
1
23
4
5
6
polymeric structure of heparin
Anticoagulant Properties of Anticoagulant Properties of HeparinHeparin
11 Inhibits the thrombin-mediated conversion of Inhibits the thrombin-mediated conversion of fibrinogen to fibrinfibrinogen to fibrin
22 Inhibits the aggregation of platelets by thrombin Inhibits the aggregation of platelets by thrombin (prolongs bleeding time)(prolongs bleeding time)
33 Inhibits activation of fibrin stabilizing enzymeInhibits activation of fibrin stabilizing enzyme
44 Inhibits activated factors XII XI IX X and IIInhibits activated factors XII XI IX X and II All available forms of heparin must be All available forms of heparin must be
administered administered parenterally since they are parenterally since they are highly charged and rapidlyhighly charged and rapidly hydrolyzed in the hydrolyzed in the GI tractGI tract
Heparin antagonist Protamine sulfate (Heparin antagonist Protamine sulfate (10mg for 10mg for 1000 unit of heparin)1000 unit of heparin)
Monitoring of heparin Monitoring of heparin
Subcutenous Subcutenous no monitoring requiredno monitoring required Intravenous Intravenous
Partial thromboplastin time (PTT normal value Partial thromboplastin time (PTT normal value ~30sec) ~30sec)
Activated clotting time ( ACT normal value ~90-Activated clotting time ( ACT normal value ~90-120sec)120sec)
Daily or more frequent if PTT ACT variesDaily or more frequent if PTT ACT varies
Mechanism Mechanism ndash measures intrinsic pathwayndash measures intrinsic pathway Therapeutic goal Therapeutic goal 2-25 times normal control value 2-25 times normal control value
ACT or aPTTACT or aPTT
Determine when to pull the femoral sheath Determine when to pull the femoral sheath Premature sheath pull can lead to bleedingPremature sheath pull can lead to bleeding Delayed removal can increase time in ICUDelayed removal can increase time in ICU Target set Target set at each siteat each site
ACT targets range from 150 ndash 220 ACT targets range from 150 ndash 220 secondsseconds
aPTT targets range from 40 ndash 70 seconds aPTT targets range from 40 ndash 70 seconds
During neuroangiography-During neuroangiography- Recommended therapeutic range of heparin in Recommended therapeutic range of heparin in
plasma is 02-08 uml ( corresponding to aPTT plasma is 02-08 uml ( corresponding to aPTT ACT values 15-25 times the baseline values)ACT values 15-25 times the baseline values)
Dose In diagnostic angiography bolus dose of Dose In diagnostic angiography bolus dose of 2500 iu is used followed by 1000 iu hour2500 iu is used followed by 1000 iu hour
Bolus dose is Bolus dose is 60 ukg to maintain the therapeutic 60 ukg to maintain the therapeutic range range If procedure continues for more than 75 If procedure continues for more than 75 minutes additional dose is required ( half of the minutes additional dose is required ( half of the initial dose for another 75 minutes) initial dose for another 75 minutes)
(AJNR 199415 51-54)
Mechanisms of HIT( Mechanisms of HIT( Heparin Heparin induced Thrombocytopeniainduced Thrombocytopenia))
Type 1Type 1 Fall in platelet count occurs within the first two Fall in platelet count occurs within the first two
days after heparin initiation often returns to days after heparin initiation often returns to normal with continued heparin administration normal with continued heparin administration and is of no clinical consequence and is of no clinical consequence
The mechanism of the thrombocytopenia is non-The mechanism of the thrombocytopenia is non-immune and appears to be due to a direct effect of immune and appears to be due to a direct effect of heparin on platelet activationheparin on platelet activation
Type 2Type 2 Approximately 03 to 3 percent of patients Approximately 03 to 3 percent of patients
receiving heparin develop an immune receiving heparin develop an immune thrombocytopenia mediated by antibodies to a thrombocytopenia mediated by antibodies to a heparin-platelet factor 4 complex heparin-platelet factor 4 complex
(AJNR 28155-158 2007)
Treatment of heparin-induced Treatment of heparin-induced thrombocytopeniathrombocytopenia
When HIT is diagnosed it is important to When HIT is diagnosed it is important to stop heparin mainly in type 2 and to avoid stop heparin mainly in type 2 and to avoid the use of LMWH the use of LMWH
Because of the increased risk of thrombosis Because of the increased risk of thrombosis however continuation of an anticoagulant however continuation of an anticoagulant must be considered must be considered
The drugs currently approved for the The drugs currently approved for the treatment of HIT in the United States are treatment of HIT in the United States are direct thrombin inhibitors argatroban and direct thrombin inhibitors argatroban and lepirudinlepirudin
WARFARIN MECHANISM OF ACTIONWARFARIN MECHANISM OF ACTION
Inactive factors II VII IX and X
Proteins S and C
Active factors II VII IX and X
Proteins S and C
Vitamin K epoxide
Vitamin K reduced
WA
RF
AR
IN
Prevents the reduction of vitamin K which is essential for Prevents the reduction of vitamin K which is essential for activation of certain factorsactivation of certain factors
Has no effect on previously formed thrombusHas no effect on previously formed thrombus
Antagonist is Vit KAntagonist is Vit K
OPTIMIZING WARFARIN THERAPYOPTIMIZING WARFARIN THERAPY
Use of large loading dose may lead to hemorrhage and Use of large loading dose may lead to hemorrhage and other complicationsother complications
Initial dose 2-5 mg once dailyInitial dose 2-5 mg once daily Maintenance dose 2-10 mg once dailyMaintenance dose 2-10 mg once daily If Immediate anticoagulation is requiredIf Immediate anticoagulation is required Heparin IS Heparin IS
started along with loading dose of warfarin 10 mg started along with loading dose of warfarin 10 mg Heparin is usually discontinued after 4-5 days Heparin is usually discontinued after 4-5 days Before Before discontinuing INR should be in therapeutic range for 2 discontinuing INR should be in therapeutic range for 2 consecutive daysconsecutive days
Daily monitoring of INR until INR is in therapeutic Daily monitoring of INR until INR is in therapeutic range then 3 times weekly for 1-2 weeks then less often range then 3 times weekly for 1-2 weeks then less often (every 4 to 6 weeks)(every 4 to 6 weeks)
OPTIMAL THERAPEUTIC RANGEOPTIMAL THERAPEUTIC RANGE
IndicationIndication INRINR
Prophylaxis of venous Prophylaxis of venous thromboembolismthromboembolism
20-3020-30
Treatment of venous Treatment of venous thromboembolismthromboembolism
20-3020-30
Atrial fibrillationAtrial fibrillation 20-3020-30
Mitral valve stenosisMitral valve stenosis 20-3020-30
Heart valve replacementHeart valve replacement
Bioprosthetic valveBioprosthetic valve
Mechanical valveMechanical valve
20-3020-30
25-3525-35
Myocardial infarctionMyocardial infarction 20-3020-30
25-35 25-35 (high risk patients)(high risk patients)
FACTORS INFLUENCING DOSE RESPONSEFACTORS INFLUENCING DOSE RESPONSE
Poor patient compliancePoor patient compliance Concomitant medicationsConcomitant medications Levels of dietary vitamin KLevels of dietary vitamin K Alcohol Inaccurate lab testingAlcohol Inaccurate lab testing Inaccurate lab testingInaccurate lab testing Hepatic dysfunctionHepatic dysfunction FeverFever
Contraindication for WarfarinContraindication for Warfarin
Hypersensitivity to warfarinHypersensitivity to warfarin Hemorrhagic tendencyHemorrhagic tendency Condition with risk of hemorrhageCondition with risk of hemorrhage Inadequate laboratory techniquesInadequate laboratory techniques Protein C amp S deficiencyProtein C amp S deficiency Vitamin K deficiencyVitamin K deficiency
SIDE EFFECTSSIDE EFFECTS
Hemorrhage Hemorrhage Skin necrosisSkin necrosis Purple toe syndromePurple toe syndrome Microembolization Microembolization TeratogenecityTeratogenecity Agranulocytosis leukopenia Agranulocytosis leukopenia Diarrhoeanausea anorexiaDiarrhoeanausea anorexia
MONITORING OF WARFARIN THERAPYMONITORING OF WARFARIN THERAPY
Prothrombin timeProthrombin time PT ratioPT ratio INR (International Normalized Ratio)INR (International Normalized Ratio)
PROTHROMBIN TIME (PT)PROTHROMBIN TIME (PT)
Time required for blood to coagulate Time required for blood to coagulate is called PT ( normal value ~10sec)is called PT ( normal value ~10sec)
Performed by adding a mixture of Performed by adding a mixture of calcium and thromboplastin to calcium and thromboplastin to citrated plasmacitrated plasma
As a control a normal blood sample is As a control a normal blood sample is tested continuouslytested continuously
PT ratio (PTR) = PT ratio (PTR) = Patientrsquos PTPatientrsquos PT Control PTControl PT
PROBLEMS WITH PTPTRPROBLEMS WITH PTPTR
Thromboplastins are extracts from Thromboplastins are extracts from brain lung or placenta of animalsbrain lung or placenta of animals
Thromboplastins from various Thromboplastins from various manufacturers differ in their manufacturers differ in their sensitivity to prolong PTsensitivity to prolong PT
May result in false control of May result in false control of anticoagulant therapyanticoagulant therapy
INTERNATIONAL NORMALISED RATIO (INR)INTERNATIONAL NORMALISED RATIO (INR)
International Normalized Ratio (INR) International Normalized Ratio (INR) a PT test with a a PT test with a formula based ratio to normalize the often variable source formula based ratio to normalize the often variable source of tissue factor (human rabbit recombinant)of tissue factor (human rabbit recombinant)
INR = [PTINR = [PTptpt] ] ISIISI
[PT[PTRefRef]]
PTPTpt pt ndash prothrombin time of patientndash prothrombin time of patient
PTPTRef Ref ndash prothrombin time of normal pooled samplendash prothrombin time of normal pooled sample
ISI ndash International Sensitivity IndexISI ndash International Sensitivity Index
Warfarin is given orally and titrated to achieve an INR of Warfarin is given orally and titrated to achieve an INR of typically 20 ndash 30typically 20 ndash 30
Heparin versus WarfarinHeparin versus Warfarin
Drug ActionMechan-ism
Moni-toring
Effective
HeparinDirect
Inhibition ofThrombin
ATIIIcofactor
APTTACT
Immediate
WarfarinDecreasesProductionof factors
Vitamin K PTDelay
3-5 days
INR
Recanalization or Antegrade Recanalization or Antegrade Reperfusion StrategiesReperfusion Strategies
Recanalization strategies focus on removing Recanalization strategies focus on removing andor dissolving the occlusive thrombus to re-andor dissolving the occlusive thrombus to re-establish antegrade flow Strategies may be establish antegrade flow Strategies may be classified into 7 different categories on the classified into 7 different categories on the basis of their primary mechanism of action basis of their primary mechanism of action 1) 1) IV andor intraarterial thrombolysis (IAT) IV andor intraarterial thrombolysis (IAT) 2) endovascular thrombectomy2) endovascular thrombectomy3) endovascular thromboaspiration 3) endovascular thromboaspiration 4) endovascular mechanical thrombus disruption or 4) endovascular mechanical thrombus disruption or
thromborrhexisthromborrhexis5) 5) transcranial or endovascular augmented transcranial or endovascular augmented
fibrinolysis fibrinolysis 6) endovascular thrombus entrapment and 6) endovascular thrombus entrapment and 7) temporary endovascular bypass7) temporary endovascular bypass
IAT in Acute Ischemic StrokeIAT in Acute Ischemic Stroke
IAT advantages over IV thrombolysisIAT advantages over IV thrombolysis Coaxial microcatheter techniques the occluded intracranial Coaxial microcatheter techniques the occluded intracranial
vessel is directly accessible and the fibrinolytic agent can be vessel is directly accessible and the fibrinolytic agent can be infused directly into the thrombusinfused directly into the thrombus
This permits a smaller dose of fibrinolytic agent to reach a This permits a smaller dose of fibrinolytic agent to reach a higher local concentration than that reached by systemic higher local concentration than that reached by systemic infusioninfusion
Allows more complete recanalization with lower total doses of Allows more complete recanalization with lower total doses of thrombolytic thrombolytic
With the smaller dose complications from systemic fibrinolytic With the smaller dose complications from systemic fibrinolytic effects including intracranial hemorrhage (ICH) can effects including intracranial hemorrhage (ICH) can theoretically be reduced theoretically be reduced
Treatment window for endovascular techniques can be Treatment window for endovascular techniques can be extended beyond the typical IV window of 3 hours extended beyond the typical IV window of 3 hours
IA techniques have led to higher recanalization rates than IV IA techniques have led to higher recanalization rates than IV thrombolysisthrombolysis
Major disadvantagesMajor disadvantages Relative complexity of the procedure the level Relative complexity of the procedure the level
of required technical expertise and its of required technical expertise and its relatively low availability relatively low availability
Delays in initiating treatmentDelays in initiating treatment InvasiveInvasive
ThrombolyticsThrombolytics
Plasminogen activators
Fibrinolytics
1 Plasminogen Activators 1 Plasminogen Activators drugs act by converting the inactive proenzyme drugs act by converting the inactive proenzyme plasminogen into the active enzyme plasmin Plasmin plasminogen into the active enzyme plasmin Plasmin digests fibrinogen fibrin monomers and cross-linked digests fibrinogen fibrin monomers and cross-linked fibrin (as found in a thrombus) into fibrin degradation fibrin (as found in a thrombus) into fibrin degradation productsproducts
First-Generation Agents First-Generation Agents StreptokinaseStreptokinase a protein derived from group C a protein derived from group C
szlig-hemolytic streptococci has a half-life of 16ndashszlig-hemolytic streptococci has a half-life of 16ndash90 minutes and low fibrin specificity This drug 90 minutes and low fibrin specificity This drug proved to have a very narrow therapeutic proved to have a very narrow therapeutic window and significant rates of ICH and window and significant rates of ICH and systemic hemorrhage18systemic hemorrhage18
UrokinaseUrokinase is a serine protease with a plasma is a serine protease with a plasma half life of 14 minutes and low fibrin specificity half life of 14 minutes and low fibrin specificity
The urokinase dose used in cerebral IAT has The urokinase dose used in cerebral IAT has ranged from 002 to 2 X106unitsranged from 002 to 2 X106units
Second-Generation Agents Second-Generation Agents Alteplase (rtPA) Alteplase (rtPA)
is a serine is a serine protease with a plasma half-life of 35 protease with a plasma half-life of 35 minutes and a high degree of fibrin affinity and minutes and a high degree of fibrin affinity and specificity specificity
Dose used in cerebral IAT has ranged between 20 Dose used in cerebral IAT has ranged between 20 and 60 mgand 60 mg
Disadvantages of alteplase include its relatively short Disadvantages of alteplase include its relatively short halflife and limited penetration into the clot matrix halflife and limited penetration into the clot matrix because of strong binding with surface fibrin which because of strong binding with surface fibrin which could delay recanalization and increase the risk of could delay recanalization and increase the risk of recurrent occlusion recurrent occlusion
Prourokinase (r-prourokinase) Prourokinase (r-prourokinase) is the proenzyme precursor of urokinase is the proenzyme precursor of urokinase T12 of 7 minutes and high fibrin specificity T12 of 7 minutes and high fibrin specificity
Third-Generation AgentsThird-Generation Agents
ReteplaseReteplase is a structurally modified is a structurally modified form of alteplase form of alteplase
with a longer half-life (15ndash18 minutes) In with a longer half-life (15ndash18 minutes) In addition it does not bind as highly to fibrin addition it does not bind as highly to fibrin unbound reteplase can thus theoretically better unbound reteplase can thus theoretically better penetrate the clot and potentially penetrate the clot and potentially improve in improve in vivo fibrinolytic activity vivo fibrinolytic activity
TenecteplaseTenecteplase is another modified form of rtPA with a longer is another modified form of rtPA with a longer
half-life (17 minutes)half-life (17 minutes) greater fibrin specificity and greater greater fibrin specificity and greater
resistance to plasminogen activator inhibitor-1 resistance to plasminogen activator inhibitor-1 IV tenecteplase in acute ischemic stroke IV tenecteplase in acute ischemic stroke
suggest that the drug is safe and promisingsuggest that the drug is safe and promising
Newer plasminogen activatorNewer plasminogen activator
DesmoteplaseDesmoteplase is a genetically engineered is a genetically engineered version of the clot-dissolving factor version of the clot-dissolving factor
found in the saliva found in the saliva of the vampire bat Desmodus rotundusof the vampire bat Desmodus rotundus moremore potent and more selective for fibrin-bound potent and more selective for fibrin-bound
plasminogen than any other known plasminogen plasminogen than any other known plasminogen activatoractivator
Unlike tissue plasminogen activator (tPA) desmoteplase Unlike tissue plasminogen activator (tPA) desmoteplase is not activated by fibrinogen or -amyloid proteins is not activated by fibrinogen or -amyloid proteins factors that may exacerbate the risk for ICH factors that may exacerbate the risk for ICH
The effect of IV administration of desmoteplase 3ndash9 The effect of IV administration of desmoteplase 3ndash9 hours after symptom onset in patients with stroke who hours after symptom onset in patients with stroke who present with mismatch on MR imaging or CT perfusion present with mismatch on MR imaging or CT perfusion
3 DefibrinogenatingFibrinogenolytic 3 DefibrinogenatingFibrinogenolytic Agents Agents
AncrodAncrod(Viprinex)(Viprinex) is is the purified fraction of the Malayan pit viper venomthe purified fraction of the Malayan pit viper venom It acts by directly cleaving and inactivating fibrinogen It acts by directly cleaving and inactivating fibrinogen
and thus indirectly promoting anticoagulation and thus indirectly promoting anticoagulation The reduction in the blood levels of fibrinogen also The reduction in the blood levels of fibrinogen also
leads to a reduced blood viscosity which may improve leads to a reduced blood viscosity which may improve blood flow to the affected areas of the brain blood flow to the affected areas of the brain
In the Stroke Treatment with Ancrod Trial 500 In the Stroke Treatment with Ancrod Trial 500 patients with stroke presenting within 3 hours of patients with stroke presenting within 3 hours of symptom onset were randomized to receive ancrod (symptom onset were randomized to receive ancrod (n n 248) or a placebo (n 252) Good outcome (Barthel 248) or a placebo (n 252) Good outcome (Barthel Index 95ndash100 at 3 months) was achieved in 4221 Index 95ndash100 at 3 months) was achieved in 4221 and 344 of the patients respectively and 344 of the patients respectively
2 Direct Fibrinolytics2 Direct Fibrinolytics
Microplasmin (Microplasmin (ThromboGenics Heverlee Belgium)ThromboGenics Heverlee Belgium) is a truncated form of plasmin that is more resistant to the effects is a truncated form of plasmin that is more resistant to the effects
of antiplasmin of antiplasmin microplasmin can be used upto 4ndash12 hours after stroke onset microplasmin can be used upto 4ndash12 hours after stroke onset There was no evidence of increased bleeding risk with There was no evidence of increased bleeding risk with
microplasminmicroplasmin
Alfimeprase (Nuvelo San Carlos Calif)Alfimeprase (Nuvelo San Carlos Calif) is a recombinant truncated form of fibrolase a fibrinolytic zinc metalloproteinase is a recombinant truncated form of fibrolase a fibrinolytic zinc metalloproteinase
isolated from the venom of the southern copperhead snake isolated from the venom of the southern copperhead snake It degrades fibrin directly and achieves thrombolysis independent It degrades fibrin directly and achieves thrombolysis independent
of plasmin formationof plasmin formation its thrombolytic activity appears to be localized to the site of its thrombolytic activity appears to be localized to the site of
delivery These properties should theoretically result in faster delivery These properties should theoretically result in faster recanalization and lower hemorrhagic conversion riskrecanalization and lower hemorrhagic conversion risk
Anti-fibrinolyticsAnti-fibrinolytics
to limit fibrinolytic activityto limit fibrinolytic activity -aminocaproic acid (EACA) -aminocaproic acid (EACA) competitively inhibitscompetitively inhibits plasminogen and plasminogen activators from plasminogen and plasminogen activators from
binding to fibrinbinding to fibrin
alpha2-antiplasminalpha2-antiplasmin a serine protease inhibitor that a serine protease inhibitor that neutralizes any free circulating plasminneutralizes any free circulating plasmin
Plasminogen activator inhibitor-1Plasminogen activator inhibitor-1 a serine protease a serine protease inhibitor that inhibits tissue-type plasminogen inhibitor that inhibits tissue-type plasminogen activatoractivator
Glycoprotein (GP) IIbIIIa antagonistsGlycoprotein (GP) IIbIIIa antagonists
such as ReoPro (abciximab) Integrilin such as ReoPro (abciximab) Integrilin (eptifibatide) or Aggrastat (tirofiban) in (eptifibatide) or Aggrastat (tirofiban) in ischemic stroke remains investigational ischemic stroke remains investigational Deshmukh et al38 reported 21 patients with Deshmukh et al38 reported 21 patients with large-vessel occlusion refractory to IAT with large-vessel occlusion refractory to IAT with rtPA who were treated with IV andor IA rtPA who were treated with IV andor IA abciximab eptifibatide or tirofiban abciximab eptifibatide or tirofiban
IA Mechanical Approaches in Acute Ischemic Stroke IA Mechanical Approaches in Acute Ischemic Stroke Mechanical strategies have several advantagesMechanical strategies have several advantages First they lessen and may even preclude the use of chemical First they lessen and may even preclude the use of chemical
thrombolytics in this manner very likely reducing the risk of ICHthrombolytics in this manner very likely reducing the risk of ICH Second by avoiding the use of chemical thrombolytics it is Second by avoiding the use of chemical thrombolytics it is
possible to extend the treatment window beyond the limit of 6ndash8 possible to extend the treatment window beyond the limit of 6ndash8 hours hours
Third mechanically fragmenting a clot increases the surface area Third mechanically fragmenting a clot increases the surface area accessible to fibrinolytic agents and allows inflow of fresh accessible to fibrinolytic agents and allows inflow of fresh plasminogen which in turn may increase the speed of plasminogen which in turn may increase the speed of thrombolysis thrombolysis
Finally clot-retrieval devices may provide faster recanalization Finally clot-retrieval devices may provide faster recanalization
The disadvantages of the mechanical The disadvantages of the mechanical approaches approaches technical difficulty of navigating mechanical technical difficulty of navigating mechanical
devices into the intracranial circulation excessive devices into the intracranial circulation excessive trauma to the vasculature (potentially leading to trauma to the vasculature (potentially leading to vasospasm vessel dissection perforation or vasospasm vessel dissection perforation or rupture) rupture)
fragmented thrombus causing distal embolization fragmented thrombus causing distal embolization into previously unaffected territories into previously unaffected territories
Nevertheless the advantages of mechanical stroke Nevertheless the advantages of mechanical stroke therapy appear to significantly outweigh its therapy appear to significantly outweigh its disadvantages and risksdisadvantages and risks
Contraindications to Thrombolytic Contraindications to Thrombolytic agents agents
Recent thoracic abdominal or Recent thoracic abdominal or intracranial surgeryintracranial surgery
Recent haemorrhagic CVA Head injury Recent haemorrhagic CVA Head injury or neoplasmor neoplasm
Bleeding ulcerBleeding ulcer Anticipated invasive procedures (arterial Anticipated invasive procedures (arterial
punctures biopsies)punctures biopsies) Concurrent hemostatic dysfunctionConcurrent hemostatic dysfunction
Monitoring of thrombolytic Monitoring of thrombolytic therapytherapy
Thrombin time Measures the availability of functional
fibrinogen Normal thrombin time is 10-14 sec Prolonged when fibrinogen level is below
75-100 mgdl
Half Life of ThrombolyticsHalf Life of ThrombolyticsAgent Administration Half Life
Streptokinase IA 60-80min
Urokinase IAIV 9-12min
rTPA IAIV 6min
Abciximab(Reopro) IAIV 12hour
Aspirin POIV 15-20min
Heparin IVSC 60min
Coumadin PO 15-25 days
Anti Platelet DrugsAnti Platelet DrugsDrug Drug Mechanism Mechanism UsesUsesAspirinAspirin Permanently inhibits Permanently inhibits
COX-1 and COX-2COX-1 and COX-2CADCAD
Stroke-TIAsStroke-TIAs
NSAIDsNSAIDs Reversibly inhibits Reversibly inhibits COX-1COX-1
LimitedLimited
DipyridamoleDipyridamole Inhibits PDE increases Inhibits PDE increases cAMPcAMP
TIAsTIAs
ThenopyridinesThenopyridines
(Ticlopidine(Ticlopidine
ClopidrgrelClopidrgrel))
Inhibits ADP Inhibits ADP
PlatAg PlatAg
TIAsStrokeTIAsStroke
CAD PVDCAD PVD
Abciximab (ReoPro)Abciximab (ReoPro)
Eptifibatide (Integrilin)Eptifibatide (Integrilin)
TirofibanTirofiban
GP IIBIIIA InhibitorsGP IIBIIIA Inhibitors
Stroke- TIAs Stroke- TIAs
MonitoringMonitoring
Bleeding timeBleeding time
Optical aggregometryOptical aggregometry
Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay
Bleeding timeBleeding time
Requires a skin incision (usually made on the ear lobe or Requires a skin incision (usually made on the ear lobe or forearm offorearm of
a depth that results in disruption of capillary loops and a depth that results in disruption of capillary loops and small vessels)small vessels)
AdvantagesAdvantages Universally availableUniversally available Relatively simple techniquesRelatively simple techniques Can be performed bedsideCan be performed bedside
DisadvantagesDisadvantages Insensitive inaccurate non-specific techniqueInsensitive inaccurate non-specific technique
Poorly reproducible (as depends on multiple variables)Poorly reproducible (as depends on multiple variables)
Optical aggregometryOptical aggregometry
Gold standard assay for platelet functionGold standard assay for platelet function Agonist induced aggregation is measuredAgonist induced aggregation is measured Different agonist are available for different Different agonist are available for different
agentsagents However require unique expertise and are not However require unique expertise and are not
universally availableuniversally available Aspirin measured with ADP or AA(gt70 Aspirin measured with ADP or AA(gt70
aggregation so resistance)aggregation so resistance) Clopidogrel( ADP gt 90 aggregation means Clopidogrel( ADP gt 90 aggregation means
resistance) resistance)
Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay
Can be performed bed sideCan be performed bed side Different assay devices with different Different assay devices with different
agonist are used for each of different agonist are used for each of different antiplatelet agents antiplatelet agents
For Aspirin AA is used (result is reported as aspirin For Aspirin AA is used (result is reported as aspirin reaction units [ARU] ARUgt 550 indicates non-reaction units [ARU] ARUgt 550 indicates non-responsiveness)responsiveness)
Verify IIbIIIa assay device uses TRAP as agonist for Verify IIbIIIa assay device uses TRAP as agonist for Abciximab and TirofibanAbciximab and Tirofiban
Practical Applications Practical Applications related to specific related to specific
Neurovascular Neurovascular interventionsinterventions
Acute ischemic StrokeAcute ischemic Stroke When an artery occludes neurons are affected When an artery occludes neurons are affected
differently depending upon the amount of residual blood differently depending upon the amount of residual blood flowflow
Normal cerebral blood flow is greater than 50 mL100 Normal cerebral blood flow is greater than 50 mL100 mgminmgmin
Once blood flow decreases to less than 20 mL100 Once blood flow decreases to less than 20 mL100 mgmin infarction occursmgmin infarction occurs
If blood flow decreases to less than 10 mL100 mgmin If blood flow decreases to less than 10 mL100 mgmin irreversible neuronal death occurs rapidly irreversible neuronal death occurs rapidly
Blood flow between 11 and 20 mL100 mgmin is thought Blood flow between 11 and 20 mL100 mgmin is thought to represent the ischemic penumbra an area where the to represent the ischemic penumbra an area where the cells are functionally silent because of ischemia but are cells are functionally silent because of ischemia but are still able to recover if blood flow is restored still able to recover if blood flow is restored
Many acute stroke therapies are targeted toward Many acute stroke therapies are targeted toward restoring flow or function to the ischemic penumbrarestoring flow or function to the ischemic penumbra
Therapeutic window in Therapeutic window in management of acute Ischemic management of acute Ischemic
StrokeStrokeThe early diagnosis of ischemic stroke is critical to the The early diagnosis of ischemic stroke is critical to the
with only a narrow therapeutic window in the first few with only a narrow therapeutic window in the first few hours following stroke ictushours following stroke ictus
Diagnosis in the first 3 hours postictus provides the Diagnosis in the first 3 hours postictus provides the opportunity for intravenous or intraarterial thrombolysis opportunity for intravenous or intraarterial thrombolysis and intra-arterial clot mechanical treatment which and intra-arterial clot mechanical treatment which improve the outcome improve the outcome
Diagnosis in the time period between 3 and 6 hours Diagnosis in the time period between 3 and 6 hours provides an opportunity for intra-arterial thrombolysis provides an opportunity for intra-arterial thrombolysis and mechanical treatment and mechanical treatment
Involvement of the posterior circulation especially the Involvement of the posterior circulation especially the basilar artery is treated by some regardless of time of basilar artery is treated by some regardless of time of onset or up until 12 to 24 hours in some practices This is onset or up until 12 to 24 hours in some practices This is related to the potentially high mortality and morbidity related to the potentially high mortality and morbidity associated with basilar artery thrombosisassociated with basilar artery thrombosis
Infarct evaluation on angiographyInfarct evaluation on angiography(CT angiography and catheter (CT angiography and catheter
angiography)angiography)CTA is an excellent first-line examination for CTA is an excellent first-line examination for
evaluation of the head and neck arteries evaluation of the head and neck arteries In comparison with catheter angiography In comparison with catheter angiography
what it gives up in resolution and dynamic what it gives up in resolution and dynamic properties it makes up for with rapid properties it makes up for with rapid acquisition of a 3-D dataset and the potential acquisition of a 3-D dataset and the potential for assessment of whole-brain perfusion and for assessment of whole-brain perfusion and better parenchymal evaluationbetter parenchymal evaluation
Moreover CTA illustrates not only arterial Moreover CTA illustrates not only arterial stenosis or occlusion but also the vessel wall stenosis or occlusion but also the vessel wall This factor is most important for evaluation of This factor is most important for evaluation of intramural dissection and thrombosed intramural dissection and thrombosed aneurysms which may both complicate aneurysms which may both complicate evaluation of stroke patientsevaluation of stroke patients
Early angiographic signs of strokes Early angiographic signs of strokes both CTA both CTA and DSA and DSA
Vessel occlusion or cutoff related to Vessel occlusion or cutoff related to thromboembolithromboemboli
aneurysms aneurysms arterial dissection arterial dissection Meniscus or flattened shape to clot Meniscus or flattened shape to clot
(recent) versus reverse meniscus (older)(recent) versus reverse meniscus (older) tram track (nonocclusive or recanalized tram track (nonocclusive or recanalized
clot) clot) delayed (antegrade) flow (manifest as delayed (antegrade) flow (manifest as
decreased whole-brain perfusion on CTA)decreased whole-brain perfusion on CTA) retrograde collateral flowretrograde collateral flow
Non-occlusive left MCA thrombus on 3-D imaging performed from CTA source data and was confirmed at catheter angiography
Therapy to be started within a 6-hr Therapy to be started within a 6-hr time to treatment (TTT) window time to treatment (TTT) window (while in case of IV thrombolysis (while in case of IV thrombolysis therapy to be started with in 3hrs)therapy to be started with in 3hrs)
Exclusion criteria Exclusion criteria Rapidly improving neurologic deficit or Rapidly improving neurologic deficit or Sustained blood pressure of gt180100 Sustained blood pressure of gt180100 Hemorrhage is detected on CTHemorrhage is detected on CT Infarct involving gt more than 13 rd Infarct involving gt more than 13 rd
territory of MCAterritory of MCA MRADWI-Perfusion mismatchlt 20MRADWI-Perfusion mismatchlt 20 Definite hypodensity on CTDefinite hypodensity on CT
Intra-arterial Thrombolysis
Fibrinolytics + AntiplateletsFibrinolytics + Antiplatelets
PlasminogenPlasminogen activators through fibrinolysis exposes activators through fibrinolysis exposes free thrombin and paradoxically stimulatesfree thrombin and paradoxically stimulates platelet platelet aggregation which leads to formation of aaggregation which leads to formation of a platelet platelet thrombus (white clot) thrombus (white clot)
This new thrombus is relatively resistant to This new thrombus is relatively resistant to fibrinolyticsfibrinolytics
So new regimen in case of acute stroke isSo new regimen in case of acute stroke is fibrinolytics + antiplatelet drugsfibrinolytics + antiplatelet drugs
rtPA + IIbIIIa inhibitors( tirofiban rtPA + IIbIIIa inhibitors( tirofiban abciximab) orabciximab) or
Urokinase + IIbIIIa Urokinase + IIbIIIa inhibitors( tirofiban abciximab)inhibitors( tirofiban abciximab)
Intra-arterial Thrombolysis Tirofiban (04 microgkgmin bolus for 3 min followed by Tirofiban (04 microgkgmin bolus for 3 min followed by
0125 ugkgmin)0125 ugkgmin)
++
Heparin (2000ndash3000 IU bolus followed by Heparin (2000ndash3000 IU bolus followed by 1000 IUhour infusion 1000 IUhour infusion
with ACT maintained bw 200-300) throughout the with ACT maintained bw 200-300) throughout the interventional procedure and for 24ndash48 hours thereafter when interventional procedure and for 24ndash48 hours thereafter when there is neither intraprocedural bleeding nor suspicion of there is neither intraprocedural bleeding nor suspicion of increased risk of bleeding increased risk of bleeding
Maximum dose of Urokinase Maximum dose of Urokinase Anterior circulation stroke - 500000 IU (mean 400000 Anterior circulation stroke - 500000 IU (mean 400000
IU range 300000ndash500000 IU)IU range 300000ndash500000 IU) Posterior circulation stroke -1000000 IU (mean 837000 Posterior circulation stroke -1000000 IU (mean 837000
IU range 300000ndash1000000 IU)IU range 300000ndash1000000 IU)American Journal of NeuroradiologyAmerican Journal of Neuroradiology 262595-2601 2005262595-2601 2005
Intravenous ThrombolysisIntravenous Thrombolysis
The first method to restore cerebral The first method to restore cerebral perfusion is clot lysis with the goal perfusion is clot lysis with the goal of re-establishing blood flow to the of re-establishing blood flow to the affected tissue affected tissue
IV thrombolysis rt-PA is the only IV thrombolysis rt-PA is the only FDA- approved treatment for AIS FDA- approved treatment for AIS
Fibrinolysis is enhanced powerfully Fibrinolysis is enhanced powerfully by rt-PAby rt-PA
Intravenous rTPA Intravenous rTPA administration administration protocolprotocol
Total dose of rt-PA 09 mgkg (maximum dose Total dose of rt-PA 09 mgkg (maximum dose 90 mg)90 mg)
Give 10 as initial IV bolusGive 10 as initial IV bolus Infuse remainder over 1 hourInfuse remainder over 1 hour Admit patient to an ICU or stroke unit for Admit patient to an ICU or stroke unit for
monitoringmonitoring Neurologic assessments every 15 minutes Neurologic assessments every 15 minutes
during infusion then every 30 minutes for next during infusion then every 30 minutes for next 6 hours then every hour until 24hours after 6 hours then every hour until 24hours after treatmenttreatment
Favorable Outcome vs Treatment Time Favorable Outcome vs Treatment Time with IV rTPAwith IV rTPA
Protocol limit = 3 hrs
Benefit ~ 45 hrs
Thromboembolism During coilingThromboembolism During coiling Most feared and frequent complication Most feared and frequent complication Reported incidence - Approx 7 Reported incidence - Approx 7 SourcesSources of Thromboembolism are of Thromboembolism are
- Clots at the aneurysmal neck during or immediately- Clots at the aneurysmal neck during or immediately after after embolization embolization
- Thrombus forming on catheters during- Thrombus forming on catheters during proceduresprocedures
- Stenosis of an adjacent artery dt coil mass- Stenosis of an adjacent artery dt coil mass or herniationor herniation
- Migration of intraaneurysmal- Migration of intraaneurysmal thrombus during coil thrombus during coil placement placement
- Slow flow dt vasospasm - Slow flow dt vasospasm
- Rare and unlikely causes are hypercoagulable- Rare and unlikely causes are hypercoagulable state such state such as antiphospholipid antibody syndrome or due to HITas antiphospholipid antibody syndrome or due to HIT
Occur more often with wide-necked aneurysms (dt Occur more often with wide-necked aneurysms (dt increased exposed surface area of thrombogenic coil increased exposed surface area of thrombogenic coil material)material)
Current regimen of endovascular Current regimen of endovascular managementmanagement
The The glycoprotein IIbIIIa antagonist tirofiban glycoprotein IIbIIIa antagonist tirofiban (04 (04 microgkgmin bolus for 30 minutes followed by infusion of microgkgmin bolus for 30 minutes followed by infusion of 0125 ugkgmin until the thrombus dissolved) 0125 ugkgmin until the thrombus dissolved)
Intraarterial thrombolysis with Intraarterial thrombolysis with urokinase or r- TPA urokinase or r- TPA increase of intravenous (IV) heparin (measured by increase of intravenous (IV) heparin (measured by
ACT) ACT) Intravenous aspirin Intravenous aspirin
Coil-related platelet aggregation (white clot) is Coil-related platelet aggregation (white clot) is unlikely to respond to fibrinolytics but has a high risk unlikely to respond to fibrinolytics but has a high risk of hemorrhage (In ISAT) all 5 patients who had of hemorrhage (In ISAT) all 5 patients who had received thrombolytic therapy with tPA to treat a received thrombolytic therapy with tPA to treat a thromboembolic complication after endovascular thromboembolic complication after endovascular treatment rebleed and all of these patients died)treatment rebleed and all of these patients died)
IntracranialIntracranial Stenting Stenting Metallic foreign body such as stent will accumulate Metallic foreign body such as stent will accumulate
thrombus in the absence of platelet inhibitionthrombus in the absence of platelet inhibition Antiplatelet drugs are important to prevent peri or Antiplatelet drugs are important to prevent peri or
post-interventional thromboembolic eventspost-interventional thromboembolic events Optimal treatment regimens has not been determined Optimal treatment regimens has not been determined
but usually but usually Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-
procedureprocedureOrOr
Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on
morning of proceduremorning of procedure
If need to use stent is not pre-planned thanIf need to use stent is not pre-planned than
Abciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkgAbciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkg IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)
Glycoprotein IIbIIIa inhibitor are not used routinely during elective Glycoprotein IIbIIIa inhibitor are not used routinely during elective stenting procedure dt increased risk of ICH stenting procedure dt increased risk of ICH
Carotid StentingCarotid Stenting
Pre-procedurePre-procedure
Double Antiplatelet therapy is routinely given Double Antiplatelet therapy is routinely given beginning at least 3beginning at least 3
days before the proceduredays before the procedure
Aspirin 325mgd+Clopidogrel 75mgdAspirin 325mgd+Clopidogrel 75mgd During procedureDuring procedure
Heparin is given with target clotting time of 250-Heparin is given with target clotting time of 250-300sec300sec
Post-procedure Post-procedure
Aspirin 325mg is continued indefinitely and Aspirin 325mg is continued indefinitely and
Clopidogrel 75mgd for at least 6 weeks Clopidogrel 75mgd for at least 6 weeks
Inclusion criteria for Local ThrombolysisInclusion criteria for Local Thrombolysis a)a) Patients in severe clinical grade on admission Patients in severe clinical grade on admission
with evidence of dural venous sinus with evidence of dural venous sinus thrombosis and restrictive venous outflow on thrombosis and restrictive venous outflow on cerebral angiogramcerebral angiogram
b)b) Patients in clinical grade 3 worsening on Patients in clinical grade 3 worsening on heparin therapy Restriction to venous heparin therapy Restriction to venous outflow was defined as an increase in brain outflow was defined as an increase in brain circulation time gt 12 s delay in the drainage circulation time gt 12 s delay in the drainage of cortical veins with cortical veins hanging of cortical veins with cortical veins hanging in spacein space
Treatment Options for Venous Thrombosis
CT Grading for Venous ThrombosisCT Grading for Venous Thrombosis Grade I no parenchymal change Grade I no parenchymal change
(hyperdense (hyperdense sinuses cortical veins empty sinuses cortical veins empty delta sign)delta sign)
Grade II non hemorrhagic venous infarct Grade II non hemorrhagic venous infarct without mass effect without mass effect
Grade III non-hemorrhagic infarct with Grade III non-hemorrhagic infarct with mass effectmass effect
Grade IV hemorrhagic venous infarct (max Grade IV hemorrhagic venous infarct (max diameter lt 3 cm) with no mass effectdiameter lt 3 cm) with no mass effect
Grade V hemorrhagic venous infarct (max Grade V hemorrhagic venous infarct (max diameter gt 3 cm) with mass effect diameter gt 3 cm) with mass effect
Local ThrombolysisLocal Thrombolysis
Femoral Jugular access was secured and a guiding Femoral Jugular access was secured and a guiding catheter was placed in the jugular bulb catheter was placed in the jugular bulb Mechanical Mechanical clot maceration clot maceration was done with the guidewire was done with the guidewire following which a microcatheter (was navigated and following which a microcatheter (was navigated and placed in the thrombosed segment of sinus confirmed placed in the thrombosed segment of sinus confirmed on a selective venogram on a selective venogram
Urokinase infusion Bolus dose of 2-6 lacs followed Urokinase infusion Bolus dose of 2-6 lacs followed by 60000 to 100000 units per hour along with by 60000 to 100000 units per hour along with periodic check venogram Along with maintenance periodic check venogram Along with maintenance systemic infusion of Heparinsystemic infusion of Heparin Other agents such as Other agents such as streptokinase altepase or rTPAstreptokinase altepase or rTPA can be also used can be also used
After thrombolysis patient should subjected to oral After thrombolysis patient should subjected to oral anticoagulation for six monthsanticoagulation for six months
Low-molecular-weight Low-molecular-weight heparinheparin
PharmacologyPharmacologyLMWH as its name suggests is a glycosaminoglycan that is approximatelyLMWH as its name suggests is a glycosaminoglycan that is approximately
one third the molecular weight of UFH It is derived from UFH through one third the molecular weight of UFH It is derived from UFH through variousvarious
depolymerization processes LMWH binds to antithrombin which in turn depolymerization processes LMWH binds to antithrombin which in turn
Neutralizes actors Xa and IIa Because LMWH lacks many of the longer Neutralizes actors Xa and IIa Because LMWH lacks many of the longer chains chains
required for binding to thrombin it has less ability to neutralize thrombin required for binding to thrombin it has less ability to neutralize thrombin
relativeto its ability to neutralize factor Xa LMWH also has less relativeto its ability to neutralize factor Xa LMWH also has less nonspecific nonspecific
binding to other proteins There is greater bioavailability with more binding to other proteins There is greater bioavailability with more predictable predictable
pharmacokinetics that eliminates the need for monitoring The smaller pharmacokinetics that eliminates the need for monitoring The smaller size also size also
allows for enhanced subcutaneous absorption when compared with UFHallows for enhanced subcutaneous absorption when compared with UFH
Three LMWH preparations are Three LMWH preparations are currently approved for use in the currently approved for use in the United States (1) enoxaparin (2) United States (1) enoxaparin (2) dalteparin and (3) tinzaparin dalteparin and (3) tinzaparin
They are all administered They are all administered subcutaneously at intervals of either subcutaneously at intervals of either once or twice daily for both once or twice daily for both prophylaxis and treatment dosesprophylaxis and treatment doses
Few Experiences of Few Experiences of ThrombolysisThrombolysis
Vickey 25 Yrs male patient presented Vickey 25 Yrs male patient presented with 12with 12thth day HO severe headache with day HO severe headache with right sided hemiplegiaright sided hemiplegia
MRI shows thrombosis of the superior MRI shows thrombosis of the superior sagittal left transverse left sigmoid sagittal left transverse left sigmoid sinuses and cortical veins in the fronto-sinuses and cortical veins in the fronto-parietal regions with eo haemorrhagic parietal regions with eo haemorrhagic infarct in the left cerebral hemisphere infarct in the left cerebral hemisphere with mass effect( Grade ndashV)with mass effect( Grade ndashV)
Sashi Srivastava 64 yrs FSashi Srivastava 64 yrs F In a follow up case of MRD with infra-renal In a follow up case of MRD with infra-renal
aortic abdominal and bilateral renal artery aortic abdominal and bilateral renal artery thrombosis renal angiogram shows filling thrombosis renal angiogram shows filling defects in the right Renal artery defects in the right Renal artery
Initially Renal angioplasty was done Initially Renal angioplasty was done Following angioplasty few thrombi are seem Following angioplasty few thrombi are seem to extends into the segmental branches and to extends into the segmental branches and causing blockage So Thrombolysis was causing blockage So Thrombolysis was plane to dissolve the run-out thrombi with plane to dissolve the run-out thrombi with urokinase urokinase
Rakesh 34yrsMRakesh 34yrsM Left SFA pseudoaneurysm with Left SFA pseudoaneurysm with
Covered stent placementCovered stent placement Pre operative antiplatelets with post Pre operative antiplatelets with post
procedure heparin Tirofiban procedure heparin Tirofiban followed by aspirin and clopidogrel followed by aspirin and clopidogrel were usedwere used
IAT may be a treatment option for selected patients IAT may be a treatment option for selected patients Possible selection criteria include Possible selection criteria include
presentation between 3 and 6 hours from symptom onsetpresentation between 3 and 6 hours from symptom onset major cerebral artery occlusion major cerebral artery occlusion severe neurologic deficits severe neurologic deficits high risk of systemic hemorrhage with IV rt-PA (eg recent high risk of systemic hemorrhage with IV rt-PA (eg recent
surgery) surgery) The MERCI (Mechanical Embolus Removal in Cerebral The MERCI (Mechanical Embolus Removal in Cerebral
Ischemia) retrievalIschemia) retrieval system system
Has been FDA-approved for recanalizing acutely occluded Has been FDA-approved for recanalizing acutely occluded cerebral arteries cerebral arteries
In the Multi-MERCI study patients who did not improve In the Multi-MERCI study patients who did not improve immediately after IV rt-PA underwent mechanical immediately after IV rt-PA underwent mechanical embolectomy within 8 hours of symptom onset embolectomy within 8 hours of symptom onset
Partial or complete recanalization occurred in 74 of Partial or complete recanalization occurred in 74 of patientspatients
with a symptomatic intracerebral hemorrhage (sICH) rate of with a symptomatic intracerebral hemorrhage (sICH) rate of 67 67
Mechanical embolectomy with the MERCI retriever may be a Mechanical embolectomy with the MERCI retriever may be a feasible and safe option for patients after IV rt-PAfeasible and safe option for patients after IV rt-PA
Penumbra stroke systemPenumbra stroke system This device combines two methods of clot This device combines two methods of clot
extraction aspiration and mechanical extraction aspiration and mechanical extraction extraction
First the clot is aspirated then a thrombus First the clot is aspirated then a thrombus removal ring can be used if necessary to removal ring can be used if necessary to remove remaining clot remove remaining clot
successful recanalizing 82successful recanalizing 82 Bridging therapyBridging therapy
06 mgkg IV rt-PA followed by IAT with IA rt-06 mgkg IV rt-PA followed by IAT with IA rt-PA (up to 20 mg)PA (up to 20 mg)
achieved a higher recanalization rateachieved a higher recanalization rate
Criteria for thrombolysis with rTPACriteria for thrombolysis with rTPA
Inclusion criteriaInclusion criteria Clinical signs and symptoms consistent with ischemic Clinical signs and symptoms consistent with ischemic
strokestroke Patient last seen normal within 3 hoursPatient last seen normal within 3 hours Measurable neurologic deficitMeasurable neurologic deficit
Exclusion criteriaExclusion criteria Any hemorrhage on neuroimaging (CT or MRI)Any hemorrhage on neuroimaging (CT or MRI) Symptoms suggestive of subarachnoid hemorrhageSymptoms suggestive of subarachnoid hemorrhage Seizure at stroke onset that is thought to contribute to Seizure at stroke onset that is thought to contribute to
neurologic deficitneurologic deficit Hypodensity greater than one third cerebral hemisphere Hypodensity greater than one third cerebral hemisphere
on CTon CT SBP greater than 185 mm Hg or DBP greater than 110 SBP greater than 185 mm Hg or DBP greater than 110
mm Hgmm Hg International normalized ratio (INR) greater than 17International normalized ratio (INR) greater than 17
Ischemic Stroke Ischemic Stroke Treatment ndash 2006Treatment ndash 2006
IV tissue plasminogen activator (tPA)IV tissue plasminogen activator (tPA) ndash ndash Only FDA-approved acute stroke drugOnly FDA-approved acute stroke drug ndash ndash 3 hour treatment window3 hour treatment window
MERCI - Concentric clot retrieval MERCI - Concentric clot retrieval devicedevice ndash ndash Rescue therapy - approved 2004Rescue therapy - approved 2004 ndash ndash Device approval (not outcomes-based)Device approval (not outcomes-based)
Off label approachesOff label approaches ndash ndash IV tPA after 3 hoursIV tPA after 3 hours ndash ndash IV-IA tPA sequential strategiesIV-IA tPA sequential strategies ndash ndash IA tPA clot angioplasty fragmentationIA tPA clot angioplasty fragmentation ndash ndash Ultrasound-assisted tPA lysisUltrasound-assisted tPA lysis
rt-PA Trials NINDSrt-PA Trials NINDS
Acute stroke - 624 patientsAcute stroke - 624 patients Treat within 3 hrsTreat within 3 hrs Intravenous 09 mgkg rt-PA vs placeboIntravenous 09 mgkg rt-PA vs placebo Hemorrhage 64 tPA 06 placeboHemorrhage 64 tPA 06 placebo Neurologic recovery better with tPA 30 Neurologic recovery better with tPA 30
more like to have minimal or no disabilitymore like to have minimal or no disability
First proven approved treatment for First proven approved treatment for strokestroke
Limitations of tPALimitations of tPA Only 4 of acute strokes receive tPAOnly 4 of acute strokes receive tPA (Kleindorfer et al Stroke 2004 35 e27-e29)(Kleindorfer et al Stroke 2004 35 e27-e29)
Only 22 of patients present within 3 hoursOnly 22 of patients present within 3 hours1048707 1048707 51 of these ineligible due to51 of these ineligible due to
bull bull Mild severityMild severity bull bull Medical or surgical historyMedical or surgical history bull bull Blood testsBlood tests
Sustained recanalization only 13Sustained recanalization only 13 (Alexandrov et al NEJM 2004 351 2170-8)(Alexandrov et al NEJM 2004 351 2170-8)
Concern for hemorrhageConcern for hemorrhage tPA potentiates apoptotic injury tPA potentiates apoptotic injury (Liu et al Nature Med 2004 101379-83)(Liu et al Nature Med 2004 101379-83)
PROACT II IA Lysis TrialPROACT II IA Lysis Trial Baseline 24 hours 8 days
Baseline 60 minutes 120 minutes
9mg IAProurokinase
Desmoteplase Trials DEDAS Desmoteplase Trials DEDAS DIASDIAS
Trial OverviewTrial Overview Double blind randomized placebo Double blind randomized placebo
controlled trialscontrolled trials IV delivery 3-9 hour time windowIV delivery 3-9 hour time window Plasminogen activator ndash from Plasminogen activator ndash from vampire bat vampire bat
salivasaliva Selection based on PWI-DWI MismatchSelection based on PWI-DWI Mismatch
MRI InclusionMRI Inclusion PWI defect at least 2 cm AND ~20 larger PWI defect at least 2 cm AND ~20 larger
than DWIthan DWI PWI should be obvious even visible on PWI should be obvious even visible on
raw imagesraw imagesMRI ExclusionMRI Exclusion
DWI gt 13 MCADWI gt 13 MCA MRA ICA occlusionMRA ICA occlusion
Desmoteplase ndash DIAS Desmoteplase ndash DIAS ResultsResults
Mechanical Thrombolysis Mechanical Thrombolysis devicesdevices
mechanical thrombolysis potentially extends the treatment mechanical thrombolysis potentially extends the treatment window because they act promptly at the site of the thrombuswindow because they act promptly at the site of the thrombus
The devices can retrieve large clots that pharmaceutical agents The devices can retrieve large clots that pharmaceutical agents may not successfully lysemay not successfully lyse
Patients treated with IV tPA may be considered for treatment of Patients treated with IV tPA may be considered for treatment of residual clot with some of these devicesresidual clot with some of these devices
suction-creating saline jets suction-creating saline jets laser energy ultrasound laser energy ultrasound a corkscrew apparatus to treat strokesa corkscrew apparatus to treat strokes The AngioJet systemThe AngioJet system uses saline jets that are directed back into the catheter to uses saline jets that are directed back into the catheter to
create a low-pressure zone around the catheter tip inducing create a low-pressure zone around the catheter tip inducing suction suction
The clot is pulled into the exhaust lumen and removed from the The clot is pulled into the exhaust lumen and removed from the vessel Although US Food and Drug Administration (FDA) has vessel Although US Food and Drug Administration (FDA) has approved this device for use in arteriovenous dialysis grafts and approved this device for use in arteriovenous dialysis grafts and fistulae and for the treatment of coronary arteries saphenous fistulae and for the treatment of coronary arteries saphenous vein grafts and peripheral vessels clinical trials for the vein grafts and peripheral vessels clinical trials for the treatment of acute stroke are no longer in progress treatment of acute stroke are no longer in progress
Most devices are used in cerebral vessels that 2-5 mm
The Latis laser device The Latis laser device used laser energy to ablate clots used laser energy to ablate clots Arteries 2-5 mm in diameter could be Arteries 2-5 mm in diameter could be
treated including the ICA M1 or M2 treated including the ICA M1 or M2 branch of the MCA A1 branch of the branch of the MCA A1 branch of the anterior cerebral artery (ACA) basilar anterior cerebral artery (ACA) basilar artery posterior cerebral artery (PCA) artery posterior cerebral artery (PCA) and vertebral and vertebral
Patients could receive treatment as late Patients could receive treatment as late as 8 hours after symptom onset in the as 8 hours after symptom onset in the anterior circulation and within 24 hours in anterior circulation and within 24 hours in the posterior circulation the posterior circulation
Endovascular Photo Acoustic Endovascular Photo Acoustic Recanalization (EPAR) Recanalization (EPAR)
A laser power source generated energy for the A laser power source generated energy for the systemsystem
The energy was delivered by means of The energy was delivered by means of fiberoptics to the tip of the catheter at the fiberoptics to the tip of the catheter at the treatment sitetreatment site
Absorption of laser light by darkly pigmented Absorption of laser light by darkly pigmented materials (ie the clot) occurred inside the 1-mm materials (ie the clot) occurred inside the 1-mm catheter tipcatheter tip
the system was designed to minimize scattering the system was designed to minimize scattering of laser light of laser light
Absorption converted photo energy to acoustic Absorption converted photo energy to acoustic energy which then emulsified the clot inside the energy which then emulsified the clot inside the catheter tip catheter tip
EKOS ultrasound( the EKOS ultrasound( the Ultrasound Thrombolytic Ultrasound Thrombolytic
Infusion Catheter) Infusion Catheter) combines the use of a distal ultrasound transducer with combines the use of a distal ultrasound transducer with
infusion of a thrombolytic agent through the infusion of a thrombolytic agent through the microcathetermicrocatheter
Ultrasound changes the structure of the clot to Ultrasound changes the structure of the clot to temporarily increase its permeability while providing an temporarily increase its permeability while providing an acoustic pressure gradient to move the drug into the clot acoustic pressure gradient to move the drug into the clot to speed its dissolution to speed its dissolution
The EKOS catheter is placed in the proximal portion of the The EKOS catheter is placed in the proximal portion of the clot clot
After a 2-mg bolus of tPA was injected through the After a 2-mg bolus of tPA was injected through the catheter catheter
the patient received a continuous infusion of IA tPA 03 the patient received a continuous infusion of IA tPA 03 mgmin to a maximum of 20 mg and simultaneous mgmin to a maximum of 20 mg and simultaneous ultrasound transmission for as long as 60 minutes ultrasound transmission for as long as 60 minutes
One patient was treated with a total of 4 units of One patient was treated with a total of 4 units of recombinant reteplase (Retavase) hand-injected over 60 recombinant reteplase (Retavase) hand-injected over 60 minutes minutes
Penumbra system Penumbra system The Penumbra system (Penumbra Inc) provides a dual The Penumbra system (Penumbra Inc) provides a dual
approach to clot extraction using aspiration followed by approach to clot extraction using aspiration followed by clot retrieval with a ring device if needed clot retrieval with a ring device if needed
Mechanical Embolus Removal in Cerebral Ischemia Mechanical Embolus Removal in Cerebral Ischemia (MERCI)(MERCI)
a corkscrew-like apparatus to remove blood clots from a corkscrew-like apparatus to remove blood clots from the brain in patients experiencing an ischemic stroke the brain in patients experiencing an ischemic stroke
The corkscrew itself resides in the catheter tip which The corkscrew itself resides in the catheter tip which shields it from the wall of the vessel until it is ready to be shields it from the wall of the vessel until it is ready to be burrowed into the clot Once lodged in the clot the device burrowed into the clot Once lodged in the clot the device and clot are withdrawn from the vessel and clot are withdrawn from the vessel
Snarelike devicesSnarelike devices Snares such as the Neuronet snare (Guidant Snares such as the Neuronet snare (Guidant
Endovascular Santa Clara CA) have been developed Endovascular Santa Clara CA) have been developed specifically for use in the treatment of strokes specifically for use in the treatment of strokes
These devices are simple in design and do not require the These devices are simple in design and do not require the clot to be amenable to emulsification clot to be amenable to emulsification
X-Sizer deviceX-Sizer device a device with small moving blades at the a device with small moving blades at the
catheter tip catheter tip This device the X-Sizer device (EndiCor Medical This device the X-Sizer device (EndiCor Medical
San Clemente CA) can be used to excise the San Clemente CA) can be used to excise the thrombus and aspirate it thrombus and aspirate it
The device was being evaluated in randomized The device was being evaluated in randomized studies of coronary vessels and in a registry of studies of coronary vessels and in a registry of patients with acute myocardial infarctionpatients with acute myocardial infarction
Although the manufacturer had modified the Although the manufacturer had modified the device for use in cerebral vessels a safety and device for use in cerebral vessels a safety and feasibility study was indefinitely suspended after feasibility study was indefinitely suspended after only 1 patient was treated with the device in only 1 patient was treated with the device in Europe Europe
Suction thrombectomySuction thrombectomy This method of mechanical thrombolysis is one of the This method of mechanical thrombolysis is one of the
simplestsimplest In this readily available technique suction is applied with In this readily available technique suction is applied with
a syringe to remove thrombus in the ICA a syringe to remove thrombus in the ICA It requires no other devicesIt requires no other devices A catheter with a large inner diameter (Brite Tip Cordis A catheter with a large inner diameter (Brite Tip Cordis
Corporation Miami FL) was placed in the symptomatic Corporation Miami FL) was placed in the symptomatic vessel and navigated over a guidewire into the thrombusvessel and navigated over a guidewire into the thrombus
A 60-mL syringe was used to aspirate the thrombus A 60-mL syringe was used to aspirate the thrombus Each patient required angioplasty and stenting of carotid Each patient required angioplasty and stenting of carotid
bifurcation stenosis and received daily aspirin and bifurcation stenosis and received daily aspirin and ticlopidine after the procedure No complications ticlopidine after the procedure No complications occurred occurred
Summary Acute Stroke Summary Acute Stroke ImagingImaging
PhysiologyPhysiology importance collaterals importance collaterals
ndash ndashGrowing role for perfusion Growing role for perfusion assessmentassessment
tPAtPA guidelines amp limitations guidelines amp limitations Signs on CT amp MRSigns on CT amp MR follow physiology follow physiology Stroke trialsStroke trials PWI-DWI mismatch PWI-DWI mismatch
ndash ndashTreat based on physiology not timeTreat based on physiology not time ProtocolsProtocols should be fast and should be fast and
comprehensivecomprehensive
The Blood Clotting MechanismThe Blood Clotting MechanismThe three mechanisms of Blood Clotting areThe three mechanisms of Blood Clotting are Vascular SpasmVascular Spasm - The smooth muscle in blood vessel - The smooth muscle in blood vessel
walls contracts immediately the blood vessel is walls contracts immediately the blood vessel is broken This response reduces blood loss for some broken This response reduces blood loss for some time while the other hemostatic mechanisms become time while the other hemostatic mechanisms become activeactive
Platelet Plug FormationPlatelet Plug Formation - When blood platelets - When blood platelets encounter a damaged blood vessel they form a encounter a damaged blood vessel they form a platelet plugplatelet plug to help to close the gap in the broken to help to close the gap in the broken blood vessel (The key stages of this process are blood vessel (The key stages of this process are called called platelet adhesionplatelet adhesion platelet release platelet release reactionreaction and and platelet aggregationplatelet aggregation))
Blood Clotting Blood Clotting (Coagulation)(Coagulation) - - Blood normally remains in its liquid state while Blood normally remains in its liquid state while
it is within the blood vessels but when it leaves it is within the blood vessels but when it leaves them the blood may thicken and form a gel them the blood may thicken and form a gel (coagulation) (coagulation)
Blood clotting (technically Blood clotting (technically blood blood coagulationcoagulation) is the process by which (liquid) ) is the process by which (liquid) blood is transformed into a solid stateblood is transformed into a solid state
bull Interventional procedures
Virchowrsquos Triad
Mechanism of blood Mechanism of blood coagulationcoagulation
HemostasisHemostasis involves a sequence of interactions of coagulation involves a sequence of interactions of coagulation
factor interactions in two pathways called the factor interactions in two pathways called the intrinsic and extrinsic coagulation cascades intrinsic and extrinsic coagulation cascades
The final common pathway involves the The final common pathway involves the transformation of prothrombin to thrombin by factor transformation of prothrombin to thrombin by factor Xa Xa
Thrombin (factor IIa) then serves to catalyze the Thrombin (factor IIa) then serves to catalyze the activation of fibrinogen to fibrin in addition to its role activation of fibrinogen to fibrin in addition to its role in feedback activation of several other clotting factorsin feedback activation of several other clotting factors
UFH LMWH and fondaparinux( saccharides) all UFH LMWH and fondaparinux( saccharides) all exert their anticoagulant effect in a similar fashion by exert their anticoagulant effect in a similar fashion by binding to and activating antithrombinbinding to and activating antithrombin that then that then neutralizes selected coagulation factorsneutralizes selected coagulation factors
Stages of blood coagulationStages of blood coagulation Formation of Formation of ProthrombinaseProthrombinase
Prothrombinase can be formed in two ways depending of which of Prothrombinase can be formed in two ways depending of which of two systems or pathways apply two systems or pathways apply
Intrinsic SystemIntrinsic System This is initiated by liquid blood making contact with a foreign This is initiated by liquid blood making contact with a foreign
surface ie something that is not part of the body surface ie something that is not part of the body Extrinsic SystemExtrinsic System
This is initiated by liquid blood making contact with damaged This is initiated by liquid blood making contact with damaged tissuetissue
Both the intrinsic and the extrinsic systems involve interactions Both the intrinsic and the extrinsic systems involve interactions between between coagulation factorscoagulation factors
2 2 ProthrombinProthrombin converted into the enzyme converted into the enzyme ThrombinThrombinProthrombinase (formed in stage 1) converts prothrombin which is Prothrombinase (formed in stage 1) converts prothrombin which is a plasma protein that is formed in the liver into the enzyme a plasma protein that is formed in the liver into the enzyme thrombinthrombin
3 3 FibrinogenFibrinogen (soluble) converted to (soluble) converted to FibrinFibrin (insoluble) (insoluble)In turn thrombin converts fibrinogen into fibrin Fibrin is insoluble In turn thrombin converts fibrinogen into fibrin Fibrin is insoluble and forms the threads that bind the clotand forms the threads that bind the clot
BLOOD COAGULATION
A sequence of reactions that are present in an inactive state in bloodKey is the conversion of the plasma protein fibrinogen to fibrin Intrinsic pathway Extrinsic pathway(activated by exposure of (activated by substances blood to damaged tissue) released from damaged tissue)
Active factors X and V
Prothrombin Thrombin
Fibrinogen Fibrin Fibrin mesh
inhibited by warfarin
inhibited by heparin
Rationale for anticoagulant Rationale for anticoagulant therapytherapy
PHARMACOLOGICAL PHARMACOLOGICAL AGENTSAGENTS
Pharmacologic AgentsPharmacologic Agents
AnticoagulantsAnticoagulants
Fibrinolytics (Agents for pharmacological Fibrinolytics (Agents for pharmacological recanalization)recanalization)
Anti platelet drugsAnti platelet drugs
Thrombin inhibitorThrombin inhibitor
ANTICOAGULANTSANTICOAGULANTS
Heparin and Low Molecular Weight Heparins Heparin and Low Molecular Weight Heparins ((eg enoxaparin dalteparin)eg enoxaparin dalteparin)
Oral anticoagulantsOral anticoagulants Coumarin Derivatves Coumarin Derivatves eg Warfarin eg Warfarin
AcenocoumarolAcenocoumarol Indandione Derivatves Indandione Derivatves eg Phenindione eg Phenindione
AnisindioneAnisindione
ThrombolyticsThrombolytics
Plasminogen activators
Fibrinolytics
Anti Platelet DrugsAnti Platelet DrugsDrug Mechanism UsesDrug Mechanism UsesAspirinAspirin Permanently inhibits Permanently inhibits
COX-1 and COX-2COX-1 and COX-2CADCAD
Stroke-TIAsStroke-TIAs
NSAIDsNSAIDs Reversibly inhibits Reversibly inhibits COX-1COX-1
LimitedLimited
DipyridamoleDipyridamole Inhibits PDE Inhibits PDE increases cAMPincreases cAMP
TIAsTIAs
ThenopyridinesThenopyridines
(Ticlopidine(Ticlopidine
Clopidegrel)Clopidegrel)
Inhibits ADP Inhibits ADP
PlatAg PlatAg
TIAsStrokeTIAsStroke
CAD PVDCAD PVD
Abciximab (ReoPro)Abciximab (ReoPro)
Eptifibatide Eptifibatide (Integrilin)(Integrilin)
TirofibaTirofibann
GP IIBIIIA InhibitorsGP IIBIIIA Inhibitors
Stroke- TIAs Stroke- TIAs
Maintainance of patency Maintainance of patency of vascular of vascular grafts catheters shunts bypassesgrafts catheters shunts bypasses
Arterial thromboembolic diseaseArterial thromboembolic diseasebull Transient ischemic attacksTransient ischemic attacksbull Stroke in evolutionStroke in evolution
Ischemic events occurs in Ischemic events occurs in 1313 of of conventional neuroangiographic conventional neuroangiographic procedures without Endovascular surgeryprocedures without Endovascular surgery
Indications for Antithrombotic Therapy in Indications for Antithrombotic Therapy in Diagnostics and Interventional ProceduresDiagnostics and Interventional Procedures
WHY TO MONITOR ANTICOAGULANT THERAPYWHY TO MONITOR ANTICOAGULANT THERAPY
Narrow therapeutic rangeNarrow therapeutic range
Can increase risk of bleedingCan increase risk of bleeding
Coagulation TestingCoagulation Testing
Monitoring therapyMonitoring therapy
Intrinsic Pathway
Extrinsic Pathway
Common Pathway
CLOT
Heparin Coumadin
Monitor with
ACT aPTT
Monitor with PTINR
Thrombolytics
Monitor with TT Fibrinogen
Monitoring of Monitoring of Anti platelet drugsAnti platelet drugs
Bleeding timeBleeding time
Optical aggregometryOptical aggregometry
Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay
HeparinHeparin
Heterogeneous 3000-30000 dalton in Heterogeneous 3000-30000 dalton in molecular weight molecular weight
Average=15000 d (~45monosaccharide Average=15000 d (~45monosaccharide chains)chains)
About About 13 of dose binds to AT III and forms 13 of dose binds to AT III and forms the AT IIIHeparinClotting Factor Complexthe AT IIIHeparinClotting Factor Complex
Complex binds to clotting factors of the Complex binds to clotting factors of the intrinsic and common pathway (Xa IIa IXa intrinsic and common pathway (Xa IIa IXa XIa XIIa XIIIa) and inactivates themXIa XIIa XIIIa) and inactivates them
Anticoagulant of choice in pregnancy (not Anticoagulant of choice in pregnancy (not crosses placenta)crosses placenta)
Heparin and Low molecular weight heparinsHeparin and Low molecular weight heparins
Structure and sequence
O
OH
OH
O
COO
O
O
CH2OH
NHSO3
OH
_
_
O
O
CH2OSO3
NHSO3
OH
_
_
O
OH
OH
O
COOO
O
CH2OSO3
NHSO3
OH
_
_
O
OSO3
OHO
COOO
O
CH2OSO3
NHCOCH3
OH
_
_ _
_
_
O
OH
OH
O
COO
1
23
4
5
6
-D-glucosamine -L-iduronic acid -D-glucuronic acid
O
O
CH2OH
NH2
OH 12
3
4
5
6
O
OH
OHO
COO_
1
23
4
5
6
polymeric structure of heparin
Anticoagulant Properties of Anticoagulant Properties of HeparinHeparin
11 Inhibits the thrombin-mediated conversion of Inhibits the thrombin-mediated conversion of fibrinogen to fibrinfibrinogen to fibrin
22 Inhibits the aggregation of platelets by thrombin Inhibits the aggregation of platelets by thrombin (prolongs bleeding time)(prolongs bleeding time)
33 Inhibits activation of fibrin stabilizing enzymeInhibits activation of fibrin stabilizing enzyme
44 Inhibits activated factors XII XI IX X and IIInhibits activated factors XII XI IX X and II All available forms of heparin must be All available forms of heparin must be
administered administered parenterally since they are parenterally since they are highly charged and rapidlyhighly charged and rapidly hydrolyzed in the hydrolyzed in the GI tractGI tract
Heparin antagonist Protamine sulfate (Heparin antagonist Protamine sulfate (10mg for 10mg for 1000 unit of heparin)1000 unit of heparin)
Monitoring of heparin Monitoring of heparin
Subcutenous Subcutenous no monitoring requiredno monitoring required Intravenous Intravenous
Partial thromboplastin time (PTT normal value Partial thromboplastin time (PTT normal value ~30sec) ~30sec)
Activated clotting time ( ACT normal value ~90-Activated clotting time ( ACT normal value ~90-120sec)120sec)
Daily or more frequent if PTT ACT variesDaily or more frequent if PTT ACT varies
Mechanism Mechanism ndash measures intrinsic pathwayndash measures intrinsic pathway Therapeutic goal Therapeutic goal 2-25 times normal control value 2-25 times normal control value
ACT or aPTTACT or aPTT
Determine when to pull the femoral sheath Determine when to pull the femoral sheath Premature sheath pull can lead to bleedingPremature sheath pull can lead to bleeding Delayed removal can increase time in ICUDelayed removal can increase time in ICU Target set Target set at each siteat each site
ACT targets range from 150 ndash 220 ACT targets range from 150 ndash 220 secondsseconds
aPTT targets range from 40 ndash 70 seconds aPTT targets range from 40 ndash 70 seconds
During neuroangiography-During neuroangiography- Recommended therapeutic range of heparin in Recommended therapeutic range of heparin in
plasma is 02-08 uml ( corresponding to aPTT plasma is 02-08 uml ( corresponding to aPTT ACT values 15-25 times the baseline values)ACT values 15-25 times the baseline values)
Dose In diagnostic angiography bolus dose of Dose In diagnostic angiography bolus dose of 2500 iu is used followed by 1000 iu hour2500 iu is used followed by 1000 iu hour
Bolus dose is Bolus dose is 60 ukg to maintain the therapeutic 60 ukg to maintain the therapeutic range range If procedure continues for more than 75 If procedure continues for more than 75 minutes additional dose is required ( half of the minutes additional dose is required ( half of the initial dose for another 75 minutes) initial dose for another 75 minutes)
(AJNR 199415 51-54)
Mechanisms of HIT( Mechanisms of HIT( Heparin Heparin induced Thrombocytopeniainduced Thrombocytopenia))
Type 1Type 1 Fall in platelet count occurs within the first two Fall in platelet count occurs within the first two
days after heparin initiation often returns to days after heparin initiation often returns to normal with continued heparin administration normal with continued heparin administration and is of no clinical consequence and is of no clinical consequence
The mechanism of the thrombocytopenia is non-The mechanism of the thrombocytopenia is non-immune and appears to be due to a direct effect of immune and appears to be due to a direct effect of heparin on platelet activationheparin on platelet activation
Type 2Type 2 Approximately 03 to 3 percent of patients Approximately 03 to 3 percent of patients
receiving heparin develop an immune receiving heparin develop an immune thrombocytopenia mediated by antibodies to a thrombocytopenia mediated by antibodies to a heparin-platelet factor 4 complex heparin-platelet factor 4 complex
(AJNR 28155-158 2007)
Treatment of heparin-induced Treatment of heparin-induced thrombocytopeniathrombocytopenia
When HIT is diagnosed it is important to When HIT is diagnosed it is important to stop heparin mainly in type 2 and to avoid stop heparin mainly in type 2 and to avoid the use of LMWH the use of LMWH
Because of the increased risk of thrombosis Because of the increased risk of thrombosis however continuation of an anticoagulant however continuation of an anticoagulant must be considered must be considered
The drugs currently approved for the The drugs currently approved for the treatment of HIT in the United States are treatment of HIT in the United States are direct thrombin inhibitors argatroban and direct thrombin inhibitors argatroban and lepirudinlepirudin
WARFARIN MECHANISM OF ACTIONWARFARIN MECHANISM OF ACTION
Inactive factors II VII IX and X
Proteins S and C
Active factors II VII IX and X
Proteins S and C
Vitamin K epoxide
Vitamin K reduced
WA
RF
AR
IN
Prevents the reduction of vitamin K which is essential for Prevents the reduction of vitamin K which is essential for activation of certain factorsactivation of certain factors
Has no effect on previously formed thrombusHas no effect on previously formed thrombus
Antagonist is Vit KAntagonist is Vit K
OPTIMIZING WARFARIN THERAPYOPTIMIZING WARFARIN THERAPY
Use of large loading dose may lead to hemorrhage and Use of large loading dose may lead to hemorrhage and other complicationsother complications
Initial dose 2-5 mg once dailyInitial dose 2-5 mg once daily Maintenance dose 2-10 mg once dailyMaintenance dose 2-10 mg once daily If Immediate anticoagulation is requiredIf Immediate anticoagulation is required Heparin IS Heparin IS
started along with loading dose of warfarin 10 mg started along with loading dose of warfarin 10 mg Heparin is usually discontinued after 4-5 days Heparin is usually discontinued after 4-5 days Before Before discontinuing INR should be in therapeutic range for 2 discontinuing INR should be in therapeutic range for 2 consecutive daysconsecutive days
Daily monitoring of INR until INR is in therapeutic Daily monitoring of INR until INR is in therapeutic range then 3 times weekly for 1-2 weeks then less often range then 3 times weekly for 1-2 weeks then less often (every 4 to 6 weeks)(every 4 to 6 weeks)
OPTIMAL THERAPEUTIC RANGEOPTIMAL THERAPEUTIC RANGE
IndicationIndication INRINR
Prophylaxis of venous Prophylaxis of venous thromboembolismthromboembolism
20-3020-30
Treatment of venous Treatment of venous thromboembolismthromboembolism
20-3020-30
Atrial fibrillationAtrial fibrillation 20-3020-30
Mitral valve stenosisMitral valve stenosis 20-3020-30
Heart valve replacementHeart valve replacement
Bioprosthetic valveBioprosthetic valve
Mechanical valveMechanical valve
20-3020-30
25-3525-35
Myocardial infarctionMyocardial infarction 20-3020-30
25-35 25-35 (high risk patients)(high risk patients)
FACTORS INFLUENCING DOSE RESPONSEFACTORS INFLUENCING DOSE RESPONSE
Poor patient compliancePoor patient compliance Concomitant medicationsConcomitant medications Levels of dietary vitamin KLevels of dietary vitamin K Alcohol Inaccurate lab testingAlcohol Inaccurate lab testing Inaccurate lab testingInaccurate lab testing Hepatic dysfunctionHepatic dysfunction FeverFever
Contraindication for WarfarinContraindication for Warfarin
Hypersensitivity to warfarinHypersensitivity to warfarin Hemorrhagic tendencyHemorrhagic tendency Condition with risk of hemorrhageCondition with risk of hemorrhage Inadequate laboratory techniquesInadequate laboratory techniques Protein C amp S deficiencyProtein C amp S deficiency Vitamin K deficiencyVitamin K deficiency
SIDE EFFECTSSIDE EFFECTS
Hemorrhage Hemorrhage Skin necrosisSkin necrosis Purple toe syndromePurple toe syndrome Microembolization Microembolization TeratogenecityTeratogenecity Agranulocytosis leukopenia Agranulocytosis leukopenia Diarrhoeanausea anorexiaDiarrhoeanausea anorexia
MONITORING OF WARFARIN THERAPYMONITORING OF WARFARIN THERAPY
Prothrombin timeProthrombin time PT ratioPT ratio INR (International Normalized Ratio)INR (International Normalized Ratio)
PROTHROMBIN TIME (PT)PROTHROMBIN TIME (PT)
Time required for blood to coagulate Time required for blood to coagulate is called PT ( normal value ~10sec)is called PT ( normal value ~10sec)
Performed by adding a mixture of Performed by adding a mixture of calcium and thromboplastin to calcium and thromboplastin to citrated plasmacitrated plasma
As a control a normal blood sample is As a control a normal blood sample is tested continuouslytested continuously
PT ratio (PTR) = PT ratio (PTR) = Patientrsquos PTPatientrsquos PT Control PTControl PT
PROBLEMS WITH PTPTRPROBLEMS WITH PTPTR
Thromboplastins are extracts from Thromboplastins are extracts from brain lung or placenta of animalsbrain lung or placenta of animals
Thromboplastins from various Thromboplastins from various manufacturers differ in their manufacturers differ in their sensitivity to prolong PTsensitivity to prolong PT
May result in false control of May result in false control of anticoagulant therapyanticoagulant therapy
INTERNATIONAL NORMALISED RATIO (INR)INTERNATIONAL NORMALISED RATIO (INR)
International Normalized Ratio (INR) International Normalized Ratio (INR) a PT test with a a PT test with a formula based ratio to normalize the often variable source formula based ratio to normalize the often variable source of tissue factor (human rabbit recombinant)of tissue factor (human rabbit recombinant)
INR = [PTINR = [PTptpt] ] ISIISI
[PT[PTRefRef]]
PTPTpt pt ndash prothrombin time of patientndash prothrombin time of patient
PTPTRef Ref ndash prothrombin time of normal pooled samplendash prothrombin time of normal pooled sample
ISI ndash International Sensitivity IndexISI ndash International Sensitivity Index
Warfarin is given orally and titrated to achieve an INR of Warfarin is given orally and titrated to achieve an INR of typically 20 ndash 30typically 20 ndash 30
Heparin versus WarfarinHeparin versus Warfarin
Drug ActionMechan-ism
Moni-toring
Effective
HeparinDirect
Inhibition ofThrombin
ATIIIcofactor
APTTACT
Immediate
WarfarinDecreasesProductionof factors
Vitamin K PTDelay
3-5 days
INR
Recanalization or Antegrade Recanalization or Antegrade Reperfusion StrategiesReperfusion Strategies
Recanalization strategies focus on removing Recanalization strategies focus on removing andor dissolving the occlusive thrombus to re-andor dissolving the occlusive thrombus to re-establish antegrade flow Strategies may be establish antegrade flow Strategies may be classified into 7 different categories on the classified into 7 different categories on the basis of their primary mechanism of action basis of their primary mechanism of action 1) 1) IV andor intraarterial thrombolysis (IAT) IV andor intraarterial thrombolysis (IAT) 2) endovascular thrombectomy2) endovascular thrombectomy3) endovascular thromboaspiration 3) endovascular thromboaspiration 4) endovascular mechanical thrombus disruption or 4) endovascular mechanical thrombus disruption or
thromborrhexisthromborrhexis5) 5) transcranial or endovascular augmented transcranial or endovascular augmented
fibrinolysis fibrinolysis 6) endovascular thrombus entrapment and 6) endovascular thrombus entrapment and 7) temporary endovascular bypass7) temporary endovascular bypass
IAT in Acute Ischemic StrokeIAT in Acute Ischemic Stroke
IAT advantages over IV thrombolysisIAT advantages over IV thrombolysis Coaxial microcatheter techniques the occluded intracranial Coaxial microcatheter techniques the occluded intracranial
vessel is directly accessible and the fibrinolytic agent can be vessel is directly accessible and the fibrinolytic agent can be infused directly into the thrombusinfused directly into the thrombus
This permits a smaller dose of fibrinolytic agent to reach a This permits a smaller dose of fibrinolytic agent to reach a higher local concentration than that reached by systemic higher local concentration than that reached by systemic infusioninfusion
Allows more complete recanalization with lower total doses of Allows more complete recanalization with lower total doses of thrombolytic thrombolytic
With the smaller dose complications from systemic fibrinolytic With the smaller dose complications from systemic fibrinolytic effects including intracranial hemorrhage (ICH) can effects including intracranial hemorrhage (ICH) can theoretically be reduced theoretically be reduced
Treatment window for endovascular techniques can be Treatment window for endovascular techniques can be extended beyond the typical IV window of 3 hours extended beyond the typical IV window of 3 hours
IA techniques have led to higher recanalization rates than IV IA techniques have led to higher recanalization rates than IV thrombolysisthrombolysis
Major disadvantagesMajor disadvantages Relative complexity of the procedure the level Relative complexity of the procedure the level
of required technical expertise and its of required technical expertise and its relatively low availability relatively low availability
Delays in initiating treatmentDelays in initiating treatment InvasiveInvasive
ThrombolyticsThrombolytics
Plasminogen activators
Fibrinolytics
1 Plasminogen Activators 1 Plasminogen Activators drugs act by converting the inactive proenzyme drugs act by converting the inactive proenzyme plasminogen into the active enzyme plasmin Plasmin plasminogen into the active enzyme plasmin Plasmin digests fibrinogen fibrin monomers and cross-linked digests fibrinogen fibrin monomers and cross-linked fibrin (as found in a thrombus) into fibrin degradation fibrin (as found in a thrombus) into fibrin degradation productsproducts
First-Generation Agents First-Generation Agents StreptokinaseStreptokinase a protein derived from group C a protein derived from group C
szlig-hemolytic streptococci has a half-life of 16ndashszlig-hemolytic streptococci has a half-life of 16ndash90 minutes and low fibrin specificity This drug 90 minutes and low fibrin specificity This drug proved to have a very narrow therapeutic proved to have a very narrow therapeutic window and significant rates of ICH and window and significant rates of ICH and systemic hemorrhage18systemic hemorrhage18
UrokinaseUrokinase is a serine protease with a plasma is a serine protease with a plasma half life of 14 minutes and low fibrin specificity half life of 14 minutes and low fibrin specificity
The urokinase dose used in cerebral IAT has The urokinase dose used in cerebral IAT has ranged from 002 to 2 X106unitsranged from 002 to 2 X106units
Second-Generation Agents Second-Generation Agents Alteplase (rtPA) Alteplase (rtPA)
is a serine is a serine protease with a plasma half-life of 35 protease with a plasma half-life of 35 minutes and a high degree of fibrin affinity and minutes and a high degree of fibrin affinity and specificity specificity
Dose used in cerebral IAT has ranged between 20 Dose used in cerebral IAT has ranged between 20 and 60 mgand 60 mg
Disadvantages of alteplase include its relatively short Disadvantages of alteplase include its relatively short halflife and limited penetration into the clot matrix halflife and limited penetration into the clot matrix because of strong binding with surface fibrin which because of strong binding with surface fibrin which could delay recanalization and increase the risk of could delay recanalization and increase the risk of recurrent occlusion recurrent occlusion
Prourokinase (r-prourokinase) Prourokinase (r-prourokinase) is the proenzyme precursor of urokinase is the proenzyme precursor of urokinase T12 of 7 minutes and high fibrin specificity T12 of 7 minutes and high fibrin specificity
Third-Generation AgentsThird-Generation Agents
ReteplaseReteplase is a structurally modified is a structurally modified form of alteplase form of alteplase
with a longer half-life (15ndash18 minutes) In with a longer half-life (15ndash18 minutes) In addition it does not bind as highly to fibrin addition it does not bind as highly to fibrin unbound reteplase can thus theoretically better unbound reteplase can thus theoretically better penetrate the clot and potentially penetrate the clot and potentially improve in improve in vivo fibrinolytic activity vivo fibrinolytic activity
TenecteplaseTenecteplase is another modified form of rtPA with a longer is another modified form of rtPA with a longer
half-life (17 minutes)half-life (17 minutes) greater fibrin specificity and greater greater fibrin specificity and greater
resistance to plasminogen activator inhibitor-1 resistance to plasminogen activator inhibitor-1 IV tenecteplase in acute ischemic stroke IV tenecteplase in acute ischemic stroke
suggest that the drug is safe and promisingsuggest that the drug is safe and promising
Newer plasminogen activatorNewer plasminogen activator
DesmoteplaseDesmoteplase is a genetically engineered is a genetically engineered version of the clot-dissolving factor version of the clot-dissolving factor
found in the saliva found in the saliva of the vampire bat Desmodus rotundusof the vampire bat Desmodus rotundus moremore potent and more selective for fibrin-bound potent and more selective for fibrin-bound
plasminogen than any other known plasminogen plasminogen than any other known plasminogen activatoractivator
Unlike tissue plasminogen activator (tPA) desmoteplase Unlike tissue plasminogen activator (tPA) desmoteplase is not activated by fibrinogen or -amyloid proteins is not activated by fibrinogen or -amyloid proteins factors that may exacerbate the risk for ICH factors that may exacerbate the risk for ICH
The effect of IV administration of desmoteplase 3ndash9 The effect of IV administration of desmoteplase 3ndash9 hours after symptom onset in patients with stroke who hours after symptom onset in patients with stroke who present with mismatch on MR imaging or CT perfusion present with mismatch on MR imaging or CT perfusion
3 DefibrinogenatingFibrinogenolytic 3 DefibrinogenatingFibrinogenolytic Agents Agents
AncrodAncrod(Viprinex)(Viprinex) is is the purified fraction of the Malayan pit viper venomthe purified fraction of the Malayan pit viper venom It acts by directly cleaving and inactivating fibrinogen It acts by directly cleaving and inactivating fibrinogen
and thus indirectly promoting anticoagulation and thus indirectly promoting anticoagulation The reduction in the blood levels of fibrinogen also The reduction in the blood levels of fibrinogen also
leads to a reduced blood viscosity which may improve leads to a reduced blood viscosity which may improve blood flow to the affected areas of the brain blood flow to the affected areas of the brain
In the Stroke Treatment with Ancrod Trial 500 In the Stroke Treatment with Ancrod Trial 500 patients with stroke presenting within 3 hours of patients with stroke presenting within 3 hours of symptom onset were randomized to receive ancrod (symptom onset were randomized to receive ancrod (n n 248) or a placebo (n 252) Good outcome (Barthel 248) or a placebo (n 252) Good outcome (Barthel Index 95ndash100 at 3 months) was achieved in 4221 Index 95ndash100 at 3 months) was achieved in 4221 and 344 of the patients respectively and 344 of the patients respectively
2 Direct Fibrinolytics2 Direct Fibrinolytics
Microplasmin (Microplasmin (ThromboGenics Heverlee Belgium)ThromboGenics Heverlee Belgium) is a truncated form of plasmin that is more resistant to the effects is a truncated form of plasmin that is more resistant to the effects
of antiplasmin of antiplasmin microplasmin can be used upto 4ndash12 hours after stroke onset microplasmin can be used upto 4ndash12 hours after stroke onset There was no evidence of increased bleeding risk with There was no evidence of increased bleeding risk with
microplasminmicroplasmin
Alfimeprase (Nuvelo San Carlos Calif)Alfimeprase (Nuvelo San Carlos Calif) is a recombinant truncated form of fibrolase a fibrinolytic zinc metalloproteinase is a recombinant truncated form of fibrolase a fibrinolytic zinc metalloproteinase
isolated from the venom of the southern copperhead snake isolated from the venom of the southern copperhead snake It degrades fibrin directly and achieves thrombolysis independent It degrades fibrin directly and achieves thrombolysis independent
of plasmin formationof plasmin formation its thrombolytic activity appears to be localized to the site of its thrombolytic activity appears to be localized to the site of
delivery These properties should theoretically result in faster delivery These properties should theoretically result in faster recanalization and lower hemorrhagic conversion riskrecanalization and lower hemorrhagic conversion risk
Anti-fibrinolyticsAnti-fibrinolytics
to limit fibrinolytic activityto limit fibrinolytic activity -aminocaproic acid (EACA) -aminocaproic acid (EACA) competitively inhibitscompetitively inhibits plasminogen and plasminogen activators from plasminogen and plasminogen activators from
binding to fibrinbinding to fibrin
alpha2-antiplasminalpha2-antiplasmin a serine protease inhibitor that a serine protease inhibitor that neutralizes any free circulating plasminneutralizes any free circulating plasmin
Plasminogen activator inhibitor-1Plasminogen activator inhibitor-1 a serine protease a serine protease inhibitor that inhibits tissue-type plasminogen inhibitor that inhibits tissue-type plasminogen activatoractivator
Glycoprotein (GP) IIbIIIa antagonistsGlycoprotein (GP) IIbIIIa antagonists
such as ReoPro (abciximab) Integrilin such as ReoPro (abciximab) Integrilin (eptifibatide) or Aggrastat (tirofiban) in (eptifibatide) or Aggrastat (tirofiban) in ischemic stroke remains investigational ischemic stroke remains investigational Deshmukh et al38 reported 21 patients with Deshmukh et al38 reported 21 patients with large-vessel occlusion refractory to IAT with large-vessel occlusion refractory to IAT with rtPA who were treated with IV andor IA rtPA who were treated with IV andor IA abciximab eptifibatide or tirofiban abciximab eptifibatide or tirofiban
IA Mechanical Approaches in Acute Ischemic Stroke IA Mechanical Approaches in Acute Ischemic Stroke Mechanical strategies have several advantagesMechanical strategies have several advantages First they lessen and may even preclude the use of chemical First they lessen and may even preclude the use of chemical
thrombolytics in this manner very likely reducing the risk of ICHthrombolytics in this manner very likely reducing the risk of ICH Second by avoiding the use of chemical thrombolytics it is Second by avoiding the use of chemical thrombolytics it is
possible to extend the treatment window beyond the limit of 6ndash8 possible to extend the treatment window beyond the limit of 6ndash8 hours hours
Third mechanically fragmenting a clot increases the surface area Third mechanically fragmenting a clot increases the surface area accessible to fibrinolytic agents and allows inflow of fresh accessible to fibrinolytic agents and allows inflow of fresh plasminogen which in turn may increase the speed of plasminogen which in turn may increase the speed of thrombolysis thrombolysis
Finally clot-retrieval devices may provide faster recanalization Finally clot-retrieval devices may provide faster recanalization
The disadvantages of the mechanical The disadvantages of the mechanical approaches approaches technical difficulty of navigating mechanical technical difficulty of navigating mechanical
devices into the intracranial circulation excessive devices into the intracranial circulation excessive trauma to the vasculature (potentially leading to trauma to the vasculature (potentially leading to vasospasm vessel dissection perforation or vasospasm vessel dissection perforation or rupture) rupture)
fragmented thrombus causing distal embolization fragmented thrombus causing distal embolization into previously unaffected territories into previously unaffected territories
Nevertheless the advantages of mechanical stroke Nevertheless the advantages of mechanical stroke therapy appear to significantly outweigh its therapy appear to significantly outweigh its disadvantages and risksdisadvantages and risks
Contraindications to Thrombolytic Contraindications to Thrombolytic agents agents
Recent thoracic abdominal or Recent thoracic abdominal or intracranial surgeryintracranial surgery
Recent haemorrhagic CVA Head injury Recent haemorrhagic CVA Head injury or neoplasmor neoplasm
Bleeding ulcerBleeding ulcer Anticipated invasive procedures (arterial Anticipated invasive procedures (arterial
punctures biopsies)punctures biopsies) Concurrent hemostatic dysfunctionConcurrent hemostatic dysfunction
Monitoring of thrombolytic Monitoring of thrombolytic therapytherapy
Thrombin time Measures the availability of functional
fibrinogen Normal thrombin time is 10-14 sec Prolonged when fibrinogen level is below
75-100 mgdl
Half Life of ThrombolyticsHalf Life of ThrombolyticsAgent Administration Half Life
Streptokinase IA 60-80min
Urokinase IAIV 9-12min
rTPA IAIV 6min
Abciximab(Reopro) IAIV 12hour
Aspirin POIV 15-20min
Heparin IVSC 60min
Coumadin PO 15-25 days
Anti Platelet DrugsAnti Platelet DrugsDrug Drug Mechanism Mechanism UsesUsesAspirinAspirin Permanently inhibits Permanently inhibits
COX-1 and COX-2COX-1 and COX-2CADCAD
Stroke-TIAsStroke-TIAs
NSAIDsNSAIDs Reversibly inhibits Reversibly inhibits COX-1COX-1
LimitedLimited
DipyridamoleDipyridamole Inhibits PDE increases Inhibits PDE increases cAMPcAMP
TIAsTIAs
ThenopyridinesThenopyridines
(Ticlopidine(Ticlopidine
ClopidrgrelClopidrgrel))
Inhibits ADP Inhibits ADP
PlatAg PlatAg
TIAsStrokeTIAsStroke
CAD PVDCAD PVD
Abciximab (ReoPro)Abciximab (ReoPro)
Eptifibatide (Integrilin)Eptifibatide (Integrilin)
TirofibanTirofiban
GP IIBIIIA InhibitorsGP IIBIIIA Inhibitors
Stroke- TIAs Stroke- TIAs
MonitoringMonitoring
Bleeding timeBleeding time
Optical aggregometryOptical aggregometry
Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay
Bleeding timeBleeding time
Requires a skin incision (usually made on the ear lobe or Requires a skin incision (usually made on the ear lobe or forearm offorearm of
a depth that results in disruption of capillary loops and a depth that results in disruption of capillary loops and small vessels)small vessels)
AdvantagesAdvantages Universally availableUniversally available Relatively simple techniquesRelatively simple techniques Can be performed bedsideCan be performed bedside
DisadvantagesDisadvantages Insensitive inaccurate non-specific techniqueInsensitive inaccurate non-specific technique
Poorly reproducible (as depends on multiple variables)Poorly reproducible (as depends on multiple variables)
Optical aggregometryOptical aggregometry
Gold standard assay for platelet functionGold standard assay for platelet function Agonist induced aggregation is measuredAgonist induced aggregation is measured Different agonist are available for different Different agonist are available for different
agentsagents However require unique expertise and are not However require unique expertise and are not
universally availableuniversally available Aspirin measured with ADP or AA(gt70 Aspirin measured with ADP or AA(gt70
aggregation so resistance)aggregation so resistance) Clopidogrel( ADP gt 90 aggregation means Clopidogrel( ADP gt 90 aggregation means
resistance) resistance)
Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay
Can be performed bed sideCan be performed bed side Different assay devices with different Different assay devices with different
agonist are used for each of different agonist are used for each of different antiplatelet agents antiplatelet agents
For Aspirin AA is used (result is reported as aspirin For Aspirin AA is used (result is reported as aspirin reaction units [ARU] ARUgt 550 indicates non-reaction units [ARU] ARUgt 550 indicates non-responsiveness)responsiveness)
Verify IIbIIIa assay device uses TRAP as agonist for Verify IIbIIIa assay device uses TRAP as agonist for Abciximab and TirofibanAbciximab and Tirofiban
Practical Applications Practical Applications related to specific related to specific
Neurovascular Neurovascular interventionsinterventions
Acute ischemic StrokeAcute ischemic Stroke When an artery occludes neurons are affected When an artery occludes neurons are affected
differently depending upon the amount of residual blood differently depending upon the amount of residual blood flowflow
Normal cerebral blood flow is greater than 50 mL100 Normal cerebral blood flow is greater than 50 mL100 mgminmgmin
Once blood flow decreases to less than 20 mL100 Once blood flow decreases to less than 20 mL100 mgmin infarction occursmgmin infarction occurs
If blood flow decreases to less than 10 mL100 mgmin If blood flow decreases to less than 10 mL100 mgmin irreversible neuronal death occurs rapidly irreversible neuronal death occurs rapidly
Blood flow between 11 and 20 mL100 mgmin is thought Blood flow between 11 and 20 mL100 mgmin is thought to represent the ischemic penumbra an area where the to represent the ischemic penumbra an area where the cells are functionally silent because of ischemia but are cells are functionally silent because of ischemia but are still able to recover if blood flow is restored still able to recover if blood flow is restored
Many acute stroke therapies are targeted toward Many acute stroke therapies are targeted toward restoring flow or function to the ischemic penumbrarestoring flow or function to the ischemic penumbra
Therapeutic window in Therapeutic window in management of acute Ischemic management of acute Ischemic
StrokeStrokeThe early diagnosis of ischemic stroke is critical to the The early diagnosis of ischemic stroke is critical to the
with only a narrow therapeutic window in the first few with only a narrow therapeutic window in the first few hours following stroke ictushours following stroke ictus
Diagnosis in the first 3 hours postictus provides the Diagnosis in the first 3 hours postictus provides the opportunity for intravenous or intraarterial thrombolysis opportunity for intravenous or intraarterial thrombolysis and intra-arterial clot mechanical treatment which and intra-arterial clot mechanical treatment which improve the outcome improve the outcome
Diagnosis in the time period between 3 and 6 hours Diagnosis in the time period between 3 and 6 hours provides an opportunity for intra-arterial thrombolysis provides an opportunity for intra-arterial thrombolysis and mechanical treatment and mechanical treatment
Involvement of the posterior circulation especially the Involvement of the posterior circulation especially the basilar artery is treated by some regardless of time of basilar artery is treated by some regardless of time of onset or up until 12 to 24 hours in some practices This is onset or up until 12 to 24 hours in some practices This is related to the potentially high mortality and morbidity related to the potentially high mortality and morbidity associated with basilar artery thrombosisassociated with basilar artery thrombosis
Infarct evaluation on angiographyInfarct evaluation on angiography(CT angiography and catheter (CT angiography and catheter
angiography)angiography)CTA is an excellent first-line examination for CTA is an excellent first-line examination for
evaluation of the head and neck arteries evaluation of the head and neck arteries In comparison with catheter angiography In comparison with catheter angiography
what it gives up in resolution and dynamic what it gives up in resolution and dynamic properties it makes up for with rapid properties it makes up for with rapid acquisition of a 3-D dataset and the potential acquisition of a 3-D dataset and the potential for assessment of whole-brain perfusion and for assessment of whole-brain perfusion and better parenchymal evaluationbetter parenchymal evaluation
Moreover CTA illustrates not only arterial Moreover CTA illustrates not only arterial stenosis or occlusion but also the vessel wall stenosis or occlusion but also the vessel wall This factor is most important for evaluation of This factor is most important for evaluation of intramural dissection and thrombosed intramural dissection and thrombosed aneurysms which may both complicate aneurysms which may both complicate evaluation of stroke patientsevaluation of stroke patients
Early angiographic signs of strokes Early angiographic signs of strokes both CTA both CTA and DSA and DSA
Vessel occlusion or cutoff related to Vessel occlusion or cutoff related to thromboembolithromboemboli
aneurysms aneurysms arterial dissection arterial dissection Meniscus or flattened shape to clot Meniscus or flattened shape to clot
(recent) versus reverse meniscus (older)(recent) versus reverse meniscus (older) tram track (nonocclusive or recanalized tram track (nonocclusive or recanalized
clot) clot) delayed (antegrade) flow (manifest as delayed (antegrade) flow (manifest as
decreased whole-brain perfusion on CTA)decreased whole-brain perfusion on CTA) retrograde collateral flowretrograde collateral flow
Non-occlusive left MCA thrombus on 3-D imaging performed from CTA source data and was confirmed at catheter angiography
Therapy to be started within a 6-hr Therapy to be started within a 6-hr time to treatment (TTT) window time to treatment (TTT) window (while in case of IV thrombolysis (while in case of IV thrombolysis therapy to be started with in 3hrs)therapy to be started with in 3hrs)
Exclusion criteria Exclusion criteria Rapidly improving neurologic deficit or Rapidly improving neurologic deficit or Sustained blood pressure of gt180100 Sustained blood pressure of gt180100 Hemorrhage is detected on CTHemorrhage is detected on CT Infarct involving gt more than 13 rd Infarct involving gt more than 13 rd
territory of MCAterritory of MCA MRADWI-Perfusion mismatchlt 20MRADWI-Perfusion mismatchlt 20 Definite hypodensity on CTDefinite hypodensity on CT
Intra-arterial Thrombolysis
Fibrinolytics + AntiplateletsFibrinolytics + Antiplatelets
PlasminogenPlasminogen activators through fibrinolysis exposes activators through fibrinolysis exposes free thrombin and paradoxically stimulatesfree thrombin and paradoxically stimulates platelet platelet aggregation which leads to formation of aaggregation which leads to formation of a platelet platelet thrombus (white clot) thrombus (white clot)
This new thrombus is relatively resistant to This new thrombus is relatively resistant to fibrinolyticsfibrinolytics
So new regimen in case of acute stroke isSo new regimen in case of acute stroke is fibrinolytics + antiplatelet drugsfibrinolytics + antiplatelet drugs
rtPA + IIbIIIa inhibitors( tirofiban rtPA + IIbIIIa inhibitors( tirofiban abciximab) orabciximab) or
Urokinase + IIbIIIa Urokinase + IIbIIIa inhibitors( tirofiban abciximab)inhibitors( tirofiban abciximab)
Intra-arterial Thrombolysis Tirofiban (04 microgkgmin bolus for 3 min followed by Tirofiban (04 microgkgmin bolus for 3 min followed by
0125 ugkgmin)0125 ugkgmin)
++
Heparin (2000ndash3000 IU bolus followed by Heparin (2000ndash3000 IU bolus followed by 1000 IUhour infusion 1000 IUhour infusion
with ACT maintained bw 200-300) throughout the with ACT maintained bw 200-300) throughout the interventional procedure and for 24ndash48 hours thereafter when interventional procedure and for 24ndash48 hours thereafter when there is neither intraprocedural bleeding nor suspicion of there is neither intraprocedural bleeding nor suspicion of increased risk of bleeding increased risk of bleeding
Maximum dose of Urokinase Maximum dose of Urokinase Anterior circulation stroke - 500000 IU (mean 400000 Anterior circulation stroke - 500000 IU (mean 400000
IU range 300000ndash500000 IU)IU range 300000ndash500000 IU) Posterior circulation stroke -1000000 IU (mean 837000 Posterior circulation stroke -1000000 IU (mean 837000
IU range 300000ndash1000000 IU)IU range 300000ndash1000000 IU)American Journal of NeuroradiologyAmerican Journal of Neuroradiology 262595-2601 2005262595-2601 2005
Intravenous ThrombolysisIntravenous Thrombolysis
The first method to restore cerebral The first method to restore cerebral perfusion is clot lysis with the goal perfusion is clot lysis with the goal of re-establishing blood flow to the of re-establishing blood flow to the affected tissue affected tissue
IV thrombolysis rt-PA is the only IV thrombolysis rt-PA is the only FDA- approved treatment for AIS FDA- approved treatment for AIS
Fibrinolysis is enhanced powerfully Fibrinolysis is enhanced powerfully by rt-PAby rt-PA
Intravenous rTPA Intravenous rTPA administration administration protocolprotocol
Total dose of rt-PA 09 mgkg (maximum dose Total dose of rt-PA 09 mgkg (maximum dose 90 mg)90 mg)
Give 10 as initial IV bolusGive 10 as initial IV bolus Infuse remainder over 1 hourInfuse remainder over 1 hour Admit patient to an ICU or stroke unit for Admit patient to an ICU or stroke unit for
monitoringmonitoring Neurologic assessments every 15 minutes Neurologic assessments every 15 minutes
during infusion then every 30 minutes for next during infusion then every 30 minutes for next 6 hours then every hour until 24hours after 6 hours then every hour until 24hours after treatmenttreatment
Favorable Outcome vs Treatment Time Favorable Outcome vs Treatment Time with IV rTPAwith IV rTPA
Protocol limit = 3 hrs
Benefit ~ 45 hrs
Thromboembolism During coilingThromboembolism During coiling Most feared and frequent complication Most feared and frequent complication Reported incidence - Approx 7 Reported incidence - Approx 7 SourcesSources of Thromboembolism are of Thromboembolism are
- Clots at the aneurysmal neck during or immediately- Clots at the aneurysmal neck during or immediately after after embolization embolization
- Thrombus forming on catheters during- Thrombus forming on catheters during proceduresprocedures
- Stenosis of an adjacent artery dt coil mass- Stenosis of an adjacent artery dt coil mass or herniationor herniation
- Migration of intraaneurysmal- Migration of intraaneurysmal thrombus during coil thrombus during coil placement placement
- Slow flow dt vasospasm - Slow flow dt vasospasm
- Rare and unlikely causes are hypercoagulable- Rare and unlikely causes are hypercoagulable state such state such as antiphospholipid antibody syndrome or due to HITas antiphospholipid antibody syndrome or due to HIT
Occur more often with wide-necked aneurysms (dt Occur more often with wide-necked aneurysms (dt increased exposed surface area of thrombogenic coil increased exposed surface area of thrombogenic coil material)material)
Current regimen of endovascular Current regimen of endovascular managementmanagement
The The glycoprotein IIbIIIa antagonist tirofiban glycoprotein IIbIIIa antagonist tirofiban (04 (04 microgkgmin bolus for 30 minutes followed by infusion of microgkgmin bolus for 30 minutes followed by infusion of 0125 ugkgmin until the thrombus dissolved) 0125 ugkgmin until the thrombus dissolved)
Intraarterial thrombolysis with Intraarterial thrombolysis with urokinase or r- TPA urokinase or r- TPA increase of intravenous (IV) heparin (measured by increase of intravenous (IV) heparin (measured by
ACT) ACT) Intravenous aspirin Intravenous aspirin
Coil-related platelet aggregation (white clot) is Coil-related platelet aggregation (white clot) is unlikely to respond to fibrinolytics but has a high risk unlikely to respond to fibrinolytics but has a high risk of hemorrhage (In ISAT) all 5 patients who had of hemorrhage (In ISAT) all 5 patients who had received thrombolytic therapy with tPA to treat a received thrombolytic therapy with tPA to treat a thromboembolic complication after endovascular thromboembolic complication after endovascular treatment rebleed and all of these patients died)treatment rebleed and all of these patients died)
IntracranialIntracranial Stenting Stenting Metallic foreign body such as stent will accumulate Metallic foreign body such as stent will accumulate
thrombus in the absence of platelet inhibitionthrombus in the absence of platelet inhibition Antiplatelet drugs are important to prevent peri or Antiplatelet drugs are important to prevent peri or
post-interventional thromboembolic eventspost-interventional thromboembolic events Optimal treatment regimens has not been determined Optimal treatment regimens has not been determined
but usually but usually Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-
procedureprocedureOrOr
Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on
morning of proceduremorning of procedure
If need to use stent is not pre-planned thanIf need to use stent is not pre-planned than
Abciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkgAbciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkg IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)
Glycoprotein IIbIIIa inhibitor are not used routinely during elective Glycoprotein IIbIIIa inhibitor are not used routinely during elective stenting procedure dt increased risk of ICH stenting procedure dt increased risk of ICH
Carotid StentingCarotid Stenting
Pre-procedurePre-procedure
Double Antiplatelet therapy is routinely given Double Antiplatelet therapy is routinely given beginning at least 3beginning at least 3
days before the proceduredays before the procedure
Aspirin 325mgd+Clopidogrel 75mgdAspirin 325mgd+Clopidogrel 75mgd During procedureDuring procedure
Heparin is given with target clotting time of 250-Heparin is given with target clotting time of 250-300sec300sec
Post-procedure Post-procedure
Aspirin 325mg is continued indefinitely and Aspirin 325mg is continued indefinitely and
Clopidogrel 75mgd for at least 6 weeks Clopidogrel 75mgd for at least 6 weeks
Inclusion criteria for Local ThrombolysisInclusion criteria for Local Thrombolysis a)a) Patients in severe clinical grade on admission Patients in severe clinical grade on admission
with evidence of dural venous sinus with evidence of dural venous sinus thrombosis and restrictive venous outflow on thrombosis and restrictive venous outflow on cerebral angiogramcerebral angiogram
b)b) Patients in clinical grade 3 worsening on Patients in clinical grade 3 worsening on heparin therapy Restriction to venous heparin therapy Restriction to venous outflow was defined as an increase in brain outflow was defined as an increase in brain circulation time gt 12 s delay in the drainage circulation time gt 12 s delay in the drainage of cortical veins with cortical veins hanging of cortical veins with cortical veins hanging in spacein space
Treatment Options for Venous Thrombosis
CT Grading for Venous ThrombosisCT Grading for Venous Thrombosis Grade I no parenchymal change Grade I no parenchymal change
(hyperdense (hyperdense sinuses cortical veins empty sinuses cortical veins empty delta sign)delta sign)
Grade II non hemorrhagic venous infarct Grade II non hemorrhagic venous infarct without mass effect without mass effect
Grade III non-hemorrhagic infarct with Grade III non-hemorrhagic infarct with mass effectmass effect
Grade IV hemorrhagic venous infarct (max Grade IV hemorrhagic venous infarct (max diameter lt 3 cm) with no mass effectdiameter lt 3 cm) with no mass effect
Grade V hemorrhagic venous infarct (max Grade V hemorrhagic venous infarct (max diameter gt 3 cm) with mass effect diameter gt 3 cm) with mass effect
Local ThrombolysisLocal Thrombolysis
Femoral Jugular access was secured and a guiding Femoral Jugular access was secured and a guiding catheter was placed in the jugular bulb catheter was placed in the jugular bulb Mechanical Mechanical clot maceration clot maceration was done with the guidewire was done with the guidewire following which a microcatheter (was navigated and following which a microcatheter (was navigated and placed in the thrombosed segment of sinus confirmed placed in the thrombosed segment of sinus confirmed on a selective venogram on a selective venogram
Urokinase infusion Bolus dose of 2-6 lacs followed Urokinase infusion Bolus dose of 2-6 lacs followed by 60000 to 100000 units per hour along with by 60000 to 100000 units per hour along with periodic check venogram Along with maintenance periodic check venogram Along with maintenance systemic infusion of Heparinsystemic infusion of Heparin Other agents such as Other agents such as streptokinase altepase or rTPAstreptokinase altepase or rTPA can be also used can be also used
After thrombolysis patient should subjected to oral After thrombolysis patient should subjected to oral anticoagulation for six monthsanticoagulation for six months
Low-molecular-weight Low-molecular-weight heparinheparin
PharmacologyPharmacologyLMWH as its name suggests is a glycosaminoglycan that is approximatelyLMWH as its name suggests is a glycosaminoglycan that is approximately
one third the molecular weight of UFH It is derived from UFH through one third the molecular weight of UFH It is derived from UFH through variousvarious
depolymerization processes LMWH binds to antithrombin which in turn depolymerization processes LMWH binds to antithrombin which in turn
Neutralizes actors Xa and IIa Because LMWH lacks many of the longer Neutralizes actors Xa and IIa Because LMWH lacks many of the longer chains chains
required for binding to thrombin it has less ability to neutralize thrombin required for binding to thrombin it has less ability to neutralize thrombin
relativeto its ability to neutralize factor Xa LMWH also has less relativeto its ability to neutralize factor Xa LMWH also has less nonspecific nonspecific
binding to other proteins There is greater bioavailability with more binding to other proteins There is greater bioavailability with more predictable predictable
pharmacokinetics that eliminates the need for monitoring The smaller pharmacokinetics that eliminates the need for monitoring The smaller size also size also
allows for enhanced subcutaneous absorption when compared with UFHallows for enhanced subcutaneous absorption when compared with UFH
Three LMWH preparations are Three LMWH preparations are currently approved for use in the currently approved for use in the United States (1) enoxaparin (2) United States (1) enoxaparin (2) dalteparin and (3) tinzaparin dalteparin and (3) tinzaparin
They are all administered They are all administered subcutaneously at intervals of either subcutaneously at intervals of either once or twice daily for both once or twice daily for both prophylaxis and treatment dosesprophylaxis and treatment doses
Few Experiences of Few Experiences of ThrombolysisThrombolysis
Vickey 25 Yrs male patient presented Vickey 25 Yrs male patient presented with 12with 12thth day HO severe headache with day HO severe headache with right sided hemiplegiaright sided hemiplegia
MRI shows thrombosis of the superior MRI shows thrombosis of the superior sagittal left transverse left sigmoid sagittal left transverse left sigmoid sinuses and cortical veins in the fronto-sinuses and cortical veins in the fronto-parietal regions with eo haemorrhagic parietal regions with eo haemorrhagic infarct in the left cerebral hemisphere infarct in the left cerebral hemisphere with mass effect( Grade ndashV)with mass effect( Grade ndashV)
Sashi Srivastava 64 yrs FSashi Srivastava 64 yrs F In a follow up case of MRD with infra-renal In a follow up case of MRD with infra-renal
aortic abdominal and bilateral renal artery aortic abdominal and bilateral renal artery thrombosis renal angiogram shows filling thrombosis renal angiogram shows filling defects in the right Renal artery defects in the right Renal artery
Initially Renal angioplasty was done Initially Renal angioplasty was done Following angioplasty few thrombi are seem Following angioplasty few thrombi are seem to extends into the segmental branches and to extends into the segmental branches and causing blockage So Thrombolysis was causing blockage So Thrombolysis was plane to dissolve the run-out thrombi with plane to dissolve the run-out thrombi with urokinase urokinase
Rakesh 34yrsMRakesh 34yrsM Left SFA pseudoaneurysm with Left SFA pseudoaneurysm with
Covered stent placementCovered stent placement Pre operative antiplatelets with post Pre operative antiplatelets with post
procedure heparin Tirofiban procedure heparin Tirofiban followed by aspirin and clopidogrel followed by aspirin and clopidogrel were usedwere used
IAT may be a treatment option for selected patients IAT may be a treatment option for selected patients Possible selection criteria include Possible selection criteria include
presentation between 3 and 6 hours from symptom onsetpresentation between 3 and 6 hours from symptom onset major cerebral artery occlusion major cerebral artery occlusion severe neurologic deficits severe neurologic deficits high risk of systemic hemorrhage with IV rt-PA (eg recent high risk of systemic hemorrhage with IV rt-PA (eg recent
surgery) surgery) The MERCI (Mechanical Embolus Removal in Cerebral The MERCI (Mechanical Embolus Removal in Cerebral
Ischemia) retrievalIschemia) retrieval system system
Has been FDA-approved for recanalizing acutely occluded Has been FDA-approved for recanalizing acutely occluded cerebral arteries cerebral arteries
In the Multi-MERCI study patients who did not improve In the Multi-MERCI study patients who did not improve immediately after IV rt-PA underwent mechanical immediately after IV rt-PA underwent mechanical embolectomy within 8 hours of symptom onset embolectomy within 8 hours of symptom onset
Partial or complete recanalization occurred in 74 of Partial or complete recanalization occurred in 74 of patientspatients
with a symptomatic intracerebral hemorrhage (sICH) rate of with a symptomatic intracerebral hemorrhage (sICH) rate of 67 67
Mechanical embolectomy with the MERCI retriever may be a Mechanical embolectomy with the MERCI retriever may be a feasible and safe option for patients after IV rt-PAfeasible and safe option for patients after IV rt-PA
Penumbra stroke systemPenumbra stroke system This device combines two methods of clot This device combines two methods of clot
extraction aspiration and mechanical extraction aspiration and mechanical extraction extraction
First the clot is aspirated then a thrombus First the clot is aspirated then a thrombus removal ring can be used if necessary to removal ring can be used if necessary to remove remaining clot remove remaining clot
successful recanalizing 82successful recanalizing 82 Bridging therapyBridging therapy
06 mgkg IV rt-PA followed by IAT with IA rt-06 mgkg IV rt-PA followed by IAT with IA rt-PA (up to 20 mg)PA (up to 20 mg)
achieved a higher recanalization rateachieved a higher recanalization rate
Criteria for thrombolysis with rTPACriteria for thrombolysis with rTPA
Inclusion criteriaInclusion criteria Clinical signs and symptoms consistent with ischemic Clinical signs and symptoms consistent with ischemic
strokestroke Patient last seen normal within 3 hoursPatient last seen normal within 3 hours Measurable neurologic deficitMeasurable neurologic deficit
Exclusion criteriaExclusion criteria Any hemorrhage on neuroimaging (CT or MRI)Any hemorrhage on neuroimaging (CT or MRI) Symptoms suggestive of subarachnoid hemorrhageSymptoms suggestive of subarachnoid hemorrhage Seizure at stroke onset that is thought to contribute to Seizure at stroke onset that is thought to contribute to
neurologic deficitneurologic deficit Hypodensity greater than one third cerebral hemisphere Hypodensity greater than one third cerebral hemisphere
on CTon CT SBP greater than 185 mm Hg or DBP greater than 110 SBP greater than 185 mm Hg or DBP greater than 110
mm Hgmm Hg International normalized ratio (INR) greater than 17International normalized ratio (INR) greater than 17
Ischemic Stroke Ischemic Stroke Treatment ndash 2006Treatment ndash 2006
IV tissue plasminogen activator (tPA)IV tissue plasminogen activator (tPA) ndash ndash Only FDA-approved acute stroke drugOnly FDA-approved acute stroke drug ndash ndash 3 hour treatment window3 hour treatment window
MERCI - Concentric clot retrieval MERCI - Concentric clot retrieval devicedevice ndash ndash Rescue therapy - approved 2004Rescue therapy - approved 2004 ndash ndash Device approval (not outcomes-based)Device approval (not outcomes-based)
Off label approachesOff label approaches ndash ndash IV tPA after 3 hoursIV tPA after 3 hours ndash ndash IV-IA tPA sequential strategiesIV-IA tPA sequential strategies ndash ndash IA tPA clot angioplasty fragmentationIA tPA clot angioplasty fragmentation ndash ndash Ultrasound-assisted tPA lysisUltrasound-assisted tPA lysis
rt-PA Trials NINDSrt-PA Trials NINDS
Acute stroke - 624 patientsAcute stroke - 624 patients Treat within 3 hrsTreat within 3 hrs Intravenous 09 mgkg rt-PA vs placeboIntravenous 09 mgkg rt-PA vs placebo Hemorrhage 64 tPA 06 placeboHemorrhage 64 tPA 06 placebo Neurologic recovery better with tPA 30 Neurologic recovery better with tPA 30
more like to have minimal or no disabilitymore like to have minimal or no disability
First proven approved treatment for First proven approved treatment for strokestroke
Limitations of tPALimitations of tPA Only 4 of acute strokes receive tPAOnly 4 of acute strokes receive tPA (Kleindorfer et al Stroke 2004 35 e27-e29)(Kleindorfer et al Stroke 2004 35 e27-e29)
Only 22 of patients present within 3 hoursOnly 22 of patients present within 3 hours1048707 1048707 51 of these ineligible due to51 of these ineligible due to
bull bull Mild severityMild severity bull bull Medical or surgical historyMedical or surgical history bull bull Blood testsBlood tests
Sustained recanalization only 13Sustained recanalization only 13 (Alexandrov et al NEJM 2004 351 2170-8)(Alexandrov et al NEJM 2004 351 2170-8)
Concern for hemorrhageConcern for hemorrhage tPA potentiates apoptotic injury tPA potentiates apoptotic injury (Liu et al Nature Med 2004 101379-83)(Liu et al Nature Med 2004 101379-83)
PROACT II IA Lysis TrialPROACT II IA Lysis Trial Baseline 24 hours 8 days
Baseline 60 minutes 120 minutes
9mg IAProurokinase
Desmoteplase Trials DEDAS Desmoteplase Trials DEDAS DIASDIAS
Trial OverviewTrial Overview Double blind randomized placebo Double blind randomized placebo
controlled trialscontrolled trials IV delivery 3-9 hour time windowIV delivery 3-9 hour time window Plasminogen activator ndash from Plasminogen activator ndash from vampire bat vampire bat
salivasaliva Selection based on PWI-DWI MismatchSelection based on PWI-DWI Mismatch
MRI InclusionMRI Inclusion PWI defect at least 2 cm AND ~20 larger PWI defect at least 2 cm AND ~20 larger
than DWIthan DWI PWI should be obvious even visible on PWI should be obvious even visible on
raw imagesraw imagesMRI ExclusionMRI Exclusion
DWI gt 13 MCADWI gt 13 MCA MRA ICA occlusionMRA ICA occlusion
Desmoteplase ndash DIAS Desmoteplase ndash DIAS ResultsResults
Mechanical Thrombolysis Mechanical Thrombolysis devicesdevices
mechanical thrombolysis potentially extends the treatment mechanical thrombolysis potentially extends the treatment window because they act promptly at the site of the thrombuswindow because they act promptly at the site of the thrombus
The devices can retrieve large clots that pharmaceutical agents The devices can retrieve large clots that pharmaceutical agents may not successfully lysemay not successfully lyse
Patients treated with IV tPA may be considered for treatment of Patients treated with IV tPA may be considered for treatment of residual clot with some of these devicesresidual clot with some of these devices
suction-creating saline jets suction-creating saline jets laser energy ultrasound laser energy ultrasound a corkscrew apparatus to treat strokesa corkscrew apparatus to treat strokes The AngioJet systemThe AngioJet system uses saline jets that are directed back into the catheter to uses saline jets that are directed back into the catheter to
create a low-pressure zone around the catheter tip inducing create a low-pressure zone around the catheter tip inducing suction suction
The clot is pulled into the exhaust lumen and removed from the The clot is pulled into the exhaust lumen and removed from the vessel Although US Food and Drug Administration (FDA) has vessel Although US Food and Drug Administration (FDA) has approved this device for use in arteriovenous dialysis grafts and approved this device for use in arteriovenous dialysis grafts and fistulae and for the treatment of coronary arteries saphenous fistulae and for the treatment of coronary arteries saphenous vein grafts and peripheral vessels clinical trials for the vein grafts and peripheral vessels clinical trials for the treatment of acute stroke are no longer in progress treatment of acute stroke are no longer in progress
Most devices are used in cerebral vessels that 2-5 mm
The Latis laser device The Latis laser device used laser energy to ablate clots used laser energy to ablate clots Arteries 2-5 mm in diameter could be Arteries 2-5 mm in diameter could be
treated including the ICA M1 or M2 treated including the ICA M1 or M2 branch of the MCA A1 branch of the branch of the MCA A1 branch of the anterior cerebral artery (ACA) basilar anterior cerebral artery (ACA) basilar artery posterior cerebral artery (PCA) artery posterior cerebral artery (PCA) and vertebral and vertebral
Patients could receive treatment as late Patients could receive treatment as late as 8 hours after symptom onset in the as 8 hours after symptom onset in the anterior circulation and within 24 hours in anterior circulation and within 24 hours in the posterior circulation the posterior circulation
Endovascular Photo Acoustic Endovascular Photo Acoustic Recanalization (EPAR) Recanalization (EPAR)
A laser power source generated energy for the A laser power source generated energy for the systemsystem
The energy was delivered by means of The energy was delivered by means of fiberoptics to the tip of the catheter at the fiberoptics to the tip of the catheter at the treatment sitetreatment site
Absorption of laser light by darkly pigmented Absorption of laser light by darkly pigmented materials (ie the clot) occurred inside the 1-mm materials (ie the clot) occurred inside the 1-mm catheter tipcatheter tip
the system was designed to minimize scattering the system was designed to minimize scattering of laser light of laser light
Absorption converted photo energy to acoustic Absorption converted photo energy to acoustic energy which then emulsified the clot inside the energy which then emulsified the clot inside the catheter tip catheter tip
EKOS ultrasound( the EKOS ultrasound( the Ultrasound Thrombolytic Ultrasound Thrombolytic
Infusion Catheter) Infusion Catheter) combines the use of a distal ultrasound transducer with combines the use of a distal ultrasound transducer with
infusion of a thrombolytic agent through the infusion of a thrombolytic agent through the microcathetermicrocatheter
Ultrasound changes the structure of the clot to Ultrasound changes the structure of the clot to temporarily increase its permeability while providing an temporarily increase its permeability while providing an acoustic pressure gradient to move the drug into the clot acoustic pressure gradient to move the drug into the clot to speed its dissolution to speed its dissolution
The EKOS catheter is placed in the proximal portion of the The EKOS catheter is placed in the proximal portion of the clot clot
After a 2-mg bolus of tPA was injected through the After a 2-mg bolus of tPA was injected through the catheter catheter
the patient received a continuous infusion of IA tPA 03 the patient received a continuous infusion of IA tPA 03 mgmin to a maximum of 20 mg and simultaneous mgmin to a maximum of 20 mg and simultaneous ultrasound transmission for as long as 60 minutes ultrasound transmission for as long as 60 minutes
One patient was treated with a total of 4 units of One patient was treated with a total of 4 units of recombinant reteplase (Retavase) hand-injected over 60 recombinant reteplase (Retavase) hand-injected over 60 minutes minutes
Penumbra system Penumbra system The Penumbra system (Penumbra Inc) provides a dual The Penumbra system (Penumbra Inc) provides a dual
approach to clot extraction using aspiration followed by approach to clot extraction using aspiration followed by clot retrieval with a ring device if needed clot retrieval with a ring device if needed
Mechanical Embolus Removal in Cerebral Ischemia Mechanical Embolus Removal in Cerebral Ischemia (MERCI)(MERCI)
a corkscrew-like apparatus to remove blood clots from a corkscrew-like apparatus to remove blood clots from the brain in patients experiencing an ischemic stroke the brain in patients experiencing an ischemic stroke
The corkscrew itself resides in the catheter tip which The corkscrew itself resides in the catheter tip which shields it from the wall of the vessel until it is ready to be shields it from the wall of the vessel until it is ready to be burrowed into the clot Once lodged in the clot the device burrowed into the clot Once lodged in the clot the device and clot are withdrawn from the vessel and clot are withdrawn from the vessel
Snarelike devicesSnarelike devices Snares such as the Neuronet snare (Guidant Snares such as the Neuronet snare (Guidant
Endovascular Santa Clara CA) have been developed Endovascular Santa Clara CA) have been developed specifically for use in the treatment of strokes specifically for use in the treatment of strokes
These devices are simple in design and do not require the These devices are simple in design and do not require the clot to be amenable to emulsification clot to be amenable to emulsification
X-Sizer deviceX-Sizer device a device with small moving blades at the a device with small moving blades at the
catheter tip catheter tip This device the X-Sizer device (EndiCor Medical This device the X-Sizer device (EndiCor Medical
San Clemente CA) can be used to excise the San Clemente CA) can be used to excise the thrombus and aspirate it thrombus and aspirate it
The device was being evaluated in randomized The device was being evaluated in randomized studies of coronary vessels and in a registry of studies of coronary vessels and in a registry of patients with acute myocardial infarctionpatients with acute myocardial infarction
Although the manufacturer had modified the Although the manufacturer had modified the device for use in cerebral vessels a safety and device for use in cerebral vessels a safety and feasibility study was indefinitely suspended after feasibility study was indefinitely suspended after only 1 patient was treated with the device in only 1 patient was treated with the device in Europe Europe
Suction thrombectomySuction thrombectomy This method of mechanical thrombolysis is one of the This method of mechanical thrombolysis is one of the
simplestsimplest In this readily available technique suction is applied with In this readily available technique suction is applied with
a syringe to remove thrombus in the ICA a syringe to remove thrombus in the ICA It requires no other devicesIt requires no other devices A catheter with a large inner diameter (Brite Tip Cordis A catheter with a large inner diameter (Brite Tip Cordis
Corporation Miami FL) was placed in the symptomatic Corporation Miami FL) was placed in the symptomatic vessel and navigated over a guidewire into the thrombusvessel and navigated over a guidewire into the thrombus
A 60-mL syringe was used to aspirate the thrombus A 60-mL syringe was used to aspirate the thrombus Each patient required angioplasty and stenting of carotid Each patient required angioplasty and stenting of carotid
bifurcation stenosis and received daily aspirin and bifurcation stenosis and received daily aspirin and ticlopidine after the procedure No complications ticlopidine after the procedure No complications occurred occurred
Summary Acute Stroke Summary Acute Stroke ImagingImaging
PhysiologyPhysiology importance collaterals importance collaterals
ndash ndashGrowing role for perfusion Growing role for perfusion assessmentassessment
tPAtPA guidelines amp limitations guidelines amp limitations Signs on CT amp MRSigns on CT amp MR follow physiology follow physiology Stroke trialsStroke trials PWI-DWI mismatch PWI-DWI mismatch
ndash ndashTreat based on physiology not timeTreat based on physiology not time ProtocolsProtocols should be fast and should be fast and
comprehensivecomprehensive
Blood Clotting Blood Clotting (Coagulation)(Coagulation) - - Blood normally remains in its liquid state while Blood normally remains in its liquid state while
it is within the blood vessels but when it leaves it is within the blood vessels but when it leaves them the blood may thicken and form a gel them the blood may thicken and form a gel (coagulation) (coagulation)
Blood clotting (technically Blood clotting (technically blood blood coagulationcoagulation) is the process by which (liquid) ) is the process by which (liquid) blood is transformed into a solid stateblood is transformed into a solid state
bull Interventional procedures
Virchowrsquos Triad
Mechanism of blood Mechanism of blood coagulationcoagulation
HemostasisHemostasis involves a sequence of interactions of coagulation involves a sequence of interactions of coagulation
factor interactions in two pathways called the factor interactions in two pathways called the intrinsic and extrinsic coagulation cascades intrinsic and extrinsic coagulation cascades
The final common pathway involves the The final common pathway involves the transformation of prothrombin to thrombin by factor transformation of prothrombin to thrombin by factor Xa Xa
Thrombin (factor IIa) then serves to catalyze the Thrombin (factor IIa) then serves to catalyze the activation of fibrinogen to fibrin in addition to its role activation of fibrinogen to fibrin in addition to its role in feedback activation of several other clotting factorsin feedback activation of several other clotting factors
UFH LMWH and fondaparinux( saccharides) all UFH LMWH and fondaparinux( saccharides) all exert their anticoagulant effect in a similar fashion by exert their anticoagulant effect in a similar fashion by binding to and activating antithrombinbinding to and activating antithrombin that then that then neutralizes selected coagulation factorsneutralizes selected coagulation factors
Stages of blood coagulationStages of blood coagulation Formation of Formation of ProthrombinaseProthrombinase
Prothrombinase can be formed in two ways depending of which of Prothrombinase can be formed in two ways depending of which of two systems or pathways apply two systems or pathways apply
Intrinsic SystemIntrinsic System This is initiated by liquid blood making contact with a foreign This is initiated by liquid blood making contact with a foreign
surface ie something that is not part of the body surface ie something that is not part of the body Extrinsic SystemExtrinsic System
This is initiated by liquid blood making contact with damaged This is initiated by liquid blood making contact with damaged tissuetissue
Both the intrinsic and the extrinsic systems involve interactions Both the intrinsic and the extrinsic systems involve interactions between between coagulation factorscoagulation factors
2 2 ProthrombinProthrombin converted into the enzyme converted into the enzyme ThrombinThrombinProthrombinase (formed in stage 1) converts prothrombin which is Prothrombinase (formed in stage 1) converts prothrombin which is a plasma protein that is formed in the liver into the enzyme a plasma protein that is formed in the liver into the enzyme thrombinthrombin
3 3 FibrinogenFibrinogen (soluble) converted to (soluble) converted to FibrinFibrin (insoluble) (insoluble)In turn thrombin converts fibrinogen into fibrin Fibrin is insoluble In turn thrombin converts fibrinogen into fibrin Fibrin is insoluble and forms the threads that bind the clotand forms the threads that bind the clot
BLOOD COAGULATION
A sequence of reactions that are present in an inactive state in bloodKey is the conversion of the plasma protein fibrinogen to fibrin Intrinsic pathway Extrinsic pathway(activated by exposure of (activated by substances blood to damaged tissue) released from damaged tissue)
Active factors X and V
Prothrombin Thrombin
Fibrinogen Fibrin Fibrin mesh
inhibited by warfarin
inhibited by heparin
Rationale for anticoagulant Rationale for anticoagulant therapytherapy
PHARMACOLOGICAL PHARMACOLOGICAL AGENTSAGENTS
Pharmacologic AgentsPharmacologic Agents
AnticoagulantsAnticoagulants
Fibrinolytics (Agents for pharmacological Fibrinolytics (Agents for pharmacological recanalization)recanalization)
Anti platelet drugsAnti platelet drugs
Thrombin inhibitorThrombin inhibitor
ANTICOAGULANTSANTICOAGULANTS
Heparin and Low Molecular Weight Heparins Heparin and Low Molecular Weight Heparins ((eg enoxaparin dalteparin)eg enoxaparin dalteparin)
Oral anticoagulantsOral anticoagulants Coumarin Derivatves Coumarin Derivatves eg Warfarin eg Warfarin
AcenocoumarolAcenocoumarol Indandione Derivatves Indandione Derivatves eg Phenindione eg Phenindione
AnisindioneAnisindione
ThrombolyticsThrombolytics
Plasminogen activators
Fibrinolytics
Anti Platelet DrugsAnti Platelet DrugsDrug Mechanism UsesDrug Mechanism UsesAspirinAspirin Permanently inhibits Permanently inhibits
COX-1 and COX-2COX-1 and COX-2CADCAD
Stroke-TIAsStroke-TIAs
NSAIDsNSAIDs Reversibly inhibits Reversibly inhibits COX-1COX-1
LimitedLimited
DipyridamoleDipyridamole Inhibits PDE Inhibits PDE increases cAMPincreases cAMP
TIAsTIAs
ThenopyridinesThenopyridines
(Ticlopidine(Ticlopidine
Clopidegrel)Clopidegrel)
Inhibits ADP Inhibits ADP
PlatAg PlatAg
TIAsStrokeTIAsStroke
CAD PVDCAD PVD
Abciximab (ReoPro)Abciximab (ReoPro)
Eptifibatide Eptifibatide (Integrilin)(Integrilin)
TirofibaTirofibann
GP IIBIIIA InhibitorsGP IIBIIIA Inhibitors
Stroke- TIAs Stroke- TIAs
Maintainance of patency Maintainance of patency of vascular of vascular grafts catheters shunts bypassesgrafts catheters shunts bypasses
Arterial thromboembolic diseaseArterial thromboembolic diseasebull Transient ischemic attacksTransient ischemic attacksbull Stroke in evolutionStroke in evolution
Ischemic events occurs in Ischemic events occurs in 1313 of of conventional neuroangiographic conventional neuroangiographic procedures without Endovascular surgeryprocedures without Endovascular surgery
Indications for Antithrombotic Therapy in Indications for Antithrombotic Therapy in Diagnostics and Interventional ProceduresDiagnostics and Interventional Procedures
WHY TO MONITOR ANTICOAGULANT THERAPYWHY TO MONITOR ANTICOAGULANT THERAPY
Narrow therapeutic rangeNarrow therapeutic range
Can increase risk of bleedingCan increase risk of bleeding
Coagulation TestingCoagulation Testing
Monitoring therapyMonitoring therapy
Intrinsic Pathway
Extrinsic Pathway
Common Pathway
CLOT
Heparin Coumadin
Monitor with
ACT aPTT
Monitor with PTINR
Thrombolytics
Monitor with TT Fibrinogen
Monitoring of Monitoring of Anti platelet drugsAnti platelet drugs
Bleeding timeBleeding time
Optical aggregometryOptical aggregometry
Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay
HeparinHeparin
Heterogeneous 3000-30000 dalton in Heterogeneous 3000-30000 dalton in molecular weight molecular weight
Average=15000 d (~45monosaccharide Average=15000 d (~45monosaccharide chains)chains)
About About 13 of dose binds to AT III and forms 13 of dose binds to AT III and forms the AT IIIHeparinClotting Factor Complexthe AT IIIHeparinClotting Factor Complex
Complex binds to clotting factors of the Complex binds to clotting factors of the intrinsic and common pathway (Xa IIa IXa intrinsic and common pathway (Xa IIa IXa XIa XIIa XIIIa) and inactivates themXIa XIIa XIIIa) and inactivates them
Anticoagulant of choice in pregnancy (not Anticoagulant of choice in pregnancy (not crosses placenta)crosses placenta)
Heparin and Low molecular weight heparinsHeparin and Low molecular weight heparins
Structure and sequence
O
OH
OH
O
COO
O
O
CH2OH
NHSO3
OH
_
_
O
O
CH2OSO3
NHSO3
OH
_
_
O
OH
OH
O
COOO
O
CH2OSO3
NHSO3
OH
_
_
O
OSO3
OHO
COOO
O
CH2OSO3
NHCOCH3
OH
_
_ _
_
_
O
OH
OH
O
COO
1
23
4
5
6
-D-glucosamine -L-iduronic acid -D-glucuronic acid
O
O
CH2OH
NH2
OH 12
3
4
5
6
O
OH
OHO
COO_
1
23
4
5
6
polymeric structure of heparin
Anticoagulant Properties of Anticoagulant Properties of HeparinHeparin
11 Inhibits the thrombin-mediated conversion of Inhibits the thrombin-mediated conversion of fibrinogen to fibrinfibrinogen to fibrin
22 Inhibits the aggregation of platelets by thrombin Inhibits the aggregation of platelets by thrombin (prolongs bleeding time)(prolongs bleeding time)
33 Inhibits activation of fibrin stabilizing enzymeInhibits activation of fibrin stabilizing enzyme
44 Inhibits activated factors XII XI IX X and IIInhibits activated factors XII XI IX X and II All available forms of heparin must be All available forms of heparin must be
administered administered parenterally since they are parenterally since they are highly charged and rapidlyhighly charged and rapidly hydrolyzed in the hydrolyzed in the GI tractGI tract
Heparin antagonist Protamine sulfate (Heparin antagonist Protamine sulfate (10mg for 10mg for 1000 unit of heparin)1000 unit of heparin)
Monitoring of heparin Monitoring of heparin
Subcutenous Subcutenous no monitoring requiredno monitoring required Intravenous Intravenous
Partial thromboplastin time (PTT normal value Partial thromboplastin time (PTT normal value ~30sec) ~30sec)
Activated clotting time ( ACT normal value ~90-Activated clotting time ( ACT normal value ~90-120sec)120sec)
Daily or more frequent if PTT ACT variesDaily or more frequent if PTT ACT varies
Mechanism Mechanism ndash measures intrinsic pathwayndash measures intrinsic pathway Therapeutic goal Therapeutic goal 2-25 times normal control value 2-25 times normal control value
ACT or aPTTACT or aPTT
Determine when to pull the femoral sheath Determine when to pull the femoral sheath Premature sheath pull can lead to bleedingPremature sheath pull can lead to bleeding Delayed removal can increase time in ICUDelayed removal can increase time in ICU Target set Target set at each siteat each site
ACT targets range from 150 ndash 220 ACT targets range from 150 ndash 220 secondsseconds
aPTT targets range from 40 ndash 70 seconds aPTT targets range from 40 ndash 70 seconds
During neuroangiography-During neuroangiography- Recommended therapeutic range of heparin in Recommended therapeutic range of heparin in
plasma is 02-08 uml ( corresponding to aPTT plasma is 02-08 uml ( corresponding to aPTT ACT values 15-25 times the baseline values)ACT values 15-25 times the baseline values)
Dose In diagnostic angiography bolus dose of Dose In diagnostic angiography bolus dose of 2500 iu is used followed by 1000 iu hour2500 iu is used followed by 1000 iu hour
Bolus dose is Bolus dose is 60 ukg to maintain the therapeutic 60 ukg to maintain the therapeutic range range If procedure continues for more than 75 If procedure continues for more than 75 minutes additional dose is required ( half of the minutes additional dose is required ( half of the initial dose for another 75 minutes) initial dose for another 75 minutes)
(AJNR 199415 51-54)
Mechanisms of HIT( Mechanisms of HIT( Heparin Heparin induced Thrombocytopeniainduced Thrombocytopenia))
Type 1Type 1 Fall in platelet count occurs within the first two Fall in platelet count occurs within the first two
days after heparin initiation often returns to days after heparin initiation often returns to normal with continued heparin administration normal with continued heparin administration and is of no clinical consequence and is of no clinical consequence
The mechanism of the thrombocytopenia is non-The mechanism of the thrombocytopenia is non-immune and appears to be due to a direct effect of immune and appears to be due to a direct effect of heparin on platelet activationheparin on platelet activation
Type 2Type 2 Approximately 03 to 3 percent of patients Approximately 03 to 3 percent of patients
receiving heparin develop an immune receiving heparin develop an immune thrombocytopenia mediated by antibodies to a thrombocytopenia mediated by antibodies to a heparin-platelet factor 4 complex heparin-platelet factor 4 complex
(AJNR 28155-158 2007)
Treatment of heparin-induced Treatment of heparin-induced thrombocytopeniathrombocytopenia
When HIT is diagnosed it is important to When HIT is diagnosed it is important to stop heparin mainly in type 2 and to avoid stop heparin mainly in type 2 and to avoid the use of LMWH the use of LMWH
Because of the increased risk of thrombosis Because of the increased risk of thrombosis however continuation of an anticoagulant however continuation of an anticoagulant must be considered must be considered
The drugs currently approved for the The drugs currently approved for the treatment of HIT in the United States are treatment of HIT in the United States are direct thrombin inhibitors argatroban and direct thrombin inhibitors argatroban and lepirudinlepirudin
WARFARIN MECHANISM OF ACTIONWARFARIN MECHANISM OF ACTION
Inactive factors II VII IX and X
Proteins S and C
Active factors II VII IX and X
Proteins S and C
Vitamin K epoxide
Vitamin K reduced
WA
RF
AR
IN
Prevents the reduction of vitamin K which is essential for Prevents the reduction of vitamin K which is essential for activation of certain factorsactivation of certain factors
Has no effect on previously formed thrombusHas no effect on previously formed thrombus
Antagonist is Vit KAntagonist is Vit K
OPTIMIZING WARFARIN THERAPYOPTIMIZING WARFARIN THERAPY
Use of large loading dose may lead to hemorrhage and Use of large loading dose may lead to hemorrhage and other complicationsother complications
Initial dose 2-5 mg once dailyInitial dose 2-5 mg once daily Maintenance dose 2-10 mg once dailyMaintenance dose 2-10 mg once daily If Immediate anticoagulation is requiredIf Immediate anticoagulation is required Heparin IS Heparin IS
started along with loading dose of warfarin 10 mg started along with loading dose of warfarin 10 mg Heparin is usually discontinued after 4-5 days Heparin is usually discontinued after 4-5 days Before Before discontinuing INR should be in therapeutic range for 2 discontinuing INR should be in therapeutic range for 2 consecutive daysconsecutive days
Daily monitoring of INR until INR is in therapeutic Daily monitoring of INR until INR is in therapeutic range then 3 times weekly for 1-2 weeks then less often range then 3 times weekly for 1-2 weeks then less often (every 4 to 6 weeks)(every 4 to 6 weeks)
OPTIMAL THERAPEUTIC RANGEOPTIMAL THERAPEUTIC RANGE
IndicationIndication INRINR
Prophylaxis of venous Prophylaxis of venous thromboembolismthromboembolism
20-3020-30
Treatment of venous Treatment of venous thromboembolismthromboembolism
20-3020-30
Atrial fibrillationAtrial fibrillation 20-3020-30
Mitral valve stenosisMitral valve stenosis 20-3020-30
Heart valve replacementHeart valve replacement
Bioprosthetic valveBioprosthetic valve
Mechanical valveMechanical valve
20-3020-30
25-3525-35
Myocardial infarctionMyocardial infarction 20-3020-30
25-35 25-35 (high risk patients)(high risk patients)
FACTORS INFLUENCING DOSE RESPONSEFACTORS INFLUENCING DOSE RESPONSE
Poor patient compliancePoor patient compliance Concomitant medicationsConcomitant medications Levels of dietary vitamin KLevels of dietary vitamin K Alcohol Inaccurate lab testingAlcohol Inaccurate lab testing Inaccurate lab testingInaccurate lab testing Hepatic dysfunctionHepatic dysfunction FeverFever
Contraindication for WarfarinContraindication for Warfarin
Hypersensitivity to warfarinHypersensitivity to warfarin Hemorrhagic tendencyHemorrhagic tendency Condition with risk of hemorrhageCondition with risk of hemorrhage Inadequate laboratory techniquesInadequate laboratory techniques Protein C amp S deficiencyProtein C amp S deficiency Vitamin K deficiencyVitamin K deficiency
SIDE EFFECTSSIDE EFFECTS
Hemorrhage Hemorrhage Skin necrosisSkin necrosis Purple toe syndromePurple toe syndrome Microembolization Microembolization TeratogenecityTeratogenecity Agranulocytosis leukopenia Agranulocytosis leukopenia Diarrhoeanausea anorexiaDiarrhoeanausea anorexia
MONITORING OF WARFARIN THERAPYMONITORING OF WARFARIN THERAPY
Prothrombin timeProthrombin time PT ratioPT ratio INR (International Normalized Ratio)INR (International Normalized Ratio)
PROTHROMBIN TIME (PT)PROTHROMBIN TIME (PT)
Time required for blood to coagulate Time required for blood to coagulate is called PT ( normal value ~10sec)is called PT ( normal value ~10sec)
Performed by adding a mixture of Performed by adding a mixture of calcium and thromboplastin to calcium and thromboplastin to citrated plasmacitrated plasma
As a control a normal blood sample is As a control a normal blood sample is tested continuouslytested continuously
PT ratio (PTR) = PT ratio (PTR) = Patientrsquos PTPatientrsquos PT Control PTControl PT
PROBLEMS WITH PTPTRPROBLEMS WITH PTPTR
Thromboplastins are extracts from Thromboplastins are extracts from brain lung or placenta of animalsbrain lung or placenta of animals
Thromboplastins from various Thromboplastins from various manufacturers differ in their manufacturers differ in their sensitivity to prolong PTsensitivity to prolong PT
May result in false control of May result in false control of anticoagulant therapyanticoagulant therapy
INTERNATIONAL NORMALISED RATIO (INR)INTERNATIONAL NORMALISED RATIO (INR)
International Normalized Ratio (INR) International Normalized Ratio (INR) a PT test with a a PT test with a formula based ratio to normalize the often variable source formula based ratio to normalize the often variable source of tissue factor (human rabbit recombinant)of tissue factor (human rabbit recombinant)
INR = [PTINR = [PTptpt] ] ISIISI
[PT[PTRefRef]]
PTPTpt pt ndash prothrombin time of patientndash prothrombin time of patient
PTPTRef Ref ndash prothrombin time of normal pooled samplendash prothrombin time of normal pooled sample
ISI ndash International Sensitivity IndexISI ndash International Sensitivity Index
Warfarin is given orally and titrated to achieve an INR of Warfarin is given orally and titrated to achieve an INR of typically 20 ndash 30typically 20 ndash 30
Heparin versus WarfarinHeparin versus Warfarin
Drug ActionMechan-ism
Moni-toring
Effective
HeparinDirect
Inhibition ofThrombin
ATIIIcofactor
APTTACT
Immediate
WarfarinDecreasesProductionof factors
Vitamin K PTDelay
3-5 days
INR
Recanalization or Antegrade Recanalization or Antegrade Reperfusion StrategiesReperfusion Strategies
Recanalization strategies focus on removing Recanalization strategies focus on removing andor dissolving the occlusive thrombus to re-andor dissolving the occlusive thrombus to re-establish antegrade flow Strategies may be establish antegrade flow Strategies may be classified into 7 different categories on the classified into 7 different categories on the basis of their primary mechanism of action basis of their primary mechanism of action 1) 1) IV andor intraarterial thrombolysis (IAT) IV andor intraarterial thrombolysis (IAT) 2) endovascular thrombectomy2) endovascular thrombectomy3) endovascular thromboaspiration 3) endovascular thromboaspiration 4) endovascular mechanical thrombus disruption or 4) endovascular mechanical thrombus disruption or
thromborrhexisthromborrhexis5) 5) transcranial or endovascular augmented transcranial or endovascular augmented
fibrinolysis fibrinolysis 6) endovascular thrombus entrapment and 6) endovascular thrombus entrapment and 7) temporary endovascular bypass7) temporary endovascular bypass
IAT in Acute Ischemic StrokeIAT in Acute Ischemic Stroke
IAT advantages over IV thrombolysisIAT advantages over IV thrombolysis Coaxial microcatheter techniques the occluded intracranial Coaxial microcatheter techniques the occluded intracranial
vessel is directly accessible and the fibrinolytic agent can be vessel is directly accessible and the fibrinolytic agent can be infused directly into the thrombusinfused directly into the thrombus
This permits a smaller dose of fibrinolytic agent to reach a This permits a smaller dose of fibrinolytic agent to reach a higher local concentration than that reached by systemic higher local concentration than that reached by systemic infusioninfusion
Allows more complete recanalization with lower total doses of Allows more complete recanalization with lower total doses of thrombolytic thrombolytic
With the smaller dose complications from systemic fibrinolytic With the smaller dose complications from systemic fibrinolytic effects including intracranial hemorrhage (ICH) can effects including intracranial hemorrhage (ICH) can theoretically be reduced theoretically be reduced
Treatment window for endovascular techniques can be Treatment window for endovascular techniques can be extended beyond the typical IV window of 3 hours extended beyond the typical IV window of 3 hours
IA techniques have led to higher recanalization rates than IV IA techniques have led to higher recanalization rates than IV thrombolysisthrombolysis
Major disadvantagesMajor disadvantages Relative complexity of the procedure the level Relative complexity of the procedure the level
of required technical expertise and its of required technical expertise and its relatively low availability relatively low availability
Delays in initiating treatmentDelays in initiating treatment InvasiveInvasive
ThrombolyticsThrombolytics
Plasminogen activators
Fibrinolytics
1 Plasminogen Activators 1 Plasminogen Activators drugs act by converting the inactive proenzyme drugs act by converting the inactive proenzyme plasminogen into the active enzyme plasmin Plasmin plasminogen into the active enzyme plasmin Plasmin digests fibrinogen fibrin monomers and cross-linked digests fibrinogen fibrin monomers and cross-linked fibrin (as found in a thrombus) into fibrin degradation fibrin (as found in a thrombus) into fibrin degradation productsproducts
First-Generation Agents First-Generation Agents StreptokinaseStreptokinase a protein derived from group C a protein derived from group C
szlig-hemolytic streptococci has a half-life of 16ndashszlig-hemolytic streptococci has a half-life of 16ndash90 minutes and low fibrin specificity This drug 90 minutes and low fibrin specificity This drug proved to have a very narrow therapeutic proved to have a very narrow therapeutic window and significant rates of ICH and window and significant rates of ICH and systemic hemorrhage18systemic hemorrhage18
UrokinaseUrokinase is a serine protease with a plasma is a serine protease with a plasma half life of 14 minutes and low fibrin specificity half life of 14 minutes and low fibrin specificity
The urokinase dose used in cerebral IAT has The urokinase dose used in cerebral IAT has ranged from 002 to 2 X106unitsranged from 002 to 2 X106units
Second-Generation Agents Second-Generation Agents Alteplase (rtPA) Alteplase (rtPA)
is a serine is a serine protease with a plasma half-life of 35 protease with a plasma half-life of 35 minutes and a high degree of fibrin affinity and minutes and a high degree of fibrin affinity and specificity specificity
Dose used in cerebral IAT has ranged between 20 Dose used in cerebral IAT has ranged between 20 and 60 mgand 60 mg
Disadvantages of alteplase include its relatively short Disadvantages of alteplase include its relatively short halflife and limited penetration into the clot matrix halflife and limited penetration into the clot matrix because of strong binding with surface fibrin which because of strong binding with surface fibrin which could delay recanalization and increase the risk of could delay recanalization and increase the risk of recurrent occlusion recurrent occlusion
Prourokinase (r-prourokinase) Prourokinase (r-prourokinase) is the proenzyme precursor of urokinase is the proenzyme precursor of urokinase T12 of 7 minutes and high fibrin specificity T12 of 7 minutes and high fibrin specificity
Third-Generation AgentsThird-Generation Agents
ReteplaseReteplase is a structurally modified is a structurally modified form of alteplase form of alteplase
with a longer half-life (15ndash18 minutes) In with a longer half-life (15ndash18 minutes) In addition it does not bind as highly to fibrin addition it does not bind as highly to fibrin unbound reteplase can thus theoretically better unbound reteplase can thus theoretically better penetrate the clot and potentially penetrate the clot and potentially improve in improve in vivo fibrinolytic activity vivo fibrinolytic activity
TenecteplaseTenecteplase is another modified form of rtPA with a longer is another modified form of rtPA with a longer
half-life (17 minutes)half-life (17 minutes) greater fibrin specificity and greater greater fibrin specificity and greater
resistance to plasminogen activator inhibitor-1 resistance to plasminogen activator inhibitor-1 IV tenecteplase in acute ischemic stroke IV tenecteplase in acute ischemic stroke
suggest that the drug is safe and promisingsuggest that the drug is safe and promising
Newer plasminogen activatorNewer plasminogen activator
DesmoteplaseDesmoteplase is a genetically engineered is a genetically engineered version of the clot-dissolving factor version of the clot-dissolving factor
found in the saliva found in the saliva of the vampire bat Desmodus rotundusof the vampire bat Desmodus rotundus moremore potent and more selective for fibrin-bound potent and more selective for fibrin-bound
plasminogen than any other known plasminogen plasminogen than any other known plasminogen activatoractivator
Unlike tissue plasminogen activator (tPA) desmoteplase Unlike tissue plasminogen activator (tPA) desmoteplase is not activated by fibrinogen or -amyloid proteins is not activated by fibrinogen or -amyloid proteins factors that may exacerbate the risk for ICH factors that may exacerbate the risk for ICH
The effect of IV administration of desmoteplase 3ndash9 The effect of IV administration of desmoteplase 3ndash9 hours after symptom onset in patients with stroke who hours after symptom onset in patients with stroke who present with mismatch on MR imaging or CT perfusion present with mismatch on MR imaging or CT perfusion
3 DefibrinogenatingFibrinogenolytic 3 DefibrinogenatingFibrinogenolytic Agents Agents
AncrodAncrod(Viprinex)(Viprinex) is is the purified fraction of the Malayan pit viper venomthe purified fraction of the Malayan pit viper venom It acts by directly cleaving and inactivating fibrinogen It acts by directly cleaving and inactivating fibrinogen
and thus indirectly promoting anticoagulation and thus indirectly promoting anticoagulation The reduction in the blood levels of fibrinogen also The reduction in the blood levels of fibrinogen also
leads to a reduced blood viscosity which may improve leads to a reduced blood viscosity which may improve blood flow to the affected areas of the brain blood flow to the affected areas of the brain
In the Stroke Treatment with Ancrod Trial 500 In the Stroke Treatment with Ancrod Trial 500 patients with stroke presenting within 3 hours of patients with stroke presenting within 3 hours of symptom onset were randomized to receive ancrod (symptom onset were randomized to receive ancrod (n n 248) or a placebo (n 252) Good outcome (Barthel 248) or a placebo (n 252) Good outcome (Barthel Index 95ndash100 at 3 months) was achieved in 4221 Index 95ndash100 at 3 months) was achieved in 4221 and 344 of the patients respectively and 344 of the patients respectively
2 Direct Fibrinolytics2 Direct Fibrinolytics
Microplasmin (Microplasmin (ThromboGenics Heverlee Belgium)ThromboGenics Heverlee Belgium) is a truncated form of plasmin that is more resistant to the effects is a truncated form of plasmin that is more resistant to the effects
of antiplasmin of antiplasmin microplasmin can be used upto 4ndash12 hours after stroke onset microplasmin can be used upto 4ndash12 hours after stroke onset There was no evidence of increased bleeding risk with There was no evidence of increased bleeding risk with
microplasminmicroplasmin
Alfimeprase (Nuvelo San Carlos Calif)Alfimeprase (Nuvelo San Carlos Calif) is a recombinant truncated form of fibrolase a fibrinolytic zinc metalloproteinase is a recombinant truncated form of fibrolase a fibrinolytic zinc metalloproteinase
isolated from the venom of the southern copperhead snake isolated from the venom of the southern copperhead snake It degrades fibrin directly and achieves thrombolysis independent It degrades fibrin directly and achieves thrombolysis independent
of plasmin formationof plasmin formation its thrombolytic activity appears to be localized to the site of its thrombolytic activity appears to be localized to the site of
delivery These properties should theoretically result in faster delivery These properties should theoretically result in faster recanalization and lower hemorrhagic conversion riskrecanalization and lower hemorrhagic conversion risk
Anti-fibrinolyticsAnti-fibrinolytics
to limit fibrinolytic activityto limit fibrinolytic activity -aminocaproic acid (EACA) -aminocaproic acid (EACA) competitively inhibitscompetitively inhibits plasminogen and plasminogen activators from plasminogen and plasminogen activators from
binding to fibrinbinding to fibrin
alpha2-antiplasminalpha2-antiplasmin a serine protease inhibitor that a serine protease inhibitor that neutralizes any free circulating plasminneutralizes any free circulating plasmin
Plasminogen activator inhibitor-1Plasminogen activator inhibitor-1 a serine protease a serine protease inhibitor that inhibits tissue-type plasminogen inhibitor that inhibits tissue-type plasminogen activatoractivator
Glycoprotein (GP) IIbIIIa antagonistsGlycoprotein (GP) IIbIIIa antagonists
such as ReoPro (abciximab) Integrilin such as ReoPro (abciximab) Integrilin (eptifibatide) or Aggrastat (tirofiban) in (eptifibatide) or Aggrastat (tirofiban) in ischemic stroke remains investigational ischemic stroke remains investigational Deshmukh et al38 reported 21 patients with Deshmukh et al38 reported 21 patients with large-vessel occlusion refractory to IAT with large-vessel occlusion refractory to IAT with rtPA who were treated with IV andor IA rtPA who were treated with IV andor IA abciximab eptifibatide or tirofiban abciximab eptifibatide or tirofiban
IA Mechanical Approaches in Acute Ischemic Stroke IA Mechanical Approaches in Acute Ischemic Stroke Mechanical strategies have several advantagesMechanical strategies have several advantages First they lessen and may even preclude the use of chemical First they lessen and may even preclude the use of chemical
thrombolytics in this manner very likely reducing the risk of ICHthrombolytics in this manner very likely reducing the risk of ICH Second by avoiding the use of chemical thrombolytics it is Second by avoiding the use of chemical thrombolytics it is
possible to extend the treatment window beyond the limit of 6ndash8 possible to extend the treatment window beyond the limit of 6ndash8 hours hours
Third mechanically fragmenting a clot increases the surface area Third mechanically fragmenting a clot increases the surface area accessible to fibrinolytic agents and allows inflow of fresh accessible to fibrinolytic agents and allows inflow of fresh plasminogen which in turn may increase the speed of plasminogen which in turn may increase the speed of thrombolysis thrombolysis
Finally clot-retrieval devices may provide faster recanalization Finally clot-retrieval devices may provide faster recanalization
The disadvantages of the mechanical The disadvantages of the mechanical approaches approaches technical difficulty of navigating mechanical technical difficulty of navigating mechanical
devices into the intracranial circulation excessive devices into the intracranial circulation excessive trauma to the vasculature (potentially leading to trauma to the vasculature (potentially leading to vasospasm vessel dissection perforation or vasospasm vessel dissection perforation or rupture) rupture)
fragmented thrombus causing distal embolization fragmented thrombus causing distal embolization into previously unaffected territories into previously unaffected territories
Nevertheless the advantages of mechanical stroke Nevertheless the advantages of mechanical stroke therapy appear to significantly outweigh its therapy appear to significantly outweigh its disadvantages and risksdisadvantages and risks
Contraindications to Thrombolytic Contraindications to Thrombolytic agents agents
Recent thoracic abdominal or Recent thoracic abdominal or intracranial surgeryintracranial surgery
Recent haemorrhagic CVA Head injury Recent haemorrhagic CVA Head injury or neoplasmor neoplasm
Bleeding ulcerBleeding ulcer Anticipated invasive procedures (arterial Anticipated invasive procedures (arterial
punctures biopsies)punctures biopsies) Concurrent hemostatic dysfunctionConcurrent hemostatic dysfunction
Monitoring of thrombolytic Monitoring of thrombolytic therapytherapy
Thrombin time Measures the availability of functional
fibrinogen Normal thrombin time is 10-14 sec Prolonged when fibrinogen level is below
75-100 mgdl
Half Life of ThrombolyticsHalf Life of ThrombolyticsAgent Administration Half Life
Streptokinase IA 60-80min
Urokinase IAIV 9-12min
rTPA IAIV 6min
Abciximab(Reopro) IAIV 12hour
Aspirin POIV 15-20min
Heparin IVSC 60min
Coumadin PO 15-25 days
Anti Platelet DrugsAnti Platelet DrugsDrug Drug Mechanism Mechanism UsesUsesAspirinAspirin Permanently inhibits Permanently inhibits
COX-1 and COX-2COX-1 and COX-2CADCAD
Stroke-TIAsStroke-TIAs
NSAIDsNSAIDs Reversibly inhibits Reversibly inhibits COX-1COX-1
LimitedLimited
DipyridamoleDipyridamole Inhibits PDE increases Inhibits PDE increases cAMPcAMP
TIAsTIAs
ThenopyridinesThenopyridines
(Ticlopidine(Ticlopidine
ClopidrgrelClopidrgrel))
Inhibits ADP Inhibits ADP
PlatAg PlatAg
TIAsStrokeTIAsStroke
CAD PVDCAD PVD
Abciximab (ReoPro)Abciximab (ReoPro)
Eptifibatide (Integrilin)Eptifibatide (Integrilin)
TirofibanTirofiban
GP IIBIIIA InhibitorsGP IIBIIIA Inhibitors
Stroke- TIAs Stroke- TIAs
MonitoringMonitoring
Bleeding timeBleeding time
Optical aggregometryOptical aggregometry
Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay
Bleeding timeBleeding time
Requires a skin incision (usually made on the ear lobe or Requires a skin incision (usually made on the ear lobe or forearm offorearm of
a depth that results in disruption of capillary loops and a depth that results in disruption of capillary loops and small vessels)small vessels)
AdvantagesAdvantages Universally availableUniversally available Relatively simple techniquesRelatively simple techniques Can be performed bedsideCan be performed bedside
DisadvantagesDisadvantages Insensitive inaccurate non-specific techniqueInsensitive inaccurate non-specific technique
Poorly reproducible (as depends on multiple variables)Poorly reproducible (as depends on multiple variables)
Optical aggregometryOptical aggregometry
Gold standard assay for platelet functionGold standard assay for platelet function Agonist induced aggregation is measuredAgonist induced aggregation is measured Different agonist are available for different Different agonist are available for different
agentsagents However require unique expertise and are not However require unique expertise and are not
universally availableuniversally available Aspirin measured with ADP or AA(gt70 Aspirin measured with ADP or AA(gt70
aggregation so resistance)aggregation so resistance) Clopidogrel( ADP gt 90 aggregation means Clopidogrel( ADP gt 90 aggregation means
resistance) resistance)
Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay
Can be performed bed sideCan be performed bed side Different assay devices with different Different assay devices with different
agonist are used for each of different agonist are used for each of different antiplatelet agents antiplatelet agents
For Aspirin AA is used (result is reported as aspirin For Aspirin AA is used (result is reported as aspirin reaction units [ARU] ARUgt 550 indicates non-reaction units [ARU] ARUgt 550 indicates non-responsiveness)responsiveness)
Verify IIbIIIa assay device uses TRAP as agonist for Verify IIbIIIa assay device uses TRAP as agonist for Abciximab and TirofibanAbciximab and Tirofiban
Practical Applications Practical Applications related to specific related to specific
Neurovascular Neurovascular interventionsinterventions
Acute ischemic StrokeAcute ischemic Stroke When an artery occludes neurons are affected When an artery occludes neurons are affected
differently depending upon the amount of residual blood differently depending upon the amount of residual blood flowflow
Normal cerebral blood flow is greater than 50 mL100 Normal cerebral blood flow is greater than 50 mL100 mgminmgmin
Once blood flow decreases to less than 20 mL100 Once blood flow decreases to less than 20 mL100 mgmin infarction occursmgmin infarction occurs
If blood flow decreases to less than 10 mL100 mgmin If blood flow decreases to less than 10 mL100 mgmin irreversible neuronal death occurs rapidly irreversible neuronal death occurs rapidly
Blood flow between 11 and 20 mL100 mgmin is thought Blood flow between 11 and 20 mL100 mgmin is thought to represent the ischemic penumbra an area where the to represent the ischemic penumbra an area where the cells are functionally silent because of ischemia but are cells are functionally silent because of ischemia but are still able to recover if blood flow is restored still able to recover if blood flow is restored
Many acute stroke therapies are targeted toward Many acute stroke therapies are targeted toward restoring flow or function to the ischemic penumbrarestoring flow or function to the ischemic penumbra
Therapeutic window in Therapeutic window in management of acute Ischemic management of acute Ischemic
StrokeStrokeThe early diagnosis of ischemic stroke is critical to the The early diagnosis of ischemic stroke is critical to the
with only a narrow therapeutic window in the first few with only a narrow therapeutic window in the first few hours following stroke ictushours following stroke ictus
Diagnosis in the first 3 hours postictus provides the Diagnosis in the first 3 hours postictus provides the opportunity for intravenous or intraarterial thrombolysis opportunity for intravenous or intraarterial thrombolysis and intra-arterial clot mechanical treatment which and intra-arterial clot mechanical treatment which improve the outcome improve the outcome
Diagnosis in the time period between 3 and 6 hours Diagnosis in the time period between 3 and 6 hours provides an opportunity for intra-arterial thrombolysis provides an opportunity for intra-arterial thrombolysis and mechanical treatment and mechanical treatment
Involvement of the posterior circulation especially the Involvement of the posterior circulation especially the basilar artery is treated by some regardless of time of basilar artery is treated by some regardless of time of onset or up until 12 to 24 hours in some practices This is onset or up until 12 to 24 hours in some practices This is related to the potentially high mortality and morbidity related to the potentially high mortality and morbidity associated with basilar artery thrombosisassociated with basilar artery thrombosis
Infarct evaluation on angiographyInfarct evaluation on angiography(CT angiography and catheter (CT angiography and catheter
angiography)angiography)CTA is an excellent first-line examination for CTA is an excellent first-line examination for
evaluation of the head and neck arteries evaluation of the head and neck arteries In comparison with catheter angiography In comparison with catheter angiography
what it gives up in resolution and dynamic what it gives up in resolution and dynamic properties it makes up for with rapid properties it makes up for with rapid acquisition of a 3-D dataset and the potential acquisition of a 3-D dataset and the potential for assessment of whole-brain perfusion and for assessment of whole-brain perfusion and better parenchymal evaluationbetter parenchymal evaluation
Moreover CTA illustrates not only arterial Moreover CTA illustrates not only arterial stenosis or occlusion but also the vessel wall stenosis or occlusion but also the vessel wall This factor is most important for evaluation of This factor is most important for evaluation of intramural dissection and thrombosed intramural dissection and thrombosed aneurysms which may both complicate aneurysms which may both complicate evaluation of stroke patientsevaluation of stroke patients
Early angiographic signs of strokes Early angiographic signs of strokes both CTA both CTA and DSA and DSA
Vessel occlusion or cutoff related to Vessel occlusion or cutoff related to thromboembolithromboemboli
aneurysms aneurysms arterial dissection arterial dissection Meniscus or flattened shape to clot Meniscus or flattened shape to clot
(recent) versus reverse meniscus (older)(recent) versus reverse meniscus (older) tram track (nonocclusive or recanalized tram track (nonocclusive or recanalized
clot) clot) delayed (antegrade) flow (manifest as delayed (antegrade) flow (manifest as
decreased whole-brain perfusion on CTA)decreased whole-brain perfusion on CTA) retrograde collateral flowretrograde collateral flow
Non-occlusive left MCA thrombus on 3-D imaging performed from CTA source data and was confirmed at catheter angiography
Therapy to be started within a 6-hr Therapy to be started within a 6-hr time to treatment (TTT) window time to treatment (TTT) window (while in case of IV thrombolysis (while in case of IV thrombolysis therapy to be started with in 3hrs)therapy to be started with in 3hrs)
Exclusion criteria Exclusion criteria Rapidly improving neurologic deficit or Rapidly improving neurologic deficit or Sustained blood pressure of gt180100 Sustained blood pressure of gt180100 Hemorrhage is detected on CTHemorrhage is detected on CT Infarct involving gt more than 13 rd Infarct involving gt more than 13 rd
territory of MCAterritory of MCA MRADWI-Perfusion mismatchlt 20MRADWI-Perfusion mismatchlt 20 Definite hypodensity on CTDefinite hypodensity on CT
Intra-arterial Thrombolysis
Fibrinolytics + AntiplateletsFibrinolytics + Antiplatelets
PlasminogenPlasminogen activators through fibrinolysis exposes activators through fibrinolysis exposes free thrombin and paradoxically stimulatesfree thrombin and paradoxically stimulates platelet platelet aggregation which leads to formation of aaggregation which leads to formation of a platelet platelet thrombus (white clot) thrombus (white clot)
This new thrombus is relatively resistant to This new thrombus is relatively resistant to fibrinolyticsfibrinolytics
So new regimen in case of acute stroke isSo new regimen in case of acute stroke is fibrinolytics + antiplatelet drugsfibrinolytics + antiplatelet drugs
rtPA + IIbIIIa inhibitors( tirofiban rtPA + IIbIIIa inhibitors( tirofiban abciximab) orabciximab) or
Urokinase + IIbIIIa Urokinase + IIbIIIa inhibitors( tirofiban abciximab)inhibitors( tirofiban abciximab)
Intra-arterial Thrombolysis Tirofiban (04 microgkgmin bolus for 3 min followed by Tirofiban (04 microgkgmin bolus for 3 min followed by
0125 ugkgmin)0125 ugkgmin)
++
Heparin (2000ndash3000 IU bolus followed by Heparin (2000ndash3000 IU bolus followed by 1000 IUhour infusion 1000 IUhour infusion
with ACT maintained bw 200-300) throughout the with ACT maintained bw 200-300) throughout the interventional procedure and for 24ndash48 hours thereafter when interventional procedure and for 24ndash48 hours thereafter when there is neither intraprocedural bleeding nor suspicion of there is neither intraprocedural bleeding nor suspicion of increased risk of bleeding increased risk of bleeding
Maximum dose of Urokinase Maximum dose of Urokinase Anterior circulation stroke - 500000 IU (mean 400000 Anterior circulation stroke - 500000 IU (mean 400000
IU range 300000ndash500000 IU)IU range 300000ndash500000 IU) Posterior circulation stroke -1000000 IU (mean 837000 Posterior circulation stroke -1000000 IU (mean 837000
IU range 300000ndash1000000 IU)IU range 300000ndash1000000 IU)American Journal of NeuroradiologyAmerican Journal of Neuroradiology 262595-2601 2005262595-2601 2005
Intravenous ThrombolysisIntravenous Thrombolysis
The first method to restore cerebral The first method to restore cerebral perfusion is clot lysis with the goal perfusion is clot lysis with the goal of re-establishing blood flow to the of re-establishing blood flow to the affected tissue affected tissue
IV thrombolysis rt-PA is the only IV thrombolysis rt-PA is the only FDA- approved treatment for AIS FDA- approved treatment for AIS
Fibrinolysis is enhanced powerfully Fibrinolysis is enhanced powerfully by rt-PAby rt-PA
Intravenous rTPA Intravenous rTPA administration administration protocolprotocol
Total dose of rt-PA 09 mgkg (maximum dose Total dose of rt-PA 09 mgkg (maximum dose 90 mg)90 mg)
Give 10 as initial IV bolusGive 10 as initial IV bolus Infuse remainder over 1 hourInfuse remainder over 1 hour Admit patient to an ICU or stroke unit for Admit patient to an ICU or stroke unit for
monitoringmonitoring Neurologic assessments every 15 minutes Neurologic assessments every 15 minutes
during infusion then every 30 minutes for next during infusion then every 30 minutes for next 6 hours then every hour until 24hours after 6 hours then every hour until 24hours after treatmenttreatment
Favorable Outcome vs Treatment Time Favorable Outcome vs Treatment Time with IV rTPAwith IV rTPA
Protocol limit = 3 hrs
Benefit ~ 45 hrs
Thromboembolism During coilingThromboembolism During coiling Most feared and frequent complication Most feared and frequent complication Reported incidence - Approx 7 Reported incidence - Approx 7 SourcesSources of Thromboembolism are of Thromboembolism are
- Clots at the aneurysmal neck during or immediately- Clots at the aneurysmal neck during or immediately after after embolization embolization
- Thrombus forming on catheters during- Thrombus forming on catheters during proceduresprocedures
- Stenosis of an adjacent artery dt coil mass- Stenosis of an adjacent artery dt coil mass or herniationor herniation
- Migration of intraaneurysmal- Migration of intraaneurysmal thrombus during coil thrombus during coil placement placement
- Slow flow dt vasospasm - Slow flow dt vasospasm
- Rare and unlikely causes are hypercoagulable- Rare and unlikely causes are hypercoagulable state such state such as antiphospholipid antibody syndrome or due to HITas antiphospholipid antibody syndrome or due to HIT
Occur more often with wide-necked aneurysms (dt Occur more often with wide-necked aneurysms (dt increased exposed surface area of thrombogenic coil increased exposed surface area of thrombogenic coil material)material)
Current regimen of endovascular Current regimen of endovascular managementmanagement
The The glycoprotein IIbIIIa antagonist tirofiban glycoprotein IIbIIIa antagonist tirofiban (04 (04 microgkgmin bolus for 30 minutes followed by infusion of microgkgmin bolus for 30 minutes followed by infusion of 0125 ugkgmin until the thrombus dissolved) 0125 ugkgmin until the thrombus dissolved)
Intraarterial thrombolysis with Intraarterial thrombolysis with urokinase or r- TPA urokinase or r- TPA increase of intravenous (IV) heparin (measured by increase of intravenous (IV) heparin (measured by
ACT) ACT) Intravenous aspirin Intravenous aspirin
Coil-related platelet aggregation (white clot) is Coil-related platelet aggregation (white clot) is unlikely to respond to fibrinolytics but has a high risk unlikely to respond to fibrinolytics but has a high risk of hemorrhage (In ISAT) all 5 patients who had of hemorrhage (In ISAT) all 5 patients who had received thrombolytic therapy with tPA to treat a received thrombolytic therapy with tPA to treat a thromboembolic complication after endovascular thromboembolic complication after endovascular treatment rebleed and all of these patients died)treatment rebleed and all of these patients died)
IntracranialIntracranial Stenting Stenting Metallic foreign body such as stent will accumulate Metallic foreign body such as stent will accumulate
thrombus in the absence of platelet inhibitionthrombus in the absence of platelet inhibition Antiplatelet drugs are important to prevent peri or Antiplatelet drugs are important to prevent peri or
post-interventional thromboembolic eventspost-interventional thromboembolic events Optimal treatment regimens has not been determined Optimal treatment regimens has not been determined
but usually but usually Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-
procedureprocedureOrOr
Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on
morning of proceduremorning of procedure
If need to use stent is not pre-planned thanIf need to use stent is not pre-planned than
Abciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkgAbciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkg IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)
Glycoprotein IIbIIIa inhibitor are not used routinely during elective Glycoprotein IIbIIIa inhibitor are not used routinely during elective stenting procedure dt increased risk of ICH stenting procedure dt increased risk of ICH
Carotid StentingCarotid Stenting
Pre-procedurePre-procedure
Double Antiplatelet therapy is routinely given Double Antiplatelet therapy is routinely given beginning at least 3beginning at least 3
days before the proceduredays before the procedure
Aspirin 325mgd+Clopidogrel 75mgdAspirin 325mgd+Clopidogrel 75mgd During procedureDuring procedure
Heparin is given with target clotting time of 250-Heparin is given with target clotting time of 250-300sec300sec
Post-procedure Post-procedure
Aspirin 325mg is continued indefinitely and Aspirin 325mg is continued indefinitely and
Clopidogrel 75mgd for at least 6 weeks Clopidogrel 75mgd for at least 6 weeks
Inclusion criteria for Local ThrombolysisInclusion criteria for Local Thrombolysis a)a) Patients in severe clinical grade on admission Patients in severe clinical grade on admission
with evidence of dural venous sinus with evidence of dural venous sinus thrombosis and restrictive venous outflow on thrombosis and restrictive venous outflow on cerebral angiogramcerebral angiogram
b)b) Patients in clinical grade 3 worsening on Patients in clinical grade 3 worsening on heparin therapy Restriction to venous heparin therapy Restriction to venous outflow was defined as an increase in brain outflow was defined as an increase in brain circulation time gt 12 s delay in the drainage circulation time gt 12 s delay in the drainage of cortical veins with cortical veins hanging of cortical veins with cortical veins hanging in spacein space
Treatment Options for Venous Thrombosis
CT Grading for Venous ThrombosisCT Grading for Venous Thrombosis Grade I no parenchymal change Grade I no parenchymal change
(hyperdense (hyperdense sinuses cortical veins empty sinuses cortical veins empty delta sign)delta sign)
Grade II non hemorrhagic venous infarct Grade II non hemorrhagic venous infarct without mass effect without mass effect
Grade III non-hemorrhagic infarct with Grade III non-hemorrhagic infarct with mass effectmass effect
Grade IV hemorrhagic venous infarct (max Grade IV hemorrhagic venous infarct (max diameter lt 3 cm) with no mass effectdiameter lt 3 cm) with no mass effect
Grade V hemorrhagic venous infarct (max Grade V hemorrhagic venous infarct (max diameter gt 3 cm) with mass effect diameter gt 3 cm) with mass effect
Local ThrombolysisLocal Thrombolysis
Femoral Jugular access was secured and a guiding Femoral Jugular access was secured and a guiding catheter was placed in the jugular bulb catheter was placed in the jugular bulb Mechanical Mechanical clot maceration clot maceration was done with the guidewire was done with the guidewire following which a microcatheter (was navigated and following which a microcatheter (was navigated and placed in the thrombosed segment of sinus confirmed placed in the thrombosed segment of sinus confirmed on a selective venogram on a selective venogram
Urokinase infusion Bolus dose of 2-6 lacs followed Urokinase infusion Bolus dose of 2-6 lacs followed by 60000 to 100000 units per hour along with by 60000 to 100000 units per hour along with periodic check venogram Along with maintenance periodic check venogram Along with maintenance systemic infusion of Heparinsystemic infusion of Heparin Other agents such as Other agents such as streptokinase altepase or rTPAstreptokinase altepase or rTPA can be also used can be also used
After thrombolysis patient should subjected to oral After thrombolysis patient should subjected to oral anticoagulation for six monthsanticoagulation for six months
Low-molecular-weight Low-molecular-weight heparinheparin
PharmacologyPharmacologyLMWH as its name suggests is a glycosaminoglycan that is approximatelyLMWH as its name suggests is a glycosaminoglycan that is approximately
one third the molecular weight of UFH It is derived from UFH through one third the molecular weight of UFH It is derived from UFH through variousvarious
depolymerization processes LMWH binds to antithrombin which in turn depolymerization processes LMWH binds to antithrombin which in turn
Neutralizes actors Xa and IIa Because LMWH lacks many of the longer Neutralizes actors Xa and IIa Because LMWH lacks many of the longer chains chains
required for binding to thrombin it has less ability to neutralize thrombin required for binding to thrombin it has less ability to neutralize thrombin
relativeto its ability to neutralize factor Xa LMWH also has less relativeto its ability to neutralize factor Xa LMWH also has less nonspecific nonspecific
binding to other proteins There is greater bioavailability with more binding to other proteins There is greater bioavailability with more predictable predictable
pharmacokinetics that eliminates the need for monitoring The smaller pharmacokinetics that eliminates the need for monitoring The smaller size also size also
allows for enhanced subcutaneous absorption when compared with UFHallows for enhanced subcutaneous absorption when compared with UFH
Three LMWH preparations are Three LMWH preparations are currently approved for use in the currently approved for use in the United States (1) enoxaparin (2) United States (1) enoxaparin (2) dalteparin and (3) tinzaparin dalteparin and (3) tinzaparin
They are all administered They are all administered subcutaneously at intervals of either subcutaneously at intervals of either once or twice daily for both once or twice daily for both prophylaxis and treatment dosesprophylaxis and treatment doses
Few Experiences of Few Experiences of ThrombolysisThrombolysis
Vickey 25 Yrs male patient presented Vickey 25 Yrs male patient presented with 12with 12thth day HO severe headache with day HO severe headache with right sided hemiplegiaright sided hemiplegia
MRI shows thrombosis of the superior MRI shows thrombosis of the superior sagittal left transverse left sigmoid sagittal left transverse left sigmoid sinuses and cortical veins in the fronto-sinuses and cortical veins in the fronto-parietal regions with eo haemorrhagic parietal regions with eo haemorrhagic infarct in the left cerebral hemisphere infarct in the left cerebral hemisphere with mass effect( Grade ndashV)with mass effect( Grade ndashV)
Sashi Srivastava 64 yrs FSashi Srivastava 64 yrs F In a follow up case of MRD with infra-renal In a follow up case of MRD with infra-renal
aortic abdominal and bilateral renal artery aortic abdominal and bilateral renal artery thrombosis renal angiogram shows filling thrombosis renal angiogram shows filling defects in the right Renal artery defects in the right Renal artery
Initially Renal angioplasty was done Initially Renal angioplasty was done Following angioplasty few thrombi are seem Following angioplasty few thrombi are seem to extends into the segmental branches and to extends into the segmental branches and causing blockage So Thrombolysis was causing blockage So Thrombolysis was plane to dissolve the run-out thrombi with plane to dissolve the run-out thrombi with urokinase urokinase
Rakesh 34yrsMRakesh 34yrsM Left SFA pseudoaneurysm with Left SFA pseudoaneurysm with
Covered stent placementCovered stent placement Pre operative antiplatelets with post Pre operative antiplatelets with post
procedure heparin Tirofiban procedure heparin Tirofiban followed by aspirin and clopidogrel followed by aspirin and clopidogrel were usedwere used
IAT may be a treatment option for selected patients IAT may be a treatment option for selected patients Possible selection criteria include Possible selection criteria include
presentation between 3 and 6 hours from symptom onsetpresentation between 3 and 6 hours from symptom onset major cerebral artery occlusion major cerebral artery occlusion severe neurologic deficits severe neurologic deficits high risk of systemic hemorrhage with IV rt-PA (eg recent high risk of systemic hemorrhage with IV rt-PA (eg recent
surgery) surgery) The MERCI (Mechanical Embolus Removal in Cerebral The MERCI (Mechanical Embolus Removal in Cerebral
Ischemia) retrievalIschemia) retrieval system system
Has been FDA-approved for recanalizing acutely occluded Has been FDA-approved for recanalizing acutely occluded cerebral arteries cerebral arteries
In the Multi-MERCI study patients who did not improve In the Multi-MERCI study patients who did not improve immediately after IV rt-PA underwent mechanical immediately after IV rt-PA underwent mechanical embolectomy within 8 hours of symptom onset embolectomy within 8 hours of symptom onset
Partial or complete recanalization occurred in 74 of Partial or complete recanalization occurred in 74 of patientspatients
with a symptomatic intracerebral hemorrhage (sICH) rate of with a symptomatic intracerebral hemorrhage (sICH) rate of 67 67
Mechanical embolectomy with the MERCI retriever may be a Mechanical embolectomy with the MERCI retriever may be a feasible and safe option for patients after IV rt-PAfeasible and safe option for patients after IV rt-PA
Penumbra stroke systemPenumbra stroke system This device combines two methods of clot This device combines two methods of clot
extraction aspiration and mechanical extraction aspiration and mechanical extraction extraction
First the clot is aspirated then a thrombus First the clot is aspirated then a thrombus removal ring can be used if necessary to removal ring can be used if necessary to remove remaining clot remove remaining clot
successful recanalizing 82successful recanalizing 82 Bridging therapyBridging therapy
06 mgkg IV rt-PA followed by IAT with IA rt-06 mgkg IV rt-PA followed by IAT with IA rt-PA (up to 20 mg)PA (up to 20 mg)
achieved a higher recanalization rateachieved a higher recanalization rate
Criteria for thrombolysis with rTPACriteria for thrombolysis with rTPA
Inclusion criteriaInclusion criteria Clinical signs and symptoms consistent with ischemic Clinical signs and symptoms consistent with ischemic
strokestroke Patient last seen normal within 3 hoursPatient last seen normal within 3 hours Measurable neurologic deficitMeasurable neurologic deficit
Exclusion criteriaExclusion criteria Any hemorrhage on neuroimaging (CT or MRI)Any hemorrhage on neuroimaging (CT or MRI) Symptoms suggestive of subarachnoid hemorrhageSymptoms suggestive of subarachnoid hemorrhage Seizure at stroke onset that is thought to contribute to Seizure at stroke onset that is thought to contribute to
neurologic deficitneurologic deficit Hypodensity greater than one third cerebral hemisphere Hypodensity greater than one third cerebral hemisphere
on CTon CT SBP greater than 185 mm Hg or DBP greater than 110 SBP greater than 185 mm Hg or DBP greater than 110
mm Hgmm Hg International normalized ratio (INR) greater than 17International normalized ratio (INR) greater than 17
Ischemic Stroke Ischemic Stroke Treatment ndash 2006Treatment ndash 2006
IV tissue plasminogen activator (tPA)IV tissue plasminogen activator (tPA) ndash ndash Only FDA-approved acute stroke drugOnly FDA-approved acute stroke drug ndash ndash 3 hour treatment window3 hour treatment window
MERCI - Concentric clot retrieval MERCI - Concentric clot retrieval devicedevice ndash ndash Rescue therapy - approved 2004Rescue therapy - approved 2004 ndash ndash Device approval (not outcomes-based)Device approval (not outcomes-based)
Off label approachesOff label approaches ndash ndash IV tPA after 3 hoursIV tPA after 3 hours ndash ndash IV-IA tPA sequential strategiesIV-IA tPA sequential strategies ndash ndash IA tPA clot angioplasty fragmentationIA tPA clot angioplasty fragmentation ndash ndash Ultrasound-assisted tPA lysisUltrasound-assisted tPA lysis
rt-PA Trials NINDSrt-PA Trials NINDS
Acute stroke - 624 patientsAcute stroke - 624 patients Treat within 3 hrsTreat within 3 hrs Intravenous 09 mgkg rt-PA vs placeboIntravenous 09 mgkg rt-PA vs placebo Hemorrhage 64 tPA 06 placeboHemorrhage 64 tPA 06 placebo Neurologic recovery better with tPA 30 Neurologic recovery better with tPA 30
more like to have minimal or no disabilitymore like to have minimal or no disability
First proven approved treatment for First proven approved treatment for strokestroke
Limitations of tPALimitations of tPA Only 4 of acute strokes receive tPAOnly 4 of acute strokes receive tPA (Kleindorfer et al Stroke 2004 35 e27-e29)(Kleindorfer et al Stroke 2004 35 e27-e29)
Only 22 of patients present within 3 hoursOnly 22 of patients present within 3 hours1048707 1048707 51 of these ineligible due to51 of these ineligible due to
bull bull Mild severityMild severity bull bull Medical or surgical historyMedical or surgical history bull bull Blood testsBlood tests
Sustained recanalization only 13Sustained recanalization only 13 (Alexandrov et al NEJM 2004 351 2170-8)(Alexandrov et al NEJM 2004 351 2170-8)
Concern for hemorrhageConcern for hemorrhage tPA potentiates apoptotic injury tPA potentiates apoptotic injury (Liu et al Nature Med 2004 101379-83)(Liu et al Nature Med 2004 101379-83)
PROACT II IA Lysis TrialPROACT II IA Lysis Trial Baseline 24 hours 8 days
Baseline 60 minutes 120 minutes
9mg IAProurokinase
Desmoteplase Trials DEDAS Desmoteplase Trials DEDAS DIASDIAS
Trial OverviewTrial Overview Double blind randomized placebo Double blind randomized placebo
controlled trialscontrolled trials IV delivery 3-9 hour time windowIV delivery 3-9 hour time window Plasminogen activator ndash from Plasminogen activator ndash from vampire bat vampire bat
salivasaliva Selection based on PWI-DWI MismatchSelection based on PWI-DWI Mismatch
MRI InclusionMRI Inclusion PWI defect at least 2 cm AND ~20 larger PWI defect at least 2 cm AND ~20 larger
than DWIthan DWI PWI should be obvious even visible on PWI should be obvious even visible on
raw imagesraw imagesMRI ExclusionMRI Exclusion
DWI gt 13 MCADWI gt 13 MCA MRA ICA occlusionMRA ICA occlusion
Desmoteplase ndash DIAS Desmoteplase ndash DIAS ResultsResults
Mechanical Thrombolysis Mechanical Thrombolysis devicesdevices
mechanical thrombolysis potentially extends the treatment mechanical thrombolysis potentially extends the treatment window because they act promptly at the site of the thrombuswindow because they act promptly at the site of the thrombus
The devices can retrieve large clots that pharmaceutical agents The devices can retrieve large clots that pharmaceutical agents may not successfully lysemay not successfully lyse
Patients treated with IV tPA may be considered for treatment of Patients treated with IV tPA may be considered for treatment of residual clot with some of these devicesresidual clot with some of these devices
suction-creating saline jets suction-creating saline jets laser energy ultrasound laser energy ultrasound a corkscrew apparatus to treat strokesa corkscrew apparatus to treat strokes The AngioJet systemThe AngioJet system uses saline jets that are directed back into the catheter to uses saline jets that are directed back into the catheter to
create a low-pressure zone around the catheter tip inducing create a low-pressure zone around the catheter tip inducing suction suction
The clot is pulled into the exhaust lumen and removed from the The clot is pulled into the exhaust lumen and removed from the vessel Although US Food and Drug Administration (FDA) has vessel Although US Food and Drug Administration (FDA) has approved this device for use in arteriovenous dialysis grafts and approved this device for use in arteriovenous dialysis grafts and fistulae and for the treatment of coronary arteries saphenous fistulae and for the treatment of coronary arteries saphenous vein grafts and peripheral vessels clinical trials for the vein grafts and peripheral vessels clinical trials for the treatment of acute stroke are no longer in progress treatment of acute stroke are no longer in progress
Most devices are used in cerebral vessels that 2-5 mm
The Latis laser device The Latis laser device used laser energy to ablate clots used laser energy to ablate clots Arteries 2-5 mm in diameter could be Arteries 2-5 mm in diameter could be
treated including the ICA M1 or M2 treated including the ICA M1 or M2 branch of the MCA A1 branch of the branch of the MCA A1 branch of the anterior cerebral artery (ACA) basilar anterior cerebral artery (ACA) basilar artery posterior cerebral artery (PCA) artery posterior cerebral artery (PCA) and vertebral and vertebral
Patients could receive treatment as late Patients could receive treatment as late as 8 hours after symptom onset in the as 8 hours after symptom onset in the anterior circulation and within 24 hours in anterior circulation and within 24 hours in the posterior circulation the posterior circulation
Endovascular Photo Acoustic Endovascular Photo Acoustic Recanalization (EPAR) Recanalization (EPAR)
A laser power source generated energy for the A laser power source generated energy for the systemsystem
The energy was delivered by means of The energy was delivered by means of fiberoptics to the tip of the catheter at the fiberoptics to the tip of the catheter at the treatment sitetreatment site
Absorption of laser light by darkly pigmented Absorption of laser light by darkly pigmented materials (ie the clot) occurred inside the 1-mm materials (ie the clot) occurred inside the 1-mm catheter tipcatheter tip
the system was designed to minimize scattering the system was designed to minimize scattering of laser light of laser light
Absorption converted photo energy to acoustic Absorption converted photo energy to acoustic energy which then emulsified the clot inside the energy which then emulsified the clot inside the catheter tip catheter tip
EKOS ultrasound( the EKOS ultrasound( the Ultrasound Thrombolytic Ultrasound Thrombolytic
Infusion Catheter) Infusion Catheter) combines the use of a distal ultrasound transducer with combines the use of a distal ultrasound transducer with
infusion of a thrombolytic agent through the infusion of a thrombolytic agent through the microcathetermicrocatheter
Ultrasound changes the structure of the clot to Ultrasound changes the structure of the clot to temporarily increase its permeability while providing an temporarily increase its permeability while providing an acoustic pressure gradient to move the drug into the clot acoustic pressure gradient to move the drug into the clot to speed its dissolution to speed its dissolution
The EKOS catheter is placed in the proximal portion of the The EKOS catheter is placed in the proximal portion of the clot clot
After a 2-mg bolus of tPA was injected through the After a 2-mg bolus of tPA was injected through the catheter catheter
the patient received a continuous infusion of IA tPA 03 the patient received a continuous infusion of IA tPA 03 mgmin to a maximum of 20 mg and simultaneous mgmin to a maximum of 20 mg and simultaneous ultrasound transmission for as long as 60 minutes ultrasound transmission for as long as 60 minutes
One patient was treated with a total of 4 units of One patient was treated with a total of 4 units of recombinant reteplase (Retavase) hand-injected over 60 recombinant reteplase (Retavase) hand-injected over 60 minutes minutes
Penumbra system Penumbra system The Penumbra system (Penumbra Inc) provides a dual The Penumbra system (Penumbra Inc) provides a dual
approach to clot extraction using aspiration followed by approach to clot extraction using aspiration followed by clot retrieval with a ring device if needed clot retrieval with a ring device if needed
Mechanical Embolus Removal in Cerebral Ischemia Mechanical Embolus Removal in Cerebral Ischemia (MERCI)(MERCI)
a corkscrew-like apparatus to remove blood clots from a corkscrew-like apparatus to remove blood clots from the brain in patients experiencing an ischemic stroke the brain in patients experiencing an ischemic stroke
The corkscrew itself resides in the catheter tip which The corkscrew itself resides in the catheter tip which shields it from the wall of the vessel until it is ready to be shields it from the wall of the vessel until it is ready to be burrowed into the clot Once lodged in the clot the device burrowed into the clot Once lodged in the clot the device and clot are withdrawn from the vessel and clot are withdrawn from the vessel
Snarelike devicesSnarelike devices Snares such as the Neuronet snare (Guidant Snares such as the Neuronet snare (Guidant
Endovascular Santa Clara CA) have been developed Endovascular Santa Clara CA) have been developed specifically for use in the treatment of strokes specifically for use in the treatment of strokes
These devices are simple in design and do not require the These devices are simple in design and do not require the clot to be amenable to emulsification clot to be amenable to emulsification
X-Sizer deviceX-Sizer device a device with small moving blades at the a device with small moving blades at the
catheter tip catheter tip This device the X-Sizer device (EndiCor Medical This device the X-Sizer device (EndiCor Medical
San Clemente CA) can be used to excise the San Clemente CA) can be used to excise the thrombus and aspirate it thrombus and aspirate it
The device was being evaluated in randomized The device was being evaluated in randomized studies of coronary vessels and in a registry of studies of coronary vessels and in a registry of patients with acute myocardial infarctionpatients with acute myocardial infarction
Although the manufacturer had modified the Although the manufacturer had modified the device for use in cerebral vessels a safety and device for use in cerebral vessels a safety and feasibility study was indefinitely suspended after feasibility study was indefinitely suspended after only 1 patient was treated with the device in only 1 patient was treated with the device in Europe Europe
Suction thrombectomySuction thrombectomy This method of mechanical thrombolysis is one of the This method of mechanical thrombolysis is one of the
simplestsimplest In this readily available technique suction is applied with In this readily available technique suction is applied with
a syringe to remove thrombus in the ICA a syringe to remove thrombus in the ICA It requires no other devicesIt requires no other devices A catheter with a large inner diameter (Brite Tip Cordis A catheter with a large inner diameter (Brite Tip Cordis
Corporation Miami FL) was placed in the symptomatic Corporation Miami FL) was placed in the symptomatic vessel and navigated over a guidewire into the thrombusvessel and navigated over a guidewire into the thrombus
A 60-mL syringe was used to aspirate the thrombus A 60-mL syringe was used to aspirate the thrombus Each patient required angioplasty and stenting of carotid Each patient required angioplasty and stenting of carotid
bifurcation stenosis and received daily aspirin and bifurcation stenosis and received daily aspirin and ticlopidine after the procedure No complications ticlopidine after the procedure No complications occurred occurred
Summary Acute Stroke Summary Acute Stroke ImagingImaging
PhysiologyPhysiology importance collaterals importance collaterals
ndash ndashGrowing role for perfusion Growing role for perfusion assessmentassessment
tPAtPA guidelines amp limitations guidelines amp limitations Signs on CT amp MRSigns on CT amp MR follow physiology follow physiology Stroke trialsStroke trials PWI-DWI mismatch PWI-DWI mismatch
ndash ndashTreat based on physiology not timeTreat based on physiology not time ProtocolsProtocols should be fast and should be fast and
comprehensivecomprehensive
bull Interventional procedures
Virchowrsquos Triad
Mechanism of blood Mechanism of blood coagulationcoagulation
HemostasisHemostasis involves a sequence of interactions of coagulation involves a sequence of interactions of coagulation
factor interactions in two pathways called the factor interactions in two pathways called the intrinsic and extrinsic coagulation cascades intrinsic and extrinsic coagulation cascades
The final common pathway involves the The final common pathway involves the transformation of prothrombin to thrombin by factor transformation of prothrombin to thrombin by factor Xa Xa
Thrombin (factor IIa) then serves to catalyze the Thrombin (factor IIa) then serves to catalyze the activation of fibrinogen to fibrin in addition to its role activation of fibrinogen to fibrin in addition to its role in feedback activation of several other clotting factorsin feedback activation of several other clotting factors
UFH LMWH and fondaparinux( saccharides) all UFH LMWH and fondaparinux( saccharides) all exert their anticoagulant effect in a similar fashion by exert their anticoagulant effect in a similar fashion by binding to and activating antithrombinbinding to and activating antithrombin that then that then neutralizes selected coagulation factorsneutralizes selected coagulation factors
Stages of blood coagulationStages of blood coagulation Formation of Formation of ProthrombinaseProthrombinase
Prothrombinase can be formed in two ways depending of which of Prothrombinase can be formed in two ways depending of which of two systems or pathways apply two systems or pathways apply
Intrinsic SystemIntrinsic System This is initiated by liquid blood making contact with a foreign This is initiated by liquid blood making contact with a foreign
surface ie something that is not part of the body surface ie something that is not part of the body Extrinsic SystemExtrinsic System
This is initiated by liquid blood making contact with damaged This is initiated by liquid blood making contact with damaged tissuetissue
Both the intrinsic and the extrinsic systems involve interactions Both the intrinsic and the extrinsic systems involve interactions between between coagulation factorscoagulation factors
2 2 ProthrombinProthrombin converted into the enzyme converted into the enzyme ThrombinThrombinProthrombinase (formed in stage 1) converts prothrombin which is Prothrombinase (formed in stage 1) converts prothrombin which is a plasma protein that is formed in the liver into the enzyme a plasma protein that is formed in the liver into the enzyme thrombinthrombin
3 3 FibrinogenFibrinogen (soluble) converted to (soluble) converted to FibrinFibrin (insoluble) (insoluble)In turn thrombin converts fibrinogen into fibrin Fibrin is insoluble In turn thrombin converts fibrinogen into fibrin Fibrin is insoluble and forms the threads that bind the clotand forms the threads that bind the clot
BLOOD COAGULATION
A sequence of reactions that are present in an inactive state in bloodKey is the conversion of the plasma protein fibrinogen to fibrin Intrinsic pathway Extrinsic pathway(activated by exposure of (activated by substances blood to damaged tissue) released from damaged tissue)
Active factors X and V
Prothrombin Thrombin
Fibrinogen Fibrin Fibrin mesh
inhibited by warfarin
inhibited by heparin
Rationale for anticoagulant Rationale for anticoagulant therapytherapy
PHARMACOLOGICAL PHARMACOLOGICAL AGENTSAGENTS
Pharmacologic AgentsPharmacologic Agents
AnticoagulantsAnticoagulants
Fibrinolytics (Agents for pharmacological Fibrinolytics (Agents for pharmacological recanalization)recanalization)
Anti platelet drugsAnti platelet drugs
Thrombin inhibitorThrombin inhibitor
ANTICOAGULANTSANTICOAGULANTS
Heparin and Low Molecular Weight Heparins Heparin and Low Molecular Weight Heparins ((eg enoxaparin dalteparin)eg enoxaparin dalteparin)
Oral anticoagulantsOral anticoagulants Coumarin Derivatves Coumarin Derivatves eg Warfarin eg Warfarin
AcenocoumarolAcenocoumarol Indandione Derivatves Indandione Derivatves eg Phenindione eg Phenindione
AnisindioneAnisindione
ThrombolyticsThrombolytics
Plasminogen activators
Fibrinolytics
Anti Platelet DrugsAnti Platelet DrugsDrug Mechanism UsesDrug Mechanism UsesAspirinAspirin Permanently inhibits Permanently inhibits
COX-1 and COX-2COX-1 and COX-2CADCAD
Stroke-TIAsStroke-TIAs
NSAIDsNSAIDs Reversibly inhibits Reversibly inhibits COX-1COX-1
LimitedLimited
DipyridamoleDipyridamole Inhibits PDE Inhibits PDE increases cAMPincreases cAMP
TIAsTIAs
ThenopyridinesThenopyridines
(Ticlopidine(Ticlopidine
Clopidegrel)Clopidegrel)
Inhibits ADP Inhibits ADP
PlatAg PlatAg
TIAsStrokeTIAsStroke
CAD PVDCAD PVD
Abciximab (ReoPro)Abciximab (ReoPro)
Eptifibatide Eptifibatide (Integrilin)(Integrilin)
TirofibaTirofibann
GP IIBIIIA InhibitorsGP IIBIIIA Inhibitors
Stroke- TIAs Stroke- TIAs
Maintainance of patency Maintainance of patency of vascular of vascular grafts catheters shunts bypassesgrafts catheters shunts bypasses
Arterial thromboembolic diseaseArterial thromboembolic diseasebull Transient ischemic attacksTransient ischemic attacksbull Stroke in evolutionStroke in evolution
Ischemic events occurs in Ischemic events occurs in 1313 of of conventional neuroangiographic conventional neuroangiographic procedures without Endovascular surgeryprocedures without Endovascular surgery
Indications for Antithrombotic Therapy in Indications for Antithrombotic Therapy in Diagnostics and Interventional ProceduresDiagnostics and Interventional Procedures
WHY TO MONITOR ANTICOAGULANT THERAPYWHY TO MONITOR ANTICOAGULANT THERAPY
Narrow therapeutic rangeNarrow therapeutic range
Can increase risk of bleedingCan increase risk of bleeding
Coagulation TestingCoagulation Testing
Monitoring therapyMonitoring therapy
Intrinsic Pathway
Extrinsic Pathway
Common Pathway
CLOT
Heparin Coumadin
Monitor with
ACT aPTT
Monitor with PTINR
Thrombolytics
Monitor with TT Fibrinogen
Monitoring of Monitoring of Anti platelet drugsAnti platelet drugs
Bleeding timeBleeding time
Optical aggregometryOptical aggregometry
Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay
HeparinHeparin
Heterogeneous 3000-30000 dalton in Heterogeneous 3000-30000 dalton in molecular weight molecular weight
Average=15000 d (~45monosaccharide Average=15000 d (~45monosaccharide chains)chains)
About About 13 of dose binds to AT III and forms 13 of dose binds to AT III and forms the AT IIIHeparinClotting Factor Complexthe AT IIIHeparinClotting Factor Complex
Complex binds to clotting factors of the Complex binds to clotting factors of the intrinsic and common pathway (Xa IIa IXa intrinsic and common pathway (Xa IIa IXa XIa XIIa XIIIa) and inactivates themXIa XIIa XIIIa) and inactivates them
Anticoagulant of choice in pregnancy (not Anticoagulant of choice in pregnancy (not crosses placenta)crosses placenta)
Heparin and Low molecular weight heparinsHeparin and Low molecular weight heparins
Structure and sequence
O
OH
OH
O
COO
O
O
CH2OH
NHSO3
OH
_
_
O
O
CH2OSO3
NHSO3
OH
_
_
O
OH
OH
O
COOO
O
CH2OSO3
NHSO3
OH
_
_
O
OSO3
OHO
COOO
O
CH2OSO3
NHCOCH3
OH
_
_ _
_
_
O
OH
OH
O
COO
1
23
4
5
6
-D-glucosamine -L-iduronic acid -D-glucuronic acid
O
O
CH2OH
NH2
OH 12
3
4
5
6
O
OH
OHO
COO_
1
23
4
5
6
polymeric structure of heparin
Anticoagulant Properties of Anticoagulant Properties of HeparinHeparin
11 Inhibits the thrombin-mediated conversion of Inhibits the thrombin-mediated conversion of fibrinogen to fibrinfibrinogen to fibrin
22 Inhibits the aggregation of platelets by thrombin Inhibits the aggregation of platelets by thrombin (prolongs bleeding time)(prolongs bleeding time)
33 Inhibits activation of fibrin stabilizing enzymeInhibits activation of fibrin stabilizing enzyme
44 Inhibits activated factors XII XI IX X and IIInhibits activated factors XII XI IX X and II All available forms of heparin must be All available forms of heparin must be
administered administered parenterally since they are parenterally since they are highly charged and rapidlyhighly charged and rapidly hydrolyzed in the hydrolyzed in the GI tractGI tract
Heparin antagonist Protamine sulfate (Heparin antagonist Protamine sulfate (10mg for 10mg for 1000 unit of heparin)1000 unit of heparin)
Monitoring of heparin Monitoring of heparin
Subcutenous Subcutenous no monitoring requiredno monitoring required Intravenous Intravenous
Partial thromboplastin time (PTT normal value Partial thromboplastin time (PTT normal value ~30sec) ~30sec)
Activated clotting time ( ACT normal value ~90-Activated clotting time ( ACT normal value ~90-120sec)120sec)
Daily or more frequent if PTT ACT variesDaily or more frequent if PTT ACT varies
Mechanism Mechanism ndash measures intrinsic pathwayndash measures intrinsic pathway Therapeutic goal Therapeutic goal 2-25 times normal control value 2-25 times normal control value
ACT or aPTTACT or aPTT
Determine when to pull the femoral sheath Determine when to pull the femoral sheath Premature sheath pull can lead to bleedingPremature sheath pull can lead to bleeding Delayed removal can increase time in ICUDelayed removal can increase time in ICU Target set Target set at each siteat each site
ACT targets range from 150 ndash 220 ACT targets range from 150 ndash 220 secondsseconds
aPTT targets range from 40 ndash 70 seconds aPTT targets range from 40 ndash 70 seconds
During neuroangiography-During neuroangiography- Recommended therapeutic range of heparin in Recommended therapeutic range of heparin in
plasma is 02-08 uml ( corresponding to aPTT plasma is 02-08 uml ( corresponding to aPTT ACT values 15-25 times the baseline values)ACT values 15-25 times the baseline values)
Dose In diagnostic angiography bolus dose of Dose In diagnostic angiography bolus dose of 2500 iu is used followed by 1000 iu hour2500 iu is used followed by 1000 iu hour
Bolus dose is Bolus dose is 60 ukg to maintain the therapeutic 60 ukg to maintain the therapeutic range range If procedure continues for more than 75 If procedure continues for more than 75 minutes additional dose is required ( half of the minutes additional dose is required ( half of the initial dose for another 75 minutes) initial dose for another 75 minutes)
(AJNR 199415 51-54)
Mechanisms of HIT( Mechanisms of HIT( Heparin Heparin induced Thrombocytopeniainduced Thrombocytopenia))
Type 1Type 1 Fall in platelet count occurs within the first two Fall in platelet count occurs within the first two
days after heparin initiation often returns to days after heparin initiation often returns to normal with continued heparin administration normal with continued heparin administration and is of no clinical consequence and is of no clinical consequence
The mechanism of the thrombocytopenia is non-The mechanism of the thrombocytopenia is non-immune and appears to be due to a direct effect of immune and appears to be due to a direct effect of heparin on platelet activationheparin on platelet activation
Type 2Type 2 Approximately 03 to 3 percent of patients Approximately 03 to 3 percent of patients
receiving heparin develop an immune receiving heparin develop an immune thrombocytopenia mediated by antibodies to a thrombocytopenia mediated by antibodies to a heparin-platelet factor 4 complex heparin-platelet factor 4 complex
(AJNR 28155-158 2007)
Treatment of heparin-induced Treatment of heparin-induced thrombocytopeniathrombocytopenia
When HIT is diagnosed it is important to When HIT is diagnosed it is important to stop heparin mainly in type 2 and to avoid stop heparin mainly in type 2 and to avoid the use of LMWH the use of LMWH
Because of the increased risk of thrombosis Because of the increased risk of thrombosis however continuation of an anticoagulant however continuation of an anticoagulant must be considered must be considered
The drugs currently approved for the The drugs currently approved for the treatment of HIT in the United States are treatment of HIT in the United States are direct thrombin inhibitors argatroban and direct thrombin inhibitors argatroban and lepirudinlepirudin
WARFARIN MECHANISM OF ACTIONWARFARIN MECHANISM OF ACTION
Inactive factors II VII IX and X
Proteins S and C
Active factors II VII IX and X
Proteins S and C
Vitamin K epoxide
Vitamin K reduced
WA
RF
AR
IN
Prevents the reduction of vitamin K which is essential for Prevents the reduction of vitamin K which is essential for activation of certain factorsactivation of certain factors
Has no effect on previously formed thrombusHas no effect on previously formed thrombus
Antagonist is Vit KAntagonist is Vit K
OPTIMIZING WARFARIN THERAPYOPTIMIZING WARFARIN THERAPY
Use of large loading dose may lead to hemorrhage and Use of large loading dose may lead to hemorrhage and other complicationsother complications
Initial dose 2-5 mg once dailyInitial dose 2-5 mg once daily Maintenance dose 2-10 mg once dailyMaintenance dose 2-10 mg once daily If Immediate anticoagulation is requiredIf Immediate anticoagulation is required Heparin IS Heparin IS
started along with loading dose of warfarin 10 mg started along with loading dose of warfarin 10 mg Heparin is usually discontinued after 4-5 days Heparin is usually discontinued after 4-5 days Before Before discontinuing INR should be in therapeutic range for 2 discontinuing INR should be in therapeutic range for 2 consecutive daysconsecutive days
Daily monitoring of INR until INR is in therapeutic Daily monitoring of INR until INR is in therapeutic range then 3 times weekly for 1-2 weeks then less often range then 3 times weekly for 1-2 weeks then less often (every 4 to 6 weeks)(every 4 to 6 weeks)
OPTIMAL THERAPEUTIC RANGEOPTIMAL THERAPEUTIC RANGE
IndicationIndication INRINR
Prophylaxis of venous Prophylaxis of venous thromboembolismthromboembolism
20-3020-30
Treatment of venous Treatment of venous thromboembolismthromboembolism
20-3020-30
Atrial fibrillationAtrial fibrillation 20-3020-30
Mitral valve stenosisMitral valve stenosis 20-3020-30
Heart valve replacementHeart valve replacement
Bioprosthetic valveBioprosthetic valve
Mechanical valveMechanical valve
20-3020-30
25-3525-35
Myocardial infarctionMyocardial infarction 20-3020-30
25-35 25-35 (high risk patients)(high risk patients)
FACTORS INFLUENCING DOSE RESPONSEFACTORS INFLUENCING DOSE RESPONSE
Poor patient compliancePoor patient compliance Concomitant medicationsConcomitant medications Levels of dietary vitamin KLevels of dietary vitamin K Alcohol Inaccurate lab testingAlcohol Inaccurate lab testing Inaccurate lab testingInaccurate lab testing Hepatic dysfunctionHepatic dysfunction FeverFever
Contraindication for WarfarinContraindication for Warfarin
Hypersensitivity to warfarinHypersensitivity to warfarin Hemorrhagic tendencyHemorrhagic tendency Condition with risk of hemorrhageCondition with risk of hemorrhage Inadequate laboratory techniquesInadequate laboratory techniques Protein C amp S deficiencyProtein C amp S deficiency Vitamin K deficiencyVitamin K deficiency
SIDE EFFECTSSIDE EFFECTS
Hemorrhage Hemorrhage Skin necrosisSkin necrosis Purple toe syndromePurple toe syndrome Microembolization Microembolization TeratogenecityTeratogenecity Agranulocytosis leukopenia Agranulocytosis leukopenia Diarrhoeanausea anorexiaDiarrhoeanausea anorexia
MONITORING OF WARFARIN THERAPYMONITORING OF WARFARIN THERAPY
Prothrombin timeProthrombin time PT ratioPT ratio INR (International Normalized Ratio)INR (International Normalized Ratio)
PROTHROMBIN TIME (PT)PROTHROMBIN TIME (PT)
Time required for blood to coagulate Time required for blood to coagulate is called PT ( normal value ~10sec)is called PT ( normal value ~10sec)
Performed by adding a mixture of Performed by adding a mixture of calcium and thromboplastin to calcium and thromboplastin to citrated plasmacitrated plasma
As a control a normal blood sample is As a control a normal blood sample is tested continuouslytested continuously
PT ratio (PTR) = PT ratio (PTR) = Patientrsquos PTPatientrsquos PT Control PTControl PT
PROBLEMS WITH PTPTRPROBLEMS WITH PTPTR
Thromboplastins are extracts from Thromboplastins are extracts from brain lung or placenta of animalsbrain lung or placenta of animals
Thromboplastins from various Thromboplastins from various manufacturers differ in their manufacturers differ in their sensitivity to prolong PTsensitivity to prolong PT
May result in false control of May result in false control of anticoagulant therapyanticoagulant therapy
INTERNATIONAL NORMALISED RATIO (INR)INTERNATIONAL NORMALISED RATIO (INR)
International Normalized Ratio (INR) International Normalized Ratio (INR) a PT test with a a PT test with a formula based ratio to normalize the often variable source formula based ratio to normalize the often variable source of tissue factor (human rabbit recombinant)of tissue factor (human rabbit recombinant)
INR = [PTINR = [PTptpt] ] ISIISI
[PT[PTRefRef]]
PTPTpt pt ndash prothrombin time of patientndash prothrombin time of patient
PTPTRef Ref ndash prothrombin time of normal pooled samplendash prothrombin time of normal pooled sample
ISI ndash International Sensitivity IndexISI ndash International Sensitivity Index
Warfarin is given orally and titrated to achieve an INR of Warfarin is given orally and titrated to achieve an INR of typically 20 ndash 30typically 20 ndash 30
Heparin versus WarfarinHeparin versus Warfarin
Drug ActionMechan-ism
Moni-toring
Effective
HeparinDirect
Inhibition ofThrombin
ATIIIcofactor
APTTACT
Immediate
WarfarinDecreasesProductionof factors
Vitamin K PTDelay
3-5 days
INR
Recanalization or Antegrade Recanalization or Antegrade Reperfusion StrategiesReperfusion Strategies
Recanalization strategies focus on removing Recanalization strategies focus on removing andor dissolving the occlusive thrombus to re-andor dissolving the occlusive thrombus to re-establish antegrade flow Strategies may be establish antegrade flow Strategies may be classified into 7 different categories on the classified into 7 different categories on the basis of their primary mechanism of action basis of their primary mechanism of action 1) 1) IV andor intraarterial thrombolysis (IAT) IV andor intraarterial thrombolysis (IAT) 2) endovascular thrombectomy2) endovascular thrombectomy3) endovascular thromboaspiration 3) endovascular thromboaspiration 4) endovascular mechanical thrombus disruption or 4) endovascular mechanical thrombus disruption or
thromborrhexisthromborrhexis5) 5) transcranial or endovascular augmented transcranial or endovascular augmented
fibrinolysis fibrinolysis 6) endovascular thrombus entrapment and 6) endovascular thrombus entrapment and 7) temporary endovascular bypass7) temporary endovascular bypass
IAT in Acute Ischemic StrokeIAT in Acute Ischemic Stroke
IAT advantages over IV thrombolysisIAT advantages over IV thrombolysis Coaxial microcatheter techniques the occluded intracranial Coaxial microcatheter techniques the occluded intracranial
vessel is directly accessible and the fibrinolytic agent can be vessel is directly accessible and the fibrinolytic agent can be infused directly into the thrombusinfused directly into the thrombus
This permits a smaller dose of fibrinolytic agent to reach a This permits a smaller dose of fibrinolytic agent to reach a higher local concentration than that reached by systemic higher local concentration than that reached by systemic infusioninfusion
Allows more complete recanalization with lower total doses of Allows more complete recanalization with lower total doses of thrombolytic thrombolytic
With the smaller dose complications from systemic fibrinolytic With the smaller dose complications from systemic fibrinolytic effects including intracranial hemorrhage (ICH) can effects including intracranial hemorrhage (ICH) can theoretically be reduced theoretically be reduced
Treatment window for endovascular techniques can be Treatment window for endovascular techniques can be extended beyond the typical IV window of 3 hours extended beyond the typical IV window of 3 hours
IA techniques have led to higher recanalization rates than IV IA techniques have led to higher recanalization rates than IV thrombolysisthrombolysis
Major disadvantagesMajor disadvantages Relative complexity of the procedure the level Relative complexity of the procedure the level
of required technical expertise and its of required technical expertise and its relatively low availability relatively low availability
Delays in initiating treatmentDelays in initiating treatment InvasiveInvasive
ThrombolyticsThrombolytics
Plasminogen activators
Fibrinolytics
1 Plasminogen Activators 1 Plasminogen Activators drugs act by converting the inactive proenzyme drugs act by converting the inactive proenzyme plasminogen into the active enzyme plasmin Plasmin plasminogen into the active enzyme plasmin Plasmin digests fibrinogen fibrin monomers and cross-linked digests fibrinogen fibrin monomers and cross-linked fibrin (as found in a thrombus) into fibrin degradation fibrin (as found in a thrombus) into fibrin degradation productsproducts
First-Generation Agents First-Generation Agents StreptokinaseStreptokinase a protein derived from group C a protein derived from group C
szlig-hemolytic streptococci has a half-life of 16ndashszlig-hemolytic streptococci has a half-life of 16ndash90 minutes and low fibrin specificity This drug 90 minutes and low fibrin specificity This drug proved to have a very narrow therapeutic proved to have a very narrow therapeutic window and significant rates of ICH and window and significant rates of ICH and systemic hemorrhage18systemic hemorrhage18
UrokinaseUrokinase is a serine protease with a plasma is a serine protease with a plasma half life of 14 minutes and low fibrin specificity half life of 14 minutes and low fibrin specificity
The urokinase dose used in cerebral IAT has The urokinase dose used in cerebral IAT has ranged from 002 to 2 X106unitsranged from 002 to 2 X106units
Second-Generation Agents Second-Generation Agents Alteplase (rtPA) Alteplase (rtPA)
is a serine is a serine protease with a plasma half-life of 35 protease with a plasma half-life of 35 minutes and a high degree of fibrin affinity and minutes and a high degree of fibrin affinity and specificity specificity
Dose used in cerebral IAT has ranged between 20 Dose used in cerebral IAT has ranged between 20 and 60 mgand 60 mg
Disadvantages of alteplase include its relatively short Disadvantages of alteplase include its relatively short halflife and limited penetration into the clot matrix halflife and limited penetration into the clot matrix because of strong binding with surface fibrin which because of strong binding with surface fibrin which could delay recanalization and increase the risk of could delay recanalization and increase the risk of recurrent occlusion recurrent occlusion
Prourokinase (r-prourokinase) Prourokinase (r-prourokinase) is the proenzyme precursor of urokinase is the proenzyme precursor of urokinase T12 of 7 minutes and high fibrin specificity T12 of 7 minutes and high fibrin specificity
Third-Generation AgentsThird-Generation Agents
ReteplaseReteplase is a structurally modified is a structurally modified form of alteplase form of alteplase
with a longer half-life (15ndash18 minutes) In with a longer half-life (15ndash18 minutes) In addition it does not bind as highly to fibrin addition it does not bind as highly to fibrin unbound reteplase can thus theoretically better unbound reteplase can thus theoretically better penetrate the clot and potentially penetrate the clot and potentially improve in improve in vivo fibrinolytic activity vivo fibrinolytic activity
TenecteplaseTenecteplase is another modified form of rtPA with a longer is another modified form of rtPA with a longer
half-life (17 minutes)half-life (17 minutes) greater fibrin specificity and greater greater fibrin specificity and greater
resistance to plasminogen activator inhibitor-1 resistance to plasminogen activator inhibitor-1 IV tenecteplase in acute ischemic stroke IV tenecteplase in acute ischemic stroke
suggest that the drug is safe and promisingsuggest that the drug is safe and promising
Newer plasminogen activatorNewer plasminogen activator
DesmoteplaseDesmoteplase is a genetically engineered is a genetically engineered version of the clot-dissolving factor version of the clot-dissolving factor
found in the saliva found in the saliva of the vampire bat Desmodus rotundusof the vampire bat Desmodus rotundus moremore potent and more selective for fibrin-bound potent and more selective for fibrin-bound
plasminogen than any other known plasminogen plasminogen than any other known plasminogen activatoractivator
Unlike tissue plasminogen activator (tPA) desmoteplase Unlike tissue plasminogen activator (tPA) desmoteplase is not activated by fibrinogen or -amyloid proteins is not activated by fibrinogen or -amyloid proteins factors that may exacerbate the risk for ICH factors that may exacerbate the risk for ICH
The effect of IV administration of desmoteplase 3ndash9 The effect of IV administration of desmoteplase 3ndash9 hours after symptom onset in patients with stroke who hours after symptom onset in patients with stroke who present with mismatch on MR imaging or CT perfusion present with mismatch on MR imaging or CT perfusion
3 DefibrinogenatingFibrinogenolytic 3 DefibrinogenatingFibrinogenolytic Agents Agents
AncrodAncrod(Viprinex)(Viprinex) is is the purified fraction of the Malayan pit viper venomthe purified fraction of the Malayan pit viper venom It acts by directly cleaving and inactivating fibrinogen It acts by directly cleaving and inactivating fibrinogen
and thus indirectly promoting anticoagulation and thus indirectly promoting anticoagulation The reduction in the blood levels of fibrinogen also The reduction in the blood levels of fibrinogen also
leads to a reduced blood viscosity which may improve leads to a reduced blood viscosity which may improve blood flow to the affected areas of the brain blood flow to the affected areas of the brain
In the Stroke Treatment with Ancrod Trial 500 In the Stroke Treatment with Ancrod Trial 500 patients with stroke presenting within 3 hours of patients with stroke presenting within 3 hours of symptom onset were randomized to receive ancrod (symptom onset were randomized to receive ancrod (n n 248) or a placebo (n 252) Good outcome (Barthel 248) or a placebo (n 252) Good outcome (Barthel Index 95ndash100 at 3 months) was achieved in 4221 Index 95ndash100 at 3 months) was achieved in 4221 and 344 of the patients respectively and 344 of the patients respectively
2 Direct Fibrinolytics2 Direct Fibrinolytics
Microplasmin (Microplasmin (ThromboGenics Heverlee Belgium)ThromboGenics Heverlee Belgium) is a truncated form of plasmin that is more resistant to the effects is a truncated form of plasmin that is more resistant to the effects
of antiplasmin of antiplasmin microplasmin can be used upto 4ndash12 hours after stroke onset microplasmin can be used upto 4ndash12 hours after stroke onset There was no evidence of increased bleeding risk with There was no evidence of increased bleeding risk with
microplasminmicroplasmin
Alfimeprase (Nuvelo San Carlos Calif)Alfimeprase (Nuvelo San Carlos Calif) is a recombinant truncated form of fibrolase a fibrinolytic zinc metalloproteinase is a recombinant truncated form of fibrolase a fibrinolytic zinc metalloproteinase
isolated from the venom of the southern copperhead snake isolated from the venom of the southern copperhead snake It degrades fibrin directly and achieves thrombolysis independent It degrades fibrin directly and achieves thrombolysis independent
of plasmin formationof plasmin formation its thrombolytic activity appears to be localized to the site of its thrombolytic activity appears to be localized to the site of
delivery These properties should theoretically result in faster delivery These properties should theoretically result in faster recanalization and lower hemorrhagic conversion riskrecanalization and lower hemorrhagic conversion risk
Anti-fibrinolyticsAnti-fibrinolytics
to limit fibrinolytic activityto limit fibrinolytic activity -aminocaproic acid (EACA) -aminocaproic acid (EACA) competitively inhibitscompetitively inhibits plasminogen and plasminogen activators from plasminogen and plasminogen activators from
binding to fibrinbinding to fibrin
alpha2-antiplasminalpha2-antiplasmin a serine protease inhibitor that a serine protease inhibitor that neutralizes any free circulating plasminneutralizes any free circulating plasmin
Plasminogen activator inhibitor-1Plasminogen activator inhibitor-1 a serine protease a serine protease inhibitor that inhibits tissue-type plasminogen inhibitor that inhibits tissue-type plasminogen activatoractivator
Glycoprotein (GP) IIbIIIa antagonistsGlycoprotein (GP) IIbIIIa antagonists
such as ReoPro (abciximab) Integrilin such as ReoPro (abciximab) Integrilin (eptifibatide) or Aggrastat (tirofiban) in (eptifibatide) or Aggrastat (tirofiban) in ischemic stroke remains investigational ischemic stroke remains investigational Deshmukh et al38 reported 21 patients with Deshmukh et al38 reported 21 patients with large-vessel occlusion refractory to IAT with large-vessel occlusion refractory to IAT with rtPA who were treated with IV andor IA rtPA who were treated with IV andor IA abciximab eptifibatide or tirofiban abciximab eptifibatide or tirofiban
IA Mechanical Approaches in Acute Ischemic Stroke IA Mechanical Approaches in Acute Ischemic Stroke Mechanical strategies have several advantagesMechanical strategies have several advantages First they lessen and may even preclude the use of chemical First they lessen and may even preclude the use of chemical
thrombolytics in this manner very likely reducing the risk of ICHthrombolytics in this manner very likely reducing the risk of ICH Second by avoiding the use of chemical thrombolytics it is Second by avoiding the use of chemical thrombolytics it is
possible to extend the treatment window beyond the limit of 6ndash8 possible to extend the treatment window beyond the limit of 6ndash8 hours hours
Third mechanically fragmenting a clot increases the surface area Third mechanically fragmenting a clot increases the surface area accessible to fibrinolytic agents and allows inflow of fresh accessible to fibrinolytic agents and allows inflow of fresh plasminogen which in turn may increase the speed of plasminogen which in turn may increase the speed of thrombolysis thrombolysis
Finally clot-retrieval devices may provide faster recanalization Finally clot-retrieval devices may provide faster recanalization
The disadvantages of the mechanical The disadvantages of the mechanical approaches approaches technical difficulty of navigating mechanical technical difficulty of navigating mechanical
devices into the intracranial circulation excessive devices into the intracranial circulation excessive trauma to the vasculature (potentially leading to trauma to the vasculature (potentially leading to vasospasm vessel dissection perforation or vasospasm vessel dissection perforation or rupture) rupture)
fragmented thrombus causing distal embolization fragmented thrombus causing distal embolization into previously unaffected territories into previously unaffected territories
Nevertheless the advantages of mechanical stroke Nevertheless the advantages of mechanical stroke therapy appear to significantly outweigh its therapy appear to significantly outweigh its disadvantages and risksdisadvantages and risks
Contraindications to Thrombolytic Contraindications to Thrombolytic agents agents
Recent thoracic abdominal or Recent thoracic abdominal or intracranial surgeryintracranial surgery
Recent haemorrhagic CVA Head injury Recent haemorrhagic CVA Head injury or neoplasmor neoplasm
Bleeding ulcerBleeding ulcer Anticipated invasive procedures (arterial Anticipated invasive procedures (arterial
punctures biopsies)punctures biopsies) Concurrent hemostatic dysfunctionConcurrent hemostatic dysfunction
Monitoring of thrombolytic Monitoring of thrombolytic therapytherapy
Thrombin time Measures the availability of functional
fibrinogen Normal thrombin time is 10-14 sec Prolonged when fibrinogen level is below
75-100 mgdl
Half Life of ThrombolyticsHalf Life of ThrombolyticsAgent Administration Half Life
Streptokinase IA 60-80min
Urokinase IAIV 9-12min
rTPA IAIV 6min
Abciximab(Reopro) IAIV 12hour
Aspirin POIV 15-20min
Heparin IVSC 60min
Coumadin PO 15-25 days
Anti Platelet DrugsAnti Platelet DrugsDrug Drug Mechanism Mechanism UsesUsesAspirinAspirin Permanently inhibits Permanently inhibits
COX-1 and COX-2COX-1 and COX-2CADCAD
Stroke-TIAsStroke-TIAs
NSAIDsNSAIDs Reversibly inhibits Reversibly inhibits COX-1COX-1
LimitedLimited
DipyridamoleDipyridamole Inhibits PDE increases Inhibits PDE increases cAMPcAMP
TIAsTIAs
ThenopyridinesThenopyridines
(Ticlopidine(Ticlopidine
ClopidrgrelClopidrgrel))
Inhibits ADP Inhibits ADP
PlatAg PlatAg
TIAsStrokeTIAsStroke
CAD PVDCAD PVD
Abciximab (ReoPro)Abciximab (ReoPro)
Eptifibatide (Integrilin)Eptifibatide (Integrilin)
TirofibanTirofiban
GP IIBIIIA InhibitorsGP IIBIIIA Inhibitors
Stroke- TIAs Stroke- TIAs
MonitoringMonitoring
Bleeding timeBleeding time
Optical aggregometryOptical aggregometry
Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay
Bleeding timeBleeding time
Requires a skin incision (usually made on the ear lobe or Requires a skin incision (usually made on the ear lobe or forearm offorearm of
a depth that results in disruption of capillary loops and a depth that results in disruption of capillary loops and small vessels)small vessels)
AdvantagesAdvantages Universally availableUniversally available Relatively simple techniquesRelatively simple techniques Can be performed bedsideCan be performed bedside
DisadvantagesDisadvantages Insensitive inaccurate non-specific techniqueInsensitive inaccurate non-specific technique
Poorly reproducible (as depends on multiple variables)Poorly reproducible (as depends on multiple variables)
Optical aggregometryOptical aggregometry
Gold standard assay for platelet functionGold standard assay for platelet function Agonist induced aggregation is measuredAgonist induced aggregation is measured Different agonist are available for different Different agonist are available for different
agentsagents However require unique expertise and are not However require unique expertise and are not
universally availableuniversally available Aspirin measured with ADP or AA(gt70 Aspirin measured with ADP or AA(gt70
aggregation so resistance)aggregation so resistance) Clopidogrel( ADP gt 90 aggregation means Clopidogrel( ADP gt 90 aggregation means
resistance) resistance)
Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay
Can be performed bed sideCan be performed bed side Different assay devices with different Different assay devices with different
agonist are used for each of different agonist are used for each of different antiplatelet agents antiplatelet agents
For Aspirin AA is used (result is reported as aspirin For Aspirin AA is used (result is reported as aspirin reaction units [ARU] ARUgt 550 indicates non-reaction units [ARU] ARUgt 550 indicates non-responsiveness)responsiveness)
Verify IIbIIIa assay device uses TRAP as agonist for Verify IIbIIIa assay device uses TRAP as agonist for Abciximab and TirofibanAbciximab and Tirofiban
Practical Applications Practical Applications related to specific related to specific
Neurovascular Neurovascular interventionsinterventions
Acute ischemic StrokeAcute ischemic Stroke When an artery occludes neurons are affected When an artery occludes neurons are affected
differently depending upon the amount of residual blood differently depending upon the amount of residual blood flowflow
Normal cerebral blood flow is greater than 50 mL100 Normal cerebral blood flow is greater than 50 mL100 mgminmgmin
Once blood flow decreases to less than 20 mL100 Once blood flow decreases to less than 20 mL100 mgmin infarction occursmgmin infarction occurs
If blood flow decreases to less than 10 mL100 mgmin If blood flow decreases to less than 10 mL100 mgmin irreversible neuronal death occurs rapidly irreversible neuronal death occurs rapidly
Blood flow between 11 and 20 mL100 mgmin is thought Blood flow between 11 and 20 mL100 mgmin is thought to represent the ischemic penumbra an area where the to represent the ischemic penumbra an area where the cells are functionally silent because of ischemia but are cells are functionally silent because of ischemia but are still able to recover if blood flow is restored still able to recover if blood flow is restored
Many acute stroke therapies are targeted toward Many acute stroke therapies are targeted toward restoring flow or function to the ischemic penumbrarestoring flow or function to the ischemic penumbra
Therapeutic window in Therapeutic window in management of acute Ischemic management of acute Ischemic
StrokeStrokeThe early diagnosis of ischemic stroke is critical to the The early diagnosis of ischemic stroke is critical to the
with only a narrow therapeutic window in the first few with only a narrow therapeutic window in the first few hours following stroke ictushours following stroke ictus
Diagnosis in the first 3 hours postictus provides the Diagnosis in the first 3 hours postictus provides the opportunity for intravenous or intraarterial thrombolysis opportunity for intravenous or intraarterial thrombolysis and intra-arterial clot mechanical treatment which and intra-arterial clot mechanical treatment which improve the outcome improve the outcome
Diagnosis in the time period between 3 and 6 hours Diagnosis in the time period between 3 and 6 hours provides an opportunity for intra-arterial thrombolysis provides an opportunity for intra-arterial thrombolysis and mechanical treatment and mechanical treatment
Involvement of the posterior circulation especially the Involvement of the posterior circulation especially the basilar artery is treated by some regardless of time of basilar artery is treated by some regardless of time of onset or up until 12 to 24 hours in some practices This is onset or up until 12 to 24 hours in some practices This is related to the potentially high mortality and morbidity related to the potentially high mortality and morbidity associated with basilar artery thrombosisassociated with basilar artery thrombosis
Infarct evaluation on angiographyInfarct evaluation on angiography(CT angiography and catheter (CT angiography and catheter
angiography)angiography)CTA is an excellent first-line examination for CTA is an excellent first-line examination for
evaluation of the head and neck arteries evaluation of the head and neck arteries In comparison with catheter angiography In comparison with catheter angiography
what it gives up in resolution and dynamic what it gives up in resolution and dynamic properties it makes up for with rapid properties it makes up for with rapid acquisition of a 3-D dataset and the potential acquisition of a 3-D dataset and the potential for assessment of whole-brain perfusion and for assessment of whole-brain perfusion and better parenchymal evaluationbetter parenchymal evaluation
Moreover CTA illustrates not only arterial Moreover CTA illustrates not only arterial stenosis or occlusion but also the vessel wall stenosis or occlusion but also the vessel wall This factor is most important for evaluation of This factor is most important for evaluation of intramural dissection and thrombosed intramural dissection and thrombosed aneurysms which may both complicate aneurysms which may both complicate evaluation of stroke patientsevaluation of stroke patients
Early angiographic signs of strokes Early angiographic signs of strokes both CTA both CTA and DSA and DSA
Vessel occlusion or cutoff related to Vessel occlusion or cutoff related to thromboembolithromboemboli
aneurysms aneurysms arterial dissection arterial dissection Meniscus or flattened shape to clot Meniscus or flattened shape to clot
(recent) versus reverse meniscus (older)(recent) versus reverse meniscus (older) tram track (nonocclusive or recanalized tram track (nonocclusive or recanalized
clot) clot) delayed (antegrade) flow (manifest as delayed (antegrade) flow (manifest as
decreased whole-brain perfusion on CTA)decreased whole-brain perfusion on CTA) retrograde collateral flowretrograde collateral flow
Non-occlusive left MCA thrombus on 3-D imaging performed from CTA source data and was confirmed at catheter angiography
Therapy to be started within a 6-hr Therapy to be started within a 6-hr time to treatment (TTT) window time to treatment (TTT) window (while in case of IV thrombolysis (while in case of IV thrombolysis therapy to be started with in 3hrs)therapy to be started with in 3hrs)
Exclusion criteria Exclusion criteria Rapidly improving neurologic deficit or Rapidly improving neurologic deficit or Sustained blood pressure of gt180100 Sustained blood pressure of gt180100 Hemorrhage is detected on CTHemorrhage is detected on CT Infarct involving gt more than 13 rd Infarct involving gt more than 13 rd
territory of MCAterritory of MCA MRADWI-Perfusion mismatchlt 20MRADWI-Perfusion mismatchlt 20 Definite hypodensity on CTDefinite hypodensity on CT
Intra-arterial Thrombolysis
Fibrinolytics + AntiplateletsFibrinolytics + Antiplatelets
PlasminogenPlasminogen activators through fibrinolysis exposes activators through fibrinolysis exposes free thrombin and paradoxically stimulatesfree thrombin and paradoxically stimulates platelet platelet aggregation which leads to formation of aaggregation which leads to formation of a platelet platelet thrombus (white clot) thrombus (white clot)
This new thrombus is relatively resistant to This new thrombus is relatively resistant to fibrinolyticsfibrinolytics
So new regimen in case of acute stroke isSo new regimen in case of acute stroke is fibrinolytics + antiplatelet drugsfibrinolytics + antiplatelet drugs
rtPA + IIbIIIa inhibitors( tirofiban rtPA + IIbIIIa inhibitors( tirofiban abciximab) orabciximab) or
Urokinase + IIbIIIa Urokinase + IIbIIIa inhibitors( tirofiban abciximab)inhibitors( tirofiban abciximab)
Intra-arterial Thrombolysis Tirofiban (04 microgkgmin bolus for 3 min followed by Tirofiban (04 microgkgmin bolus for 3 min followed by
0125 ugkgmin)0125 ugkgmin)
++
Heparin (2000ndash3000 IU bolus followed by Heparin (2000ndash3000 IU bolus followed by 1000 IUhour infusion 1000 IUhour infusion
with ACT maintained bw 200-300) throughout the with ACT maintained bw 200-300) throughout the interventional procedure and for 24ndash48 hours thereafter when interventional procedure and for 24ndash48 hours thereafter when there is neither intraprocedural bleeding nor suspicion of there is neither intraprocedural bleeding nor suspicion of increased risk of bleeding increased risk of bleeding
Maximum dose of Urokinase Maximum dose of Urokinase Anterior circulation stroke - 500000 IU (mean 400000 Anterior circulation stroke - 500000 IU (mean 400000
IU range 300000ndash500000 IU)IU range 300000ndash500000 IU) Posterior circulation stroke -1000000 IU (mean 837000 Posterior circulation stroke -1000000 IU (mean 837000
IU range 300000ndash1000000 IU)IU range 300000ndash1000000 IU)American Journal of NeuroradiologyAmerican Journal of Neuroradiology 262595-2601 2005262595-2601 2005
Intravenous ThrombolysisIntravenous Thrombolysis
The first method to restore cerebral The first method to restore cerebral perfusion is clot lysis with the goal perfusion is clot lysis with the goal of re-establishing blood flow to the of re-establishing blood flow to the affected tissue affected tissue
IV thrombolysis rt-PA is the only IV thrombolysis rt-PA is the only FDA- approved treatment for AIS FDA- approved treatment for AIS
Fibrinolysis is enhanced powerfully Fibrinolysis is enhanced powerfully by rt-PAby rt-PA
Intravenous rTPA Intravenous rTPA administration administration protocolprotocol
Total dose of rt-PA 09 mgkg (maximum dose Total dose of rt-PA 09 mgkg (maximum dose 90 mg)90 mg)
Give 10 as initial IV bolusGive 10 as initial IV bolus Infuse remainder over 1 hourInfuse remainder over 1 hour Admit patient to an ICU or stroke unit for Admit patient to an ICU or stroke unit for
monitoringmonitoring Neurologic assessments every 15 minutes Neurologic assessments every 15 minutes
during infusion then every 30 minutes for next during infusion then every 30 minutes for next 6 hours then every hour until 24hours after 6 hours then every hour until 24hours after treatmenttreatment
Favorable Outcome vs Treatment Time Favorable Outcome vs Treatment Time with IV rTPAwith IV rTPA
Protocol limit = 3 hrs
Benefit ~ 45 hrs
Thromboembolism During coilingThromboembolism During coiling Most feared and frequent complication Most feared and frequent complication Reported incidence - Approx 7 Reported incidence - Approx 7 SourcesSources of Thromboembolism are of Thromboembolism are
- Clots at the aneurysmal neck during or immediately- Clots at the aneurysmal neck during or immediately after after embolization embolization
- Thrombus forming on catheters during- Thrombus forming on catheters during proceduresprocedures
- Stenosis of an adjacent artery dt coil mass- Stenosis of an adjacent artery dt coil mass or herniationor herniation
- Migration of intraaneurysmal- Migration of intraaneurysmal thrombus during coil thrombus during coil placement placement
- Slow flow dt vasospasm - Slow flow dt vasospasm
- Rare and unlikely causes are hypercoagulable- Rare and unlikely causes are hypercoagulable state such state such as antiphospholipid antibody syndrome or due to HITas antiphospholipid antibody syndrome or due to HIT
Occur more often with wide-necked aneurysms (dt Occur more often with wide-necked aneurysms (dt increased exposed surface area of thrombogenic coil increased exposed surface area of thrombogenic coil material)material)
Current regimen of endovascular Current regimen of endovascular managementmanagement
The The glycoprotein IIbIIIa antagonist tirofiban glycoprotein IIbIIIa antagonist tirofiban (04 (04 microgkgmin bolus for 30 minutes followed by infusion of microgkgmin bolus for 30 minutes followed by infusion of 0125 ugkgmin until the thrombus dissolved) 0125 ugkgmin until the thrombus dissolved)
Intraarterial thrombolysis with Intraarterial thrombolysis with urokinase or r- TPA urokinase or r- TPA increase of intravenous (IV) heparin (measured by increase of intravenous (IV) heparin (measured by
ACT) ACT) Intravenous aspirin Intravenous aspirin
Coil-related platelet aggregation (white clot) is Coil-related platelet aggregation (white clot) is unlikely to respond to fibrinolytics but has a high risk unlikely to respond to fibrinolytics but has a high risk of hemorrhage (In ISAT) all 5 patients who had of hemorrhage (In ISAT) all 5 patients who had received thrombolytic therapy with tPA to treat a received thrombolytic therapy with tPA to treat a thromboembolic complication after endovascular thromboembolic complication after endovascular treatment rebleed and all of these patients died)treatment rebleed and all of these patients died)
IntracranialIntracranial Stenting Stenting Metallic foreign body such as stent will accumulate Metallic foreign body such as stent will accumulate
thrombus in the absence of platelet inhibitionthrombus in the absence of platelet inhibition Antiplatelet drugs are important to prevent peri or Antiplatelet drugs are important to prevent peri or
post-interventional thromboembolic eventspost-interventional thromboembolic events Optimal treatment regimens has not been determined Optimal treatment regimens has not been determined
but usually but usually Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-
procedureprocedureOrOr
Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on
morning of proceduremorning of procedure
If need to use stent is not pre-planned thanIf need to use stent is not pre-planned than
Abciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkgAbciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkg IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)
Glycoprotein IIbIIIa inhibitor are not used routinely during elective Glycoprotein IIbIIIa inhibitor are not used routinely during elective stenting procedure dt increased risk of ICH stenting procedure dt increased risk of ICH
Carotid StentingCarotid Stenting
Pre-procedurePre-procedure
Double Antiplatelet therapy is routinely given Double Antiplatelet therapy is routinely given beginning at least 3beginning at least 3
days before the proceduredays before the procedure
Aspirin 325mgd+Clopidogrel 75mgdAspirin 325mgd+Clopidogrel 75mgd During procedureDuring procedure
Heparin is given with target clotting time of 250-Heparin is given with target clotting time of 250-300sec300sec
Post-procedure Post-procedure
Aspirin 325mg is continued indefinitely and Aspirin 325mg is continued indefinitely and
Clopidogrel 75mgd for at least 6 weeks Clopidogrel 75mgd for at least 6 weeks
Inclusion criteria for Local ThrombolysisInclusion criteria for Local Thrombolysis a)a) Patients in severe clinical grade on admission Patients in severe clinical grade on admission
with evidence of dural venous sinus with evidence of dural venous sinus thrombosis and restrictive venous outflow on thrombosis and restrictive venous outflow on cerebral angiogramcerebral angiogram
b)b) Patients in clinical grade 3 worsening on Patients in clinical grade 3 worsening on heparin therapy Restriction to venous heparin therapy Restriction to venous outflow was defined as an increase in brain outflow was defined as an increase in brain circulation time gt 12 s delay in the drainage circulation time gt 12 s delay in the drainage of cortical veins with cortical veins hanging of cortical veins with cortical veins hanging in spacein space
Treatment Options for Venous Thrombosis
CT Grading for Venous ThrombosisCT Grading for Venous Thrombosis Grade I no parenchymal change Grade I no parenchymal change
(hyperdense (hyperdense sinuses cortical veins empty sinuses cortical veins empty delta sign)delta sign)
Grade II non hemorrhagic venous infarct Grade II non hemorrhagic venous infarct without mass effect without mass effect
Grade III non-hemorrhagic infarct with Grade III non-hemorrhagic infarct with mass effectmass effect
Grade IV hemorrhagic venous infarct (max Grade IV hemorrhagic venous infarct (max diameter lt 3 cm) with no mass effectdiameter lt 3 cm) with no mass effect
Grade V hemorrhagic venous infarct (max Grade V hemorrhagic venous infarct (max diameter gt 3 cm) with mass effect diameter gt 3 cm) with mass effect
Local ThrombolysisLocal Thrombolysis
Femoral Jugular access was secured and a guiding Femoral Jugular access was secured and a guiding catheter was placed in the jugular bulb catheter was placed in the jugular bulb Mechanical Mechanical clot maceration clot maceration was done with the guidewire was done with the guidewire following which a microcatheter (was navigated and following which a microcatheter (was navigated and placed in the thrombosed segment of sinus confirmed placed in the thrombosed segment of sinus confirmed on a selective venogram on a selective venogram
Urokinase infusion Bolus dose of 2-6 lacs followed Urokinase infusion Bolus dose of 2-6 lacs followed by 60000 to 100000 units per hour along with by 60000 to 100000 units per hour along with periodic check venogram Along with maintenance periodic check venogram Along with maintenance systemic infusion of Heparinsystemic infusion of Heparin Other agents such as Other agents such as streptokinase altepase or rTPAstreptokinase altepase or rTPA can be also used can be also used
After thrombolysis patient should subjected to oral After thrombolysis patient should subjected to oral anticoagulation for six monthsanticoagulation for six months
Low-molecular-weight Low-molecular-weight heparinheparin
PharmacologyPharmacologyLMWH as its name suggests is a glycosaminoglycan that is approximatelyLMWH as its name suggests is a glycosaminoglycan that is approximately
one third the molecular weight of UFH It is derived from UFH through one third the molecular weight of UFH It is derived from UFH through variousvarious
depolymerization processes LMWH binds to antithrombin which in turn depolymerization processes LMWH binds to antithrombin which in turn
Neutralizes actors Xa and IIa Because LMWH lacks many of the longer Neutralizes actors Xa and IIa Because LMWH lacks many of the longer chains chains
required for binding to thrombin it has less ability to neutralize thrombin required for binding to thrombin it has less ability to neutralize thrombin
relativeto its ability to neutralize factor Xa LMWH also has less relativeto its ability to neutralize factor Xa LMWH also has less nonspecific nonspecific
binding to other proteins There is greater bioavailability with more binding to other proteins There is greater bioavailability with more predictable predictable
pharmacokinetics that eliminates the need for monitoring The smaller pharmacokinetics that eliminates the need for monitoring The smaller size also size also
allows for enhanced subcutaneous absorption when compared with UFHallows for enhanced subcutaneous absorption when compared with UFH
Three LMWH preparations are Three LMWH preparations are currently approved for use in the currently approved for use in the United States (1) enoxaparin (2) United States (1) enoxaparin (2) dalteparin and (3) tinzaparin dalteparin and (3) tinzaparin
They are all administered They are all administered subcutaneously at intervals of either subcutaneously at intervals of either once or twice daily for both once or twice daily for both prophylaxis and treatment dosesprophylaxis and treatment doses
Few Experiences of Few Experiences of ThrombolysisThrombolysis
Vickey 25 Yrs male patient presented Vickey 25 Yrs male patient presented with 12with 12thth day HO severe headache with day HO severe headache with right sided hemiplegiaright sided hemiplegia
MRI shows thrombosis of the superior MRI shows thrombosis of the superior sagittal left transverse left sigmoid sagittal left transverse left sigmoid sinuses and cortical veins in the fronto-sinuses and cortical veins in the fronto-parietal regions with eo haemorrhagic parietal regions with eo haemorrhagic infarct in the left cerebral hemisphere infarct in the left cerebral hemisphere with mass effect( Grade ndashV)with mass effect( Grade ndashV)
Sashi Srivastava 64 yrs FSashi Srivastava 64 yrs F In a follow up case of MRD with infra-renal In a follow up case of MRD with infra-renal
aortic abdominal and bilateral renal artery aortic abdominal and bilateral renal artery thrombosis renal angiogram shows filling thrombosis renal angiogram shows filling defects in the right Renal artery defects in the right Renal artery
Initially Renal angioplasty was done Initially Renal angioplasty was done Following angioplasty few thrombi are seem Following angioplasty few thrombi are seem to extends into the segmental branches and to extends into the segmental branches and causing blockage So Thrombolysis was causing blockage So Thrombolysis was plane to dissolve the run-out thrombi with plane to dissolve the run-out thrombi with urokinase urokinase
Rakesh 34yrsMRakesh 34yrsM Left SFA pseudoaneurysm with Left SFA pseudoaneurysm with
Covered stent placementCovered stent placement Pre operative antiplatelets with post Pre operative antiplatelets with post
procedure heparin Tirofiban procedure heparin Tirofiban followed by aspirin and clopidogrel followed by aspirin and clopidogrel were usedwere used
IAT may be a treatment option for selected patients IAT may be a treatment option for selected patients Possible selection criteria include Possible selection criteria include
presentation between 3 and 6 hours from symptom onsetpresentation between 3 and 6 hours from symptom onset major cerebral artery occlusion major cerebral artery occlusion severe neurologic deficits severe neurologic deficits high risk of systemic hemorrhage with IV rt-PA (eg recent high risk of systemic hemorrhage with IV rt-PA (eg recent
surgery) surgery) The MERCI (Mechanical Embolus Removal in Cerebral The MERCI (Mechanical Embolus Removal in Cerebral
Ischemia) retrievalIschemia) retrieval system system
Has been FDA-approved for recanalizing acutely occluded Has been FDA-approved for recanalizing acutely occluded cerebral arteries cerebral arteries
In the Multi-MERCI study patients who did not improve In the Multi-MERCI study patients who did not improve immediately after IV rt-PA underwent mechanical immediately after IV rt-PA underwent mechanical embolectomy within 8 hours of symptom onset embolectomy within 8 hours of symptom onset
Partial or complete recanalization occurred in 74 of Partial or complete recanalization occurred in 74 of patientspatients
with a symptomatic intracerebral hemorrhage (sICH) rate of with a symptomatic intracerebral hemorrhage (sICH) rate of 67 67
Mechanical embolectomy with the MERCI retriever may be a Mechanical embolectomy with the MERCI retriever may be a feasible and safe option for patients after IV rt-PAfeasible and safe option for patients after IV rt-PA
Penumbra stroke systemPenumbra stroke system This device combines two methods of clot This device combines two methods of clot
extraction aspiration and mechanical extraction aspiration and mechanical extraction extraction
First the clot is aspirated then a thrombus First the clot is aspirated then a thrombus removal ring can be used if necessary to removal ring can be used if necessary to remove remaining clot remove remaining clot
successful recanalizing 82successful recanalizing 82 Bridging therapyBridging therapy
06 mgkg IV rt-PA followed by IAT with IA rt-06 mgkg IV rt-PA followed by IAT with IA rt-PA (up to 20 mg)PA (up to 20 mg)
achieved a higher recanalization rateachieved a higher recanalization rate
Criteria for thrombolysis with rTPACriteria for thrombolysis with rTPA
Inclusion criteriaInclusion criteria Clinical signs and symptoms consistent with ischemic Clinical signs and symptoms consistent with ischemic
strokestroke Patient last seen normal within 3 hoursPatient last seen normal within 3 hours Measurable neurologic deficitMeasurable neurologic deficit
Exclusion criteriaExclusion criteria Any hemorrhage on neuroimaging (CT or MRI)Any hemorrhage on neuroimaging (CT or MRI) Symptoms suggestive of subarachnoid hemorrhageSymptoms suggestive of subarachnoid hemorrhage Seizure at stroke onset that is thought to contribute to Seizure at stroke onset that is thought to contribute to
neurologic deficitneurologic deficit Hypodensity greater than one third cerebral hemisphere Hypodensity greater than one third cerebral hemisphere
on CTon CT SBP greater than 185 mm Hg or DBP greater than 110 SBP greater than 185 mm Hg or DBP greater than 110
mm Hgmm Hg International normalized ratio (INR) greater than 17International normalized ratio (INR) greater than 17
Ischemic Stroke Ischemic Stroke Treatment ndash 2006Treatment ndash 2006
IV tissue plasminogen activator (tPA)IV tissue plasminogen activator (tPA) ndash ndash Only FDA-approved acute stroke drugOnly FDA-approved acute stroke drug ndash ndash 3 hour treatment window3 hour treatment window
MERCI - Concentric clot retrieval MERCI - Concentric clot retrieval devicedevice ndash ndash Rescue therapy - approved 2004Rescue therapy - approved 2004 ndash ndash Device approval (not outcomes-based)Device approval (not outcomes-based)
Off label approachesOff label approaches ndash ndash IV tPA after 3 hoursIV tPA after 3 hours ndash ndash IV-IA tPA sequential strategiesIV-IA tPA sequential strategies ndash ndash IA tPA clot angioplasty fragmentationIA tPA clot angioplasty fragmentation ndash ndash Ultrasound-assisted tPA lysisUltrasound-assisted tPA lysis
rt-PA Trials NINDSrt-PA Trials NINDS
Acute stroke - 624 patientsAcute stroke - 624 patients Treat within 3 hrsTreat within 3 hrs Intravenous 09 mgkg rt-PA vs placeboIntravenous 09 mgkg rt-PA vs placebo Hemorrhage 64 tPA 06 placeboHemorrhage 64 tPA 06 placebo Neurologic recovery better with tPA 30 Neurologic recovery better with tPA 30
more like to have minimal or no disabilitymore like to have minimal or no disability
First proven approved treatment for First proven approved treatment for strokestroke
Limitations of tPALimitations of tPA Only 4 of acute strokes receive tPAOnly 4 of acute strokes receive tPA (Kleindorfer et al Stroke 2004 35 e27-e29)(Kleindorfer et al Stroke 2004 35 e27-e29)
Only 22 of patients present within 3 hoursOnly 22 of patients present within 3 hours1048707 1048707 51 of these ineligible due to51 of these ineligible due to
bull bull Mild severityMild severity bull bull Medical or surgical historyMedical or surgical history bull bull Blood testsBlood tests
Sustained recanalization only 13Sustained recanalization only 13 (Alexandrov et al NEJM 2004 351 2170-8)(Alexandrov et al NEJM 2004 351 2170-8)
Concern for hemorrhageConcern for hemorrhage tPA potentiates apoptotic injury tPA potentiates apoptotic injury (Liu et al Nature Med 2004 101379-83)(Liu et al Nature Med 2004 101379-83)
PROACT II IA Lysis TrialPROACT II IA Lysis Trial Baseline 24 hours 8 days
Baseline 60 minutes 120 minutes
9mg IAProurokinase
Desmoteplase Trials DEDAS Desmoteplase Trials DEDAS DIASDIAS
Trial OverviewTrial Overview Double blind randomized placebo Double blind randomized placebo
controlled trialscontrolled trials IV delivery 3-9 hour time windowIV delivery 3-9 hour time window Plasminogen activator ndash from Plasminogen activator ndash from vampire bat vampire bat
salivasaliva Selection based on PWI-DWI MismatchSelection based on PWI-DWI Mismatch
MRI InclusionMRI Inclusion PWI defect at least 2 cm AND ~20 larger PWI defect at least 2 cm AND ~20 larger
than DWIthan DWI PWI should be obvious even visible on PWI should be obvious even visible on
raw imagesraw imagesMRI ExclusionMRI Exclusion
DWI gt 13 MCADWI gt 13 MCA MRA ICA occlusionMRA ICA occlusion
Desmoteplase ndash DIAS Desmoteplase ndash DIAS ResultsResults
Mechanical Thrombolysis Mechanical Thrombolysis devicesdevices
mechanical thrombolysis potentially extends the treatment mechanical thrombolysis potentially extends the treatment window because they act promptly at the site of the thrombuswindow because they act promptly at the site of the thrombus
The devices can retrieve large clots that pharmaceutical agents The devices can retrieve large clots that pharmaceutical agents may not successfully lysemay not successfully lyse
Patients treated with IV tPA may be considered for treatment of Patients treated with IV tPA may be considered for treatment of residual clot with some of these devicesresidual clot with some of these devices
suction-creating saline jets suction-creating saline jets laser energy ultrasound laser energy ultrasound a corkscrew apparatus to treat strokesa corkscrew apparatus to treat strokes The AngioJet systemThe AngioJet system uses saline jets that are directed back into the catheter to uses saline jets that are directed back into the catheter to
create a low-pressure zone around the catheter tip inducing create a low-pressure zone around the catheter tip inducing suction suction
The clot is pulled into the exhaust lumen and removed from the The clot is pulled into the exhaust lumen and removed from the vessel Although US Food and Drug Administration (FDA) has vessel Although US Food and Drug Administration (FDA) has approved this device for use in arteriovenous dialysis grafts and approved this device for use in arteriovenous dialysis grafts and fistulae and for the treatment of coronary arteries saphenous fistulae and for the treatment of coronary arteries saphenous vein grafts and peripheral vessels clinical trials for the vein grafts and peripheral vessels clinical trials for the treatment of acute stroke are no longer in progress treatment of acute stroke are no longer in progress
Most devices are used in cerebral vessels that 2-5 mm
The Latis laser device The Latis laser device used laser energy to ablate clots used laser energy to ablate clots Arteries 2-5 mm in diameter could be Arteries 2-5 mm in diameter could be
treated including the ICA M1 or M2 treated including the ICA M1 or M2 branch of the MCA A1 branch of the branch of the MCA A1 branch of the anterior cerebral artery (ACA) basilar anterior cerebral artery (ACA) basilar artery posterior cerebral artery (PCA) artery posterior cerebral artery (PCA) and vertebral and vertebral
Patients could receive treatment as late Patients could receive treatment as late as 8 hours after symptom onset in the as 8 hours after symptom onset in the anterior circulation and within 24 hours in anterior circulation and within 24 hours in the posterior circulation the posterior circulation
Endovascular Photo Acoustic Endovascular Photo Acoustic Recanalization (EPAR) Recanalization (EPAR)
A laser power source generated energy for the A laser power source generated energy for the systemsystem
The energy was delivered by means of The energy was delivered by means of fiberoptics to the tip of the catheter at the fiberoptics to the tip of the catheter at the treatment sitetreatment site
Absorption of laser light by darkly pigmented Absorption of laser light by darkly pigmented materials (ie the clot) occurred inside the 1-mm materials (ie the clot) occurred inside the 1-mm catheter tipcatheter tip
the system was designed to minimize scattering the system was designed to minimize scattering of laser light of laser light
Absorption converted photo energy to acoustic Absorption converted photo energy to acoustic energy which then emulsified the clot inside the energy which then emulsified the clot inside the catheter tip catheter tip
EKOS ultrasound( the EKOS ultrasound( the Ultrasound Thrombolytic Ultrasound Thrombolytic
Infusion Catheter) Infusion Catheter) combines the use of a distal ultrasound transducer with combines the use of a distal ultrasound transducer with
infusion of a thrombolytic agent through the infusion of a thrombolytic agent through the microcathetermicrocatheter
Ultrasound changes the structure of the clot to Ultrasound changes the structure of the clot to temporarily increase its permeability while providing an temporarily increase its permeability while providing an acoustic pressure gradient to move the drug into the clot acoustic pressure gradient to move the drug into the clot to speed its dissolution to speed its dissolution
The EKOS catheter is placed in the proximal portion of the The EKOS catheter is placed in the proximal portion of the clot clot
After a 2-mg bolus of tPA was injected through the After a 2-mg bolus of tPA was injected through the catheter catheter
the patient received a continuous infusion of IA tPA 03 the patient received a continuous infusion of IA tPA 03 mgmin to a maximum of 20 mg and simultaneous mgmin to a maximum of 20 mg and simultaneous ultrasound transmission for as long as 60 minutes ultrasound transmission for as long as 60 minutes
One patient was treated with a total of 4 units of One patient was treated with a total of 4 units of recombinant reteplase (Retavase) hand-injected over 60 recombinant reteplase (Retavase) hand-injected over 60 minutes minutes
Penumbra system Penumbra system The Penumbra system (Penumbra Inc) provides a dual The Penumbra system (Penumbra Inc) provides a dual
approach to clot extraction using aspiration followed by approach to clot extraction using aspiration followed by clot retrieval with a ring device if needed clot retrieval with a ring device if needed
Mechanical Embolus Removal in Cerebral Ischemia Mechanical Embolus Removal in Cerebral Ischemia (MERCI)(MERCI)
a corkscrew-like apparatus to remove blood clots from a corkscrew-like apparatus to remove blood clots from the brain in patients experiencing an ischemic stroke the brain in patients experiencing an ischemic stroke
The corkscrew itself resides in the catheter tip which The corkscrew itself resides in the catheter tip which shields it from the wall of the vessel until it is ready to be shields it from the wall of the vessel until it is ready to be burrowed into the clot Once lodged in the clot the device burrowed into the clot Once lodged in the clot the device and clot are withdrawn from the vessel and clot are withdrawn from the vessel
Snarelike devicesSnarelike devices Snares such as the Neuronet snare (Guidant Snares such as the Neuronet snare (Guidant
Endovascular Santa Clara CA) have been developed Endovascular Santa Clara CA) have been developed specifically for use in the treatment of strokes specifically for use in the treatment of strokes
These devices are simple in design and do not require the These devices are simple in design and do not require the clot to be amenable to emulsification clot to be amenable to emulsification
X-Sizer deviceX-Sizer device a device with small moving blades at the a device with small moving blades at the
catheter tip catheter tip This device the X-Sizer device (EndiCor Medical This device the X-Sizer device (EndiCor Medical
San Clemente CA) can be used to excise the San Clemente CA) can be used to excise the thrombus and aspirate it thrombus and aspirate it
The device was being evaluated in randomized The device was being evaluated in randomized studies of coronary vessels and in a registry of studies of coronary vessels and in a registry of patients with acute myocardial infarctionpatients with acute myocardial infarction
Although the manufacturer had modified the Although the manufacturer had modified the device for use in cerebral vessels a safety and device for use in cerebral vessels a safety and feasibility study was indefinitely suspended after feasibility study was indefinitely suspended after only 1 patient was treated with the device in only 1 patient was treated with the device in Europe Europe
Suction thrombectomySuction thrombectomy This method of mechanical thrombolysis is one of the This method of mechanical thrombolysis is one of the
simplestsimplest In this readily available technique suction is applied with In this readily available technique suction is applied with
a syringe to remove thrombus in the ICA a syringe to remove thrombus in the ICA It requires no other devicesIt requires no other devices A catheter with a large inner diameter (Brite Tip Cordis A catheter with a large inner diameter (Brite Tip Cordis
Corporation Miami FL) was placed in the symptomatic Corporation Miami FL) was placed in the symptomatic vessel and navigated over a guidewire into the thrombusvessel and navigated over a guidewire into the thrombus
A 60-mL syringe was used to aspirate the thrombus A 60-mL syringe was used to aspirate the thrombus Each patient required angioplasty and stenting of carotid Each patient required angioplasty and stenting of carotid
bifurcation stenosis and received daily aspirin and bifurcation stenosis and received daily aspirin and ticlopidine after the procedure No complications ticlopidine after the procedure No complications occurred occurred
Summary Acute Stroke Summary Acute Stroke ImagingImaging
PhysiologyPhysiology importance collaterals importance collaterals
ndash ndashGrowing role for perfusion Growing role for perfusion assessmentassessment
tPAtPA guidelines amp limitations guidelines amp limitations Signs on CT amp MRSigns on CT amp MR follow physiology follow physiology Stroke trialsStroke trials PWI-DWI mismatch PWI-DWI mismatch
ndash ndashTreat based on physiology not timeTreat based on physiology not time ProtocolsProtocols should be fast and should be fast and
comprehensivecomprehensive
Mechanism of blood Mechanism of blood coagulationcoagulation
HemostasisHemostasis involves a sequence of interactions of coagulation involves a sequence of interactions of coagulation
factor interactions in two pathways called the factor interactions in two pathways called the intrinsic and extrinsic coagulation cascades intrinsic and extrinsic coagulation cascades
The final common pathway involves the The final common pathway involves the transformation of prothrombin to thrombin by factor transformation of prothrombin to thrombin by factor Xa Xa
Thrombin (factor IIa) then serves to catalyze the Thrombin (factor IIa) then serves to catalyze the activation of fibrinogen to fibrin in addition to its role activation of fibrinogen to fibrin in addition to its role in feedback activation of several other clotting factorsin feedback activation of several other clotting factors
UFH LMWH and fondaparinux( saccharides) all UFH LMWH and fondaparinux( saccharides) all exert their anticoagulant effect in a similar fashion by exert their anticoagulant effect in a similar fashion by binding to and activating antithrombinbinding to and activating antithrombin that then that then neutralizes selected coagulation factorsneutralizes selected coagulation factors
Stages of blood coagulationStages of blood coagulation Formation of Formation of ProthrombinaseProthrombinase
Prothrombinase can be formed in two ways depending of which of Prothrombinase can be formed in two ways depending of which of two systems or pathways apply two systems or pathways apply
Intrinsic SystemIntrinsic System This is initiated by liquid blood making contact with a foreign This is initiated by liquid blood making contact with a foreign
surface ie something that is not part of the body surface ie something that is not part of the body Extrinsic SystemExtrinsic System
This is initiated by liquid blood making contact with damaged This is initiated by liquid blood making contact with damaged tissuetissue
Both the intrinsic and the extrinsic systems involve interactions Both the intrinsic and the extrinsic systems involve interactions between between coagulation factorscoagulation factors
2 2 ProthrombinProthrombin converted into the enzyme converted into the enzyme ThrombinThrombinProthrombinase (formed in stage 1) converts prothrombin which is Prothrombinase (formed in stage 1) converts prothrombin which is a plasma protein that is formed in the liver into the enzyme a plasma protein that is formed in the liver into the enzyme thrombinthrombin
3 3 FibrinogenFibrinogen (soluble) converted to (soluble) converted to FibrinFibrin (insoluble) (insoluble)In turn thrombin converts fibrinogen into fibrin Fibrin is insoluble In turn thrombin converts fibrinogen into fibrin Fibrin is insoluble and forms the threads that bind the clotand forms the threads that bind the clot
BLOOD COAGULATION
A sequence of reactions that are present in an inactive state in bloodKey is the conversion of the plasma protein fibrinogen to fibrin Intrinsic pathway Extrinsic pathway(activated by exposure of (activated by substances blood to damaged tissue) released from damaged tissue)
Active factors X and V
Prothrombin Thrombin
Fibrinogen Fibrin Fibrin mesh
inhibited by warfarin
inhibited by heparin
Rationale for anticoagulant Rationale for anticoagulant therapytherapy
PHARMACOLOGICAL PHARMACOLOGICAL AGENTSAGENTS
Pharmacologic AgentsPharmacologic Agents
AnticoagulantsAnticoagulants
Fibrinolytics (Agents for pharmacological Fibrinolytics (Agents for pharmacological recanalization)recanalization)
Anti platelet drugsAnti platelet drugs
Thrombin inhibitorThrombin inhibitor
ANTICOAGULANTSANTICOAGULANTS
Heparin and Low Molecular Weight Heparins Heparin and Low Molecular Weight Heparins ((eg enoxaparin dalteparin)eg enoxaparin dalteparin)
Oral anticoagulantsOral anticoagulants Coumarin Derivatves Coumarin Derivatves eg Warfarin eg Warfarin
AcenocoumarolAcenocoumarol Indandione Derivatves Indandione Derivatves eg Phenindione eg Phenindione
AnisindioneAnisindione
ThrombolyticsThrombolytics
Plasminogen activators
Fibrinolytics
Anti Platelet DrugsAnti Platelet DrugsDrug Mechanism UsesDrug Mechanism UsesAspirinAspirin Permanently inhibits Permanently inhibits
COX-1 and COX-2COX-1 and COX-2CADCAD
Stroke-TIAsStroke-TIAs
NSAIDsNSAIDs Reversibly inhibits Reversibly inhibits COX-1COX-1
LimitedLimited
DipyridamoleDipyridamole Inhibits PDE Inhibits PDE increases cAMPincreases cAMP
TIAsTIAs
ThenopyridinesThenopyridines
(Ticlopidine(Ticlopidine
Clopidegrel)Clopidegrel)
Inhibits ADP Inhibits ADP
PlatAg PlatAg
TIAsStrokeTIAsStroke
CAD PVDCAD PVD
Abciximab (ReoPro)Abciximab (ReoPro)
Eptifibatide Eptifibatide (Integrilin)(Integrilin)
TirofibaTirofibann
GP IIBIIIA InhibitorsGP IIBIIIA Inhibitors
Stroke- TIAs Stroke- TIAs
Maintainance of patency Maintainance of patency of vascular of vascular grafts catheters shunts bypassesgrafts catheters shunts bypasses
Arterial thromboembolic diseaseArterial thromboembolic diseasebull Transient ischemic attacksTransient ischemic attacksbull Stroke in evolutionStroke in evolution
Ischemic events occurs in Ischemic events occurs in 1313 of of conventional neuroangiographic conventional neuroangiographic procedures without Endovascular surgeryprocedures without Endovascular surgery
Indications for Antithrombotic Therapy in Indications for Antithrombotic Therapy in Diagnostics and Interventional ProceduresDiagnostics and Interventional Procedures
WHY TO MONITOR ANTICOAGULANT THERAPYWHY TO MONITOR ANTICOAGULANT THERAPY
Narrow therapeutic rangeNarrow therapeutic range
Can increase risk of bleedingCan increase risk of bleeding
Coagulation TestingCoagulation Testing
Monitoring therapyMonitoring therapy
Intrinsic Pathway
Extrinsic Pathway
Common Pathway
CLOT
Heparin Coumadin
Monitor with
ACT aPTT
Monitor with PTINR
Thrombolytics
Monitor with TT Fibrinogen
Monitoring of Monitoring of Anti platelet drugsAnti platelet drugs
Bleeding timeBleeding time
Optical aggregometryOptical aggregometry
Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay
HeparinHeparin
Heterogeneous 3000-30000 dalton in Heterogeneous 3000-30000 dalton in molecular weight molecular weight
Average=15000 d (~45monosaccharide Average=15000 d (~45monosaccharide chains)chains)
About About 13 of dose binds to AT III and forms 13 of dose binds to AT III and forms the AT IIIHeparinClotting Factor Complexthe AT IIIHeparinClotting Factor Complex
Complex binds to clotting factors of the Complex binds to clotting factors of the intrinsic and common pathway (Xa IIa IXa intrinsic and common pathway (Xa IIa IXa XIa XIIa XIIIa) and inactivates themXIa XIIa XIIIa) and inactivates them
Anticoagulant of choice in pregnancy (not Anticoagulant of choice in pregnancy (not crosses placenta)crosses placenta)
Heparin and Low molecular weight heparinsHeparin and Low molecular weight heparins
Structure and sequence
O
OH
OH
O
COO
O
O
CH2OH
NHSO3
OH
_
_
O
O
CH2OSO3
NHSO3
OH
_
_
O
OH
OH
O
COOO
O
CH2OSO3
NHSO3
OH
_
_
O
OSO3
OHO
COOO
O
CH2OSO3
NHCOCH3
OH
_
_ _
_
_
O
OH
OH
O
COO
1
23
4
5
6
-D-glucosamine -L-iduronic acid -D-glucuronic acid
O
O
CH2OH
NH2
OH 12
3
4
5
6
O
OH
OHO
COO_
1
23
4
5
6
polymeric structure of heparin
Anticoagulant Properties of Anticoagulant Properties of HeparinHeparin
11 Inhibits the thrombin-mediated conversion of Inhibits the thrombin-mediated conversion of fibrinogen to fibrinfibrinogen to fibrin
22 Inhibits the aggregation of platelets by thrombin Inhibits the aggregation of platelets by thrombin (prolongs bleeding time)(prolongs bleeding time)
33 Inhibits activation of fibrin stabilizing enzymeInhibits activation of fibrin stabilizing enzyme
44 Inhibits activated factors XII XI IX X and IIInhibits activated factors XII XI IX X and II All available forms of heparin must be All available forms of heparin must be
administered administered parenterally since they are parenterally since they are highly charged and rapidlyhighly charged and rapidly hydrolyzed in the hydrolyzed in the GI tractGI tract
Heparin antagonist Protamine sulfate (Heparin antagonist Protamine sulfate (10mg for 10mg for 1000 unit of heparin)1000 unit of heparin)
Monitoring of heparin Monitoring of heparin
Subcutenous Subcutenous no monitoring requiredno monitoring required Intravenous Intravenous
Partial thromboplastin time (PTT normal value Partial thromboplastin time (PTT normal value ~30sec) ~30sec)
Activated clotting time ( ACT normal value ~90-Activated clotting time ( ACT normal value ~90-120sec)120sec)
Daily or more frequent if PTT ACT variesDaily or more frequent if PTT ACT varies
Mechanism Mechanism ndash measures intrinsic pathwayndash measures intrinsic pathway Therapeutic goal Therapeutic goal 2-25 times normal control value 2-25 times normal control value
ACT or aPTTACT or aPTT
Determine when to pull the femoral sheath Determine when to pull the femoral sheath Premature sheath pull can lead to bleedingPremature sheath pull can lead to bleeding Delayed removal can increase time in ICUDelayed removal can increase time in ICU Target set Target set at each siteat each site
ACT targets range from 150 ndash 220 ACT targets range from 150 ndash 220 secondsseconds
aPTT targets range from 40 ndash 70 seconds aPTT targets range from 40 ndash 70 seconds
During neuroangiography-During neuroangiography- Recommended therapeutic range of heparin in Recommended therapeutic range of heparin in
plasma is 02-08 uml ( corresponding to aPTT plasma is 02-08 uml ( corresponding to aPTT ACT values 15-25 times the baseline values)ACT values 15-25 times the baseline values)
Dose In diagnostic angiography bolus dose of Dose In diagnostic angiography bolus dose of 2500 iu is used followed by 1000 iu hour2500 iu is used followed by 1000 iu hour
Bolus dose is Bolus dose is 60 ukg to maintain the therapeutic 60 ukg to maintain the therapeutic range range If procedure continues for more than 75 If procedure continues for more than 75 minutes additional dose is required ( half of the minutes additional dose is required ( half of the initial dose for another 75 minutes) initial dose for another 75 minutes)
(AJNR 199415 51-54)
Mechanisms of HIT( Mechanisms of HIT( Heparin Heparin induced Thrombocytopeniainduced Thrombocytopenia))
Type 1Type 1 Fall in platelet count occurs within the first two Fall in platelet count occurs within the first two
days after heparin initiation often returns to days after heparin initiation often returns to normal with continued heparin administration normal with continued heparin administration and is of no clinical consequence and is of no clinical consequence
The mechanism of the thrombocytopenia is non-The mechanism of the thrombocytopenia is non-immune and appears to be due to a direct effect of immune and appears to be due to a direct effect of heparin on platelet activationheparin on platelet activation
Type 2Type 2 Approximately 03 to 3 percent of patients Approximately 03 to 3 percent of patients
receiving heparin develop an immune receiving heparin develop an immune thrombocytopenia mediated by antibodies to a thrombocytopenia mediated by antibodies to a heparin-platelet factor 4 complex heparin-platelet factor 4 complex
(AJNR 28155-158 2007)
Treatment of heparin-induced Treatment of heparin-induced thrombocytopeniathrombocytopenia
When HIT is diagnosed it is important to When HIT is diagnosed it is important to stop heparin mainly in type 2 and to avoid stop heparin mainly in type 2 and to avoid the use of LMWH the use of LMWH
Because of the increased risk of thrombosis Because of the increased risk of thrombosis however continuation of an anticoagulant however continuation of an anticoagulant must be considered must be considered
The drugs currently approved for the The drugs currently approved for the treatment of HIT in the United States are treatment of HIT in the United States are direct thrombin inhibitors argatroban and direct thrombin inhibitors argatroban and lepirudinlepirudin
WARFARIN MECHANISM OF ACTIONWARFARIN MECHANISM OF ACTION
Inactive factors II VII IX and X
Proteins S and C
Active factors II VII IX and X
Proteins S and C
Vitamin K epoxide
Vitamin K reduced
WA
RF
AR
IN
Prevents the reduction of vitamin K which is essential for Prevents the reduction of vitamin K which is essential for activation of certain factorsactivation of certain factors
Has no effect on previously formed thrombusHas no effect on previously formed thrombus
Antagonist is Vit KAntagonist is Vit K
OPTIMIZING WARFARIN THERAPYOPTIMIZING WARFARIN THERAPY
Use of large loading dose may lead to hemorrhage and Use of large loading dose may lead to hemorrhage and other complicationsother complications
Initial dose 2-5 mg once dailyInitial dose 2-5 mg once daily Maintenance dose 2-10 mg once dailyMaintenance dose 2-10 mg once daily If Immediate anticoagulation is requiredIf Immediate anticoagulation is required Heparin IS Heparin IS
started along with loading dose of warfarin 10 mg started along with loading dose of warfarin 10 mg Heparin is usually discontinued after 4-5 days Heparin is usually discontinued after 4-5 days Before Before discontinuing INR should be in therapeutic range for 2 discontinuing INR should be in therapeutic range for 2 consecutive daysconsecutive days
Daily monitoring of INR until INR is in therapeutic Daily monitoring of INR until INR is in therapeutic range then 3 times weekly for 1-2 weeks then less often range then 3 times weekly for 1-2 weeks then less often (every 4 to 6 weeks)(every 4 to 6 weeks)
OPTIMAL THERAPEUTIC RANGEOPTIMAL THERAPEUTIC RANGE
IndicationIndication INRINR
Prophylaxis of venous Prophylaxis of venous thromboembolismthromboembolism
20-3020-30
Treatment of venous Treatment of venous thromboembolismthromboembolism
20-3020-30
Atrial fibrillationAtrial fibrillation 20-3020-30
Mitral valve stenosisMitral valve stenosis 20-3020-30
Heart valve replacementHeart valve replacement
Bioprosthetic valveBioprosthetic valve
Mechanical valveMechanical valve
20-3020-30
25-3525-35
Myocardial infarctionMyocardial infarction 20-3020-30
25-35 25-35 (high risk patients)(high risk patients)
FACTORS INFLUENCING DOSE RESPONSEFACTORS INFLUENCING DOSE RESPONSE
Poor patient compliancePoor patient compliance Concomitant medicationsConcomitant medications Levels of dietary vitamin KLevels of dietary vitamin K Alcohol Inaccurate lab testingAlcohol Inaccurate lab testing Inaccurate lab testingInaccurate lab testing Hepatic dysfunctionHepatic dysfunction FeverFever
Contraindication for WarfarinContraindication for Warfarin
Hypersensitivity to warfarinHypersensitivity to warfarin Hemorrhagic tendencyHemorrhagic tendency Condition with risk of hemorrhageCondition with risk of hemorrhage Inadequate laboratory techniquesInadequate laboratory techniques Protein C amp S deficiencyProtein C amp S deficiency Vitamin K deficiencyVitamin K deficiency
SIDE EFFECTSSIDE EFFECTS
Hemorrhage Hemorrhage Skin necrosisSkin necrosis Purple toe syndromePurple toe syndrome Microembolization Microembolization TeratogenecityTeratogenecity Agranulocytosis leukopenia Agranulocytosis leukopenia Diarrhoeanausea anorexiaDiarrhoeanausea anorexia
MONITORING OF WARFARIN THERAPYMONITORING OF WARFARIN THERAPY
Prothrombin timeProthrombin time PT ratioPT ratio INR (International Normalized Ratio)INR (International Normalized Ratio)
PROTHROMBIN TIME (PT)PROTHROMBIN TIME (PT)
Time required for blood to coagulate Time required for blood to coagulate is called PT ( normal value ~10sec)is called PT ( normal value ~10sec)
Performed by adding a mixture of Performed by adding a mixture of calcium and thromboplastin to calcium and thromboplastin to citrated plasmacitrated plasma
As a control a normal blood sample is As a control a normal blood sample is tested continuouslytested continuously
PT ratio (PTR) = PT ratio (PTR) = Patientrsquos PTPatientrsquos PT Control PTControl PT
PROBLEMS WITH PTPTRPROBLEMS WITH PTPTR
Thromboplastins are extracts from Thromboplastins are extracts from brain lung or placenta of animalsbrain lung or placenta of animals
Thromboplastins from various Thromboplastins from various manufacturers differ in their manufacturers differ in their sensitivity to prolong PTsensitivity to prolong PT
May result in false control of May result in false control of anticoagulant therapyanticoagulant therapy
INTERNATIONAL NORMALISED RATIO (INR)INTERNATIONAL NORMALISED RATIO (INR)
International Normalized Ratio (INR) International Normalized Ratio (INR) a PT test with a a PT test with a formula based ratio to normalize the often variable source formula based ratio to normalize the often variable source of tissue factor (human rabbit recombinant)of tissue factor (human rabbit recombinant)
INR = [PTINR = [PTptpt] ] ISIISI
[PT[PTRefRef]]
PTPTpt pt ndash prothrombin time of patientndash prothrombin time of patient
PTPTRef Ref ndash prothrombin time of normal pooled samplendash prothrombin time of normal pooled sample
ISI ndash International Sensitivity IndexISI ndash International Sensitivity Index
Warfarin is given orally and titrated to achieve an INR of Warfarin is given orally and titrated to achieve an INR of typically 20 ndash 30typically 20 ndash 30
Heparin versus WarfarinHeparin versus Warfarin
Drug ActionMechan-ism
Moni-toring
Effective
HeparinDirect
Inhibition ofThrombin
ATIIIcofactor
APTTACT
Immediate
WarfarinDecreasesProductionof factors
Vitamin K PTDelay
3-5 days
INR
Recanalization or Antegrade Recanalization or Antegrade Reperfusion StrategiesReperfusion Strategies
Recanalization strategies focus on removing Recanalization strategies focus on removing andor dissolving the occlusive thrombus to re-andor dissolving the occlusive thrombus to re-establish antegrade flow Strategies may be establish antegrade flow Strategies may be classified into 7 different categories on the classified into 7 different categories on the basis of their primary mechanism of action basis of their primary mechanism of action 1) 1) IV andor intraarterial thrombolysis (IAT) IV andor intraarterial thrombolysis (IAT) 2) endovascular thrombectomy2) endovascular thrombectomy3) endovascular thromboaspiration 3) endovascular thromboaspiration 4) endovascular mechanical thrombus disruption or 4) endovascular mechanical thrombus disruption or
thromborrhexisthromborrhexis5) 5) transcranial or endovascular augmented transcranial or endovascular augmented
fibrinolysis fibrinolysis 6) endovascular thrombus entrapment and 6) endovascular thrombus entrapment and 7) temporary endovascular bypass7) temporary endovascular bypass
IAT in Acute Ischemic StrokeIAT in Acute Ischemic Stroke
IAT advantages over IV thrombolysisIAT advantages over IV thrombolysis Coaxial microcatheter techniques the occluded intracranial Coaxial microcatheter techniques the occluded intracranial
vessel is directly accessible and the fibrinolytic agent can be vessel is directly accessible and the fibrinolytic agent can be infused directly into the thrombusinfused directly into the thrombus
This permits a smaller dose of fibrinolytic agent to reach a This permits a smaller dose of fibrinolytic agent to reach a higher local concentration than that reached by systemic higher local concentration than that reached by systemic infusioninfusion
Allows more complete recanalization with lower total doses of Allows more complete recanalization with lower total doses of thrombolytic thrombolytic
With the smaller dose complications from systemic fibrinolytic With the smaller dose complications from systemic fibrinolytic effects including intracranial hemorrhage (ICH) can effects including intracranial hemorrhage (ICH) can theoretically be reduced theoretically be reduced
Treatment window for endovascular techniques can be Treatment window for endovascular techniques can be extended beyond the typical IV window of 3 hours extended beyond the typical IV window of 3 hours
IA techniques have led to higher recanalization rates than IV IA techniques have led to higher recanalization rates than IV thrombolysisthrombolysis
Major disadvantagesMajor disadvantages Relative complexity of the procedure the level Relative complexity of the procedure the level
of required technical expertise and its of required technical expertise and its relatively low availability relatively low availability
Delays in initiating treatmentDelays in initiating treatment InvasiveInvasive
ThrombolyticsThrombolytics
Plasminogen activators
Fibrinolytics
1 Plasminogen Activators 1 Plasminogen Activators drugs act by converting the inactive proenzyme drugs act by converting the inactive proenzyme plasminogen into the active enzyme plasmin Plasmin plasminogen into the active enzyme plasmin Plasmin digests fibrinogen fibrin monomers and cross-linked digests fibrinogen fibrin monomers and cross-linked fibrin (as found in a thrombus) into fibrin degradation fibrin (as found in a thrombus) into fibrin degradation productsproducts
First-Generation Agents First-Generation Agents StreptokinaseStreptokinase a protein derived from group C a protein derived from group C
szlig-hemolytic streptococci has a half-life of 16ndashszlig-hemolytic streptococci has a half-life of 16ndash90 minutes and low fibrin specificity This drug 90 minutes and low fibrin specificity This drug proved to have a very narrow therapeutic proved to have a very narrow therapeutic window and significant rates of ICH and window and significant rates of ICH and systemic hemorrhage18systemic hemorrhage18
UrokinaseUrokinase is a serine protease with a plasma is a serine protease with a plasma half life of 14 minutes and low fibrin specificity half life of 14 minutes and low fibrin specificity
The urokinase dose used in cerebral IAT has The urokinase dose used in cerebral IAT has ranged from 002 to 2 X106unitsranged from 002 to 2 X106units
Second-Generation Agents Second-Generation Agents Alteplase (rtPA) Alteplase (rtPA)
is a serine is a serine protease with a plasma half-life of 35 protease with a plasma half-life of 35 minutes and a high degree of fibrin affinity and minutes and a high degree of fibrin affinity and specificity specificity
Dose used in cerebral IAT has ranged between 20 Dose used in cerebral IAT has ranged between 20 and 60 mgand 60 mg
Disadvantages of alteplase include its relatively short Disadvantages of alteplase include its relatively short halflife and limited penetration into the clot matrix halflife and limited penetration into the clot matrix because of strong binding with surface fibrin which because of strong binding with surface fibrin which could delay recanalization and increase the risk of could delay recanalization and increase the risk of recurrent occlusion recurrent occlusion
Prourokinase (r-prourokinase) Prourokinase (r-prourokinase) is the proenzyme precursor of urokinase is the proenzyme precursor of urokinase T12 of 7 minutes and high fibrin specificity T12 of 7 minutes and high fibrin specificity
Third-Generation AgentsThird-Generation Agents
ReteplaseReteplase is a structurally modified is a structurally modified form of alteplase form of alteplase
with a longer half-life (15ndash18 minutes) In with a longer half-life (15ndash18 minutes) In addition it does not bind as highly to fibrin addition it does not bind as highly to fibrin unbound reteplase can thus theoretically better unbound reteplase can thus theoretically better penetrate the clot and potentially penetrate the clot and potentially improve in improve in vivo fibrinolytic activity vivo fibrinolytic activity
TenecteplaseTenecteplase is another modified form of rtPA with a longer is another modified form of rtPA with a longer
half-life (17 minutes)half-life (17 minutes) greater fibrin specificity and greater greater fibrin specificity and greater
resistance to plasminogen activator inhibitor-1 resistance to plasminogen activator inhibitor-1 IV tenecteplase in acute ischemic stroke IV tenecteplase in acute ischemic stroke
suggest that the drug is safe and promisingsuggest that the drug is safe and promising
Newer plasminogen activatorNewer plasminogen activator
DesmoteplaseDesmoteplase is a genetically engineered is a genetically engineered version of the clot-dissolving factor version of the clot-dissolving factor
found in the saliva found in the saliva of the vampire bat Desmodus rotundusof the vampire bat Desmodus rotundus moremore potent and more selective for fibrin-bound potent and more selective for fibrin-bound
plasminogen than any other known plasminogen plasminogen than any other known plasminogen activatoractivator
Unlike tissue plasminogen activator (tPA) desmoteplase Unlike tissue plasminogen activator (tPA) desmoteplase is not activated by fibrinogen or -amyloid proteins is not activated by fibrinogen or -amyloid proteins factors that may exacerbate the risk for ICH factors that may exacerbate the risk for ICH
The effect of IV administration of desmoteplase 3ndash9 The effect of IV administration of desmoteplase 3ndash9 hours after symptom onset in patients with stroke who hours after symptom onset in patients with stroke who present with mismatch on MR imaging or CT perfusion present with mismatch on MR imaging or CT perfusion
3 DefibrinogenatingFibrinogenolytic 3 DefibrinogenatingFibrinogenolytic Agents Agents
AncrodAncrod(Viprinex)(Viprinex) is is the purified fraction of the Malayan pit viper venomthe purified fraction of the Malayan pit viper venom It acts by directly cleaving and inactivating fibrinogen It acts by directly cleaving and inactivating fibrinogen
and thus indirectly promoting anticoagulation and thus indirectly promoting anticoagulation The reduction in the blood levels of fibrinogen also The reduction in the blood levels of fibrinogen also
leads to a reduced blood viscosity which may improve leads to a reduced blood viscosity which may improve blood flow to the affected areas of the brain blood flow to the affected areas of the brain
In the Stroke Treatment with Ancrod Trial 500 In the Stroke Treatment with Ancrod Trial 500 patients with stroke presenting within 3 hours of patients with stroke presenting within 3 hours of symptom onset were randomized to receive ancrod (symptom onset were randomized to receive ancrod (n n 248) or a placebo (n 252) Good outcome (Barthel 248) or a placebo (n 252) Good outcome (Barthel Index 95ndash100 at 3 months) was achieved in 4221 Index 95ndash100 at 3 months) was achieved in 4221 and 344 of the patients respectively and 344 of the patients respectively
2 Direct Fibrinolytics2 Direct Fibrinolytics
Microplasmin (Microplasmin (ThromboGenics Heverlee Belgium)ThromboGenics Heverlee Belgium) is a truncated form of plasmin that is more resistant to the effects is a truncated form of plasmin that is more resistant to the effects
of antiplasmin of antiplasmin microplasmin can be used upto 4ndash12 hours after stroke onset microplasmin can be used upto 4ndash12 hours after stroke onset There was no evidence of increased bleeding risk with There was no evidence of increased bleeding risk with
microplasminmicroplasmin
Alfimeprase (Nuvelo San Carlos Calif)Alfimeprase (Nuvelo San Carlos Calif) is a recombinant truncated form of fibrolase a fibrinolytic zinc metalloproteinase is a recombinant truncated form of fibrolase a fibrinolytic zinc metalloproteinase
isolated from the venom of the southern copperhead snake isolated from the venom of the southern copperhead snake It degrades fibrin directly and achieves thrombolysis independent It degrades fibrin directly and achieves thrombolysis independent
of plasmin formationof plasmin formation its thrombolytic activity appears to be localized to the site of its thrombolytic activity appears to be localized to the site of
delivery These properties should theoretically result in faster delivery These properties should theoretically result in faster recanalization and lower hemorrhagic conversion riskrecanalization and lower hemorrhagic conversion risk
Anti-fibrinolyticsAnti-fibrinolytics
to limit fibrinolytic activityto limit fibrinolytic activity -aminocaproic acid (EACA) -aminocaproic acid (EACA) competitively inhibitscompetitively inhibits plasminogen and plasminogen activators from plasminogen and plasminogen activators from
binding to fibrinbinding to fibrin
alpha2-antiplasminalpha2-antiplasmin a serine protease inhibitor that a serine protease inhibitor that neutralizes any free circulating plasminneutralizes any free circulating plasmin
Plasminogen activator inhibitor-1Plasminogen activator inhibitor-1 a serine protease a serine protease inhibitor that inhibits tissue-type plasminogen inhibitor that inhibits tissue-type plasminogen activatoractivator
Glycoprotein (GP) IIbIIIa antagonistsGlycoprotein (GP) IIbIIIa antagonists
such as ReoPro (abciximab) Integrilin such as ReoPro (abciximab) Integrilin (eptifibatide) or Aggrastat (tirofiban) in (eptifibatide) or Aggrastat (tirofiban) in ischemic stroke remains investigational ischemic stroke remains investigational Deshmukh et al38 reported 21 patients with Deshmukh et al38 reported 21 patients with large-vessel occlusion refractory to IAT with large-vessel occlusion refractory to IAT with rtPA who were treated with IV andor IA rtPA who were treated with IV andor IA abciximab eptifibatide or tirofiban abciximab eptifibatide or tirofiban
IA Mechanical Approaches in Acute Ischemic Stroke IA Mechanical Approaches in Acute Ischemic Stroke Mechanical strategies have several advantagesMechanical strategies have several advantages First they lessen and may even preclude the use of chemical First they lessen and may even preclude the use of chemical
thrombolytics in this manner very likely reducing the risk of ICHthrombolytics in this manner very likely reducing the risk of ICH Second by avoiding the use of chemical thrombolytics it is Second by avoiding the use of chemical thrombolytics it is
possible to extend the treatment window beyond the limit of 6ndash8 possible to extend the treatment window beyond the limit of 6ndash8 hours hours
Third mechanically fragmenting a clot increases the surface area Third mechanically fragmenting a clot increases the surface area accessible to fibrinolytic agents and allows inflow of fresh accessible to fibrinolytic agents and allows inflow of fresh plasminogen which in turn may increase the speed of plasminogen which in turn may increase the speed of thrombolysis thrombolysis
Finally clot-retrieval devices may provide faster recanalization Finally clot-retrieval devices may provide faster recanalization
The disadvantages of the mechanical The disadvantages of the mechanical approaches approaches technical difficulty of navigating mechanical technical difficulty of navigating mechanical
devices into the intracranial circulation excessive devices into the intracranial circulation excessive trauma to the vasculature (potentially leading to trauma to the vasculature (potentially leading to vasospasm vessel dissection perforation or vasospasm vessel dissection perforation or rupture) rupture)
fragmented thrombus causing distal embolization fragmented thrombus causing distal embolization into previously unaffected territories into previously unaffected territories
Nevertheless the advantages of mechanical stroke Nevertheless the advantages of mechanical stroke therapy appear to significantly outweigh its therapy appear to significantly outweigh its disadvantages and risksdisadvantages and risks
Contraindications to Thrombolytic Contraindications to Thrombolytic agents agents
Recent thoracic abdominal or Recent thoracic abdominal or intracranial surgeryintracranial surgery
Recent haemorrhagic CVA Head injury Recent haemorrhagic CVA Head injury or neoplasmor neoplasm
Bleeding ulcerBleeding ulcer Anticipated invasive procedures (arterial Anticipated invasive procedures (arterial
punctures biopsies)punctures biopsies) Concurrent hemostatic dysfunctionConcurrent hemostatic dysfunction
Monitoring of thrombolytic Monitoring of thrombolytic therapytherapy
Thrombin time Measures the availability of functional
fibrinogen Normal thrombin time is 10-14 sec Prolonged when fibrinogen level is below
75-100 mgdl
Half Life of ThrombolyticsHalf Life of ThrombolyticsAgent Administration Half Life
Streptokinase IA 60-80min
Urokinase IAIV 9-12min
rTPA IAIV 6min
Abciximab(Reopro) IAIV 12hour
Aspirin POIV 15-20min
Heparin IVSC 60min
Coumadin PO 15-25 days
Anti Platelet DrugsAnti Platelet DrugsDrug Drug Mechanism Mechanism UsesUsesAspirinAspirin Permanently inhibits Permanently inhibits
COX-1 and COX-2COX-1 and COX-2CADCAD
Stroke-TIAsStroke-TIAs
NSAIDsNSAIDs Reversibly inhibits Reversibly inhibits COX-1COX-1
LimitedLimited
DipyridamoleDipyridamole Inhibits PDE increases Inhibits PDE increases cAMPcAMP
TIAsTIAs
ThenopyridinesThenopyridines
(Ticlopidine(Ticlopidine
ClopidrgrelClopidrgrel))
Inhibits ADP Inhibits ADP
PlatAg PlatAg
TIAsStrokeTIAsStroke
CAD PVDCAD PVD
Abciximab (ReoPro)Abciximab (ReoPro)
Eptifibatide (Integrilin)Eptifibatide (Integrilin)
TirofibanTirofiban
GP IIBIIIA InhibitorsGP IIBIIIA Inhibitors
Stroke- TIAs Stroke- TIAs
MonitoringMonitoring
Bleeding timeBleeding time
Optical aggregometryOptical aggregometry
Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay
Bleeding timeBleeding time
Requires a skin incision (usually made on the ear lobe or Requires a skin incision (usually made on the ear lobe or forearm offorearm of
a depth that results in disruption of capillary loops and a depth that results in disruption of capillary loops and small vessels)small vessels)
AdvantagesAdvantages Universally availableUniversally available Relatively simple techniquesRelatively simple techniques Can be performed bedsideCan be performed bedside
DisadvantagesDisadvantages Insensitive inaccurate non-specific techniqueInsensitive inaccurate non-specific technique
Poorly reproducible (as depends on multiple variables)Poorly reproducible (as depends on multiple variables)
Optical aggregometryOptical aggregometry
Gold standard assay for platelet functionGold standard assay for platelet function Agonist induced aggregation is measuredAgonist induced aggregation is measured Different agonist are available for different Different agonist are available for different
agentsagents However require unique expertise and are not However require unique expertise and are not
universally availableuniversally available Aspirin measured with ADP or AA(gt70 Aspirin measured with ADP or AA(gt70
aggregation so resistance)aggregation so resistance) Clopidogrel( ADP gt 90 aggregation means Clopidogrel( ADP gt 90 aggregation means
resistance) resistance)
Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay
Can be performed bed sideCan be performed bed side Different assay devices with different Different assay devices with different
agonist are used for each of different agonist are used for each of different antiplatelet agents antiplatelet agents
For Aspirin AA is used (result is reported as aspirin For Aspirin AA is used (result is reported as aspirin reaction units [ARU] ARUgt 550 indicates non-reaction units [ARU] ARUgt 550 indicates non-responsiveness)responsiveness)
Verify IIbIIIa assay device uses TRAP as agonist for Verify IIbIIIa assay device uses TRAP as agonist for Abciximab and TirofibanAbciximab and Tirofiban
Practical Applications Practical Applications related to specific related to specific
Neurovascular Neurovascular interventionsinterventions
Acute ischemic StrokeAcute ischemic Stroke When an artery occludes neurons are affected When an artery occludes neurons are affected
differently depending upon the amount of residual blood differently depending upon the amount of residual blood flowflow
Normal cerebral blood flow is greater than 50 mL100 Normal cerebral blood flow is greater than 50 mL100 mgminmgmin
Once blood flow decreases to less than 20 mL100 Once blood flow decreases to less than 20 mL100 mgmin infarction occursmgmin infarction occurs
If blood flow decreases to less than 10 mL100 mgmin If blood flow decreases to less than 10 mL100 mgmin irreversible neuronal death occurs rapidly irreversible neuronal death occurs rapidly
Blood flow between 11 and 20 mL100 mgmin is thought Blood flow between 11 and 20 mL100 mgmin is thought to represent the ischemic penumbra an area where the to represent the ischemic penumbra an area where the cells are functionally silent because of ischemia but are cells are functionally silent because of ischemia but are still able to recover if blood flow is restored still able to recover if blood flow is restored
Many acute stroke therapies are targeted toward Many acute stroke therapies are targeted toward restoring flow or function to the ischemic penumbrarestoring flow or function to the ischemic penumbra
Therapeutic window in Therapeutic window in management of acute Ischemic management of acute Ischemic
StrokeStrokeThe early diagnosis of ischemic stroke is critical to the The early diagnosis of ischemic stroke is critical to the
with only a narrow therapeutic window in the first few with only a narrow therapeutic window in the first few hours following stroke ictushours following stroke ictus
Diagnosis in the first 3 hours postictus provides the Diagnosis in the first 3 hours postictus provides the opportunity for intravenous or intraarterial thrombolysis opportunity for intravenous or intraarterial thrombolysis and intra-arterial clot mechanical treatment which and intra-arterial clot mechanical treatment which improve the outcome improve the outcome
Diagnosis in the time period between 3 and 6 hours Diagnosis in the time period between 3 and 6 hours provides an opportunity for intra-arterial thrombolysis provides an opportunity for intra-arterial thrombolysis and mechanical treatment and mechanical treatment
Involvement of the posterior circulation especially the Involvement of the posterior circulation especially the basilar artery is treated by some regardless of time of basilar artery is treated by some regardless of time of onset or up until 12 to 24 hours in some practices This is onset or up until 12 to 24 hours in some practices This is related to the potentially high mortality and morbidity related to the potentially high mortality and morbidity associated with basilar artery thrombosisassociated with basilar artery thrombosis
Infarct evaluation on angiographyInfarct evaluation on angiography(CT angiography and catheter (CT angiography and catheter
angiography)angiography)CTA is an excellent first-line examination for CTA is an excellent first-line examination for
evaluation of the head and neck arteries evaluation of the head and neck arteries In comparison with catheter angiography In comparison with catheter angiography
what it gives up in resolution and dynamic what it gives up in resolution and dynamic properties it makes up for with rapid properties it makes up for with rapid acquisition of a 3-D dataset and the potential acquisition of a 3-D dataset and the potential for assessment of whole-brain perfusion and for assessment of whole-brain perfusion and better parenchymal evaluationbetter parenchymal evaluation
Moreover CTA illustrates not only arterial Moreover CTA illustrates not only arterial stenosis or occlusion but also the vessel wall stenosis or occlusion but also the vessel wall This factor is most important for evaluation of This factor is most important for evaluation of intramural dissection and thrombosed intramural dissection and thrombosed aneurysms which may both complicate aneurysms which may both complicate evaluation of stroke patientsevaluation of stroke patients
Early angiographic signs of strokes Early angiographic signs of strokes both CTA both CTA and DSA and DSA
Vessel occlusion or cutoff related to Vessel occlusion or cutoff related to thromboembolithromboemboli
aneurysms aneurysms arterial dissection arterial dissection Meniscus or flattened shape to clot Meniscus or flattened shape to clot
(recent) versus reverse meniscus (older)(recent) versus reverse meniscus (older) tram track (nonocclusive or recanalized tram track (nonocclusive or recanalized
clot) clot) delayed (antegrade) flow (manifest as delayed (antegrade) flow (manifest as
decreased whole-brain perfusion on CTA)decreased whole-brain perfusion on CTA) retrograde collateral flowretrograde collateral flow
Non-occlusive left MCA thrombus on 3-D imaging performed from CTA source data and was confirmed at catheter angiography
Therapy to be started within a 6-hr Therapy to be started within a 6-hr time to treatment (TTT) window time to treatment (TTT) window (while in case of IV thrombolysis (while in case of IV thrombolysis therapy to be started with in 3hrs)therapy to be started with in 3hrs)
Exclusion criteria Exclusion criteria Rapidly improving neurologic deficit or Rapidly improving neurologic deficit or Sustained blood pressure of gt180100 Sustained blood pressure of gt180100 Hemorrhage is detected on CTHemorrhage is detected on CT Infarct involving gt more than 13 rd Infarct involving gt more than 13 rd
territory of MCAterritory of MCA MRADWI-Perfusion mismatchlt 20MRADWI-Perfusion mismatchlt 20 Definite hypodensity on CTDefinite hypodensity on CT
Intra-arterial Thrombolysis
Fibrinolytics + AntiplateletsFibrinolytics + Antiplatelets
PlasminogenPlasminogen activators through fibrinolysis exposes activators through fibrinolysis exposes free thrombin and paradoxically stimulatesfree thrombin and paradoxically stimulates platelet platelet aggregation which leads to formation of aaggregation which leads to formation of a platelet platelet thrombus (white clot) thrombus (white clot)
This new thrombus is relatively resistant to This new thrombus is relatively resistant to fibrinolyticsfibrinolytics
So new regimen in case of acute stroke isSo new regimen in case of acute stroke is fibrinolytics + antiplatelet drugsfibrinolytics + antiplatelet drugs
rtPA + IIbIIIa inhibitors( tirofiban rtPA + IIbIIIa inhibitors( tirofiban abciximab) orabciximab) or
Urokinase + IIbIIIa Urokinase + IIbIIIa inhibitors( tirofiban abciximab)inhibitors( tirofiban abciximab)
Intra-arterial Thrombolysis Tirofiban (04 microgkgmin bolus for 3 min followed by Tirofiban (04 microgkgmin bolus for 3 min followed by
0125 ugkgmin)0125 ugkgmin)
++
Heparin (2000ndash3000 IU bolus followed by Heparin (2000ndash3000 IU bolus followed by 1000 IUhour infusion 1000 IUhour infusion
with ACT maintained bw 200-300) throughout the with ACT maintained bw 200-300) throughout the interventional procedure and for 24ndash48 hours thereafter when interventional procedure and for 24ndash48 hours thereafter when there is neither intraprocedural bleeding nor suspicion of there is neither intraprocedural bleeding nor suspicion of increased risk of bleeding increased risk of bleeding
Maximum dose of Urokinase Maximum dose of Urokinase Anterior circulation stroke - 500000 IU (mean 400000 Anterior circulation stroke - 500000 IU (mean 400000
IU range 300000ndash500000 IU)IU range 300000ndash500000 IU) Posterior circulation stroke -1000000 IU (mean 837000 Posterior circulation stroke -1000000 IU (mean 837000
IU range 300000ndash1000000 IU)IU range 300000ndash1000000 IU)American Journal of NeuroradiologyAmerican Journal of Neuroradiology 262595-2601 2005262595-2601 2005
Intravenous ThrombolysisIntravenous Thrombolysis
The first method to restore cerebral The first method to restore cerebral perfusion is clot lysis with the goal perfusion is clot lysis with the goal of re-establishing blood flow to the of re-establishing blood flow to the affected tissue affected tissue
IV thrombolysis rt-PA is the only IV thrombolysis rt-PA is the only FDA- approved treatment for AIS FDA- approved treatment for AIS
Fibrinolysis is enhanced powerfully Fibrinolysis is enhanced powerfully by rt-PAby rt-PA
Intravenous rTPA Intravenous rTPA administration administration protocolprotocol
Total dose of rt-PA 09 mgkg (maximum dose Total dose of rt-PA 09 mgkg (maximum dose 90 mg)90 mg)
Give 10 as initial IV bolusGive 10 as initial IV bolus Infuse remainder over 1 hourInfuse remainder over 1 hour Admit patient to an ICU or stroke unit for Admit patient to an ICU or stroke unit for
monitoringmonitoring Neurologic assessments every 15 minutes Neurologic assessments every 15 minutes
during infusion then every 30 minutes for next during infusion then every 30 minutes for next 6 hours then every hour until 24hours after 6 hours then every hour until 24hours after treatmenttreatment
Favorable Outcome vs Treatment Time Favorable Outcome vs Treatment Time with IV rTPAwith IV rTPA
Protocol limit = 3 hrs
Benefit ~ 45 hrs
Thromboembolism During coilingThromboembolism During coiling Most feared and frequent complication Most feared and frequent complication Reported incidence - Approx 7 Reported incidence - Approx 7 SourcesSources of Thromboembolism are of Thromboembolism are
- Clots at the aneurysmal neck during or immediately- Clots at the aneurysmal neck during or immediately after after embolization embolization
- Thrombus forming on catheters during- Thrombus forming on catheters during proceduresprocedures
- Stenosis of an adjacent artery dt coil mass- Stenosis of an adjacent artery dt coil mass or herniationor herniation
- Migration of intraaneurysmal- Migration of intraaneurysmal thrombus during coil thrombus during coil placement placement
- Slow flow dt vasospasm - Slow flow dt vasospasm
- Rare and unlikely causes are hypercoagulable- Rare and unlikely causes are hypercoagulable state such state such as antiphospholipid antibody syndrome or due to HITas antiphospholipid antibody syndrome or due to HIT
Occur more often with wide-necked aneurysms (dt Occur more often with wide-necked aneurysms (dt increased exposed surface area of thrombogenic coil increased exposed surface area of thrombogenic coil material)material)
Current regimen of endovascular Current regimen of endovascular managementmanagement
The The glycoprotein IIbIIIa antagonist tirofiban glycoprotein IIbIIIa antagonist tirofiban (04 (04 microgkgmin bolus for 30 minutes followed by infusion of microgkgmin bolus for 30 minutes followed by infusion of 0125 ugkgmin until the thrombus dissolved) 0125 ugkgmin until the thrombus dissolved)
Intraarterial thrombolysis with Intraarterial thrombolysis with urokinase or r- TPA urokinase or r- TPA increase of intravenous (IV) heparin (measured by increase of intravenous (IV) heparin (measured by
ACT) ACT) Intravenous aspirin Intravenous aspirin
Coil-related platelet aggregation (white clot) is Coil-related platelet aggregation (white clot) is unlikely to respond to fibrinolytics but has a high risk unlikely to respond to fibrinolytics but has a high risk of hemorrhage (In ISAT) all 5 patients who had of hemorrhage (In ISAT) all 5 patients who had received thrombolytic therapy with tPA to treat a received thrombolytic therapy with tPA to treat a thromboembolic complication after endovascular thromboembolic complication after endovascular treatment rebleed and all of these patients died)treatment rebleed and all of these patients died)
IntracranialIntracranial Stenting Stenting Metallic foreign body such as stent will accumulate Metallic foreign body such as stent will accumulate
thrombus in the absence of platelet inhibitionthrombus in the absence of platelet inhibition Antiplatelet drugs are important to prevent peri or Antiplatelet drugs are important to prevent peri or
post-interventional thromboembolic eventspost-interventional thromboembolic events Optimal treatment regimens has not been determined Optimal treatment regimens has not been determined
but usually but usually Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-
procedureprocedureOrOr
Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on
morning of proceduremorning of procedure
If need to use stent is not pre-planned thanIf need to use stent is not pre-planned than
Abciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkgAbciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkg IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)
Glycoprotein IIbIIIa inhibitor are not used routinely during elective Glycoprotein IIbIIIa inhibitor are not used routinely during elective stenting procedure dt increased risk of ICH stenting procedure dt increased risk of ICH
Carotid StentingCarotid Stenting
Pre-procedurePre-procedure
Double Antiplatelet therapy is routinely given Double Antiplatelet therapy is routinely given beginning at least 3beginning at least 3
days before the proceduredays before the procedure
Aspirin 325mgd+Clopidogrel 75mgdAspirin 325mgd+Clopidogrel 75mgd During procedureDuring procedure
Heparin is given with target clotting time of 250-Heparin is given with target clotting time of 250-300sec300sec
Post-procedure Post-procedure
Aspirin 325mg is continued indefinitely and Aspirin 325mg is continued indefinitely and
Clopidogrel 75mgd for at least 6 weeks Clopidogrel 75mgd for at least 6 weeks
Inclusion criteria for Local ThrombolysisInclusion criteria for Local Thrombolysis a)a) Patients in severe clinical grade on admission Patients in severe clinical grade on admission
with evidence of dural venous sinus with evidence of dural venous sinus thrombosis and restrictive venous outflow on thrombosis and restrictive venous outflow on cerebral angiogramcerebral angiogram
b)b) Patients in clinical grade 3 worsening on Patients in clinical grade 3 worsening on heparin therapy Restriction to venous heparin therapy Restriction to venous outflow was defined as an increase in brain outflow was defined as an increase in brain circulation time gt 12 s delay in the drainage circulation time gt 12 s delay in the drainage of cortical veins with cortical veins hanging of cortical veins with cortical veins hanging in spacein space
Treatment Options for Venous Thrombosis
CT Grading for Venous ThrombosisCT Grading for Venous Thrombosis Grade I no parenchymal change Grade I no parenchymal change
(hyperdense (hyperdense sinuses cortical veins empty sinuses cortical veins empty delta sign)delta sign)
Grade II non hemorrhagic venous infarct Grade II non hemorrhagic venous infarct without mass effect without mass effect
Grade III non-hemorrhagic infarct with Grade III non-hemorrhagic infarct with mass effectmass effect
Grade IV hemorrhagic venous infarct (max Grade IV hemorrhagic venous infarct (max diameter lt 3 cm) with no mass effectdiameter lt 3 cm) with no mass effect
Grade V hemorrhagic venous infarct (max Grade V hemorrhagic venous infarct (max diameter gt 3 cm) with mass effect diameter gt 3 cm) with mass effect
Local ThrombolysisLocal Thrombolysis
Femoral Jugular access was secured and a guiding Femoral Jugular access was secured and a guiding catheter was placed in the jugular bulb catheter was placed in the jugular bulb Mechanical Mechanical clot maceration clot maceration was done with the guidewire was done with the guidewire following which a microcatheter (was navigated and following which a microcatheter (was navigated and placed in the thrombosed segment of sinus confirmed placed in the thrombosed segment of sinus confirmed on a selective venogram on a selective venogram
Urokinase infusion Bolus dose of 2-6 lacs followed Urokinase infusion Bolus dose of 2-6 lacs followed by 60000 to 100000 units per hour along with by 60000 to 100000 units per hour along with periodic check venogram Along with maintenance periodic check venogram Along with maintenance systemic infusion of Heparinsystemic infusion of Heparin Other agents such as Other agents such as streptokinase altepase or rTPAstreptokinase altepase or rTPA can be also used can be also used
After thrombolysis patient should subjected to oral After thrombolysis patient should subjected to oral anticoagulation for six monthsanticoagulation for six months
Low-molecular-weight Low-molecular-weight heparinheparin
PharmacologyPharmacologyLMWH as its name suggests is a glycosaminoglycan that is approximatelyLMWH as its name suggests is a glycosaminoglycan that is approximately
one third the molecular weight of UFH It is derived from UFH through one third the molecular weight of UFH It is derived from UFH through variousvarious
depolymerization processes LMWH binds to antithrombin which in turn depolymerization processes LMWH binds to antithrombin which in turn
Neutralizes actors Xa and IIa Because LMWH lacks many of the longer Neutralizes actors Xa and IIa Because LMWH lacks many of the longer chains chains
required for binding to thrombin it has less ability to neutralize thrombin required for binding to thrombin it has less ability to neutralize thrombin
relativeto its ability to neutralize factor Xa LMWH also has less relativeto its ability to neutralize factor Xa LMWH also has less nonspecific nonspecific
binding to other proteins There is greater bioavailability with more binding to other proteins There is greater bioavailability with more predictable predictable
pharmacokinetics that eliminates the need for monitoring The smaller pharmacokinetics that eliminates the need for monitoring The smaller size also size also
allows for enhanced subcutaneous absorption when compared with UFHallows for enhanced subcutaneous absorption when compared with UFH
Three LMWH preparations are Three LMWH preparations are currently approved for use in the currently approved for use in the United States (1) enoxaparin (2) United States (1) enoxaparin (2) dalteparin and (3) tinzaparin dalteparin and (3) tinzaparin
They are all administered They are all administered subcutaneously at intervals of either subcutaneously at intervals of either once or twice daily for both once or twice daily for both prophylaxis and treatment dosesprophylaxis and treatment doses
Few Experiences of Few Experiences of ThrombolysisThrombolysis
Vickey 25 Yrs male patient presented Vickey 25 Yrs male patient presented with 12with 12thth day HO severe headache with day HO severe headache with right sided hemiplegiaright sided hemiplegia
MRI shows thrombosis of the superior MRI shows thrombosis of the superior sagittal left transverse left sigmoid sagittal left transverse left sigmoid sinuses and cortical veins in the fronto-sinuses and cortical veins in the fronto-parietal regions with eo haemorrhagic parietal regions with eo haemorrhagic infarct in the left cerebral hemisphere infarct in the left cerebral hemisphere with mass effect( Grade ndashV)with mass effect( Grade ndashV)
Sashi Srivastava 64 yrs FSashi Srivastava 64 yrs F In a follow up case of MRD with infra-renal In a follow up case of MRD with infra-renal
aortic abdominal and bilateral renal artery aortic abdominal and bilateral renal artery thrombosis renal angiogram shows filling thrombosis renal angiogram shows filling defects in the right Renal artery defects in the right Renal artery
Initially Renal angioplasty was done Initially Renal angioplasty was done Following angioplasty few thrombi are seem Following angioplasty few thrombi are seem to extends into the segmental branches and to extends into the segmental branches and causing blockage So Thrombolysis was causing blockage So Thrombolysis was plane to dissolve the run-out thrombi with plane to dissolve the run-out thrombi with urokinase urokinase
Rakesh 34yrsMRakesh 34yrsM Left SFA pseudoaneurysm with Left SFA pseudoaneurysm with
Covered stent placementCovered stent placement Pre operative antiplatelets with post Pre operative antiplatelets with post
procedure heparin Tirofiban procedure heparin Tirofiban followed by aspirin and clopidogrel followed by aspirin and clopidogrel were usedwere used
IAT may be a treatment option for selected patients IAT may be a treatment option for selected patients Possible selection criteria include Possible selection criteria include
presentation between 3 and 6 hours from symptom onsetpresentation between 3 and 6 hours from symptom onset major cerebral artery occlusion major cerebral artery occlusion severe neurologic deficits severe neurologic deficits high risk of systemic hemorrhage with IV rt-PA (eg recent high risk of systemic hemorrhage with IV rt-PA (eg recent
surgery) surgery) The MERCI (Mechanical Embolus Removal in Cerebral The MERCI (Mechanical Embolus Removal in Cerebral
Ischemia) retrievalIschemia) retrieval system system
Has been FDA-approved for recanalizing acutely occluded Has been FDA-approved for recanalizing acutely occluded cerebral arteries cerebral arteries
In the Multi-MERCI study patients who did not improve In the Multi-MERCI study patients who did not improve immediately after IV rt-PA underwent mechanical immediately after IV rt-PA underwent mechanical embolectomy within 8 hours of symptom onset embolectomy within 8 hours of symptom onset
Partial or complete recanalization occurred in 74 of Partial or complete recanalization occurred in 74 of patientspatients
with a symptomatic intracerebral hemorrhage (sICH) rate of with a symptomatic intracerebral hemorrhage (sICH) rate of 67 67
Mechanical embolectomy with the MERCI retriever may be a Mechanical embolectomy with the MERCI retriever may be a feasible and safe option for patients after IV rt-PAfeasible and safe option for patients after IV rt-PA
Penumbra stroke systemPenumbra stroke system This device combines two methods of clot This device combines two methods of clot
extraction aspiration and mechanical extraction aspiration and mechanical extraction extraction
First the clot is aspirated then a thrombus First the clot is aspirated then a thrombus removal ring can be used if necessary to removal ring can be used if necessary to remove remaining clot remove remaining clot
successful recanalizing 82successful recanalizing 82 Bridging therapyBridging therapy
06 mgkg IV rt-PA followed by IAT with IA rt-06 mgkg IV rt-PA followed by IAT with IA rt-PA (up to 20 mg)PA (up to 20 mg)
achieved a higher recanalization rateachieved a higher recanalization rate
Criteria for thrombolysis with rTPACriteria for thrombolysis with rTPA
Inclusion criteriaInclusion criteria Clinical signs and symptoms consistent with ischemic Clinical signs and symptoms consistent with ischemic
strokestroke Patient last seen normal within 3 hoursPatient last seen normal within 3 hours Measurable neurologic deficitMeasurable neurologic deficit
Exclusion criteriaExclusion criteria Any hemorrhage on neuroimaging (CT or MRI)Any hemorrhage on neuroimaging (CT or MRI) Symptoms suggestive of subarachnoid hemorrhageSymptoms suggestive of subarachnoid hemorrhage Seizure at stroke onset that is thought to contribute to Seizure at stroke onset that is thought to contribute to
neurologic deficitneurologic deficit Hypodensity greater than one third cerebral hemisphere Hypodensity greater than one third cerebral hemisphere
on CTon CT SBP greater than 185 mm Hg or DBP greater than 110 SBP greater than 185 mm Hg or DBP greater than 110
mm Hgmm Hg International normalized ratio (INR) greater than 17International normalized ratio (INR) greater than 17
Ischemic Stroke Ischemic Stroke Treatment ndash 2006Treatment ndash 2006
IV tissue plasminogen activator (tPA)IV tissue plasminogen activator (tPA) ndash ndash Only FDA-approved acute stroke drugOnly FDA-approved acute stroke drug ndash ndash 3 hour treatment window3 hour treatment window
MERCI - Concentric clot retrieval MERCI - Concentric clot retrieval devicedevice ndash ndash Rescue therapy - approved 2004Rescue therapy - approved 2004 ndash ndash Device approval (not outcomes-based)Device approval (not outcomes-based)
Off label approachesOff label approaches ndash ndash IV tPA after 3 hoursIV tPA after 3 hours ndash ndash IV-IA tPA sequential strategiesIV-IA tPA sequential strategies ndash ndash IA tPA clot angioplasty fragmentationIA tPA clot angioplasty fragmentation ndash ndash Ultrasound-assisted tPA lysisUltrasound-assisted tPA lysis
rt-PA Trials NINDSrt-PA Trials NINDS
Acute stroke - 624 patientsAcute stroke - 624 patients Treat within 3 hrsTreat within 3 hrs Intravenous 09 mgkg rt-PA vs placeboIntravenous 09 mgkg rt-PA vs placebo Hemorrhage 64 tPA 06 placeboHemorrhage 64 tPA 06 placebo Neurologic recovery better with tPA 30 Neurologic recovery better with tPA 30
more like to have minimal or no disabilitymore like to have minimal or no disability
First proven approved treatment for First proven approved treatment for strokestroke
Limitations of tPALimitations of tPA Only 4 of acute strokes receive tPAOnly 4 of acute strokes receive tPA (Kleindorfer et al Stroke 2004 35 e27-e29)(Kleindorfer et al Stroke 2004 35 e27-e29)
Only 22 of patients present within 3 hoursOnly 22 of patients present within 3 hours1048707 1048707 51 of these ineligible due to51 of these ineligible due to
bull bull Mild severityMild severity bull bull Medical or surgical historyMedical or surgical history bull bull Blood testsBlood tests
Sustained recanalization only 13Sustained recanalization only 13 (Alexandrov et al NEJM 2004 351 2170-8)(Alexandrov et al NEJM 2004 351 2170-8)
Concern for hemorrhageConcern for hemorrhage tPA potentiates apoptotic injury tPA potentiates apoptotic injury (Liu et al Nature Med 2004 101379-83)(Liu et al Nature Med 2004 101379-83)
PROACT II IA Lysis TrialPROACT II IA Lysis Trial Baseline 24 hours 8 days
Baseline 60 minutes 120 minutes
9mg IAProurokinase
Desmoteplase Trials DEDAS Desmoteplase Trials DEDAS DIASDIAS
Trial OverviewTrial Overview Double blind randomized placebo Double blind randomized placebo
controlled trialscontrolled trials IV delivery 3-9 hour time windowIV delivery 3-9 hour time window Plasminogen activator ndash from Plasminogen activator ndash from vampire bat vampire bat
salivasaliva Selection based on PWI-DWI MismatchSelection based on PWI-DWI Mismatch
MRI InclusionMRI Inclusion PWI defect at least 2 cm AND ~20 larger PWI defect at least 2 cm AND ~20 larger
than DWIthan DWI PWI should be obvious even visible on PWI should be obvious even visible on
raw imagesraw imagesMRI ExclusionMRI Exclusion
DWI gt 13 MCADWI gt 13 MCA MRA ICA occlusionMRA ICA occlusion
Desmoteplase ndash DIAS Desmoteplase ndash DIAS ResultsResults
Mechanical Thrombolysis Mechanical Thrombolysis devicesdevices
mechanical thrombolysis potentially extends the treatment mechanical thrombolysis potentially extends the treatment window because they act promptly at the site of the thrombuswindow because they act promptly at the site of the thrombus
The devices can retrieve large clots that pharmaceutical agents The devices can retrieve large clots that pharmaceutical agents may not successfully lysemay not successfully lyse
Patients treated with IV tPA may be considered for treatment of Patients treated with IV tPA may be considered for treatment of residual clot with some of these devicesresidual clot with some of these devices
suction-creating saline jets suction-creating saline jets laser energy ultrasound laser energy ultrasound a corkscrew apparatus to treat strokesa corkscrew apparatus to treat strokes The AngioJet systemThe AngioJet system uses saline jets that are directed back into the catheter to uses saline jets that are directed back into the catheter to
create a low-pressure zone around the catheter tip inducing create a low-pressure zone around the catheter tip inducing suction suction
The clot is pulled into the exhaust lumen and removed from the The clot is pulled into the exhaust lumen and removed from the vessel Although US Food and Drug Administration (FDA) has vessel Although US Food and Drug Administration (FDA) has approved this device for use in arteriovenous dialysis grafts and approved this device for use in arteriovenous dialysis grafts and fistulae and for the treatment of coronary arteries saphenous fistulae and for the treatment of coronary arteries saphenous vein grafts and peripheral vessels clinical trials for the vein grafts and peripheral vessels clinical trials for the treatment of acute stroke are no longer in progress treatment of acute stroke are no longer in progress
Most devices are used in cerebral vessels that 2-5 mm
The Latis laser device The Latis laser device used laser energy to ablate clots used laser energy to ablate clots Arteries 2-5 mm in diameter could be Arteries 2-5 mm in diameter could be
treated including the ICA M1 or M2 treated including the ICA M1 or M2 branch of the MCA A1 branch of the branch of the MCA A1 branch of the anterior cerebral artery (ACA) basilar anterior cerebral artery (ACA) basilar artery posterior cerebral artery (PCA) artery posterior cerebral artery (PCA) and vertebral and vertebral
Patients could receive treatment as late Patients could receive treatment as late as 8 hours after symptom onset in the as 8 hours after symptom onset in the anterior circulation and within 24 hours in anterior circulation and within 24 hours in the posterior circulation the posterior circulation
Endovascular Photo Acoustic Endovascular Photo Acoustic Recanalization (EPAR) Recanalization (EPAR)
A laser power source generated energy for the A laser power source generated energy for the systemsystem
The energy was delivered by means of The energy was delivered by means of fiberoptics to the tip of the catheter at the fiberoptics to the tip of the catheter at the treatment sitetreatment site
Absorption of laser light by darkly pigmented Absorption of laser light by darkly pigmented materials (ie the clot) occurred inside the 1-mm materials (ie the clot) occurred inside the 1-mm catheter tipcatheter tip
the system was designed to minimize scattering the system was designed to minimize scattering of laser light of laser light
Absorption converted photo energy to acoustic Absorption converted photo energy to acoustic energy which then emulsified the clot inside the energy which then emulsified the clot inside the catheter tip catheter tip
EKOS ultrasound( the EKOS ultrasound( the Ultrasound Thrombolytic Ultrasound Thrombolytic
Infusion Catheter) Infusion Catheter) combines the use of a distal ultrasound transducer with combines the use of a distal ultrasound transducer with
infusion of a thrombolytic agent through the infusion of a thrombolytic agent through the microcathetermicrocatheter
Ultrasound changes the structure of the clot to Ultrasound changes the structure of the clot to temporarily increase its permeability while providing an temporarily increase its permeability while providing an acoustic pressure gradient to move the drug into the clot acoustic pressure gradient to move the drug into the clot to speed its dissolution to speed its dissolution
The EKOS catheter is placed in the proximal portion of the The EKOS catheter is placed in the proximal portion of the clot clot
After a 2-mg bolus of tPA was injected through the After a 2-mg bolus of tPA was injected through the catheter catheter
the patient received a continuous infusion of IA tPA 03 the patient received a continuous infusion of IA tPA 03 mgmin to a maximum of 20 mg and simultaneous mgmin to a maximum of 20 mg and simultaneous ultrasound transmission for as long as 60 minutes ultrasound transmission for as long as 60 minutes
One patient was treated with a total of 4 units of One patient was treated with a total of 4 units of recombinant reteplase (Retavase) hand-injected over 60 recombinant reteplase (Retavase) hand-injected over 60 minutes minutes
Penumbra system Penumbra system The Penumbra system (Penumbra Inc) provides a dual The Penumbra system (Penumbra Inc) provides a dual
approach to clot extraction using aspiration followed by approach to clot extraction using aspiration followed by clot retrieval with a ring device if needed clot retrieval with a ring device if needed
Mechanical Embolus Removal in Cerebral Ischemia Mechanical Embolus Removal in Cerebral Ischemia (MERCI)(MERCI)
a corkscrew-like apparatus to remove blood clots from a corkscrew-like apparatus to remove blood clots from the brain in patients experiencing an ischemic stroke the brain in patients experiencing an ischemic stroke
The corkscrew itself resides in the catheter tip which The corkscrew itself resides in the catheter tip which shields it from the wall of the vessel until it is ready to be shields it from the wall of the vessel until it is ready to be burrowed into the clot Once lodged in the clot the device burrowed into the clot Once lodged in the clot the device and clot are withdrawn from the vessel and clot are withdrawn from the vessel
Snarelike devicesSnarelike devices Snares such as the Neuronet snare (Guidant Snares such as the Neuronet snare (Guidant
Endovascular Santa Clara CA) have been developed Endovascular Santa Clara CA) have been developed specifically for use in the treatment of strokes specifically for use in the treatment of strokes
These devices are simple in design and do not require the These devices are simple in design and do not require the clot to be amenable to emulsification clot to be amenable to emulsification
X-Sizer deviceX-Sizer device a device with small moving blades at the a device with small moving blades at the
catheter tip catheter tip This device the X-Sizer device (EndiCor Medical This device the X-Sizer device (EndiCor Medical
San Clemente CA) can be used to excise the San Clemente CA) can be used to excise the thrombus and aspirate it thrombus and aspirate it
The device was being evaluated in randomized The device was being evaluated in randomized studies of coronary vessels and in a registry of studies of coronary vessels and in a registry of patients with acute myocardial infarctionpatients with acute myocardial infarction
Although the manufacturer had modified the Although the manufacturer had modified the device for use in cerebral vessels a safety and device for use in cerebral vessels a safety and feasibility study was indefinitely suspended after feasibility study was indefinitely suspended after only 1 patient was treated with the device in only 1 patient was treated with the device in Europe Europe
Suction thrombectomySuction thrombectomy This method of mechanical thrombolysis is one of the This method of mechanical thrombolysis is one of the
simplestsimplest In this readily available technique suction is applied with In this readily available technique suction is applied with
a syringe to remove thrombus in the ICA a syringe to remove thrombus in the ICA It requires no other devicesIt requires no other devices A catheter with a large inner diameter (Brite Tip Cordis A catheter with a large inner diameter (Brite Tip Cordis
Corporation Miami FL) was placed in the symptomatic Corporation Miami FL) was placed in the symptomatic vessel and navigated over a guidewire into the thrombusvessel and navigated over a guidewire into the thrombus
A 60-mL syringe was used to aspirate the thrombus A 60-mL syringe was used to aspirate the thrombus Each patient required angioplasty and stenting of carotid Each patient required angioplasty and stenting of carotid
bifurcation stenosis and received daily aspirin and bifurcation stenosis and received daily aspirin and ticlopidine after the procedure No complications ticlopidine after the procedure No complications occurred occurred
Summary Acute Stroke Summary Acute Stroke ImagingImaging
PhysiologyPhysiology importance collaterals importance collaterals
ndash ndashGrowing role for perfusion Growing role for perfusion assessmentassessment
tPAtPA guidelines amp limitations guidelines amp limitations Signs on CT amp MRSigns on CT amp MR follow physiology follow physiology Stroke trialsStroke trials PWI-DWI mismatch PWI-DWI mismatch
ndash ndashTreat based on physiology not timeTreat based on physiology not time ProtocolsProtocols should be fast and should be fast and
comprehensivecomprehensive
HemostasisHemostasis involves a sequence of interactions of coagulation involves a sequence of interactions of coagulation
factor interactions in two pathways called the factor interactions in two pathways called the intrinsic and extrinsic coagulation cascades intrinsic and extrinsic coagulation cascades
The final common pathway involves the The final common pathway involves the transformation of prothrombin to thrombin by factor transformation of prothrombin to thrombin by factor Xa Xa
Thrombin (factor IIa) then serves to catalyze the Thrombin (factor IIa) then serves to catalyze the activation of fibrinogen to fibrin in addition to its role activation of fibrinogen to fibrin in addition to its role in feedback activation of several other clotting factorsin feedback activation of several other clotting factors
UFH LMWH and fondaparinux( saccharides) all UFH LMWH and fondaparinux( saccharides) all exert their anticoagulant effect in a similar fashion by exert their anticoagulant effect in a similar fashion by binding to and activating antithrombinbinding to and activating antithrombin that then that then neutralizes selected coagulation factorsneutralizes selected coagulation factors
Stages of blood coagulationStages of blood coagulation Formation of Formation of ProthrombinaseProthrombinase
Prothrombinase can be formed in two ways depending of which of Prothrombinase can be formed in two ways depending of which of two systems or pathways apply two systems or pathways apply
Intrinsic SystemIntrinsic System This is initiated by liquid blood making contact with a foreign This is initiated by liquid blood making contact with a foreign
surface ie something that is not part of the body surface ie something that is not part of the body Extrinsic SystemExtrinsic System
This is initiated by liquid blood making contact with damaged This is initiated by liquid blood making contact with damaged tissuetissue
Both the intrinsic and the extrinsic systems involve interactions Both the intrinsic and the extrinsic systems involve interactions between between coagulation factorscoagulation factors
2 2 ProthrombinProthrombin converted into the enzyme converted into the enzyme ThrombinThrombinProthrombinase (formed in stage 1) converts prothrombin which is Prothrombinase (formed in stage 1) converts prothrombin which is a plasma protein that is formed in the liver into the enzyme a plasma protein that is formed in the liver into the enzyme thrombinthrombin
3 3 FibrinogenFibrinogen (soluble) converted to (soluble) converted to FibrinFibrin (insoluble) (insoluble)In turn thrombin converts fibrinogen into fibrin Fibrin is insoluble In turn thrombin converts fibrinogen into fibrin Fibrin is insoluble and forms the threads that bind the clotand forms the threads that bind the clot
BLOOD COAGULATION
A sequence of reactions that are present in an inactive state in bloodKey is the conversion of the plasma protein fibrinogen to fibrin Intrinsic pathway Extrinsic pathway(activated by exposure of (activated by substances blood to damaged tissue) released from damaged tissue)
Active factors X and V
Prothrombin Thrombin
Fibrinogen Fibrin Fibrin mesh
inhibited by warfarin
inhibited by heparin
Rationale for anticoagulant Rationale for anticoagulant therapytherapy
PHARMACOLOGICAL PHARMACOLOGICAL AGENTSAGENTS
Pharmacologic AgentsPharmacologic Agents
AnticoagulantsAnticoagulants
Fibrinolytics (Agents for pharmacological Fibrinolytics (Agents for pharmacological recanalization)recanalization)
Anti platelet drugsAnti platelet drugs
Thrombin inhibitorThrombin inhibitor
ANTICOAGULANTSANTICOAGULANTS
Heparin and Low Molecular Weight Heparins Heparin and Low Molecular Weight Heparins ((eg enoxaparin dalteparin)eg enoxaparin dalteparin)
Oral anticoagulantsOral anticoagulants Coumarin Derivatves Coumarin Derivatves eg Warfarin eg Warfarin
AcenocoumarolAcenocoumarol Indandione Derivatves Indandione Derivatves eg Phenindione eg Phenindione
AnisindioneAnisindione
ThrombolyticsThrombolytics
Plasminogen activators
Fibrinolytics
Anti Platelet DrugsAnti Platelet DrugsDrug Mechanism UsesDrug Mechanism UsesAspirinAspirin Permanently inhibits Permanently inhibits
COX-1 and COX-2COX-1 and COX-2CADCAD
Stroke-TIAsStroke-TIAs
NSAIDsNSAIDs Reversibly inhibits Reversibly inhibits COX-1COX-1
LimitedLimited
DipyridamoleDipyridamole Inhibits PDE Inhibits PDE increases cAMPincreases cAMP
TIAsTIAs
ThenopyridinesThenopyridines
(Ticlopidine(Ticlopidine
Clopidegrel)Clopidegrel)
Inhibits ADP Inhibits ADP
PlatAg PlatAg
TIAsStrokeTIAsStroke
CAD PVDCAD PVD
Abciximab (ReoPro)Abciximab (ReoPro)
Eptifibatide Eptifibatide (Integrilin)(Integrilin)
TirofibaTirofibann
GP IIBIIIA InhibitorsGP IIBIIIA Inhibitors
Stroke- TIAs Stroke- TIAs
Maintainance of patency Maintainance of patency of vascular of vascular grafts catheters shunts bypassesgrafts catheters shunts bypasses
Arterial thromboembolic diseaseArterial thromboembolic diseasebull Transient ischemic attacksTransient ischemic attacksbull Stroke in evolutionStroke in evolution
Ischemic events occurs in Ischemic events occurs in 1313 of of conventional neuroangiographic conventional neuroangiographic procedures without Endovascular surgeryprocedures without Endovascular surgery
Indications for Antithrombotic Therapy in Indications for Antithrombotic Therapy in Diagnostics and Interventional ProceduresDiagnostics and Interventional Procedures
WHY TO MONITOR ANTICOAGULANT THERAPYWHY TO MONITOR ANTICOAGULANT THERAPY
Narrow therapeutic rangeNarrow therapeutic range
Can increase risk of bleedingCan increase risk of bleeding
Coagulation TestingCoagulation Testing
Monitoring therapyMonitoring therapy
Intrinsic Pathway
Extrinsic Pathway
Common Pathway
CLOT
Heparin Coumadin
Monitor with
ACT aPTT
Monitor with PTINR
Thrombolytics
Monitor with TT Fibrinogen
Monitoring of Monitoring of Anti platelet drugsAnti platelet drugs
Bleeding timeBleeding time
Optical aggregometryOptical aggregometry
Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay
HeparinHeparin
Heterogeneous 3000-30000 dalton in Heterogeneous 3000-30000 dalton in molecular weight molecular weight
Average=15000 d (~45monosaccharide Average=15000 d (~45monosaccharide chains)chains)
About About 13 of dose binds to AT III and forms 13 of dose binds to AT III and forms the AT IIIHeparinClotting Factor Complexthe AT IIIHeparinClotting Factor Complex
Complex binds to clotting factors of the Complex binds to clotting factors of the intrinsic and common pathway (Xa IIa IXa intrinsic and common pathway (Xa IIa IXa XIa XIIa XIIIa) and inactivates themXIa XIIa XIIIa) and inactivates them
Anticoagulant of choice in pregnancy (not Anticoagulant of choice in pregnancy (not crosses placenta)crosses placenta)
Heparin and Low molecular weight heparinsHeparin and Low molecular weight heparins
Structure and sequence
O
OH
OH
O
COO
O
O
CH2OH
NHSO3
OH
_
_
O
O
CH2OSO3
NHSO3
OH
_
_
O
OH
OH
O
COOO
O
CH2OSO3
NHSO3
OH
_
_
O
OSO3
OHO
COOO
O
CH2OSO3
NHCOCH3
OH
_
_ _
_
_
O
OH
OH
O
COO
1
23
4
5
6
-D-glucosamine -L-iduronic acid -D-glucuronic acid
O
O
CH2OH
NH2
OH 12
3
4
5
6
O
OH
OHO
COO_
1
23
4
5
6
polymeric structure of heparin
Anticoagulant Properties of Anticoagulant Properties of HeparinHeparin
11 Inhibits the thrombin-mediated conversion of Inhibits the thrombin-mediated conversion of fibrinogen to fibrinfibrinogen to fibrin
22 Inhibits the aggregation of platelets by thrombin Inhibits the aggregation of platelets by thrombin (prolongs bleeding time)(prolongs bleeding time)
33 Inhibits activation of fibrin stabilizing enzymeInhibits activation of fibrin stabilizing enzyme
44 Inhibits activated factors XII XI IX X and IIInhibits activated factors XII XI IX X and II All available forms of heparin must be All available forms of heparin must be
administered administered parenterally since they are parenterally since they are highly charged and rapidlyhighly charged and rapidly hydrolyzed in the hydrolyzed in the GI tractGI tract
Heparin antagonist Protamine sulfate (Heparin antagonist Protamine sulfate (10mg for 10mg for 1000 unit of heparin)1000 unit of heparin)
Monitoring of heparin Monitoring of heparin
Subcutenous Subcutenous no monitoring requiredno monitoring required Intravenous Intravenous
Partial thromboplastin time (PTT normal value Partial thromboplastin time (PTT normal value ~30sec) ~30sec)
Activated clotting time ( ACT normal value ~90-Activated clotting time ( ACT normal value ~90-120sec)120sec)
Daily or more frequent if PTT ACT variesDaily or more frequent if PTT ACT varies
Mechanism Mechanism ndash measures intrinsic pathwayndash measures intrinsic pathway Therapeutic goal Therapeutic goal 2-25 times normal control value 2-25 times normal control value
ACT or aPTTACT or aPTT
Determine when to pull the femoral sheath Determine when to pull the femoral sheath Premature sheath pull can lead to bleedingPremature sheath pull can lead to bleeding Delayed removal can increase time in ICUDelayed removal can increase time in ICU Target set Target set at each siteat each site
ACT targets range from 150 ndash 220 ACT targets range from 150 ndash 220 secondsseconds
aPTT targets range from 40 ndash 70 seconds aPTT targets range from 40 ndash 70 seconds
During neuroangiography-During neuroangiography- Recommended therapeutic range of heparin in Recommended therapeutic range of heparin in
plasma is 02-08 uml ( corresponding to aPTT plasma is 02-08 uml ( corresponding to aPTT ACT values 15-25 times the baseline values)ACT values 15-25 times the baseline values)
Dose In diagnostic angiography bolus dose of Dose In diagnostic angiography bolus dose of 2500 iu is used followed by 1000 iu hour2500 iu is used followed by 1000 iu hour
Bolus dose is Bolus dose is 60 ukg to maintain the therapeutic 60 ukg to maintain the therapeutic range range If procedure continues for more than 75 If procedure continues for more than 75 minutes additional dose is required ( half of the minutes additional dose is required ( half of the initial dose for another 75 minutes) initial dose for another 75 minutes)
(AJNR 199415 51-54)
Mechanisms of HIT( Mechanisms of HIT( Heparin Heparin induced Thrombocytopeniainduced Thrombocytopenia))
Type 1Type 1 Fall in platelet count occurs within the first two Fall in platelet count occurs within the first two
days after heparin initiation often returns to days after heparin initiation often returns to normal with continued heparin administration normal with continued heparin administration and is of no clinical consequence and is of no clinical consequence
The mechanism of the thrombocytopenia is non-The mechanism of the thrombocytopenia is non-immune and appears to be due to a direct effect of immune and appears to be due to a direct effect of heparin on platelet activationheparin on platelet activation
Type 2Type 2 Approximately 03 to 3 percent of patients Approximately 03 to 3 percent of patients
receiving heparin develop an immune receiving heparin develop an immune thrombocytopenia mediated by antibodies to a thrombocytopenia mediated by antibodies to a heparin-platelet factor 4 complex heparin-platelet factor 4 complex
(AJNR 28155-158 2007)
Treatment of heparin-induced Treatment of heparin-induced thrombocytopeniathrombocytopenia
When HIT is diagnosed it is important to When HIT is diagnosed it is important to stop heparin mainly in type 2 and to avoid stop heparin mainly in type 2 and to avoid the use of LMWH the use of LMWH
Because of the increased risk of thrombosis Because of the increased risk of thrombosis however continuation of an anticoagulant however continuation of an anticoagulant must be considered must be considered
The drugs currently approved for the The drugs currently approved for the treatment of HIT in the United States are treatment of HIT in the United States are direct thrombin inhibitors argatroban and direct thrombin inhibitors argatroban and lepirudinlepirudin
WARFARIN MECHANISM OF ACTIONWARFARIN MECHANISM OF ACTION
Inactive factors II VII IX and X
Proteins S and C
Active factors II VII IX and X
Proteins S and C
Vitamin K epoxide
Vitamin K reduced
WA
RF
AR
IN
Prevents the reduction of vitamin K which is essential for Prevents the reduction of vitamin K which is essential for activation of certain factorsactivation of certain factors
Has no effect on previously formed thrombusHas no effect on previously formed thrombus
Antagonist is Vit KAntagonist is Vit K
OPTIMIZING WARFARIN THERAPYOPTIMIZING WARFARIN THERAPY
Use of large loading dose may lead to hemorrhage and Use of large loading dose may lead to hemorrhage and other complicationsother complications
Initial dose 2-5 mg once dailyInitial dose 2-5 mg once daily Maintenance dose 2-10 mg once dailyMaintenance dose 2-10 mg once daily If Immediate anticoagulation is requiredIf Immediate anticoagulation is required Heparin IS Heparin IS
started along with loading dose of warfarin 10 mg started along with loading dose of warfarin 10 mg Heparin is usually discontinued after 4-5 days Heparin is usually discontinued after 4-5 days Before Before discontinuing INR should be in therapeutic range for 2 discontinuing INR should be in therapeutic range for 2 consecutive daysconsecutive days
Daily monitoring of INR until INR is in therapeutic Daily monitoring of INR until INR is in therapeutic range then 3 times weekly for 1-2 weeks then less often range then 3 times weekly for 1-2 weeks then less often (every 4 to 6 weeks)(every 4 to 6 weeks)
OPTIMAL THERAPEUTIC RANGEOPTIMAL THERAPEUTIC RANGE
IndicationIndication INRINR
Prophylaxis of venous Prophylaxis of venous thromboembolismthromboembolism
20-3020-30
Treatment of venous Treatment of venous thromboembolismthromboembolism
20-3020-30
Atrial fibrillationAtrial fibrillation 20-3020-30
Mitral valve stenosisMitral valve stenosis 20-3020-30
Heart valve replacementHeart valve replacement
Bioprosthetic valveBioprosthetic valve
Mechanical valveMechanical valve
20-3020-30
25-3525-35
Myocardial infarctionMyocardial infarction 20-3020-30
25-35 25-35 (high risk patients)(high risk patients)
FACTORS INFLUENCING DOSE RESPONSEFACTORS INFLUENCING DOSE RESPONSE
Poor patient compliancePoor patient compliance Concomitant medicationsConcomitant medications Levels of dietary vitamin KLevels of dietary vitamin K Alcohol Inaccurate lab testingAlcohol Inaccurate lab testing Inaccurate lab testingInaccurate lab testing Hepatic dysfunctionHepatic dysfunction FeverFever
Contraindication for WarfarinContraindication for Warfarin
Hypersensitivity to warfarinHypersensitivity to warfarin Hemorrhagic tendencyHemorrhagic tendency Condition with risk of hemorrhageCondition with risk of hemorrhage Inadequate laboratory techniquesInadequate laboratory techniques Protein C amp S deficiencyProtein C amp S deficiency Vitamin K deficiencyVitamin K deficiency
SIDE EFFECTSSIDE EFFECTS
Hemorrhage Hemorrhage Skin necrosisSkin necrosis Purple toe syndromePurple toe syndrome Microembolization Microembolization TeratogenecityTeratogenecity Agranulocytosis leukopenia Agranulocytosis leukopenia Diarrhoeanausea anorexiaDiarrhoeanausea anorexia
MONITORING OF WARFARIN THERAPYMONITORING OF WARFARIN THERAPY
Prothrombin timeProthrombin time PT ratioPT ratio INR (International Normalized Ratio)INR (International Normalized Ratio)
PROTHROMBIN TIME (PT)PROTHROMBIN TIME (PT)
Time required for blood to coagulate Time required for blood to coagulate is called PT ( normal value ~10sec)is called PT ( normal value ~10sec)
Performed by adding a mixture of Performed by adding a mixture of calcium and thromboplastin to calcium and thromboplastin to citrated plasmacitrated plasma
As a control a normal blood sample is As a control a normal blood sample is tested continuouslytested continuously
PT ratio (PTR) = PT ratio (PTR) = Patientrsquos PTPatientrsquos PT Control PTControl PT
PROBLEMS WITH PTPTRPROBLEMS WITH PTPTR
Thromboplastins are extracts from Thromboplastins are extracts from brain lung or placenta of animalsbrain lung or placenta of animals
Thromboplastins from various Thromboplastins from various manufacturers differ in their manufacturers differ in their sensitivity to prolong PTsensitivity to prolong PT
May result in false control of May result in false control of anticoagulant therapyanticoagulant therapy
INTERNATIONAL NORMALISED RATIO (INR)INTERNATIONAL NORMALISED RATIO (INR)
International Normalized Ratio (INR) International Normalized Ratio (INR) a PT test with a a PT test with a formula based ratio to normalize the often variable source formula based ratio to normalize the often variable source of tissue factor (human rabbit recombinant)of tissue factor (human rabbit recombinant)
INR = [PTINR = [PTptpt] ] ISIISI
[PT[PTRefRef]]
PTPTpt pt ndash prothrombin time of patientndash prothrombin time of patient
PTPTRef Ref ndash prothrombin time of normal pooled samplendash prothrombin time of normal pooled sample
ISI ndash International Sensitivity IndexISI ndash International Sensitivity Index
Warfarin is given orally and titrated to achieve an INR of Warfarin is given orally and titrated to achieve an INR of typically 20 ndash 30typically 20 ndash 30
Heparin versus WarfarinHeparin versus Warfarin
Drug ActionMechan-ism
Moni-toring
Effective
HeparinDirect
Inhibition ofThrombin
ATIIIcofactor
APTTACT
Immediate
WarfarinDecreasesProductionof factors
Vitamin K PTDelay
3-5 days
INR
Recanalization or Antegrade Recanalization or Antegrade Reperfusion StrategiesReperfusion Strategies
Recanalization strategies focus on removing Recanalization strategies focus on removing andor dissolving the occlusive thrombus to re-andor dissolving the occlusive thrombus to re-establish antegrade flow Strategies may be establish antegrade flow Strategies may be classified into 7 different categories on the classified into 7 different categories on the basis of their primary mechanism of action basis of their primary mechanism of action 1) 1) IV andor intraarterial thrombolysis (IAT) IV andor intraarterial thrombolysis (IAT) 2) endovascular thrombectomy2) endovascular thrombectomy3) endovascular thromboaspiration 3) endovascular thromboaspiration 4) endovascular mechanical thrombus disruption or 4) endovascular mechanical thrombus disruption or
thromborrhexisthromborrhexis5) 5) transcranial or endovascular augmented transcranial or endovascular augmented
fibrinolysis fibrinolysis 6) endovascular thrombus entrapment and 6) endovascular thrombus entrapment and 7) temporary endovascular bypass7) temporary endovascular bypass
IAT in Acute Ischemic StrokeIAT in Acute Ischemic Stroke
IAT advantages over IV thrombolysisIAT advantages over IV thrombolysis Coaxial microcatheter techniques the occluded intracranial Coaxial microcatheter techniques the occluded intracranial
vessel is directly accessible and the fibrinolytic agent can be vessel is directly accessible and the fibrinolytic agent can be infused directly into the thrombusinfused directly into the thrombus
This permits a smaller dose of fibrinolytic agent to reach a This permits a smaller dose of fibrinolytic agent to reach a higher local concentration than that reached by systemic higher local concentration than that reached by systemic infusioninfusion
Allows more complete recanalization with lower total doses of Allows more complete recanalization with lower total doses of thrombolytic thrombolytic
With the smaller dose complications from systemic fibrinolytic With the smaller dose complications from systemic fibrinolytic effects including intracranial hemorrhage (ICH) can effects including intracranial hemorrhage (ICH) can theoretically be reduced theoretically be reduced
Treatment window for endovascular techniques can be Treatment window for endovascular techniques can be extended beyond the typical IV window of 3 hours extended beyond the typical IV window of 3 hours
IA techniques have led to higher recanalization rates than IV IA techniques have led to higher recanalization rates than IV thrombolysisthrombolysis
Major disadvantagesMajor disadvantages Relative complexity of the procedure the level Relative complexity of the procedure the level
of required technical expertise and its of required technical expertise and its relatively low availability relatively low availability
Delays in initiating treatmentDelays in initiating treatment InvasiveInvasive
ThrombolyticsThrombolytics
Plasminogen activators
Fibrinolytics
1 Plasminogen Activators 1 Plasminogen Activators drugs act by converting the inactive proenzyme drugs act by converting the inactive proenzyme plasminogen into the active enzyme plasmin Plasmin plasminogen into the active enzyme plasmin Plasmin digests fibrinogen fibrin monomers and cross-linked digests fibrinogen fibrin monomers and cross-linked fibrin (as found in a thrombus) into fibrin degradation fibrin (as found in a thrombus) into fibrin degradation productsproducts
First-Generation Agents First-Generation Agents StreptokinaseStreptokinase a protein derived from group C a protein derived from group C
szlig-hemolytic streptococci has a half-life of 16ndashszlig-hemolytic streptococci has a half-life of 16ndash90 minutes and low fibrin specificity This drug 90 minutes and low fibrin specificity This drug proved to have a very narrow therapeutic proved to have a very narrow therapeutic window and significant rates of ICH and window and significant rates of ICH and systemic hemorrhage18systemic hemorrhage18
UrokinaseUrokinase is a serine protease with a plasma is a serine protease with a plasma half life of 14 minutes and low fibrin specificity half life of 14 minutes and low fibrin specificity
The urokinase dose used in cerebral IAT has The urokinase dose used in cerebral IAT has ranged from 002 to 2 X106unitsranged from 002 to 2 X106units
Second-Generation Agents Second-Generation Agents Alteplase (rtPA) Alteplase (rtPA)
is a serine is a serine protease with a plasma half-life of 35 protease with a plasma half-life of 35 minutes and a high degree of fibrin affinity and minutes and a high degree of fibrin affinity and specificity specificity
Dose used in cerebral IAT has ranged between 20 Dose used in cerebral IAT has ranged between 20 and 60 mgand 60 mg
Disadvantages of alteplase include its relatively short Disadvantages of alteplase include its relatively short halflife and limited penetration into the clot matrix halflife and limited penetration into the clot matrix because of strong binding with surface fibrin which because of strong binding with surface fibrin which could delay recanalization and increase the risk of could delay recanalization and increase the risk of recurrent occlusion recurrent occlusion
Prourokinase (r-prourokinase) Prourokinase (r-prourokinase) is the proenzyme precursor of urokinase is the proenzyme precursor of urokinase T12 of 7 minutes and high fibrin specificity T12 of 7 minutes and high fibrin specificity
Third-Generation AgentsThird-Generation Agents
ReteplaseReteplase is a structurally modified is a structurally modified form of alteplase form of alteplase
with a longer half-life (15ndash18 minutes) In with a longer half-life (15ndash18 minutes) In addition it does not bind as highly to fibrin addition it does not bind as highly to fibrin unbound reteplase can thus theoretically better unbound reteplase can thus theoretically better penetrate the clot and potentially penetrate the clot and potentially improve in improve in vivo fibrinolytic activity vivo fibrinolytic activity
TenecteplaseTenecteplase is another modified form of rtPA with a longer is another modified form of rtPA with a longer
half-life (17 minutes)half-life (17 minutes) greater fibrin specificity and greater greater fibrin specificity and greater
resistance to plasminogen activator inhibitor-1 resistance to plasminogen activator inhibitor-1 IV tenecteplase in acute ischemic stroke IV tenecteplase in acute ischemic stroke
suggest that the drug is safe and promisingsuggest that the drug is safe and promising
Newer plasminogen activatorNewer plasminogen activator
DesmoteplaseDesmoteplase is a genetically engineered is a genetically engineered version of the clot-dissolving factor version of the clot-dissolving factor
found in the saliva found in the saliva of the vampire bat Desmodus rotundusof the vampire bat Desmodus rotundus moremore potent and more selective for fibrin-bound potent and more selective for fibrin-bound
plasminogen than any other known plasminogen plasminogen than any other known plasminogen activatoractivator
Unlike tissue plasminogen activator (tPA) desmoteplase Unlike tissue plasminogen activator (tPA) desmoteplase is not activated by fibrinogen or -amyloid proteins is not activated by fibrinogen or -amyloid proteins factors that may exacerbate the risk for ICH factors that may exacerbate the risk for ICH
The effect of IV administration of desmoteplase 3ndash9 The effect of IV administration of desmoteplase 3ndash9 hours after symptom onset in patients with stroke who hours after symptom onset in patients with stroke who present with mismatch on MR imaging or CT perfusion present with mismatch on MR imaging or CT perfusion
3 DefibrinogenatingFibrinogenolytic 3 DefibrinogenatingFibrinogenolytic Agents Agents
AncrodAncrod(Viprinex)(Viprinex) is is the purified fraction of the Malayan pit viper venomthe purified fraction of the Malayan pit viper venom It acts by directly cleaving and inactivating fibrinogen It acts by directly cleaving and inactivating fibrinogen
and thus indirectly promoting anticoagulation and thus indirectly promoting anticoagulation The reduction in the blood levels of fibrinogen also The reduction in the blood levels of fibrinogen also
leads to a reduced blood viscosity which may improve leads to a reduced blood viscosity which may improve blood flow to the affected areas of the brain blood flow to the affected areas of the brain
In the Stroke Treatment with Ancrod Trial 500 In the Stroke Treatment with Ancrod Trial 500 patients with stroke presenting within 3 hours of patients with stroke presenting within 3 hours of symptom onset were randomized to receive ancrod (symptom onset were randomized to receive ancrod (n n 248) or a placebo (n 252) Good outcome (Barthel 248) or a placebo (n 252) Good outcome (Barthel Index 95ndash100 at 3 months) was achieved in 4221 Index 95ndash100 at 3 months) was achieved in 4221 and 344 of the patients respectively and 344 of the patients respectively
2 Direct Fibrinolytics2 Direct Fibrinolytics
Microplasmin (Microplasmin (ThromboGenics Heverlee Belgium)ThromboGenics Heverlee Belgium) is a truncated form of plasmin that is more resistant to the effects is a truncated form of plasmin that is more resistant to the effects
of antiplasmin of antiplasmin microplasmin can be used upto 4ndash12 hours after stroke onset microplasmin can be used upto 4ndash12 hours after stroke onset There was no evidence of increased bleeding risk with There was no evidence of increased bleeding risk with
microplasminmicroplasmin
Alfimeprase (Nuvelo San Carlos Calif)Alfimeprase (Nuvelo San Carlos Calif) is a recombinant truncated form of fibrolase a fibrinolytic zinc metalloproteinase is a recombinant truncated form of fibrolase a fibrinolytic zinc metalloproteinase
isolated from the venom of the southern copperhead snake isolated from the venom of the southern copperhead snake It degrades fibrin directly and achieves thrombolysis independent It degrades fibrin directly and achieves thrombolysis independent
of plasmin formationof plasmin formation its thrombolytic activity appears to be localized to the site of its thrombolytic activity appears to be localized to the site of
delivery These properties should theoretically result in faster delivery These properties should theoretically result in faster recanalization and lower hemorrhagic conversion riskrecanalization and lower hemorrhagic conversion risk
Anti-fibrinolyticsAnti-fibrinolytics
to limit fibrinolytic activityto limit fibrinolytic activity -aminocaproic acid (EACA) -aminocaproic acid (EACA) competitively inhibitscompetitively inhibits plasminogen and plasminogen activators from plasminogen and plasminogen activators from
binding to fibrinbinding to fibrin
alpha2-antiplasminalpha2-antiplasmin a serine protease inhibitor that a serine protease inhibitor that neutralizes any free circulating plasminneutralizes any free circulating plasmin
Plasminogen activator inhibitor-1Plasminogen activator inhibitor-1 a serine protease a serine protease inhibitor that inhibits tissue-type plasminogen inhibitor that inhibits tissue-type plasminogen activatoractivator
Glycoprotein (GP) IIbIIIa antagonistsGlycoprotein (GP) IIbIIIa antagonists
such as ReoPro (abciximab) Integrilin such as ReoPro (abciximab) Integrilin (eptifibatide) or Aggrastat (tirofiban) in (eptifibatide) or Aggrastat (tirofiban) in ischemic stroke remains investigational ischemic stroke remains investigational Deshmukh et al38 reported 21 patients with Deshmukh et al38 reported 21 patients with large-vessel occlusion refractory to IAT with large-vessel occlusion refractory to IAT with rtPA who were treated with IV andor IA rtPA who were treated with IV andor IA abciximab eptifibatide or tirofiban abciximab eptifibatide or tirofiban
IA Mechanical Approaches in Acute Ischemic Stroke IA Mechanical Approaches in Acute Ischemic Stroke Mechanical strategies have several advantagesMechanical strategies have several advantages First they lessen and may even preclude the use of chemical First they lessen and may even preclude the use of chemical
thrombolytics in this manner very likely reducing the risk of ICHthrombolytics in this manner very likely reducing the risk of ICH Second by avoiding the use of chemical thrombolytics it is Second by avoiding the use of chemical thrombolytics it is
possible to extend the treatment window beyond the limit of 6ndash8 possible to extend the treatment window beyond the limit of 6ndash8 hours hours
Third mechanically fragmenting a clot increases the surface area Third mechanically fragmenting a clot increases the surface area accessible to fibrinolytic agents and allows inflow of fresh accessible to fibrinolytic agents and allows inflow of fresh plasminogen which in turn may increase the speed of plasminogen which in turn may increase the speed of thrombolysis thrombolysis
Finally clot-retrieval devices may provide faster recanalization Finally clot-retrieval devices may provide faster recanalization
The disadvantages of the mechanical The disadvantages of the mechanical approaches approaches technical difficulty of navigating mechanical technical difficulty of navigating mechanical
devices into the intracranial circulation excessive devices into the intracranial circulation excessive trauma to the vasculature (potentially leading to trauma to the vasculature (potentially leading to vasospasm vessel dissection perforation or vasospasm vessel dissection perforation or rupture) rupture)
fragmented thrombus causing distal embolization fragmented thrombus causing distal embolization into previously unaffected territories into previously unaffected territories
Nevertheless the advantages of mechanical stroke Nevertheless the advantages of mechanical stroke therapy appear to significantly outweigh its therapy appear to significantly outweigh its disadvantages and risksdisadvantages and risks
Contraindications to Thrombolytic Contraindications to Thrombolytic agents agents
Recent thoracic abdominal or Recent thoracic abdominal or intracranial surgeryintracranial surgery
Recent haemorrhagic CVA Head injury Recent haemorrhagic CVA Head injury or neoplasmor neoplasm
Bleeding ulcerBleeding ulcer Anticipated invasive procedures (arterial Anticipated invasive procedures (arterial
punctures biopsies)punctures biopsies) Concurrent hemostatic dysfunctionConcurrent hemostatic dysfunction
Monitoring of thrombolytic Monitoring of thrombolytic therapytherapy
Thrombin time Measures the availability of functional
fibrinogen Normal thrombin time is 10-14 sec Prolonged when fibrinogen level is below
75-100 mgdl
Half Life of ThrombolyticsHalf Life of ThrombolyticsAgent Administration Half Life
Streptokinase IA 60-80min
Urokinase IAIV 9-12min
rTPA IAIV 6min
Abciximab(Reopro) IAIV 12hour
Aspirin POIV 15-20min
Heparin IVSC 60min
Coumadin PO 15-25 days
Anti Platelet DrugsAnti Platelet DrugsDrug Drug Mechanism Mechanism UsesUsesAspirinAspirin Permanently inhibits Permanently inhibits
COX-1 and COX-2COX-1 and COX-2CADCAD
Stroke-TIAsStroke-TIAs
NSAIDsNSAIDs Reversibly inhibits Reversibly inhibits COX-1COX-1
LimitedLimited
DipyridamoleDipyridamole Inhibits PDE increases Inhibits PDE increases cAMPcAMP
TIAsTIAs
ThenopyridinesThenopyridines
(Ticlopidine(Ticlopidine
ClopidrgrelClopidrgrel))
Inhibits ADP Inhibits ADP
PlatAg PlatAg
TIAsStrokeTIAsStroke
CAD PVDCAD PVD
Abciximab (ReoPro)Abciximab (ReoPro)
Eptifibatide (Integrilin)Eptifibatide (Integrilin)
TirofibanTirofiban
GP IIBIIIA InhibitorsGP IIBIIIA Inhibitors
Stroke- TIAs Stroke- TIAs
MonitoringMonitoring
Bleeding timeBleeding time
Optical aggregometryOptical aggregometry
Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay
Bleeding timeBleeding time
Requires a skin incision (usually made on the ear lobe or Requires a skin incision (usually made on the ear lobe or forearm offorearm of
a depth that results in disruption of capillary loops and a depth that results in disruption of capillary loops and small vessels)small vessels)
AdvantagesAdvantages Universally availableUniversally available Relatively simple techniquesRelatively simple techniques Can be performed bedsideCan be performed bedside
DisadvantagesDisadvantages Insensitive inaccurate non-specific techniqueInsensitive inaccurate non-specific technique
Poorly reproducible (as depends on multiple variables)Poorly reproducible (as depends on multiple variables)
Optical aggregometryOptical aggregometry
Gold standard assay for platelet functionGold standard assay for platelet function Agonist induced aggregation is measuredAgonist induced aggregation is measured Different agonist are available for different Different agonist are available for different
agentsagents However require unique expertise and are not However require unique expertise and are not
universally availableuniversally available Aspirin measured with ADP or AA(gt70 Aspirin measured with ADP or AA(gt70
aggregation so resistance)aggregation so resistance) Clopidogrel( ADP gt 90 aggregation means Clopidogrel( ADP gt 90 aggregation means
resistance) resistance)
Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay
Can be performed bed sideCan be performed bed side Different assay devices with different Different assay devices with different
agonist are used for each of different agonist are used for each of different antiplatelet agents antiplatelet agents
For Aspirin AA is used (result is reported as aspirin For Aspirin AA is used (result is reported as aspirin reaction units [ARU] ARUgt 550 indicates non-reaction units [ARU] ARUgt 550 indicates non-responsiveness)responsiveness)
Verify IIbIIIa assay device uses TRAP as agonist for Verify IIbIIIa assay device uses TRAP as agonist for Abciximab and TirofibanAbciximab and Tirofiban
Practical Applications Practical Applications related to specific related to specific
Neurovascular Neurovascular interventionsinterventions
Acute ischemic StrokeAcute ischemic Stroke When an artery occludes neurons are affected When an artery occludes neurons are affected
differently depending upon the amount of residual blood differently depending upon the amount of residual blood flowflow
Normal cerebral blood flow is greater than 50 mL100 Normal cerebral blood flow is greater than 50 mL100 mgminmgmin
Once blood flow decreases to less than 20 mL100 Once blood flow decreases to less than 20 mL100 mgmin infarction occursmgmin infarction occurs
If blood flow decreases to less than 10 mL100 mgmin If blood flow decreases to less than 10 mL100 mgmin irreversible neuronal death occurs rapidly irreversible neuronal death occurs rapidly
Blood flow between 11 and 20 mL100 mgmin is thought Blood flow between 11 and 20 mL100 mgmin is thought to represent the ischemic penumbra an area where the to represent the ischemic penumbra an area where the cells are functionally silent because of ischemia but are cells are functionally silent because of ischemia but are still able to recover if blood flow is restored still able to recover if blood flow is restored
Many acute stroke therapies are targeted toward Many acute stroke therapies are targeted toward restoring flow or function to the ischemic penumbrarestoring flow or function to the ischemic penumbra
Therapeutic window in Therapeutic window in management of acute Ischemic management of acute Ischemic
StrokeStrokeThe early diagnosis of ischemic stroke is critical to the The early diagnosis of ischemic stroke is critical to the
with only a narrow therapeutic window in the first few with only a narrow therapeutic window in the first few hours following stroke ictushours following stroke ictus
Diagnosis in the first 3 hours postictus provides the Diagnosis in the first 3 hours postictus provides the opportunity for intravenous or intraarterial thrombolysis opportunity for intravenous or intraarterial thrombolysis and intra-arterial clot mechanical treatment which and intra-arterial clot mechanical treatment which improve the outcome improve the outcome
Diagnosis in the time period between 3 and 6 hours Diagnosis in the time period between 3 and 6 hours provides an opportunity for intra-arterial thrombolysis provides an opportunity for intra-arterial thrombolysis and mechanical treatment and mechanical treatment
Involvement of the posterior circulation especially the Involvement of the posterior circulation especially the basilar artery is treated by some regardless of time of basilar artery is treated by some regardless of time of onset or up until 12 to 24 hours in some practices This is onset or up until 12 to 24 hours in some practices This is related to the potentially high mortality and morbidity related to the potentially high mortality and morbidity associated with basilar artery thrombosisassociated with basilar artery thrombosis
Infarct evaluation on angiographyInfarct evaluation on angiography(CT angiography and catheter (CT angiography and catheter
angiography)angiography)CTA is an excellent first-line examination for CTA is an excellent first-line examination for
evaluation of the head and neck arteries evaluation of the head and neck arteries In comparison with catheter angiography In comparison with catheter angiography
what it gives up in resolution and dynamic what it gives up in resolution and dynamic properties it makes up for with rapid properties it makes up for with rapid acquisition of a 3-D dataset and the potential acquisition of a 3-D dataset and the potential for assessment of whole-brain perfusion and for assessment of whole-brain perfusion and better parenchymal evaluationbetter parenchymal evaluation
Moreover CTA illustrates not only arterial Moreover CTA illustrates not only arterial stenosis or occlusion but also the vessel wall stenosis or occlusion but also the vessel wall This factor is most important for evaluation of This factor is most important for evaluation of intramural dissection and thrombosed intramural dissection and thrombosed aneurysms which may both complicate aneurysms which may both complicate evaluation of stroke patientsevaluation of stroke patients
Early angiographic signs of strokes Early angiographic signs of strokes both CTA both CTA and DSA and DSA
Vessel occlusion or cutoff related to Vessel occlusion or cutoff related to thromboembolithromboemboli
aneurysms aneurysms arterial dissection arterial dissection Meniscus or flattened shape to clot Meniscus or flattened shape to clot
(recent) versus reverse meniscus (older)(recent) versus reverse meniscus (older) tram track (nonocclusive or recanalized tram track (nonocclusive or recanalized
clot) clot) delayed (antegrade) flow (manifest as delayed (antegrade) flow (manifest as
decreased whole-brain perfusion on CTA)decreased whole-brain perfusion on CTA) retrograde collateral flowretrograde collateral flow
Non-occlusive left MCA thrombus on 3-D imaging performed from CTA source data and was confirmed at catheter angiography
Therapy to be started within a 6-hr Therapy to be started within a 6-hr time to treatment (TTT) window time to treatment (TTT) window (while in case of IV thrombolysis (while in case of IV thrombolysis therapy to be started with in 3hrs)therapy to be started with in 3hrs)
Exclusion criteria Exclusion criteria Rapidly improving neurologic deficit or Rapidly improving neurologic deficit or Sustained blood pressure of gt180100 Sustained blood pressure of gt180100 Hemorrhage is detected on CTHemorrhage is detected on CT Infarct involving gt more than 13 rd Infarct involving gt more than 13 rd
territory of MCAterritory of MCA MRADWI-Perfusion mismatchlt 20MRADWI-Perfusion mismatchlt 20 Definite hypodensity on CTDefinite hypodensity on CT
Intra-arterial Thrombolysis
Fibrinolytics + AntiplateletsFibrinolytics + Antiplatelets
PlasminogenPlasminogen activators through fibrinolysis exposes activators through fibrinolysis exposes free thrombin and paradoxically stimulatesfree thrombin and paradoxically stimulates platelet platelet aggregation which leads to formation of aaggregation which leads to formation of a platelet platelet thrombus (white clot) thrombus (white clot)
This new thrombus is relatively resistant to This new thrombus is relatively resistant to fibrinolyticsfibrinolytics
So new regimen in case of acute stroke isSo new regimen in case of acute stroke is fibrinolytics + antiplatelet drugsfibrinolytics + antiplatelet drugs
rtPA + IIbIIIa inhibitors( tirofiban rtPA + IIbIIIa inhibitors( tirofiban abciximab) orabciximab) or
Urokinase + IIbIIIa Urokinase + IIbIIIa inhibitors( tirofiban abciximab)inhibitors( tirofiban abciximab)
Intra-arterial Thrombolysis Tirofiban (04 microgkgmin bolus for 3 min followed by Tirofiban (04 microgkgmin bolus for 3 min followed by
0125 ugkgmin)0125 ugkgmin)
++
Heparin (2000ndash3000 IU bolus followed by Heparin (2000ndash3000 IU bolus followed by 1000 IUhour infusion 1000 IUhour infusion
with ACT maintained bw 200-300) throughout the with ACT maintained bw 200-300) throughout the interventional procedure and for 24ndash48 hours thereafter when interventional procedure and for 24ndash48 hours thereafter when there is neither intraprocedural bleeding nor suspicion of there is neither intraprocedural bleeding nor suspicion of increased risk of bleeding increased risk of bleeding
Maximum dose of Urokinase Maximum dose of Urokinase Anterior circulation stroke - 500000 IU (mean 400000 Anterior circulation stroke - 500000 IU (mean 400000
IU range 300000ndash500000 IU)IU range 300000ndash500000 IU) Posterior circulation stroke -1000000 IU (mean 837000 Posterior circulation stroke -1000000 IU (mean 837000
IU range 300000ndash1000000 IU)IU range 300000ndash1000000 IU)American Journal of NeuroradiologyAmerican Journal of Neuroradiology 262595-2601 2005262595-2601 2005
Intravenous ThrombolysisIntravenous Thrombolysis
The first method to restore cerebral The first method to restore cerebral perfusion is clot lysis with the goal perfusion is clot lysis with the goal of re-establishing blood flow to the of re-establishing blood flow to the affected tissue affected tissue
IV thrombolysis rt-PA is the only IV thrombolysis rt-PA is the only FDA- approved treatment for AIS FDA- approved treatment for AIS
Fibrinolysis is enhanced powerfully Fibrinolysis is enhanced powerfully by rt-PAby rt-PA
Intravenous rTPA Intravenous rTPA administration administration protocolprotocol
Total dose of rt-PA 09 mgkg (maximum dose Total dose of rt-PA 09 mgkg (maximum dose 90 mg)90 mg)
Give 10 as initial IV bolusGive 10 as initial IV bolus Infuse remainder over 1 hourInfuse remainder over 1 hour Admit patient to an ICU or stroke unit for Admit patient to an ICU or stroke unit for
monitoringmonitoring Neurologic assessments every 15 minutes Neurologic assessments every 15 minutes
during infusion then every 30 minutes for next during infusion then every 30 minutes for next 6 hours then every hour until 24hours after 6 hours then every hour until 24hours after treatmenttreatment
Favorable Outcome vs Treatment Time Favorable Outcome vs Treatment Time with IV rTPAwith IV rTPA
Protocol limit = 3 hrs
Benefit ~ 45 hrs
Thromboembolism During coilingThromboembolism During coiling Most feared and frequent complication Most feared and frequent complication Reported incidence - Approx 7 Reported incidence - Approx 7 SourcesSources of Thromboembolism are of Thromboembolism are
- Clots at the aneurysmal neck during or immediately- Clots at the aneurysmal neck during or immediately after after embolization embolization
- Thrombus forming on catheters during- Thrombus forming on catheters during proceduresprocedures
- Stenosis of an adjacent artery dt coil mass- Stenosis of an adjacent artery dt coil mass or herniationor herniation
- Migration of intraaneurysmal- Migration of intraaneurysmal thrombus during coil thrombus during coil placement placement
- Slow flow dt vasospasm - Slow flow dt vasospasm
- Rare and unlikely causes are hypercoagulable- Rare and unlikely causes are hypercoagulable state such state such as antiphospholipid antibody syndrome or due to HITas antiphospholipid antibody syndrome or due to HIT
Occur more often with wide-necked aneurysms (dt Occur more often with wide-necked aneurysms (dt increased exposed surface area of thrombogenic coil increased exposed surface area of thrombogenic coil material)material)
Current regimen of endovascular Current regimen of endovascular managementmanagement
The The glycoprotein IIbIIIa antagonist tirofiban glycoprotein IIbIIIa antagonist tirofiban (04 (04 microgkgmin bolus for 30 minutes followed by infusion of microgkgmin bolus for 30 minutes followed by infusion of 0125 ugkgmin until the thrombus dissolved) 0125 ugkgmin until the thrombus dissolved)
Intraarterial thrombolysis with Intraarterial thrombolysis with urokinase or r- TPA urokinase or r- TPA increase of intravenous (IV) heparin (measured by increase of intravenous (IV) heparin (measured by
ACT) ACT) Intravenous aspirin Intravenous aspirin
Coil-related platelet aggregation (white clot) is Coil-related platelet aggregation (white clot) is unlikely to respond to fibrinolytics but has a high risk unlikely to respond to fibrinolytics but has a high risk of hemorrhage (In ISAT) all 5 patients who had of hemorrhage (In ISAT) all 5 patients who had received thrombolytic therapy with tPA to treat a received thrombolytic therapy with tPA to treat a thromboembolic complication after endovascular thromboembolic complication after endovascular treatment rebleed and all of these patients died)treatment rebleed and all of these patients died)
IntracranialIntracranial Stenting Stenting Metallic foreign body such as stent will accumulate Metallic foreign body such as stent will accumulate
thrombus in the absence of platelet inhibitionthrombus in the absence of platelet inhibition Antiplatelet drugs are important to prevent peri or Antiplatelet drugs are important to prevent peri or
post-interventional thromboembolic eventspost-interventional thromboembolic events Optimal treatment regimens has not been determined Optimal treatment regimens has not been determined
but usually but usually Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-
procedureprocedureOrOr
Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on
morning of proceduremorning of procedure
If need to use stent is not pre-planned thanIf need to use stent is not pre-planned than
Abciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkgAbciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkg IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)
Glycoprotein IIbIIIa inhibitor are not used routinely during elective Glycoprotein IIbIIIa inhibitor are not used routinely during elective stenting procedure dt increased risk of ICH stenting procedure dt increased risk of ICH
Carotid StentingCarotid Stenting
Pre-procedurePre-procedure
Double Antiplatelet therapy is routinely given Double Antiplatelet therapy is routinely given beginning at least 3beginning at least 3
days before the proceduredays before the procedure
Aspirin 325mgd+Clopidogrel 75mgdAspirin 325mgd+Clopidogrel 75mgd During procedureDuring procedure
Heparin is given with target clotting time of 250-Heparin is given with target clotting time of 250-300sec300sec
Post-procedure Post-procedure
Aspirin 325mg is continued indefinitely and Aspirin 325mg is continued indefinitely and
Clopidogrel 75mgd for at least 6 weeks Clopidogrel 75mgd for at least 6 weeks
Inclusion criteria for Local ThrombolysisInclusion criteria for Local Thrombolysis a)a) Patients in severe clinical grade on admission Patients in severe clinical grade on admission
with evidence of dural venous sinus with evidence of dural venous sinus thrombosis and restrictive venous outflow on thrombosis and restrictive venous outflow on cerebral angiogramcerebral angiogram
b)b) Patients in clinical grade 3 worsening on Patients in clinical grade 3 worsening on heparin therapy Restriction to venous heparin therapy Restriction to venous outflow was defined as an increase in brain outflow was defined as an increase in brain circulation time gt 12 s delay in the drainage circulation time gt 12 s delay in the drainage of cortical veins with cortical veins hanging of cortical veins with cortical veins hanging in spacein space
Treatment Options for Venous Thrombosis
CT Grading for Venous ThrombosisCT Grading for Venous Thrombosis Grade I no parenchymal change Grade I no parenchymal change
(hyperdense (hyperdense sinuses cortical veins empty sinuses cortical veins empty delta sign)delta sign)
Grade II non hemorrhagic venous infarct Grade II non hemorrhagic venous infarct without mass effect without mass effect
Grade III non-hemorrhagic infarct with Grade III non-hemorrhagic infarct with mass effectmass effect
Grade IV hemorrhagic venous infarct (max Grade IV hemorrhagic venous infarct (max diameter lt 3 cm) with no mass effectdiameter lt 3 cm) with no mass effect
Grade V hemorrhagic venous infarct (max Grade V hemorrhagic venous infarct (max diameter gt 3 cm) with mass effect diameter gt 3 cm) with mass effect
Local ThrombolysisLocal Thrombolysis
Femoral Jugular access was secured and a guiding Femoral Jugular access was secured and a guiding catheter was placed in the jugular bulb catheter was placed in the jugular bulb Mechanical Mechanical clot maceration clot maceration was done with the guidewire was done with the guidewire following which a microcatheter (was navigated and following which a microcatheter (was navigated and placed in the thrombosed segment of sinus confirmed placed in the thrombosed segment of sinus confirmed on a selective venogram on a selective venogram
Urokinase infusion Bolus dose of 2-6 lacs followed Urokinase infusion Bolus dose of 2-6 lacs followed by 60000 to 100000 units per hour along with by 60000 to 100000 units per hour along with periodic check venogram Along with maintenance periodic check venogram Along with maintenance systemic infusion of Heparinsystemic infusion of Heparin Other agents such as Other agents such as streptokinase altepase or rTPAstreptokinase altepase or rTPA can be also used can be also used
After thrombolysis patient should subjected to oral After thrombolysis patient should subjected to oral anticoagulation for six monthsanticoagulation for six months
Low-molecular-weight Low-molecular-weight heparinheparin
PharmacologyPharmacologyLMWH as its name suggests is a glycosaminoglycan that is approximatelyLMWH as its name suggests is a glycosaminoglycan that is approximately
one third the molecular weight of UFH It is derived from UFH through one third the molecular weight of UFH It is derived from UFH through variousvarious
depolymerization processes LMWH binds to antithrombin which in turn depolymerization processes LMWH binds to antithrombin which in turn
Neutralizes actors Xa and IIa Because LMWH lacks many of the longer Neutralizes actors Xa and IIa Because LMWH lacks many of the longer chains chains
required for binding to thrombin it has less ability to neutralize thrombin required for binding to thrombin it has less ability to neutralize thrombin
relativeto its ability to neutralize factor Xa LMWH also has less relativeto its ability to neutralize factor Xa LMWH also has less nonspecific nonspecific
binding to other proteins There is greater bioavailability with more binding to other proteins There is greater bioavailability with more predictable predictable
pharmacokinetics that eliminates the need for monitoring The smaller pharmacokinetics that eliminates the need for monitoring The smaller size also size also
allows for enhanced subcutaneous absorption when compared with UFHallows for enhanced subcutaneous absorption when compared with UFH
Three LMWH preparations are Three LMWH preparations are currently approved for use in the currently approved for use in the United States (1) enoxaparin (2) United States (1) enoxaparin (2) dalteparin and (3) tinzaparin dalteparin and (3) tinzaparin
They are all administered They are all administered subcutaneously at intervals of either subcutaneously at intervals of either once or twice daily for both once or twice daily for both prophylaxis and treatment dosesprophylaxis and treatment doses
Few Experiences of Few Experiences of ThrombolysisThrombolysis
Vickey 25 Yrs male patient presented Vickey 25 Yrs male patient presented with 12with 12thth day HO severe headache with day HO severe headache with right sided hemiplegiaright sided hemiplegia
MRI shows thrombosis of the superior MRI shows thrombosis of the superior sagittal left transverse left sigmoid sagittal left transverse left sigmoid sinuses and cortical veins in the fronto-sinuses and cortical veins in the fronto-parietal regions with eo haemorrhagic parietal regions with eo haemorrhagic infarct in the left cerebral hemisphere infarct in the left cerebral hemisphere with mass effect( Grade ndashV)with mass effect( Grade ndashV)
Sashi Srivastava 64 yrs FSashi Srivastava 64 yrs F In a follow up case of MRD with infra-renal In a follow up case of MRD with infra-renal
aortic abdominal and bilateral renal artery aortic abdominal and bilateral renal artery thrombosis renal angiogram shows filling thrombosis renal angiogram shows filling defects in the right Renal artery defects in the right Renal artery
Initially Renal angioplasty was done Initially Renal angioplasty was done Following angioplasty few thrombi are seem Following angioplasty few thrombi are seem to extends into the segmental branches and to extends into the segmental branches and causing blockage So Thrombolysis was causing blockage So Thrombolysis was plane to dissolve the run-out thrombi with plane to dissolve the run-out thrombi with urokinase urokinase
Rakesh 34yrsMRakesh 34yrsM Left SFA pseudoaneurysm with Left SFA pseudoaneurysm with
Covered stent placementCovered stent placement Pre operative antiplatelets with post Pre operative antiplatelets with post
procedure heparin Tirofiban procedure heparin Tirofiban followed by aspirin and clopidogrel followed by aspirin and clopidogrel were usedwere used
IAT may be a treatment option for selected patients IAT may be a treatment option for selected patients Possible selection criteria include Possible selection criteria include
presentation between 3 and 6 hours from symptom onsetpresentation between 3 and 6 hours from symptom onset major cerebral artery occlusion major cerebral artery occlusion severe neurologic deficits severe neurologic deficits high risk of systemic hemorrhage with IV rt-PA (eg recent high risk of systemic hemorrhage with IV rt-PA (eg recent
surgery) surgery) The MERCI (Mechanical Embolus Removal in Cerebral The MERCI (Mechanical Embolus Removal in Cerebral
Ischemia) retrievalIschemia) retrieval system system
Has been FDA-approved for recanalizing acutely occluded Has been FDA-approved for recanalizing acutely occluded cerebral arteries cerebral arteries
In the Multi-MERCI study patients who did not improve In the Multi-MERCI study patients who did not improve immediately after IV rt-PA underwent mechanical immediately after IV rt-PA underwent mechanical embolectomy within 8 hours of symptom onset embolectomy within 8 hours of symptom onset
Partial or complete recanalization occurred in 74 of Partial or complete recanalization occurred in 74 of patientspatients
with a symptomatic intracerebral hemorrhage (sICH) rate of with a symptomatic intracerebral hemorrhage (sICH) rate of 67 67
Mechanical embolectomy with the MERCI retriever may be a Mechanical embolectomy with the MERCI retriever may be a feasible and safe option for patients after IV rt-PAfeasible and safe option for patients after IV rt-PA
Penumbra stroke systemPenumbra stroke system This device combines two methods of clot This device combines two methods of clot
extraction aspiration and mechanical extraction aspiration and mechanical extraction extraction
First the clot is aspirated then a thrombus First the clot is aspirated then a thrombus removal ring can be used if necessary to removal ring can be used if necessary to remove remaining clot remove remaining clot
successful recanalizing 82successful recanalizing 82 Bridging therapyBridging therapy
06 mgkg IV rt-PA followed by IAT with IA rt-06 mgkg IV rt-PA followed by IAT with IA rt-PA (up to 20 mg)PA (up to 20 mg)
achieved a higher recanalization rateachieved a higher recanalization rate
Criteria for thrombolysis with rTPACriteria for thrombolysis with rTPA
Inclusion criteriaInclusion criteria Clinical signs and symptoms consistent with ischemic Clinical signs and symptoms consistent with ischemic
strokestroke Patient last seen normal within 3 hoursPatient last seen normal within 3 hours Measurable neurologic deficitMeasurable neurologic deficit
Exclusion criteriaExclusion criteria Any hemorrhage on neuroimaging (CT or MRI)Any hemorrhage on neuroimaging (CT or MRI) Symptoms suggestive of subarachnoid hemorrhageSymptoms suggestive of subarachnoid hemorrhage Seizure at stroke onset that is thought to contribute to Seizure at stroke onset that is thought to contribute to
neurologic deficitneurologic deficit Hypodensity greater than one third cerebral hemisphere Hypodensity greater than one third cerebral hemisphere
on CTon CT SBP greater than 185 mm Hg or DBP greater than 110 SBP greater than 185 mm Hg or DBP greater than 110
mm Hgmm Hg International normalized ratio (INR) greater than 17International normalized ratio (INR) greater than 17
Ischemic Stroke Ischemic Stroke Treatment ndash 2006Treatment ndash 2006
IV tissue plasminogen activator (tPA)IV tissue plasminogen activator (tPA) ndash ndash Only FDA-approved acute stroke drugOnly FDA-approved acute stroke drug ndash ndash 3 hour treatment window3 hour treatment window
MERCI - Concentric clot retrieval MERCI - Concentric clot retrieval devicedevice ndash ndash Rescue therapy - approved 2004Rescue therapy - approved 2004 ndash ndash Device approval (not outcomes-based)Device approval (not outcomes-based)
Off label approachesOff label approaches ndash ndash IV tPA after 3 hoursIV tPA after 3 hours ndash ndash IV-IA tPA sequential strategiesIV-IA tPA sequential strategies ndash ndash IA tPA clot angioplasty fragmentationIA tPA clot angioplasty fragmentation ndash ndash Ultrasound-assisted tPA lysisUltrasound-assisted tPA lysis
rt-PA Trials NINDSrt-PA Trials NINDS
Acute stroke - 624 patientsAcute stroke - 624 patients Treat within 3 hrsTreat within 3 hrs Intravenous 09 mgkg rt-PA vs placeboIntravenous 09 mgkg rt-PA vs placebo Hemorrhage 64 tPA 06 placeboHemorrhage 64 tPA 06 placebo Neurologic recovery better with tPA 30 Neurologic recovery better with tPA 30
more like to have minimal or no disabilitymore like to have minimal or no disability
First proven approved treatment for First proven approved treatment for strokestroke
Limitations of tPALimitations of tPA Only 4 of acute strokes receive tPAOnly 4 of acute strokes receive tPA (Kleindorfer et al Stroke 2004 35 e27-e29)(Kleindorfer et al Stroke 2004 35 e27-e29)
Only 22 of patients present within 3 hoursOnly 22 of patients present within 3 hours1048707 1048707 51 of these ineligible due to51 of these ineligible due to
bull bull Mild severityMild severity bull bull Medical or surgical historyMedical or surgical history bull bull Blood testsBlood tests
Sustained recanalization only 13Sustained recanalization only 13 (Alexandrov et al NEJM 2004 351 2170-8)(Alexandrov et al NEJM 2004 351 2170-8)
Concern for hemorrhageConcern for hemorrhage tPA potentiates apoptotic injury tPA potentiates apoptotic injury (Liu et al Nature Med 2004 101379-83)(Liu et al Nature Med 2004 101379-83)
PROACT II IA Lysis TrialPROACT II IA Lysis Trial Baseline 24 hours 8 days
Baseline 60 minutes 120 minutes
9mg IAProurokinase
Desmoteplase Trials DEDAS Desmoteplase Trials DEDAS DIASDIAS
Trial OverviewTrial Overview Double blind randomized placebo Double blind randomized placebo
controlled trialscontrolled trials IV delivery 3-9 hour time windowIV delivery 3-9 hour time window Plasminogen activator ndash from Plasminogen activator ndash from vampire bat vampire bat
salivasaliva Selection based on PWI-DWI MismatchSelection based on PWI-DWI Mismatch
MRI InclusionMRI Inclusion PWI defect at least 2 cm AND ~20 larger PWI defect at least 2 cm AND ~20 larger
than DWIthan DWI PWI should be obvious even visible on PWI should be obvious even visible on
raw imagesraw imagesMRI ExclusionMRI Exclusion
DWI gt 13 MCADWI gt 13 MCA MRA ICA occlusionMRA ICA occlusion
Desmoteplase ndash DIAS Desmoteplase ndash DIAS ResultsResults
Mechanical Thrombolysis Mechanical Thrombolysis devicesdevices
mechanical thrombolysis potentially extends the treatment mechanical thrombolysis potentially extends the treatment window because they act promptly at the site of the thrombuswindow because they act promptly at the site of the thrombus
The devices can retrieve large clots that pharmaceutical agents The devices can retrieve large clots that pharmaceutical agents may not successfully lysemay not successfully lyse
Patients treated with IV tPA may be considered for treatment of Patients treated with IV tPA may be considered for treatment of residual clot with some of these devicesresidual clot with some of these devices
suction-creating saline jets suction-creating saline jets laser energy ultrasound laser energy ultrasound a corkscrew apparatus to treat strokesa corkscrew apparatus to treat strokes The AngioJet systemThe AngioJet system uses saline jets that are directed back into the catheter to uses saline jets that are directed back into the catheter to
create a low-pressure zone around the catheter tip inducing create a low-pressure zone around the catheter tip inducing suction suction
The clot is pulled into the exhaust lumen and removed from the The clot is pulled into the exhaust lumen and removed from the vessel Although US Food and Drug Administration (FDA) has vessel Although US Food and Drug Administration (FDA) has approved this device for use in arteriovenous dialysis grafts and approved this device for use in arteriovenous dialysis grafts and fistulae and for the treatment of coronary arteries saphenous fistulae and for the treatment of coronary arteries saphenous vein grafts and peripheral vessels clinical trials for the vein grafts and peripheral vessels clinical trials for the treatment of acute stroke are no longer in progress treatment of acute stroke are no longer in progress
Most devices are used in cerebral vessels that 2-5 mm
The Latis laser device The Latis laser device used laser energy to ablate clots used laser energy to ablate clots Arteries 2-5 mm in diameter could be Arteries 2-5 mm in diameter could be
treated including the ICA M1 or M2 treated including the ICA M1 or M2 branch of the MCA A1 branch of the branch of the MCA A1 branch of the anterior cerebral artery (ACA) basilar anterior cerebral artery (ACA) basilar artery posterior cerebral artery (PCA) artery posterior cerebral artery (PCA) and vertebral and vertebral
Patients could receive treatment as late Patients could receive treatment as late as 8 hours after symptom onset in the as 8 hours after symptom onset in the anterior circulation and within 24 hours in anterior circulation and within 24 hours in the posterior circulation the posterior circulation
Endovascular Photo Acoustic Endovascular Photo Acoustic Recanalization (EPAR) Recanalization (EPAR)
A laser power source generated energy for the A laser power source generated energy for the systemsystem
The energy was delivered by means of The energy was delivered by means of fiberoptics to the tip of the catheter at the fiberoptics to the tip of the catheter at the treatment sitetreatment site
Absorption of laser light by darkly pigmented Absorption of laser light by darkly pigmented materials (ie the clot) occurred inside the 1-mm materials (ie the clot) occurred inside the 1-mm catheter tipcatheter tip
the system was designed to minimize scattering the system was designed to minimize scattering of laser light of laser light
Absorption converted photo energy to acoustic Absorption converted photo energy to acoustic energy which then emulsified the clot inside the energy which then emulsified the clot inside the catheter tip catheter tip
EKOS ultrasound( the EKOS ultrasound( the Ultrasound Thrombolytic Ultrasound Thrombolytic
Infusion Catheter) Infusion Catheter) combines the use of a distal ultrasound transducer with combines the use of a distal ultrasound transducer with
infusion of a thrombolytic agent through the infusion of a thrombolytic agent through the microcathetermicrocatheter
Ultrasound changes the structure of the clot to Ultrasound changes the structure of the clot to temporarily increase its permeability while providing an temporarily increase its permeability while providing an acoustic pressure gradient to move the drug into the clot acoustic pressure gradient to move the drug into the clot to speed its dissolution to speed its dissolution
The EKOS catheter is placed in the proximal portion of the The EKOS catheter is placed in the proximal portion of the clot clot
After a 2-mg bolus of tPA was injected through the After a 2-mg bolus of tPA was injected through the catheter catheter
the patient received a continuous infusion of IA tPA 03 the patient received a continuous infusion of IA tPA 03 mgmin to a maximum of 20 mg and simultaneous mgmin to a maximum of 20 mg and simultaneous ultrasound transmission for as long as 60 minutes ultrasound transmission for as long as 60 minutes
One patient was treated with a total of 4 units of One patient was treated with a total of 4 units of recombinant reteplase (Retavase) hand-injected over 60 recombinant reteplase (Retavase) hand-injected over 60 minutes minutes
Penumbra system Penumbra system The Penumbra system (Penumbra Inc) provides a dual The Penumbra system (Penumbra Inc) provides a dual
approach to clot extraction using aspiration followed by approach to clot extraction using aspiration followed by clot retrieval with a ring device if needed clot retrieval with a ring device if needed
Mechanical Embolus Removal in Cerebral Ischemia Mechanical Embolus Removal in Cerebral Ischemia (MERCI)(MERCI)
a corkscrew-like apparatus to remove blood clots from a corkscrew-like apparatus to remove blood clots from the brain in patients experiencing an ischemic stroke the brain in patients experiencing an ischemic stroke
The corkscrew itself resides in the catheter tip which The corkscrew itself resides in the catheter tip which shields it from the wall of the vessel until it is ready to be shields it from the wall of the vessel until it is ready to be burrowed into the clot Once lodged in the clot the device burrowed into the clot Once lodged in the clot the device and clot are withdrawn from the vessel and clot are withdrawn from the vessel
Snarelike devicesSnarelike devices Snares such as the Neuronet snare (Guidant Snares such as the Neuronet snare (Guidant
Endovascular Santa Clara CA) have been developed Endovascular Santa Clara CA) have been developed specifically for use in the treatment of strokes specifically for use in the treatment of strokes
These devices are simple in design and do not require the These devices are simple in design and do not require the clot to be amenable to emulsification clot to be amenable to emulsification
X-Sizer deviceX-Sizer device a device with small moving blades at the a device with small moving blades at the
catheter tip catheter tip This device the X-Sizer device (EndiCor Medical This device the X-Sizer device (EndiCor Medical
San Clemente CA) can be used to excise the San Clemente CA) can be used to excise the thrombus and aspirate it thrombus and aspirate it
The device was being evaluated in randomized The device was being evaluated in randomized studies of coronary vessels and in a registry of studies of coronary vessels and in a registry of patients with acute myocardial infarctionpatients with acute myocardial infarction
Although the manufacturer had modified the Although the manufacturer had modified the device for use in cerebral vessels a safety and device for use in cerebral vessels a safety and feasibility study was indefinitely suspended after feasibility study was indefinitely suspended after only 1 patient was treated with the device in only 1 patient was treated with the device in Europe Europe
Suction thrombectomySuction thrombectomy This method of mechanical thrombolysis is one of the This method of mechanical thrombolysis is one of the
simplestsimplest In this readily available technique suction is applied with In this readily available technique suction is applied with
a syringe to remove thrombus in the ICA a syringe to remove thrombus in the ICA It requires no other devicesIt requires no other devices A catheter with a large inner diameter (Brite Tip Cordis A catheter with a large inner diameter (Brite Tip Cordis
Corporation Miami FL) was placed in the symptomatic Corporation Miami FL) was placed in the symptomatic vessel and navigated over a guidewire into the thrombusvessel and navigated over a guidewire into the thrombus
A 60-mL syringe was used to aspirate the thrombus A 60-mL syringe was used to aspirate the thrombus Each patient required angioplasty and stenting of carotid Each patient required angioplasty and stenting of carotid
bifurcation stenosis and received daily aspirin and bifurcation stenosis and received daily aspirin and ticlopidine after the procedure No complications ticlopidine after the procedure No complications occurred occurred
Summary Acute Stroke Summary Acute Stroke ImagingImaging
PhysiologyPhysiology importance collaterals importance collaterals
ndash ndashGrowing role for perfusion Growing role for perfusion assessmentassessment
tPAtPA guidelines amp limitations guidelines amp limitations Signs on CT amp MRSigns on CT amp MR follow physiology follow physiology Stroke trialsStroke trials PWI-DWI mismatch PWI-DWI mismatch
ndash ndashTreat based on physiology not timeTreat based on physiology not time ProtocolsProtocols should be fast and should be fast and
comprehensivecomprehensive
Stages of blood coagulationStages of blood coagulation Formation of Formation of ProthrombinaseProthrombinase
Prothrombinase can be formed in two ways depending of which of Prothrombinase can be formed in two ways depending of which of two systems or pathways apply two systems or pathways apply
Intrinsic SystemIntrinsic System This is initiated by liquid blood making contact with a foreign This is initiated by liquid blood making contact with a foreign
surface ie something that is not part of the body surface ie something that is not part of the body Extrinsic SystemExtrinsic System
This is initiated by liquid blood making contact with damaged This is initiated by liquid blood making contact with damaged tissuetissue
Both the intrinsic and the extrinsic systems involve interactions Both the intrinsic and the extrinsic systems involve interactions between between coagulation factorscoagulation factors
2 2 ProthrombinProthrombin converted into the enzyme converted into the enzyme ThrombinThrombinProthrombinase (formed in stage 1) converts prothrombin which is Prothrombinase (formed in stage 1) converts prothrombin which is a plasma protein that is formed in the liver into the enzyme a plasma protein that is formed in the liver into the enzyme thrombinthrombin
3 3 FibrinogenFibrinogen (soluble) converted to (soluble) converted to FibrinFibrin (insoluble) (insoluble)In turn thrombin converts fibrinogen into fibrin Fibrin is insoluble In turn thrombin converts fibrinogen into fibrin Fibrin is insoluble and forms the threads that bind the clotand forms the threads that bind the clot
BLOOD COAGULATION
A sequence of reactions that are present in an inactive state in bloodKey is the conversion of the plasma protein fibrinogen to fibrin Intrinsic pathway Extrinsic pathway(activated by exposure of (activated by substances blood to damaged tissue) released from damaged tissue)
Active factors X and V
Prothrombin Thrombin
Fibrinogen Fibrin Fibrin mesh
inhibited by warfarin
inhibited by heparin
Rationale for anticoagulant Rationale for anticoagulant therapytherapy
PHARMACOLOGICAL PHARMACOLOGICAL AGENTSAGENTS
Pharmacologic AgentsPharmacologic Agents
AnticoagulantsAnticoagulants
Fibrinolytics (Agents for pharmacological Fibrinolytics (Agents for pharmacological recanalization)recanalization)
Anti platelet drugsAnti platelet drugs
Thrombin inhibitorThrombin inhibitor
ANTICOAGULANTSANTICOAGULANTS
Heparin and Low Molecular Weight Heparins Heparin and Low Molecular Weight Heparins ((eg enoxaparin dalteparin)eg enoxaparin dalteparin)
Oral anticoagulantsOral anticoagulants Coumarin Derivatves Coumarin Derivatves eg Warfarin eg Warfarin
AcenocoumarolAcenocoumarol Indandione Derivatves Indandione Derivatves eg Phenindione eg Phenindione
AnisindioneAnisindione
ThrombolyticsThrombolytics
Plasminogen activators
Fibrinolytics
Anti Platelet DrugsAnti Platelet DrugsDrug Mechanism UsesDrug Mechanism UsesAspirinAspirin Permanently inhibits Permanently inhibits
COX-1 and COX-2COX-1 and COX-2CADCAD
Stroke-TIAsStroke-TIAs
NSAIDsNSAIDs Reversibly inhibits Reversibly inhibits COX-1COX-1
LimitedLimited
DipyridamoleDipyridamole Inhibits PDE Inhibits PDE increases cAMPincreases cAMP
TIAsTIAs
ThenopyridinesThenopyridines
(Ticlopidine(Ticlopidine
Clopidegrel)Clopidegrel)
Inhibits ADP Inhibits ADP
PlatAg PlatAg
TIAsStrokeTIAsStroke
CAD PVDCAD PVD
Abciximab (ReoPro)Abciximab (ReoPro)
Eptifibatide Eptifibatide (Integrilin)(Integrilin)
TirofibaTirofibann
GP IIBIIIA InhibitorsGP IIBIIIA Inhibitors
Stroke- TIAs Stroke- TIAs
Maintainance of patency Maintainance of patency of vascular of vascular grafts catheters shunts bypassesgrafts catheters shunts bypasses
Arterial thromboembolic diseaseArterial thromboembolic diseasebull Transient ischemic attacksTransient ischemic attacksbull Stroke in evolutionStroke in evolution
Ischemic events occurs in Ischemic events occurs in 1313 of of conventional neuroangiographic conventional neuroangiographic procedures without Endovascular surgeryprocedures without Endovascular surgery
Indications for Antithrombotic Therapy in Indications for Antithrombotic Therapy in Diagnostics and Interventional ProceduresDiagnostics and Interventional Procedures
WHY TO MONITOR ANTICOAGULANT THERAPYWHY TO MONITOR ANTICOAGULANT THERAPY
Narrow therapeutic rangeNarrow therapeutic range
Can increase risk of bleedingCan increase risk of bleeding
Coagulation TestingCoagulation Testing
Monitoring therapyMonitoring therapy
Intrinsic Pathway
Extrinsic Pathway
Common Pathway
CLOT
Heparin Coumadin
Monitor with
ACT aPTT
Monitor with PTINR
Thrombolytics
Monitor with TT Fibrinogen
Monitoring of Monitoring of Anti platelet drugsAnti platelet drugs
Bleeding timeBleeding time
Optical aggregometryOptical aggregometry
Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay
HeparinHeparin
Heterogeneous 3000-30000 dalton in Heterogeneous 3000-30000 dalton in molecular weight molecular weight
Average=15000 d (~45monosaccharide Average=15000 d (~45monosaccharide chains)chains)
About About 13 of dose binds to AT III and forms 13 of dose binds to AT III and forms the AT IIIHeparinClotting Factor Complexthe AT IIIHeparinClotting Factor Complex
Complex binds to clotting factors of the Complex binds to clotting factors of the intrinsic and common pathway (Xa IIa IXa intrinsic and common pathway (Xa IIa IXa XIa XIIa XIIIa) and inactivates themXIa XIIa XIIIa) and inactivates them
Anticoagulant of choice in pregnancy (not Anticoagulant of choice in pregnancy (not crosses placenta)crosses placenta)
Heparin and Low molecular weight heparinsHeparin and Low molecular weight heparins
Structure and sequence
O
OH
OH
O
COO
O
O
CH2OH
NHSO3
OH
_
_
O
O
CH2OSO3
NHSO3
OH
_
_
O
OH
OH
O
COOO
O
CH2OSO3
NHSO3
OH
_
_
O
OSO3
OHO
COOO
O
CH2OSO3
NHCOCH3
OH
_
_ _
_
_
O
OH
OH
O
COO
1
23
4
5
6
-D-glucosamine -L-iduronic acid -D-glucuronic acid
O
O
CH2OH
NH2
OH 12
3
4
5
6
O
OH
OHO
COO_
1
23
4
5
6
polymeric structure of heparin
Anticoagulant Properties of Anticoagulant Properties of HeparinHeparin
11 Inhibits the thrombin-mediated conversion of Inhibits the thrombin-mediated conversion of fibrinogen to fibrinfibrinogen to fibrin
22 Inhibits the aggregation of platelets by thrombin Inhibits the aggregation of platelets by thrombin (prolongs bleeding time)(prolongs bleeding time)
33 Inhibits activation of fibrin stabilizing enzymeInhibits activation of fibrin stabilizing enzyme
44 Inhibits activated factors XII XI IX X and IIInhibits activated factors XII XI IX X and II All available forms of heparin must be All available forms of heparin must be
administered administered parenterally since they are parenterally since they are highly charged and rapidlyhighly charged and rapidly hydrolyzed in the hydrolyzed in the GI tractGI tract
Heparin antagonist Protamine sulfate (Heparin antagonist Protamine sulfate (10mg for 10mg for 1000 unit of heparin)1000 unit of heparin)
Monitoring of heparin Monitoring of heparin
Subcutenous Subcutenous no monitoring requiredno monitoring required Intravenous Intravenous
Partial thromboplastin time (PTT normal value Partial thromboplastin time (PTT normal value ~30sec) ~30sec)
Activated clotting time ( ACT normal value ~90-Activated clotting time ( ACT normal value ~90-120sec)120sec)
Daily or more frequent if PTT ACT variesDaily or more frequent if PTT ACT varies
Mechanism Mechanism ndash measures intrinsic pathwayndash measures intrinsic pathway Therapeutic goal Therapeutic goal 2-25 times normal control value 2-25 times normal control value
ACT or aPTTACT or aPTT
Determine when to pull the femoral sheath Determine when to pull the femoral sheath Premature sheath pull can lead to bleedingPremature sheath pull can lead to bleeding Delayed removal can increase time in ICUDelayed removal can increase time in ICU Target set Target set at each siteat each site
ACT targets range from 150 ndash 220 ACT targets range from 150 ndash 220 secondsseconds
aPTT targets range from 40 ndash 70 seconds aPTT targets range from 40 ndash 70 seconds
During neuroangiography-During neuroangiography- Recommended therapeutic range of heparin in Recommended therapeutic range of heparin in
plasma is 02-08 uml ( corresponding to aPTT plasma is 02-08 uml ( corresponding to aPTT ACT values 15-25 times the baseline values)ACT values 15-25 times the baseline values)
Dose In diagnostic angiography bolus dose of Dose In diagnostic angiography bolus dose of 2500 iu is used followed by 1000 iu hour2500 iu is used followed by 1000 iu hour
Bolus dose is Bolus dose is 60 ukg to maintain the therapeutic 60 ukg to maintain the therapeutic range range If procedure continues for more than 75 If procedure continues for more than 75 minutes additional dose is required ( half of the minutes additional dose is required ( half of the initial dose for another 75 minutes) initial dose for another 75 minutes)
(AJNR 199415 51-54)
Mechanisms of HIT( Mechanisms of HIT( Heparin Heparin induced Thrombocytopeniainduced Thrombocytopenia))
Type 1Type 1 Fall in platelet count occurs within the first two Fall in platelet count occurs within the first two
days after heparin initiation often returns to days after heparin initiation often returns to normal with continued heparin administration normal with continued heparin administration and is of no clinical consequence and is of no clinical consequence
The mechanism of the thrombocytopenia is non-The mechanism of the thrombocytopenia is non-immune and appears to be due to a direct effect of immune and appears to be due to a direct effect of heparin on platelet activationheparin on platelet activation
Type 2Type 2 Approximately 03 to 3 percent of patients Approximately 03 to 3 percent of patients
receiving heparin develop an immune receiving heparin develop an immune thrombocytopenia mediated by antibodies to a thrombocytopenia mediated by antibodies to a heparin-platelet factor 4 complex heparin-platelet factor 4 complex
(AJNR 28155-158 2007)
Treatment of heparin-induced Treatment of heparin-induced thrombocytopeniathrombocytopenia
When HIT is diagnosed it is important to When HIT is diagnosed it is important to stop heparin mainly in type 2 and to avoid stop heparin mainly in type 2 and to avoid the use of LMWH the use of LMWH
Because of the increased risk of thrombosis Because of the increased risk of thrombosis however continuation of an anticoagulant however continuation of an anticoagulant must be considered must be considered
The drugs currently approved for the The drugs currently approved for the treatment of HIT in the United States are treatment of HIT in the United States are direct thrombin inhibitors argatroban and direct thrombin inhibitors argatroban and lepirudinlepirudin
WARFARIN MECHANISM OF ACTIONWARFARIN MECHANISM OF ACTION
Inactive factors II VII IX and X
Proteins S and C
Active factors II VII IX and X
Proteins S and C
Vitamin K epoxide
Vitamin K reduced
WA
RF
AR
IN
Prevents the reduction of vitamin K which is essential for Prevents the reduction of vitamin K which is essential for activation of certain factorsactivation of certain factors
Has no effect on previously formed thrombusHas no effect on previously formed thrombus
Antagonist is Vit KAntagonist is Vit K
OPTIMIZING WARFARIN THERAPYOPTIMIZING WARFARIN THERAPY
Use of large loading dose may lead to hemorrhage and Use of large loading dose may lead to hemorrhage and other complicationsother complications
Initial dose 2-5 mg once dailyInitial dose 2-5 mg once daily Maintenance dose 2-10 mg once dailyMaintenance dose 2-10 mg once daily If Immediate anticoagulation is requiredIf Immediate anticoagulation is required Heparin IS Heparin IS
started along with loading dose of warfarin 10 mg started along with loading dose of warfarin 10 mg Heparin is usually discontinued after 4-5 days Heparin is usually discontinued after 4-5 days Before Before discontinuing INR should be in therapeutic range for 2 discontinuing INR should be in therapeutic range for 2 consecutive daysconsecutive days
Daily monitoring of INR until INR is in therapeutic Daily monitoring of INR until INR is in therapeutic range then 3 times weekly for 1-2 weeks then less often range then 3 times weekly for 1-2 weeks then less often (every 4 to 6 weeks)(every 4 to 6 weeks)
OPTIMAL THERAPEUTIC RANGEOPTIMAL THERAPEUTIC RANGE
IndicationIndication INRINR
Prophylaxis of venous Prophylaxis of venous thromboembolismthromboembolism
20-3020-30
Treatment of venous Treatment of venous thromboembolismthromboembolism
20-3020-30
Atrial fibrillationAtrial fibrillation 20-3020-30
Mitral valve stenosisMitral valve stenosis 20-3020-30
Heart valve replacementHeart valve replacement
Bioprosthetic valveBioprosthetic valve
Mechanical valveMechanical valve
20-3020-30
25-3525-35
Myocardial infarctionMyocardial infarction 20-3020-30
25-35 25-35 (high risk patients)(high risk patients)
FACTORS INFLUENCING DOSE RESPONSEFACTORS INFLUENCING DOSE RESPONSE
Poor patient compliancePoor patient compliance Concomitant medicationsConcomitant medications Levels of dietary vitamin KLevels of dietary vitamin K Alcohol Inaccurate lab testingAlcohol Inaccurate lab testing Inaccurate lab testingInaccurate lab testing Hepatic dysfunctionHepatic dysfunction FeverFever
Contraindication for WarfarinContraindication for Warfarin
Hypersensitivity to warfarinHypersensitivity to warfarin Hemorrhagic tendencyHemorrhagic tendency Condition with risk of hemorrhageCondition with risk of hemorrhage Inadequate laboratory techniquesInadequate laboratory techniques Protein C amp S deficiencyProtein C amp S deficiency Vitamin K deficiencyVitamin K deficiency
SIDE EFFECTSSIDE EFFECTS
Hemorrhage Hemorrhage Skin necrosisSkin necrosis Purple toe syndromePurple toe syndrome Microembolization Microembolization TeratogenecityTeratogenecity Agranulocytosis leukopenia Agranulocytosis leukopenia Diarrhoeanausea anorexiaDiarrhoeanausea anorexia
MONITORING OF WARFARIN THERAPYMONITORING OF WARFARIN THERAPY
Prothrombin timeProthrombin time PT ratioPT ratio INR (International Normalized Ratio)INR (International Normalized Ratio)
PROTHROMBIN TIME (PT)PROTHROMBIN TIME (PT)
Time required for blood to coagulate Time required for blood to coagulate is called PT ( normal value ~10sec)is called PT ( normal value ~10sec)
Performed by adding a mixture of Performed by adding a mixture of calcium and thromboplastin to calcium and thromboplastin to citrated plasmacitrated plasma
As a control a normal blood sample is As a control a normal blood sample is tested continuouslytested continuously
PT ratio (PTR) = PT ratio (PTR) = Patientrsquos PTPatientrsquos PT Control PTControl PT
PROBLEMS WITH PTPTRPROBLEMS WITH PTPTR
Thromboplastins are extracts from Thromboplastins are extracts from brain lung or placenta of animalsbrain lung or placenta of animals
Thromboplastins from various Thromboplastins from various manufacturers differ in their manufacturers differ in their sensitivity to prolong PTsensitivity to prolong PT
May result in false control of May result in false control of anticoagulant therapyanticoagulant therapy
INTERNATIONAL NORMALISED RATIO (INR)INTERNATIONAL NORMALISED RATIO (INR)
International Normalized Ratio (INR) International Normalized Ratio (INR) a PT test with a a PT test with a formula based ratio to normalize the often variable source formula based ratio to normalize the often variable source of tissue factor (human rabbit recombinant)of tissue factor (human rabbit recombinant)
INR = [PTINR = [PTptpt] ] ISIISI
[PT[PTRefRef]]
PTPTpt pt ndash prothrombin time of patientndash prothrombin time of patient
PTPTRef Ref ndash prothrombin time of normal pooled samplendash prothrombin time of normal pooled sample
ISI ndash International Sensitivity IndexISI ndash International Sensitivity Index
Warfarin is given orally and titrated to achieve an INR of Warfarin is given orally and titrated to achieve an INR of typically 20 ndash 30typically 20 ndash 30
Heparin versus WarfarinHeparin versus Warfarin
Drug ActionMechan-ism
Moni-toring
Effective
HeparinDirect
Inhibition ofThrombin
ATIIIcofactor
APTTACT
Immediate
WarfarinDecreasesProductionof factors
Vitamin K PTDelay
3-5 days
INR
Recanalization or Antegrade Recanalization or Antegrade Reperfusion StrategiesReperfusion Strategies
Recanalization strategies focus on removing Recanalization strategies focus on removing andor dissolving the occlusive thrombus to re-andor dissolving the occlusive thrombus to re-establish antegrade flow Strategies may be establish antegrade flow Strategies may be classified into 7 different categories on the classified into 7 different categories on the basis of their primary mechanism of action basis of their primary mechanism of action 1) 1) IV andor intraarterial thrombolysis (IAT) IV andor intraarterial thrombolysis (IAT) 2) endovascular thrombectomy2) endovascular thrombectomy3) endovascular thromboaspiration 3) endovascular thromboaspiration 4) endovascular mechanical thrombus disruption or 4) endovascular mechanical thrombus disruption or
thromborrhexisthromborrhexis5) 5) transcranial or endovascular augmented transcranial or endovascular augmented
fibrinolysis fibrinolysis 6) endovascular thrombus entrapment and 6) endovascular thrombus entrapment and 7) temporary endovascular bypass7) temporary endovascular bypass
IAT in Acute Ischemic StrokeIAT in Acute Ischemic Stroke
IAT advantages over IV thrombolysisIAT advantages over IV thrombolysis Coaxial microcatheter techniques the occluded intracranial Coaxial microcatheter techniques the occluded intracranial
vessel is directly accessible and the fibrinolytic agent can be vessel is directly accessible and the fibrinolytic agent can be infused directly into the thrombusinfused directly into the thrombus
This permits a smaller dose of fibrinolytic agent to reach a This permits a smaller dose of fibrinolytic agent to reach a higher local concentration than that reached by systemic higher local concentration than that reached by systemic infusioninfusion
Allows more complete recanalization with lower total doses of Allows more complete recanalization with lower total doses of thrombolytic thrombolytic
With the smaller dose complications from systemic fibrinolytic With the smaller dose complications from systemic fibrinolytic effects including intracranial hemorrhage (ICH) can effects including intracranial hemorrhage (ICH) can theoretically be reduced theoretically be reduced
Treatment window for endovascular techniques can be Treatment window for endovascular techniques can be extended beyond the typical IV window of 3 hours extended beyond the typical IV window of 3 hours
IA techniques have led to higher recanalization rates than IV IA techniques have led to higher recanalization rates than IV thrombolysisthrombolysis
Major disadvantagesMajor disadvantages Relative complexity of the procedure the level Relative complexity of the procedure the level
of required technical expertise and its of required technical expertise and its relatively low availability relatively low availability
Delays in initiating treatmentDelays in initiating treatment InvasiveInvasive
ThrombolyticsThrombolytics
Plasminogen activators
Fibrinolytics
1 Plasminogen Activators 1 Plasminogen Activators drugs act by converting the inactive proenzyme drugs act by converting the inactive proenzyme plasminogen into the active enzyme plasmin Plasmin plasminogen into the active enzyme plasmin Plasmin digests fibrinogen fibrin monomers and cross-linked digests fibrinogen fibrin monomers and cross-linked fibrin (as found in a thrombus) into fibrin degradation fibrin (as found in a thrombus) into fibrin degradation productsproducts
First-Generation Agents First-Generation Agents StreptokinaseStreptokinase a protein derived from group C a protein derived from group C
szlig-hemolytic streptococci has a half-life of 16ndashszlig-hemolytic streptococci has a half-life of 16ndash90 minutes and low fibrin specificity This drug 90 minutes and low fibrin specificity This drug proved to have a very narrow therapeutic proved to have a very narrow therapeutic window and significant rates of ICH and window and significant rates of ICH and systemic hemorrhage18systemic hemorrhage18
UrokinaseUrokinase is a serine protease with a plasma is a serine protease with a plasma half life of 14 minutes and low fibrin specificity half life of 14 minutes and low fibrin specificity
The urokinase dose used in cerebral IAT has The urokinase dose used in cerebral IAT has ranged from 002 to 2 X106unitsranged from 002 to 2 X106units
Second-Generation Agents Second-Generation Agents Alteplase (rtPA) Alteplase (rtPA)
is a serine is a serine protease with a plasma half-life of 35 protease with a plasma half-life of 35 minutes and a high degree of fibrin affinity and minutes and a high degree of fibrin affinity and specificity specificity
Dose used in cerebral IAT has ranged between 20 Dose used in cerebral IAT has ranged between 20 and 60 mgand 60 mg
Disadvantages of alteplase include its relatively short Disadvantages of alteplase include its relatively short halflife and limited penetration into the clot matrix halflife and limited penetration into the clot matrix because of strong binding with surface fibrin which because of strong binding with surface fibrin which could delay recanalization and increase the risk of could delay recanalization and increase the risk of recurrent occlusion recurrent occlusion
Prourokinase (r-prourokinase) Prourokinase (r-prourokinase) is the proenzyme precursor of urokinase is the proenzyme precursor of urokinase T12 of 7 minutes and high fibrin specificity T12 of 7 minutes and high fibrin specificity
Third-Generation AgentsThird-Generation Agents
ReteplaseReteplase is a structurally modified is a structurally modified form of alteplase form of alteplase
with a longer half-life (15ndash18 minutes) In with a longer half-life (15ndash18 minutes) In addition it does not bind as highly to fibrin addition it does not bind as highly to fibrin unbound reteplase can thus theoretically better unbound reteplase can thus theoretically better penetrate the clot and potentially penetrate the clot and potentially improve in improve in vivo fibrinolytic activity vivo fibrinolytic activity
TenecteplaseTenecteplase is another modified form of rtPA with a longer is another modified form of rtPA with a longer
half-life (17 minutes)half-life (17 minutes) greater fibrin specificity and greater greater fibrin specificity and greater
resistance to plasminogen activator inhibitor-1 resistance to plasminogen activator inhibitor-1 IV tenecteplase in acute ischemic stroke IV tenecteplase in acute ischemic stroke
suggest that the drug is safe and promisingsuggest that the drug is safe and promising
Newer plasminogen activatorNewer plasminogen activator
DesmoteplaseDesmoteplase is a genetically engineered is a genetically engineered version of the clot-dissolving factor version of the clot-dissolving factor
found in the saliva found in the saliva of the vampire bat Desmodus rotundusof the vampire bat Desmodus rotundus moremore potent and more selective for fibrin-bound potent and more selective for fibrin-bound
plasminogen than any other known plasminogen plasminogen than any other known plasminogen activatoractivator
Unlike tissue plasminogen activator (tPA) desmoteplase Unlike tissue plasminogen activator (tPA) desmoteplase is not activated by fibrinogen or -amyloid proteins is not activated by fibrinogen or -amyloid proteins factors that may exacerbate the risk for ICH factors that may exacerbate the risk for ICH
The effect of IV administration of desmoteplase 3ndash9 The effect of IV administration of desmoteplase 3ndash9 hours after symptom onset in patients with stroke who hours after symptom onset in patients with stroke who present with mismatch on MR imaging or CT perfusion present with mismatch on MR imaging or CT perfusion
3 DefibrinogenatingFibrinogenolytic 3 DefibrinogenatingFibrinogenolytic Agents Agents
AncrodAncrod(Viprinex)(Viprinex) is is the purified fraction of the Malayan pit viper venomthe purified fraction of the Malayan pit viper venom It acts by directly cleaving and inactivating fibrinogen It acts by directly cleaving and inactivating fibrinogen
and thus indirectly promoting anticoagulation and thus indirectly promoting anticoagulation The reduction in the blood levels of fibrinogen also The reduction in the blood levels of fibrinogen also
leads to a reduced blood viscosity which may improve leads to a reduced blood viscosity which may improve blood flow to the affected areas of the brain blood flow to the affected areas of the brain
In the Stroke Treatment with Ancrod Trial 500 In the Stroke Treatment with Ancrod Trial 500 patients with stroke presenting within 3 hours of patients with stroke presenting within 3 hours of symptom onset were randomized to receive ancrod (symptom onset were randomized to receive ancrod (n n 248) or a placebo (n 252) Good outcome (Barthel 248) or a placebo (n 252) Good outcome (Barthel Index 95ndash100 at 3 months) was achieved in 4221 Index 95ndash100 at 3 months) was achieved in 4221 and 344 of the patients respectively and 344 of the patients respectively
2 Direct Fibrinolytics2 Direct Fibrinolytics
Microplasmin (Microplasmin (ThromboGenics Heverlee Belgium)ThromboGenics Heverlee Belgium) is a truncated form of plasmin that is more resistant to the effects is a truncated form of plasmin that is more resistant to the effects
of antiplasmin of antiplasmin microplasmin can be used upto 4ndash12 hours after stroke onset microplasmin can be used upto 4ndash12 hours after stroke onset There was no evidence of increased bleeding risk with There was no evidence of increased bleeding risk with
microplasminmicroplasmin
Alfimeprase (Nuvelo San Carlos Calif)Alfimeprase (Nuvelo San Carlos Calif) is a recombinant truncated form of fibrolase a fibrinolytic zinc metalloproteinase is a recombinant truncated form of fibrolase a fibrinolytic zinc metalloproteinase
isolated from the venom of the southern copperhead snake isolated from the venom of the southern copperhead snake It degrades fibrin directly and achieves thrombolysis independent It degrades fibrin directly and achieves thrombolysis independent
of plasmin formationof plasmin formation its thrombolytic activity appears to be localized to the site of its thrombolytic activity appears to be localized to the site of
delivery These properties should theoretically result in faster delivery These properties should theoretically result in faster recanalization and lower hemorrhagic conversion riskrecanalization and lower hemorrhagic conversion risk
Anti-fibrinolyticsAnti-fibrinolytics
to limit fibrinolytic activityto limit fibrinolytic activity -aminocaproic acid (EACA) -aminocaproic acid (EACA) competitively inhibitscompetitively inhibits plasminogen and plasminogen activators from plasminogen and plasminogen activators from
binding to fibrinbinding to fibrin
alpha2-antiplasminalpha2-antiplasmin a serine protease inhibitor that a serine protease inhibitor that neutralizes any free circulating plasminneutralizes any free circulating plasmin
Plasminogen activator inhibitor-1Plasminogen activator inhibitor-1 a serine protease a serine protease inhibitor that inhibits tissue-type plasminogen inhibitor that inhibits tissue-type plasminogen activatoractivator
Glycoprotein (GP) IIbIIIa antagonistsGlycoprotein (GP) IIbIIIa antagonists
such as ReoPro (abciximab) Integrilin such as ReoPro (abciximab) Integrilin (eptifibatide) or Aggrastat (tirofiban) in (eptifibatide) or Aggrastat (tirofiban) in ischemic stroke remains investigational ischemic stroke remains investigational Deshmukh et al38 reported 21 patients with Deshmukh et al38 reported 21 patients with large-vessel occlusion refractory to IAT with large-vessel occlusion refractory to IAT with rtPA who were treated with IV andor IA rtPA who were treated with IV andor IA abciximab eptifibatide or tirofiban abciximab eptifibatide or tirofiban
IA Mechanical Approaches in Acute Ischemic Stroke IA Mechanical Approaches in Acute Ischemic Stroke Mechanical strategies have several advantagesMechanical strategies have several advantages First they lessen and may even preclude the use of chemical First they lessen and may even preclude the use of chemical
thrombolytics in this manner very likely reducing the risk of ICHthrombolytics in this manner very likely reducing the risk of ICH Second by avoiding the use of chemical thrombolytics it is Second by avoiding the use of chemical thrombolytics it is
possible to extend the treatment window beyond the limit of 6ndash8 possible to extend the treatment window beyond the limit of 6ndash8 hours hours
Third mechanically fragmenting a clot increases the surface area Third mechanically fragmenting a clot increases the surface area accessible to fibrinolytic agents and allows inflow of fresh accessible to fibrinolytic agents and allows inflow of fresh plasminogen which in turn may increase the speed of plasminogen which in turn may increase the speed of thrombolysis thrombolysis
Finally clot-retrieval devices may provide faster recanalization Finally clot-retrieval devices may provide faster recanalization
The disadvantages of the mechanical The disadvantages of the mechanical approaches approaches technical difficulty of navigating mechanical technical difficulty of navigating mechanical
devices into the intracranial circulation excessive devices into the intracranial circulation excessive trauma to the vasculature (potentially leading to trauma to the vasculature (potentially leading to vasospasm vessel dissection perforation or vasospasm vessel dissection perforation or rupture) rupture)
fragmented thrombus causing distal embolization fragmented thrombus causing distal embolization into previously unaffected territories into previously unaffected territories
Nevertheless the advantages of mechanical stroke Nevertheless the advantages of mechanical stroke therapy appear to significantly outweigh its therapy appear to significantly outweigh its disadvantages and risksdisadvantages and risks
Contraindications to Thrombolytic Contraindications to Thrombolytic agents agents
Recent thoracic abdominal or Recent thoracic abdominal or intracranial surgeryintracranial surgery
Recent haemorrhagic CVA Head injury Recent haemorrhagic CVA Head injury or neoplasmor neoplasm
Bleeding ulcerBleeding ulcer Anticipated invasive procedures (arterial Anticipated invasive procedures (arterial
punctures biopsies)punctures biopsies) Concurrent hemostatic dysfunctionConcurrent hemostatic dysfunction
Monitoring of thrombolytic Monitoring of thrombolytic therapytherapy
Thrombin time Measures the availability of functional
fibrinogen Normal thrombin time is 10-14 sec Prolonged when fibrinogen level is below
75-100 mgdl
Half Life of ThrombolyticsHalf Life of ThrombolyticsAgent Administration Half Life
Streptokinase IA 60-80min
Urokinase IAIV 9-12min
rTPA IAIV 6min
Abciximab(Reopro) IAIV 12hour
Aspirin POIV 15-20min
Heparin IVSC 60min
Coumadin PO 15-25 days
Anti Platelet DrugsAnti Platelet DrugsDrug Drug Mechanism Mechanism UsesUsesAspirinAspirin Permanently inhibits Permanently inhibits
COX-1 and COX-2COX-1 and COX-2CADCAD
Stroke-TIAsStroke-TIAs
NSAIDsNSAIDs Reversibly inhibits Reversibly inhibits COX-1COX-1
LimitedLimited
DipyridamoleDipyridamole Inhibits PDE increases Inhibits PDE increases cAMPcAMP
TIAsTIAs
ThenopyridinesThenopyridines
(Ticlopidine(Ticlopidine
ClopidrgrelClopidrgrel))
Inhibits ADP Inhibits ADP
PlatAg PlatAg
TIAsStrokeTIAsStroke
CAD PVDCAD PVD
Abciximab (ReoPro)Abciximab (ReoPro)
Eptifibatide (Integrilin)Eptifibatide (Integrilin)
TirofibanTirofiban
GP IIBIIIA InhibitorsGP IIBIIIA Inhibitors
Stroke- TIAs Stroke- TIAs
MonitoringMonitoring
Bleeding timeBleeding time
Optical aggregometryOptical aggregometry
Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay
Bleeding timeBleeding time
Requires a skin incision (usually made on the ear lobe or Requires a skin incision (usually made on the ear lobe or forearm offorearm of
a depth that results in disruption of capillary loops and a depth that results in disruption of capillary loops and small vessels)small vessels)
AdvantagesAdvantages Universally availableUniversally available Relatively simple techniquesRelatively simple techniques Can be performed bedsideCan be performed bedside
DisadvantagesDisadvantages Insensitive inaccurate non-specific techniqueInsensitive inaccurate non-specific technique
Poorly reproducible (as depends on multiple variables)Poorly reproducible (as depends on multiple variables)
Optical aggregometryOptical aggregometry
Gold standard assay for platelet functionGold standard assay for platelet function Agonist induced aggregation is measuredAgonist induced aggregation is measured Different agonist are available for different Different agonist are available for different
agentsagents However require unique expertise and are not However require unique expertise and are not
universally availableuniversally available Aspirin measured with ADP or AA(gt70 Aspirin measured with ADP or AA(gt70
aggregation so resistance)aggregation so resistance) Clopidogrel( ADP gt 90 aggregation means Clopidogrel( ADP gt 90 aggregation means
resistance) resistance)
Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay
Can be performed bed sideCan be performed bed side Different assay devices with different Different assay devices with different
agonist are used for each of different agonist are used for each of different antiplatelet agents antiplatelet agents
For Aspirin AA is used (result is reported as aspirin For Aspirin AA is used (result is reported as aspirin reaction units [ARU] ARUgt 550 indicates non-reaction units [ARU] ARUgt 550 indicates non-responsiveness)responsiveness)
Verify IIbIIIa assay device uses TRAP as agonist for Verify IIbIIIa assay device uses TRAP as agonist for Abciximab and TirofibanAbciximab and Tirofiban
Practical Applications Practical Applications related to specific related to specific
Neurovascular Neurovascular interventionsinterventions
Acute ischemic StrokeAcute ischemic Stroke When an artery occludes neurons are affected When an artery occludes neurons are affected
differently depending upon the amount of residual blood differently depending upon the amount of residual blood flowflow
Normal cerebral blood flow is greater than 50 mL100 Normal cerebral blood flow is greater than 50 mL100 mgminmgmin
Once blood flow decreases to less than 20 mL100 Once blood flow decreases to less than 20 mL100 mgmin infarction occursmgmin infarction occurs
If blood flow decreases to less than 10 mL100 mgmin If blood flow decreases to less than 10 mL100 mgmin irreversible neuronal death occurs rapidly irreversible neuronal death occurs rapidly
Blood flow between 11 and 20 mL100 mgmin is thought Blood flow between 11 and 20 mL100 mgmin is thought to represent the ischemic penumbra an area where the to represent the ischemic penumbra an area where the cells are functionally silent because of ischemia but are cells are functionally silent because of ischemia but are still able to recover if blood flow is restored still able to recover if blood flow is restored
Many acute stroke therapies are targeted toward Many acute stroke therapies are targeted toward restoring flow or function to the ischemic penumbrarestoring flow or function to the ischemic penumbra
Therapeutic window in Therapeutic window in management of acute Ischemic management of acute Ischemic
StrokeStrokeThe early diagnosis of ischemic stroke is critical to the The early diagnosis of ischemic stroke is critical to the
with only a narrow therapeutic window in the first few with only a narrow therapeutic window in the first few hours following stroke ictushours following stroke ictus
Diagnosis in the first 3 hours postictus provides the Diagnosis in the first 3 hours postictus provides the opportunity for intravenous or intraarterial thrombolysis opportunity for intravenous or intraarterial thrombolysis and intra-arterial clot mechanical treatment which and intra-arterial clot mechanical treatment which improve the outcome improve the outcome
Diagnosis in the time period between 3 and 6 hours Diagnosis in the time period between 3 and 6 hours provides an opportunity for intra-arterial thrombolysis provides an opportunity for intra-arterial thrombolysis and mechanical treatment and mechanical treatment
Involvement of the posterior circulation especially the Involvement of the posterior circulation especially the basilar artery is treated by some regardless of time of basilar artery is treated by some regardless of time of onset or up until 12 to 24 hours in some practices This is onset or up until 12 to 24 hours in some practices This is related to the potentially high mortality and morbidity related to the potentially high mortality and morbidity associated with basilar artery thrombosisassociated with basilar artery thrombosis
Infarct evaluation on angiographyInfarct evaluation on angiography(CT angiography and catheter (CT angiography and catheter
angiography)angiography)CTA is an excellent first-line examination for CTA is an excellent first-line examination for
evaluation of the head and neck arteries evaluation of the head and neck arteries In comparison with catheter angiography In comparison with catheter angiography
what it gives up in resolution and dynamic what it gives up in resolution and dynamic properties it makes up for with rapid properties it makes up for with rapid acquisition of a 3-D dataset and the potential acquisition of a 3-D dataset and the potential for assessment of whole-brain perfusion and for assessment of whole-brain perfusion and better parenchymal evaluationbetter parenchymal evaluation
Moreover CTA illustrates not only arterial Moreover CTA illustrates not only arterial stenosis or occlusion but also the vessel wall stenosis or occlusion but also the vessel wall This factor is most important for evaluation of This factor is most important for evaluation of intramural dissection and thrombosed intramural dissection and thrombosed aneurysms which may both complicate aneurysms which may both complicate evaluation of stroke patientsevaluation of stroke patients
Early angiographic signs of strokes Early angiographic signs of strokes both CTA both CTA and DSA and DSA
Vessel occlusion or cutoff related to Vessel occlusion or cutoff related to thromboembolithromboemboli
aneurysms aneurysms arterial dissection arterial dissection Meniscus or flattened shape to clot Meniscus or flattened shape to clot
(recent) versus reverse meniscus (older)(recent) versus reverse meniscus (older) tram track (nonocclusive or recanalized tram track (nonocclusive or recanalized
clot) clot) delayed (antegrade) flow (manifest as delayed (antegrade) flow (manifest as
decreased whole-brain perfusion on CTA)decreased whole-brain perfusion on CTA) retrograde collateral flowretrograde collateral flow
Non-occlusive left MCA thrombus on 3-D imaging performed from CTA source data and was confirmed at catheter angiography
Therapy to be started within a 6-hr Therapy to be started within a 6-hr time to treatment (TTT) window time to treatment (TTT) window (while in case of IV thrombolysis (while in case of IV thrombolysis therapy to be started with in 3hrs)therapy to be started with in 3hrs)
Exclusion criteria Exclusion criteria Rapidly improving neurologic deficit or Rapidly improving neurologic deficit or Sustained blood pressure of gt180100 Sustained blood pressure of gt180100 Hemorrhage is detected on CTHemorrhage is detected on CT Infarct involving gt more than 13 rd Infarct involving gt more than 13 rd
territory of MCAterritory of MCA MRADWI-Perfusion mismatchlt 20MRADWI-Perfusion mismatchlt 20 Definite hypodensity on CTDefinite hypodensity on CT
Intra-arterial Thrombolysis
Fibrinolytics + AntiplateletsFibrinolytics + Antiplatelets
PlasminogenPlasminogen activators through fibrinolysis exposes activators through fibrinolysis exposes free thrombin and paradoxically stimulatesfree thrombin and paradoxically stimulates platelet platelet aggregation which leads to formation of aaggregation which leads to formation of a platelet platelet thrombus (white clot) thrombus (white clot)
This new thrombus is relatively resistant to This new thrombus is relatively resistant to fibrinolyticsfibrinolytics
So new regimen in case of acute stroke isSo new regimen in case of acute stroke is fibrinolytics + antiplatelet drugsfibrinolytics + antiplatelet drugs
rtPA + IIbIIIa inhibitors( tirofiban rtPA + IIbIIIa inhibitors( tirofiban abciximab) orabciximab) or
Urokinase + IIbIIIa Urokinase + IIbIIIa inhibitors( tirofiban abciximab)inhibitors( tirofiban abciximab)
Intra-arterial Thrombolysis Tirofiban (04 microgkgmin bolus for 3 min followed by Tirofiban (04 microgkgmin bolus for 3 min followed by
0125 ugkgmin)0125 ugkgmin)
++
Heparin (2000ndash3000 IU bolus followed by Heparin (2000ndash3000 IU bolus followed by 1000 IUhour infusion 1000 IUhour infusion
with ACT maintained bw 200-300) throughout the with ACT maintained bw 200-300) throughout the interventional procedure and for 24ndash48 hours thereafter when interventional procedure and for 24ndash48 hours thereafter when there is neither intraprocedural bleeding nor suspicion of there is neither intraprocedural bleeding nor suspicion of increased risk of bleeding increased risk of bleeding
Maximum dose of Urokinase Maximum dose of Urokinase Anterior circulation stroke - 500000 IU (mean 400000 Anterior circulation stroke - 500000 IU (mean 400000
IU range 300000ndash500000 IU)IU range 300000ndash500000 IU) Posterior circulation stroke -1000000 IU (mean 837000 Posterior circulation stroke -1000000 IU (mean 837000
IU range 300000ndash1000000 IU)IU range 300000ndash1000000 IU)American Journal of NeuroradiologyAmerican Journal of Neuroradiology 262595-2601 2005262595-2601 2005
Intravenous ThrombolysisIntravenous Thrombolysis
The first method to restore cerebral The first method to restore cerebral perfusion is clot lysis with the goal perfusion is clot lysis with the goal of re-establishing blood flow to the of re-establishing blood flow to the affected tissue affected tissue
IV thrombolysis rt-PA is the only IV thrombolysis rt-PA is the only FDA- approved treatment for AIS FDA- approved treatment for AIS
Fibrinolysis is enhanced powerfully Fibrinolysis is enhanced powerfully by rt-PAby rt-PA
Intravenous rTPA Intravenous rTPA administration administration protocolprotocol
Total dose of rt-PA 09 mgkg (maximum dose Total dose of rt-PA 09 mgkg (maximum dose 90 mg)90 mg)
Give 10 as initial IV bolusGive 10 as initial IV bolus Infuse remainder over 1 hourInfuse remainder over 1 hour Admit patient to an ICU or stroke unit for Admit patient to an ICU or stroke unit for
monitoringmonitoring Neurologic assessments every 15 minutes Neurologic assessments every 15 minutes
during infusion then every 30 minutes for next during infusion then every 30 minutes for next 6 hours then every hour until 24hours after 6 hours then every hour until 24hours after treatmenttreatment
Favorable Outcome vs Treatment Time Favorable Outcome vs Treatment Time with IV rTPAwith IV rTPA
Protocol limit = 3 hrs
Benefit ~ 45 hrs
Thromboembolism During coilingThromboembolism During coiling Most feared and frequent complication Most feared and frequent complication Reported incidence - Approx 7 Reported incidence - Approx 7 SourcesSources of Thromboembolism are of Thromboembolism are
- Clots at the aneurysmal neck during or immediately- Clots at the aneurysmal neck during or immediately after after embolization embolization
- Thrombus forming on catheters during- Thrombus forming on catheters during proceduresprocedures
- Stenosis of an adjacent artery dt coil mass- Stenosis of an adjacent artery dt coil mass or herniationor herniation
- Migration of intraaneurysmal- Migration of intraaneurysmal thrombus during coil thrombus during coil placement placement
- Slow flow dt vasospasm - Slow flow dt vasospasm
- Rare and unlikely causes are hypercoagulable- Rare and unlikely causes are hypercoagulable state such state such as antiphospholipid antibody syndrome or due to HITas antiphospholipid antibody syndrome or due to HIT
Occur more often with wide-necked aneurysms (dt Occur more often with wide-necked aneurysms (dt increased exposed surface area of thrombogenic coil increased exposed surface area of thrombogenic coil material)material)
Current regimen of endovascular Current regimen of endovascular managementmanagement
The The glycoprotein IIbIIIa antagonist tirofiban glycoprotein IIbIIIa antagonist tirofiban (04 (04 microgkgmin bolus for 30 minutes followed by infusion of microgkgmin bolus for 30 minutes followed by infusion of 0125 ugkgmin until the thrombus dissolved) 0125 ugkgmin until the thrombus dissolved)
Intraarterial thrombolysis with Intraarterial thrombolysis with urokinase or r- TPA urokinase or r- TPA increase of intravenous (IV) heparin (measured by increase of intravenous (IV) heparin (measured by
ACT) ACT) Intravenous aspirin Intravenous aspirin
Coil-related platelet aggregation (white clot) is Coil-related platelet aggregation (white clot) is unlikely to respond to fibrinolytics but has a high risk unlikely to respond to fibrinolytics but has a high risk of hemorrhage (In ISAT) all 5 patients who had of hemorrhage (In ISAT) all 5 patients who had received thrombolytic therapy with tPA to treat a received thrombolytic therapy with tPA to treat a thromboembolic complication after endovascular thromboembolic complication after endovascular treatment rebleed and all of these patients died)treatment rebleed and all of these patients died)
IntracranialIntracranial Stenting Stenting Metallic foreign body such as stent will accumulate Metallic foreign body such as stent will accumulate
thrombus in the absence of platelet inhibitionthrombus in the absence of platelet inhibition Antiplatelet drugs are important to prevent peri or Antiplatelet drugs are important to prevent peri or
post-interventional thromboembolic eventspost-interventional thromboembolic events Optimal treatment regimens has not been determined Optimal treatment regimens has not been determined
but usually but usually Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-
procedureprocedureOrOr
Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on
morning of proceduremorning of procedure
If need to use stent is not pre-planned thanIf need to use stent is not pre-planned than
Abciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkgAbciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkg IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)
Glycoprotein IIbIIIa inhibitor are not used routinely during elective Glycoprotein IIbIIIa inhibitor are not used routinely during elective stenting procedure dt increased risk of ICH stenting procedure dt increased risk of ICH
Carotid StentingCarotid Stenting
Pre-procedurePre-procedure
Double Antiplatelet therapy is routinely given Double Antiplatelet therapy is routinely given beginning at least 3beginning at least 3
days before the proceduredays before the procedure
Aspirin 325mgd+Clopidogrel 75mgdAspirin 325mgd+Clopidogrel 75mgd During procedureDuring procedure
Heparin is given with target clotting time of 250-Heparin is given with target clotting time of 250-300sec300sec
Post-procedure Post-procedure
Aspirin 325mg is continued indefinitely and Aspirin 325mg is continued indefinitely and
Clopidogrel 75mgd for at least 6 weeks Clopidogrel 75mgd for at least 6 weeks
Inclusion criteria for Local ThrombolysisInclusion criteria for Local Thrombolysis a)a) Patients in severe clinical grade on admission Patients in severe clinical grade on admission
with evidence of dural venous sinus with evidence of dural venous sinus thrombosis and restrictive venous outflow on thrombosis and restrictive venous outflow on cerebral angiogramcerebral angiogram
b)b) Patients in clinical grade 3 worsening on Patients in clinical grade 3 worsening on heparin therapy Restriction to venous heparin therapy Restriction to venous outflow was defined as an increase in brain outflow was defined as an increase in brain circulation time gt 12 s delay in the drainage circulation time gt 12 s delay in the drainage of cortical veins with cortical veins hanging of cortical veins with cortical veins hanging in spacein space
Treatment Options for Venous Thrombosis
CT Grading for Venous ThrombosisCT Grading for Venous Thrombosis Grade I no parenchymal change Grade I no parenchymal change
(hyperdense (hyperdense sinuses cortical veins empty sinuses cortical veins empty delta sign)delta sign)
Grade II non hemorrhagic venous infarct Grade II non hemorrhagic venous infarct without mass effect without mass effect
Grade III non-hemorrhagic infarct with Grade III non-hemorrhagic infarct with mass effectmass effect
Grade IV hemorrhagic venous infarct (max Grade IV hemorrhagic venous infarct (max diameter lt 3 cm) with no mass effectdiameter lt 3 cm) with no mass effect
Grade V hemorrhagic venous infarct (max Grade V hemorrhagic venous infarct (max diameter gt 3 cm) with mass effect diameter gt 3 cm) with mass effect
Local ThrombolysisLocal Thrombolysis
Femoral Jugular access was secured and a guiding Femoral Jugular access was secured and a guiding catheter was placed in the jugular bulb catheter was placed in the jugular bulb Mechanical Mechanical clot maceration clot maceration was done with the guidewire was done with the guidewire following which a microcatheter (was navigated and following which a microcatheter (was navigated and placed in the thrombosed segment of sinus confirmed placed in the thrombosed segment of sinus confirmed on a selective venogram on a selective venogram
Urokinase infusion Bolus dose of 2-6 lacs followed Urokinase infusion Bolus dose of 2-6 lacs followed by 60000 to 100000 units per hour along with by 60000 to 100000 units per hour along with periodic check venogram Along with maintenance periodic check venogram Along with maintenance systemic infusion of Heparinsystemic infusion of Heparin Other agents such as Other agents such as streptokinase altepase or rTPAstreptokinase altepase or rTPA can be also used can be also used
After thrombolysis patient should subjected to oral After thrombolysis patient should subjected to oral anticoagulation for six monthsanticoagulation for six months
Low-molecular-weight Low-molecular-weight heparinheparin
PharmacologyPharmacologyLMWH as its name suggests is a glycosaminoglycan that is approximatelyLMWH as its name suggests is a glycosaminoglycan that is approximately
one third the molecular weight of UFH It is derived from UFH through one third the molecular weight of UFH It is derived from UFH through variousvarious
depolymerization processes LMWH binds to antithrombin which in turn depolymerization processes LMWH binds to antithrombin which in turn
Neutralizes actors Xa and IIa Because LMWH lacks many of the longer Neutralizes actors Xa and IIa Because LMWH lacks many of the longer chains chains
required for binding to thrombin it has less ability to neutralize thrombin required for binding to thrombin it has less ability to neutralize thrombin
relativeto its ability to neutralize factor Xa LMWH also has less relativeto its ability to neutralize factor Xa LMWH also has less nonspecific nonspecific
binding to other proteins There is greater bioavailability with more binding to other proteins There is greater bioavailability with more predictable predictable
pharmacokinetics that eliminates the need for monitoring The smaller pharmacokinetics that eliminates the need for monitoring The smaller size also size also
allows for enhanced subcutaneous absorption when compared with UFHallows for enhanced subcutaneous absorption when compared with UFH
Three LMWH preparations are Three LMWH preparations are currently approved for use in the currently approved for use in the United States (1) enoxaparin (2) United States (1) enoxaparin (2) dalteparin and (3) tinzaparin dalteparin and (3) tinzaparin
They are all administered They are all administered subcutaneously at intervals of either subcutaneously at intervals of either once or twice daily for both once or twice daily for both prophylaxis and treatment dosesprophylaxis and treatment doses
Few Experiences of Few Experiences of ThrombolysisThrombolysis
Vickey 25 Yrs male patient presented Vickey 25 Yrs male patient presented with 12with 12thth day HO severe headache with day HO severe headache with right sided hemiplegiaright sided hemiplegia
MRI shows thrombosis of the superior MRI shows thrombosis of the superior sagittal left transverse left sigmoid sagittal left transverse left sigmoid sinuses and cortical veins in the fronto-sinuses and cortical veins in the fronto-parietal regions with eo haemorrhagic parietal regions with eo haemorrhagic infarct in the left cerebral hemisphere infarct in the left cerebral hemisphere with mass effect( Grade ndashV)with mass effect( Grade ndashV)
Sashi Srivastava 64 yrs FSashi Srivastava 64 yrs F In a follow up case of MRD with infra-renal In a follow up case of MRD with infra-renal
aortic abdominal and bilateral renal artery aortic abdominal and bilateral renal artery thrombosis renal angiogram shows filling thrombosis renal angiogram shows filling defects in the right Renal artery defects in the right Renal artery
Initially Renal angioplasty was done Initially Renal angioplasty was done Following angioplasty few thrombi are seem Following angioplasty few thrombi are seem to extends into the segmental branches and to extends into the segmental branches and causing blockage So Thrombolysis was causing blockage So Thrombolysis was plane to dissolve the run-out thrombi with plane to dissolve the run-out thrombi with urokinase urokinase
Rakesh 34yrsMRakesh 34yrsM Left SFA pseudoaneurysm with Left SFA pseudoaneurysm with
Covered stent placementCovered stent placement Pre operative antiplatelets with post Pre operative antiplatelets with post
procedure heparin Tirofiban procedure heparin Tirofiban followed by aspirin and clopidogrel followed by aspirin and clopidogrel were usedwere used
IAT may be a treatment option for selected patients IAT may be a treatment option for selected patients Possible selection criteria include Possible selection criteria include
presentation between 3 and 6 hours from symptom onsetpresentation between 3 and 6 hours from symptom onset major cerebral artery occlusion major cerebral artery occlusion severe neurologic deficits severe neurologic deficits high risk of systemic hemorrhage with IV rt-PA (eg recent high risk of systemic hemorrhage with IV rt-PA (eg recent
surgery) surgery) The MERCI (Mechanical Embolus Removal in Cerebral The MERCI (Mechanical Embolus Removal in Cerebral
Ischemia) retrievalIschemia) retrieval system system
Has been FDA-approved for recanalizing acutely occluded Has been FDA-approved for recanalizing acutely occluded cerebral arteries cerebral arteries
In the Multi-MERCI study patients who did not improve In the Multi-MERCI study patients who did not improve immediately after IV rt-PA underwent mechanical immediately after IV rt-PA underwent mechanical embolectomy within 8 hours of symptom onset embolectomy within 8 hours of symptom onset
Partial or complete recanalization occurred in 74 of Partial or complete recanalization occurred in 74 of patientspatients
with a symptomatic intracerebral hemorrhage (sICH) rate of with a symptomatic intracerebral hemorrhage (sICH) rate of 67 67
Mechanical embolectomy with the MERCI retriever may be a Mechanical embolectomy with the MERCI retriever may be a feasible and safe option for patients after IV rt-PAfeasible and safe option for patients after IV rt-PA
Penumbra stroke systemPenumbra stroke system This device combines two methods of clot This device combines two methods of clot
extraction aspiration and mechanical extraction aspiration and mechanical extraction extraction
First the clot is aspirated then a thrombus First the clot is aspirated then a thrombus removal ring can be used if necessary to removal ring can be used if necessary to remove remaining clot remove remaining clot
successful recanalizing 82successful recanalizing 82 Bridging therapyBridging therapy
06 mgkg IV rt-PA followed by IAT with IA rt-06 mgkg IV rt-PA followed by IAT with IA rt-PA (up to 20 mg)PA (up to 20 mg)
achieved a higher recanalization rateachieved a higher recanalization rate
Criteria for thrombolysis with rTPACriteria for thrombolysis with rTPA
Inclusion criteriaInclusion criteria Clinical signs and symptoms consistent with ischemic Clinical signs and symptoms consistent with ischemic
strokestroke Patient last seen normal within 3 hoursPatient last seen normal within 3 hours Measurable neurologic deficitMeasurable neurologic deficit
Exclusion criteriaExclusion criteria Any hemorrhage on neuroimaging (CT or MRI)Any hemorrhage on neuroimaging (CT or MRI) Symptoms suggestive of subarachnoid hemorrhageSymptoms suggestive of subarachnoid hemorrhage Seizure at stroke onset that is thought to contribute to Seizure at stroke onset that is thought to contribute to
neurologic deficitneurologic deficit Hypodensity greater than one third cerebral hemisphere Hypodensity greater than one third cerebral hemisphere
on CTon CT SBP greater than 185 mm Hg or DBP greater than 110 SBP greater than 185 mm Hg or DBP greater than 110
mm Hgmm Hg International normalized ratio (INR) greater than 17International normalized ratio (INR) greater than 17
Ischemic Stroke Ischemic Stroke Treatment ndash 2006Treatment ndash 2006
IV tissue plasminogen activator (tPA)IV tissue plasminogen activator (tPA) ndash ndash Only FDA-approved acute stroke drugOnly FDA-approved acute stroke drug ndash ndash 3 hour treatment window3 hour treatment window
MERCI - Concentric clot retrieval MERCI - Concentric clot retrieval devicedevice ndash ndash Rescue therapy - approved 2004Rescue therapy - approved 2004 ndash ndash Device approval (not outcomes-based)Device approval (not outcomes-based)
Off label approachesOff label approaches ndash ndash IV tPA after 3 hoursIV tPA after 3 hours ndash ndash IV-IA tPA sequential strategiesIV-IA tPA sequential strategies ndash ndash IA tPA clot angioplasty fragmentationIA tPA clot angioplasty fragmentation ndash ndash Ultrasound-assisted tPA lysisUltrasound-assisted tPA lysis
rt-PA Trials NINDSrt-PA Trials NINDS
Acute stroke - 624 patientsAcute stroke - 624 patients Treat within 3 hrsTreat within 3 hrs Intravenous 09 mgkg rt-PA vs placeboIntravenous 09 mgkg rt-PA vs placebo Hemorrhage 64 tPA 06 placeboHemorrhage 64 tPA 06 placebo Neurologic recovery better with tPA 30 Neurologic recovery better with tPA 30
more like to have minimal or no disabilitymore like to have minimal or no disability
First proven approved treatment for First proven approved treatment for strokestroke
Limitations of tPALimitations of tPA Only 4 of acute strokes receive tPAOnly 4 of acute strokes receive tPA (Kleindorfer et al Stroke 2004 35 e27-e29)(Kleindorfer et al Stroke 2004 35 e27-e29)
Only 22 of patients present within 3 hoursOnly 22 of patients present within 3 hours1048707 1048707 51 of these ineligible due to51 of these ineligible due to
bull bull Mild severityMild severity bull bull Medical or surgical historyMedical or surgical history bull bull Blood testsBlood tests
Sustained recanalization only 13Sustained recanalization only 13 (Alexandrov et al NEJM 2004 351 2170-8)(Alexandrov et al NEJM 2004 351 2170-8)
Concern for hemorrhageConcern for hemorrhage tPA potentiates apoptotic injury tPA potentiates apoptotic injury (Liu et al Nature Med 2004 101379-83)(Liu et al Nature Med 2004 101379-83)
PROACT II IA Lysis TrialPROACT II IA Lysis Trial Baseline 24 hours 8 days
Baseline 60 minutes 120 minutes
9mg IAProurokinase
Desmoteplase Trials DEDAS Desmoteplase Trials DEDAS DIASDIAS
Trial OverviewTrial Overview Double blind randomized placebo Double blind randomized placebo
controlled trialscontrolled trials IV delivery 3-9 hour time windowIV delivery 3-9 hour time window Plasminogen activator ndash from Plasminogen activator ndash from vampire bat vampire bat
salivasaliva Selection based on PWI-DWI MismatchSelection based on PWI-DWI Mismatch
MRI InclusionMRI Inclusion PWI defect at least 2 cm AND ~20 larger PWI defect at least 2 cm AND ~20 larger
than DWIthan DWI PWI should be obvious even visible on PWI should be obvious even visible on
raw imagesraw imagesMRI ExclusionMRI Exclusion
DWI gt 13 MCADWI gt 13 MCA MRA ICA occlusionMRA ICA occlusion
Desmoteplase ndash DIAS Desmoteplase ndash DIAS ResultsResults
Mechanical Thrombolysis Mechanical Thrombolysis devicesdevices
mechanical thrombolysis potentially extends the treatment mechanical thrombolysis potentially extends the treatment window because they act promptly at the site of the thrombuswindow because they act promptly at the site of the thrombus
The devices can retrieve large clots that pharmaceutical agents The devices can retrieve large clots that pharmaceutical agents may not successfully lysemay not successfully lyse
Patients treated with IV tPA may be considered for treatment of Patients treated with IV tPA may be considered for treatment of residual clot with some of these devicesresidual clot with some of these devices
suction-creating saline jets suction-creating saline jets laser energy ultrasound laser energy ultrasound a corkscrew apparatus to treat strokesa corkscrew apparatus to treat strokes The AngioJet systemThe AngioJet system uses saline jets that are directed back into the catheter to uses saline jets that are directed back into the catheter to
create a low-pressure zone around the catheter tip inducing create a low-pressure zone around the catheter tip inducing suction suction
The clot is pulled into the exhaust lumen and removed from the The clot is pulled into the exhaust lumen and removed from the vessel Although US Food and Drug Administration (FDA) has vessel Although US Food and Drug Administration (FDA) has approved this device for use in arteriovenous dialysis grafts and approved this device for use in arteriovenous dialysis grafts and fistulae and for the treatment of coronary arteries saphenous fistulae and for the treatment of coronary arteries saphenous vein grafts and peripheral vessels clinical trials for the vein grafts and peripheral vessels clinical trials for the treatment of acute stroke are no longer in progress treatment of acute stroke are no longer in progress
Most devices are used in cerebral vessels that 2-5 mm
The Latis laser device The Latis laser device used laser energy to ablate clots used laser energy to ablate clots Arteries 2-5 mm in diameter could be Arteries 2-5 mm in diameter could be
treated including the ICA M1 or M2 treated including the ICA M1 or M2 branch of the MCA A1 branch of the branch of the MCA A1 branch of the anterior cerebral artery (ACA) basilar anterior cerebral artery (ACA) basilar artery posterior cerebral artery (PCA) artery posterior cerebral artery (PCA) and vertebral and vertebral
Patients could receive treatment as late Patients could receive treatment as late as 8 hours after symptom onset in the as 8 hours after symptom onset in the anterior circulation and within 24 hours in anterior circulation and within 24 hours in the posterior circulation the posterior circulation
Endovascular Photo Acoustic Endovascular Photo Acoustic Recanalization (EPAR) Recanalization (EPAR)
A laser power source generated energy for the A laser power source generated energy for the systemsystem
The energy was delivered by means of The energy was delivered by means of fiberoptics to the tip of the catheter at the fiberoptics to the tip of the catheter at the treatment sitetreatment site
Absorption of laser light by darkly pigmented Absorption of laser light by darkly pigmented materials (ie the clot) occurred inside the 1-mm materials (ie the clot) occurred inside the 1-mm catheter tipcatheter tip
the system was designed to minimize scattering the system was designed to minimize scattering of laser light of laser light
Absorption converted photo energy to acoustic Absorption converted photo energy to acoustic energy which then emulsified the clot inside the energy which then emulsified the clot inside the catheter tip catheter tip
EKOS ultrasound( the EKOS ultrasound( the Ultrasound Thrombolytic Ultrasound Thrombolytic
Infusion Catheter) Infusion Catheter) combines the use of a distal ultrasound transducer with combines the use of a distal ultrasound transducer with
infusion of a thrombolytic agent through the infusion of a thrombolytic agent through the microcathetermicrocatheter
Ultrasound changes the structure of the clot to Ultrasound changes the structure of the clot to temporarily increase its permeability while providing an temporarily increase its permeability while providing an acoustic pressure gradient to move the drug into the clot acoustic pressure gradient to move the drug into the clot to speed its dissolution to speed its dissolution
The EKOS catheter is placed in the proximal portion of the The EKOS catheter is placed in the proximal portion of the clot clot
After a 2-mg bolus of tPA was injected through the After a 2-mg bolus of tPA was injected through the catheter catheter
the patient received a continuous infusion of IA tPA 03 the patient received a continuous infusion of IA tPA 03 mgmin to a maximum of 20 mg and simultaneous mgmin to a maximum of 20 mg and simultaneous ultrasound transmission for as long as 60 minutes ultrasound transmission for as long as 60 minutes
One patient was treated with a total of 4 units of One patient was treated with a total of 4 units of recombinant reteplase (Retavase) hand-injected over 60 recombinant reteplase (Retavase) hand-injected over 60 minutes minutes
Penumbra system Penumbra system The Penumbra system (Penumbra Inc) provides a dual The Penumbra system (Penumbra Inc) provides a dual
approach to clot extraction using aspiration followed by approach to clot extraction using aspiration followed by clot retrieval with a ring device if needed clot retrieval with a ring device if needed
Mechanical Embolus Removal in Cerebral Ischemia Mechanical Embolus Removal in Cerebral Ischemia (MERCI)(MERCI)
a corkscrew-like apparatus to remove blood clots from a corkscrew-like apparatus to remove blood clots from the brain in patients experiencing an ischemic stroke the brain in patients experiencing an ischemic stroke
The corkscrew itself resides in the catheter tip which The corkscrew itself resides in the catheter tip which shields it from the wall of the vessel until it is ready to be shields it from the wall of the vessel until it is ready to be burrowed into the clot Once lodged in the clot the device burrowed into the clot Once lodged in the clot the device and clot are withdrawn from the vessel and clot are withdrawn from the vessel
Snarelike devicesSnarelike devices Snares such as the Neuronet snare (Guidant Snares such as the Neuronet snare (Guidant
Endovascular Santa Clara CA) have been developed Endovascular Santa Clara CA) have been developed specifically for use in the treatment of strokes specifically for use in the treatment of strokes
These devices are simple in design and do not require the These devices are simple in design and do not require the clot to be amenable to emulsification clot to be amenable to emulsification
X-Sizer deviceX-Sizer device a device with small moving blades at the a device with small moving blades at the
catheter tip catheter tip This device the X-Sizer device (EndiCor Medical This device the X-Sizer device (EndiCor Medical
San Clemente CA) can be used to excise the San Clemente CA) can be used to excise the thrombus and aspirate it thrombus and aspirate it
The device was being evaluated in randomized The device was being evaluated in randomized studies of coronary vessels and in a registry of studies of coronary vessels and in a registry of patients with acute myocardial infarctionpatients with acute myocardial infarction
Although the manufacturer had modified the Although the manufacturer had modified the device for use in cerebral vessels a safety and device for use in cerebral vessels a safety and feasibility study was indefinitely suspended after feasibility study was indefinitely suspended after only 1 patient was treated with the device in only 1 patient was treated with the device in Europe Europe
Suction thrombectomySuction thrombectomy This method of mechanical thrombolysis is one of the This method of mechanical thrombolysis is one of the
simplestsimplest In this readily available technique suction is applied with In this readily available technique suction is applied with
a syringe to remove thrombus in the ICA a syringe to remove thrombus in the ICA It requires no other devicesIt requires no other devices A catheter with a large inner diameter (Brite Tip Cordis A catheter with a large inner diameter (Brite Tip Cordis
Corporation Miami FL) was placed in the symptomatic Corporation Miami FL) was placed in the symptomatic vessel and navigated over a guidewire into the thrombusvessel and navigated over a guidewire into the thrombus
A 60-mL syringe was used to aspirate the thrombus A 60-mL syringe was used to aspirate the thrombus Each patient required angioplasty and stenting of carotid Each patient required angioplasty and stenting of carotid
bifurcation stenosis and received daily aspirin and bifurcation stenosis and received daily aspirin and ticlopidine after the procedure No complications ticlopidine after the procedure No complications occurred occurred
Summary Acute Stroke Summary Acute Stroke ImagingImaging
PhysiologyPhysiology importance collaterals importance collaterals
ndash ndashGrowing role for perfusion Growing role for perfusion assessmentassessment
tPAtPA guidelines amp limitations guidelines amp limitations Signs on CT amp MRSigns on CT amp MR follow physiology follow physiology Stroke trialsStroke trials PWI-DWI mismatch PWI-DWI mismatch
ndash ndashTreat based on physiology not timeTreat based on physiology not time ProtocolsProtocols should be fast and should be fast and
comprehensivecomprehensive
BLOOD COAGULATION
A sequence of reactions that are present in an inactive state in bloodKey is the conversion of the plasma protein fibrinogen to fibrin Intrinsic pathway Extrinsic pathway(activated by exposure of (activated by substances blood to damaged tissue) released from damaged tissue)
Active factors X and V
Prothrombin Thrombin
Fibrinogen Fibrin Fibrin mesh
inhibited by warfarin
inhibited by heparin
Rationale for anticoagulant Rationale for anticoagulant therapytherapy
PHARMACOLOGICAL PHARMACOLOGICAL AGENTSAGENTS
Pharmacologic AgentsPharmacologic Agents
AnticoagulantsAnticoagulants
Fibrinolytics (Agents for pharmacological Fibrinolytics (Agents for pharmacological recanalization)recanalization)
Anti platelet drugsAnti platelet drugs
Thrombin inhibitorThrombin inhibitor
ANTICOAGULANTSANTICOAGULANTS
Heparin and Low Molecular Weight Heparins Heparin and Low Molecular Weight Heparins ((eg enoxaparin dalteparin)eg enoxaparin dalteparin)
Oral anticoagulantsOral anticoagulants Coumarin Derivatves Coumarin Derivatves eg Warfarin eg Warfarin
AcenocoumarolAcenocoumarol Indandione Derivatves Indandione Derivatves eg Phenindione eg Phenindione
AnisindioneAnisindione
ThrombolyticsThrombolytics
Plasminogen activators
Fibrinolytics
Anti Platelet DrugsAnti Platelet DrugsDrug Mechanism UsesDrug Mechanism UsesAspirinAspirin Permanently inhibits Permanently inhibits
COX-1 and COX-2COX-1 and COX-2CADCAD
Stroke-TIAsStroke-TIAs
NSAIDsNSAIDs Reversibly inhibits Reversibly inhibits COX-1COX-1
LimitedLimited
DipyridamoleDipyridamole Inhibits PDE Inhibits PDE increases cAMPincreases cAMP
TIAsTIAs
ThenopyridinesThenopyridines
(Ticlopidine(Ticlopidine
Clopidegrel)Clopidegrel)
Inhibits ADP Inhibits ADP
PlatAg PlatAg
TIAsStrokeTIAsStroke
CAD PVDCAD PVD
Abciximab (ReoPro)Abciximab (ReoPro)
Eptifibatide Eptifibatide (Integrilin)(Integrilin)
TirofibaTirofibann
GP IIBIIIA InhibitorsGP IIBIIIA Inhibitors
Stroke- TIAs Stroke- TIAs
Maintainance of patency Maintainance of patency of vascular of vascular grafts catheters shunts bypassesgrafts catheters shunts bypasses
Arterial thromboembolic diseaseArterial thromboembolic diseasebull Transient ischemic attacksTransient ischemic attacksbull Stroke in evolutionStroke in evolution
Ischemic events occurs in Ischemic events occurs in 1313 of of conventional neuroangiographic conventional neuroangiographic procedures without Endovascular surgeryprocedures without Endovascular surgery
Indications for Antithrombotic Therapy in Indications for Antithrombotic Therapy in Diagnostics and Interventional ProceduresDiagnostics and Interventional Procedures
WHY TO MONITOR ANTICOAGULANT THERAPYWHY TO MONITOR ANTICOAGULANT THERAPY
Narrow therapeutic rangeNarrow therapeutic range
Can increase risk of bleedingCan increase risk of bleeding
Coagulation TestingCoagulation Testing
Monitoring therapyMonitoring therapy
Intrinsic Pathway
Extrinsic Pathway
Common Pathway
CLOT
Heparin Coumadin
Monitor with
ACT aPTT
Monitor with PTINR
Thrombolytics
Monitor with TT Fibrinogen
Monitoring of Monitoring of Anti platelet drugsAnti platelet drugs
Bleeding timeBleeding time
Optical aggregometryOptical aggregometry
Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay
HeparinHeparin
Heterogeneous 3000-30000 dalton in Heterogeneous 3000-30000 dalton in molecular weight molecular weight
Average=15000 d (~45monosaccharide Average=15000 d (~45monosaccharide chains)chains)
About About 13 of dose binds to AT III and forms 13 of dose binds to AT III and forms the AT IIIHeparinClotting Factor Complexthe AT IIIHeparinClotting Factor Complex
Complex binds to clotting factors of the Complex binds to clotting factors of the intrinsic and common pathway (Xa IIa IXa intrinsic and common pathway (Xa IIa IXa XIa XIIa XIIIa) and inactivates themXIa XIIa XIIIa) and inactivates them
Anticoagulant of choice in pregnancy (not Anticoagulant of choice in pregnancy (not crosses placenta)crosses placenta)
Heparin and Low molecular weight heparinsHeparin and Low molecular weight heparins
Structure and sequence
O
OH
OH
O
COO
O
O
CH2OH
NHSO3
OH
_
_
O
O
CH2OSO3
NHSO3
OH
_
_
O
OH
OH
O
COOO
O
CH2OSO3
NHSO3
OH
_
_
O
OSO3
OHO
COOO
O
CH2OSO3
NHCOCH3
OH
_
_ _
_
_
O
OH
OH
O
COO
1
23
4
5
6
-D-glucosamine -L-iduronic acid -D-glucuronic acid
O
O
CH2OH
NH2
OH 12
3
4
5
6
O
OH
OHO
COO_
1
23
4
5
6
polymeric structure of heparin
Anticoagulant Properties of Anticoagulant Properties of HeparinHeparin
11 Inhibits the thrombin-mediated conversion of Inhibits the thrombin-mediated conversion of fibrinogen to fibrinfibrinogen to fibrin
22 Inhibits the aggregation of platelets by thrombin Inhibits the aggregation of platelets by thrombin (prolongs bleeding time)(prolongs bleeding time)
33 Inhibits activation of fibrin stabilizing enzymeInhibits activation of fibrin stabilizing enzyme
44 Inhibits activated factors XII XI IX X and IIInhibits activated factors XII XI IX X and II All available forms of heparin must be All available forms of heparin must be
administered administered parenterally since they are parenterally since they are highly charged and rapidlyhighly charged and rapidly hydrolyzed in the hydrolyzed in the GI tractGI tract
Heparin antagonist Protamine sulfate (Heparin antagonist Protamine sulfate (10mg for 10mg for 1000 unit of heparin)1000 unit of heparin)
Monitoring of heparin Monitoring of heparin
Subcutenous Subcutenous no monitoring requiredno monitoring required Intravenous Intravenous
Partial thromboplastin time (PTT normal value Partial thromboplastin time (PTT normal value ~30sec) ~30sec)
Activated clotting time ( ACT normal value ~90-Activated clotting time ( ACT normal value ~90-120sec)120sec)
Daily or more frequent if PTT ACT variesDaily or more frequent if PTT ACT varies
Mechanism Mechanism ndash measures intrinsic pathwayndash measures intrinsic pathway Therapeutic goal Therapeutic goal 2-25 times normal control value 2-25 times normal control value
ACT or aPTTACT or aPTT
Determine when to pull the femoral sheath Determine when to pull the femoral sheath Premature sheath pull can lead to bleedingPremature sheath pull can lead to bleeding Delayed removal can increase time in ICUDelayed removal can increase time in ICU Target set Target set at each siteat each site
ACT targets range from 150 ndash 220 ACT targets range from 150 ndash 220 secondsseconds
aPTT targets range from 40 ndash 70 seconds aPTT targets range from 40 ndash 70 seconds
During neuroangiography-During neuroangiography- Recommended therapeutic range of heparin in Recommended therapeutic range of heparin in
plasma is 02-08 uml ( corresponding to aPTT plasma is 02-08 uml ( corresponding to aPTT ACT values 15-25 times the baseline values)ACT values 15-25 times the baseline values)
Dose In diagnostic angiography bolus dose of Dose In diagnostic angiography bolus dose of 2500 iu is used followed by 1000 iu hour2500 iu is used followed by 1000 iu hour
Bolus dose is Bolus dose is 60 ukg to maintain the therapeutic 60 ukg to maintain the therapeutic range range If procedure continues for more than 75 If procedure continues for more than 75 minutes additional dose is required ( half of the minutes additional dose is required ( half of the initial dose for another 75 minutes) initial dose for another 75 minutes)
(AJNR 199415 51-54)
Mechanisms of HIT( Mechanisms of HIT( Heparin Heparin induced Thrombocytopeniainduced Thrombocytopenia))
Type 1Type 1 Fall in platelet count occurs within the first two Fall in platelet count occurs within the first two
days after heparin initiation often returns to days after heparin initiation often returns to normal with continued heparin administration normal with continued heparin administration and is of no clinical consequence and is of no clinical consequence
The mechanism of the thrombocytopenia is non-The mechanism of the thrombocytopenia is non-immune and appears to be due to a direct effect of immune and appears to be due to a direct effect of heparin on platelet activationheparin on platelet activation
Type 2Type 2 Approximately 03 to 3 percent of patients Approximately 03 to 3 percent of patients
receiving heparin develop an immune receiving heparin develop an immune thrombocytopenia mediated by antibodies to a thrombocytopenia mediated by antibodies to a heparin-platelet factor 4 complex heparin-platelet factor 4 complex
(AJNR 28155-158 2007)
Treatment of heparin-induced Treatment of heparin-induced thrombocytopeniathrombocytopenia
When HIT is diagnosed it is important to When HIT is diagnosed it is important to stop heparin mainly in type 2 and to avoid stop heparin mainly in type 2 and to avoid the use of LMWH the use of LMWH
Because of the increased risk of thrombosis Because of the increased risk of thrombosis however continuation of an anticoagulant however continuation of an anticoagulant must be considered must be considered
The drugs currently approved for the The drugs currently approved for the treatment of HIT in the United States are treatment of HIT in the United States are direct thrombin inhibitors argatroban and direct thrombin inhibitors argatroban and lepirudinlepirudin
WARFARIN MECHANISM OF ACTIONWARFARIN MECHANISM OF ACTION
Inactive factors II VII IX and X
Proteins S and C
Active factors II VII IX and X
Proteins S and C
Vitamin K epoxide
Vitamin K reduced
WA
RF
AR
IN
Prevents the reduction of vitamin K which is essential for Prevents the reduction of vitamin K which is essential for activation of certain factorsactivation of certain factors
Has no effect on previously formed thrombusHas no effect on previously formed thrombus
Antagonist is Vit KAntagonist is Vit K
OPTIMIZING WARFARIN THERAPYOPTIMIZING WARFARIN THERAPY
Use of large loading dose may lead to hemorrhage and Use of large loading dose may lead to hemorrhage and other complicationsother complications
Initial dose 2-5 mg once dailyInitial dose 2-5 mg once daily Maintenance dose 2-10 mg once dailyMaintenance dose 2-10 mg once daily If Immediate anticoagulation is requiredIf Immediate anticoagulation is required Heparin IS Heparin IS
started along with loading dose of warfarin 10 mg started along with loading dose of warfarin 10 mg Heparin is usually discontinued after 4-5 days Heparin is usually discontinued after 4-5 days Before Before discontinuing INR should be in therapeutic range for 2 discontinuing INR should be in therapeutic range for 2 consecutive daysconsecutive days
Daily monitoring of INR until INR is in therapeutic Daily monitoring of INR until INR is in therapeutic range then 3 times weekly for 1-2 weeks then less often range then 3 times weekly for 1-2 weeks then less often (every 4 to 6 weeks)(every 4 to 6 weeks)
OPTIMAL THERAPEUTIC RANGEOPTIMAL THERAPEUTIC RANGE
IndicationIndication INRINR
Prophylaxis of venous Prophylaxis of venous thromboembolismthromboembolism
20-3020-30
Treatment of venous Treatment of venous thromboembolismthromboembolism
20-3020-30
Atrial fibrillationAtrial fibrillation 20-3020-30
Mitral valve stenosisMitral valve stenosis 20-3020-30
Heart valve replacementHeart valve replacement
Bioprosthetic valveBioprosthetic valve
Mechanical valveMechanical valve
20-3020-30
25-3525-35
Myocardial infarctionMyocardial infarction 20-3020-30
25-35 25-35 (high risk patients)(high risk patients)
FACTORS INFLUENCING DOSE RESPONSEFACTORS INFLUENCING DOSE RESPONSE
Poor patient compliancePoor patient compliance Concomitant medicationsConcomitant medications Levels of dietary vitamin KLevels of dietary vitamin K Alcohol Inaccurate lab testingAlcohol Inaccurate lab testing Inaccurate lab testingInaccurate lab testing Hepatic dysfunctionHepatic dysfunction FeverFever
Contraindication for WarfarinContraindication for Warfarin
Hypersensitivity to warfarinHypersensitivity to warfarin Hemorrhagic tendencyHemorrhagic tendency Condition with risk of hemorrhageCondition with risk of hemorrhage Inadequate laboratory techniquesInadequate laboratory techniques Protein C amp S deficiencyProtein C amp S deficiency Vitamin K deficiencyVitamin K deficiency
SIDE EFFECTSSIDE EFFECTS
Hemorrhage Hemorrhage Skin necrosisSkin necrosis Purple toe syndromePurple toe syndrome Microembolization Microembolization TeratogenecityTeratogenecity Agranulocytosis leukopenia Agranulocytosis leukopenia Diarrhoeanausea anorexiaDiarrhoeanausea anorexia
MONITORING OF WARFARIN THERAPYMONITORING OF WARFARIN THERAPY
Prothrombin timeProthrombin time PT ratioPT ratio INR (International Normalized Ratio)INR (International Normalized Ratio)
PROTHROMBIN TIME (PT)PROTHROMBIN TIME (PT)
Time required for blood to coagulate Time required for blood to coagulate is called PT ( normal value ~10sec)is called PT ( normal value ~10sec)
Performed by adding a mixture of Performed by adding a mixture of calcium and thromboplastin to calcium and thromboplastin to citrated plasmacitrated plasma
As a control a normal blood sample is As a control a normal blood sample is tested continuouslytested continuously
PT ratio (PTR) = PT ratio (PTR) = Patientrsquos PTPatientrsquos PT Control PTControl PT
PROBLEMS WITH PTPTRPROBLEMS WITH PTPTR
Thromboplastins are extracts from Thromboplastins are extracts from brain lung or placenta of animalsbrain lung or placenta of animals
Thromboplastins from various Thromboplastins from various manufacturers differ in their manufacturers differ in their sensitivity to prolong PTsensitivity to prolong PT
May result in false control of May result in false control of anticoagulant therapyanticoagulant therapy
INTERNATIONAL NORMALISED RATIO (INR)INTERNATIONAL NORMALISED RATIO (INR)
International Normalized Ratio (INR) International Normalized Ratio (INR) a PT test with a a PT test with a formula based ratio to normalize the often variable source formula based ratio to normalize the often variable source of tissue factor (human rabbit recombinant)of tissue factor (human rabbit recombinant)
INR = [PTINR = [PTptpt] ] ISIISI
[PT[PTRefRef]]
PTPTpt pt ndash prothrombin time of patientndash prothrombin time of patient
PTPTRef Ref ndash prothrombin time of normal pooled samplendash prothrombin time of normal pooled sample
ISI ndash International Sensitivity IndexISI ndash International Sensitivity Index
Warfarin is given orally and titrated to achieve an INR of Warfarin is given orally and titrated to achieve an INR of typically 20 ndash 30typically 20 ndash 30
Heparin versus WarfarinHeparin versus Warfarin
Drug ActionMechan-ism
Moni-toring
Effective
HeparinDirect
Inhibition ofThrombin
ATIIIcofactor
APTTACT
Immediate
WarfarinDecreasesProductionof factors
Vitamin K PTDelay
3-5 days
INR
Recanalization or Antegrade Recanalization or Antegrade Reperfusion StrategiesReperfusion Strategies
Recanalization strategies focus on removing Recanalization strategies focus on removing andor dissolving the occlusive thrombus to re-andor dissolving the occlusive thrombus to re-establish antegrade flow Strategies may be establish antegrade flow Strategies may be classified into 7 different categories on the classified into 7 different categories on the basis of their primary mechanism of action basis of their primary mechanism of action 1) 1) IV andor intraarterial thrombolysis (IAT) IV andor intraarterial thrombolysis (IAT) 2) endovascular thrombectomy2) endovascular thrombectomy3) endovascular thromboaspiration 3) endovascular thromboaspiration 4) endovascular mechanical thrombus disruption or 4) endovascular mechanical thrombus disruption or
thromborrhexisthromborrhexis5) 5) transcranial or endovascular augmented transcranial or endovascular augmented
fibrinolysis fibrinolysis 6) endovascular thrombus entrapment and 6) endovascular thrombus entrapment and 7) temporary endovascular bypass7) temporary endovascular bypass
IAT in Acute Ischemic StrokeIAT in Acute Ischemic Stroke
IAT advantages over IV thrombolysisIAT advantages over IV thrombolysis Coaxial microcatheter techniques the occluded intracranial Coaxial microcatheter techniques the occluded intracranial
vessel is directly accessible and the fibrinolytic agent can be vessel is directly accessible and the fibrinolytic agent can be infused directly into the thrombusinfused directly into the thrombus
This permits a smaller dose of fibrinolytic agent to reach a This permits a smaller dose of fibrinolytic agent to reach a higher local concentration than that reached by systemic higher local concentration than that reached by systemic infusioninfusion
Allows more complete recanalization with lower total doses of Allows more complete recanalization with lower total doses of thrombolytic thrombolytic
With the smaller dose complications from systemic fibrinolytic With the smaller dose complications from systemic fibrinolytic effects including intracranial hemorrhage (ICH) can effects including intracranial hemorrhage (ICH) can theoretically be reduced theoretically be reduced
Treatment window for endovascular techniques can be Treatment window for endovascular techniques can be extended beyond the typical IV window of 3 hours extended beyond the typical IV window of 3 hours
IA techniques have led to higher recanalization rates than IV IA techniques have led to higher recanalization rates than IV thrombolysisthrombolysis
Major disadvantagesMajor disadvantages Relative complexity of the procedure the level Relative complexity of the procedure the level
of required technical expertise and its of required technical expertise and its relatively low availability relatively low availability
Delays in initiating treatmentDelays in initiating treatment InvasiveInvasive
ThrombolyticsThrombolytics
Plasminogen activators
Fibrinolytics
1 Plasminogen Activators 1 Plasminogen Activators drugs act by converting the inactive proenzyme drugs act by converting the inactive proenzyme plasminogen into the active enzyme plasmin Plasmin plasminogen into the active enzyme plasmin Plasmin digests fibrinogen fibrin monomers and cross-linked digests fibrinogen fibrin monomers and cross-linked fibrin (as found in a thrombus) into fibrin degradation fibrin (as found in a thrombus) into fibrin degradation productsproducts
First-Generation Agents First-Generation Agents StreptokinaseStreptokinase a protein derived from group C a protein derived from group C
szlig-hemolytic streptococci has a half-life of 16ndashszlig-hemolytic streptococci has a half-life of 16ndash90 minutes and low fibrin specificity This drug 90 minutes and low fibrin specificity This drug proved to have a very narrow therapeutic proved to have a very narrow therapeutic window and significant rates of ICH and window and significant rates of ICH and systemic hemorrhage18systemic hemorrhage18
UrokinaseUrokinase is a serine protease with a plasma is a serine protease with a plasma half life of 14 minutes and low fibrin specificity half life of 14 minutes and low fibrin specificity
The urokinase dose used in cerebral IAT has The urokinase dose used in cerebral IAT has ranged from 002 to 2 X106unitsranged from 002 to 2 X106units
Second-Generation Agents Second-Generation Agents Alteplase (rtPA) Alteplase (rtPA)
is a serine is a serine protease with a plasma half-life of 35 protease with a plasma half-life of 35 minutes and a high degree of fibrin affinity and minutes and a high degree of fibrin affinity and specificity specificity
Dose used in cerebral IAT has ranged between 20 Dose used in cerebral IAT has ranged between 20 and 60 mgand 60 mg
Disadvantages of alteplase include its relatively short Disadvantages of alteplase include its relatively short halflife and limited penetration into the clot matrix halflife and limited penetration into the clot matrix because of strong binding with surface fibrin which because of strong binding with surface fibrin which could delay recanalization and increase the risk of could delay recanalization and increase the risk of recurrent occlusion recurrent occlusion
Prourokinase (r-prourokinase) Prourokinase (r-prourokinase) is the proenzyme precursor of urokinase is the proenzyme precursor of urokinase T12 of 7 minutes and high fibrin specificity T12 of 7 minutes and high fibrin specificity
Third-Generation AgentsThird-Generation Agents
ReteplaseReteplase is a structurally modified is a structurally modified form of alteplase form of alteplase
with a longer half-life (15ndash18 minutes) In with a longer half-life (15ndash18 minutes) In addition it does not bind as highly to fibrin addition it does not bind as highly to fibrin unbound reteplase can thus theoretically better unbound reteplase can thus theoretically better penetrate the clot and potentially penetrate the clot and potentially improve in improve in vivo fibrinolytic activity vivo fibrinolytic activity
TenecteplaseTenecteplase is another modified form of rtPA with a longer is another modified form of rtPA with a longer
half-life (17 minutes)half-life (17 minutes) greater fibrin specificity and greater greater fibrin specificity and greater
resistance to plasminogen activator inhibitor-1 resistance to plasminogen activator inhibitor-1 IV tenecteplase in acute ischemic stroke IV tenecteplase in acute ischemic stroke
suggest that the drug is safe and promisingsuggest that the drug is safe and promising
Newer plasminogen activatorNewer plasminogen activator
DesmoteplaseDesmoteplase is a genetically engineered is a genetically engineered version of the clot-dissolving factor version of the clot-dissolving factor
found in the saliva found in the saliva of the vampire bat Desmodus rotundusof the vampire bat Desmodus rotundus moremore potent and more selective for fibrin-bound potent and more selective for fibrin-bound
plasminogen than any other known plasminogen plasminogen than any other known plasminogen activatoractivator
Unlike tissue plasminogen activator (tPA) desmoteplase Unlike tissue plasminogen activator (tPA) desmoteplase is not activated by fibrinogen or -amyloid proteins is not activated by fibrinogen or -amyloid proteins factors that may exacerbate the risk for ICH factors that may exacerbate the risk for ICH
The effect of IV administration of desmoteplase 3ndash9 The effect of IV administration of desmoteplase 3ndash9 hours after symptom onset in patients with stroke who hours after symptom onset in patients with stroke who present with mismatch on MR imaging or CT perfusion present with mismatch on MR imaging or CT perfusion
3 DefibrinogenatingFibrinogenolytic 3 DefibrinogenatingFibrinogenolytic Agents Agents
AncrodAncrod(Viprinex)(Viprinex) is is the purified fraction of the Malayan pit viper venomthe purified fraction of the Malayan pit viper venom It acts by directly cleaving and inactivating fibrinogen It acts by directly cleaving and inactivating fibrinogen
and thus indirectly promoting anticoagulation and thus indirectly promoting anticoagulation The reduction in the blood levels of fibrinogen also The reduction in the blood levels of fibrinogen also
leads to a reduced blood viscosity which may improve leads to a reduced blood viscosity which may improve blood flow to the affected areas of the brain blood flow to the affected areas of the brain
In the Stroke Treatment with Ancrod Trial 500 In the Stroke Treatment with Ancrod Trial 500 patients with stroke presenting within 3 hours of patients with stroke presenting within 3 hours of symptom onset were randomized to receive ancrod (symptom onset were randomized to receive ancrod (n n 248) or a placebo (n 252) Good outcome (Barthel 248) or a placebo (n 252) Good outcome (Barthel Index 95ndash100 at 3 months) was achieved in 4221 Index 95ndash100 at 3 months) was achieved in 4221 and 344 of the patients respectively and 344 of the patients respectively
2 Direct Fibrinolytics2 Direct Fibrinolytics
Microplasmin (Microplasmin (ThromboGenics Heverlee Belgium)ThromboGenics Heverlee Belgium) is a truncated form of plasmin that is more resistant to the effects is a truncated form of plasmin that is more resistant to the effects
of antiplasmin of antiplasmin microplasmin can be used upto 4ndash12 hours after stroke onset microplasmin can be used upto 4ndash12 hours after stroke onset There was no evidence of increased bleeding risk with There was no evidence of increased bleeding risk with
microplasminmicroplasmin
Alfimeprase (Nuvelo San Carlos Calif)Alfimeprase (Nuvelo San Carlos Calif) is a recombinant truncated form of fibrolase a fibrinolytic zinc metalloproteinase is a recombinant truncated form of fibrolase a fibrinolytic zinc metalloproteinase
isolated from the venom of the southern copperhead snake isolated from the venom of the southern copperhead snake It degrades fibrin directly and achieves thrombolysis independent It degrades fibrin directly and achieves thrombolysis independent
of plasmin formationof plasmin formation its thrombolytic activity appears to be localized to the site of its thrombolytic activity appears to be localized to the site of
delivery These properties should theoretically result in faster delivery These properties should theoretically result in faster recanalization and lower hemorrhagic conversion riskrecanalization and lower hemorrhagic conversion risk
Anti-fibrinolyticsAnti-fibrinolytics
to limit fibrinolytic activityto limit fibrinolytic activity -aminocaproic acid (EACA) -aminocaproic acid (EACA) competitively inhibitscompetitively inhibits plasminogen and plasminogen activators from plasminogen and plasminogen activators from
binding to fibrinbinding to fibrin
alpha2-antiplasminalpha2-antiplasmin a serine protease inhibitor that a serine protease inhibitor that neutralizes any free circulating plasminneutralizes any free circulating plasmin
Plasminogen activator inhibitor-1Plasminogen activator inhibitor-1 a serine protease a serine protease inhibitor that inhibits tissue-type plasminogen inhibitor that inhibits tissue-type plasminogen activatoractivator
Glycoprotein (GP) IIbIIIa antagonistsGlycoprotein (GP) IIbIIIa antagonists
such as ReoPro (abciximab) Integrilin such as ReoPro (abciximab) Integrilin (eptifibatide) or Aggrastat (tirofiban) in (eptifibatide) or Aggrastat (tirofiban) in ischemic stroke remains investigational ischemic stroke remains investigational Deshmukh et al38 reported 21 patients with Deshmukh et al38 reported 21 patients with large-vessel occlusion refractory to IAT with large-vessel occlusion refractory to IAT with rtPA who were treated with IV andor IA rtPA who were treated with IV andor IA abciximab eptifibatide or tirofiban abciximab eptifibatide or tirofiban
IA Mechanical Approaches in Acute Ischemic Stroke IA Mechanical Approaches in Acute Ischemic Stroke Mechanical strategies have several advantagesMechanical strategies have several advantages First they lessen and may even preclude the use of chemical First they lessen and may even preclude the use of chemical
thrombolytics in this manner very likely reducing the risk of ICHthrombolytics in this manner very likely reducing the risk of ICH Second by avoiding the use of chemical thrombolytics it is Second by avoiding the use of chemical thrombolytics it is
possible to extend the treatment window beyond the limit of 6ndash8 possible to extend the treatment window beyond the limit of 6ndash8 hours hours
Third mechanically fragmenting a clot increases the surface area Third mechanically fragmenting a clot increases the surface area accessible to fibrinolytic agents and allows inflow of fresh accessible to fibrinolytic agents and allows inflow of fresh plasminogen which in turn may increase the speed of plasminogen which in turn may increase the speed of thrombolysis thrombolysis
Finally clot-retrieval devices may provide faster recanalization Finally clot-retrieval devices may provide faster recanalization
The disadvantages of the mechanical The disadvantages of the mechanical approaches approaches technical difficulty of navigating mechanical technical difficulty of navigating mechanical
devices into the intracranial circulation excessive devices into the intracranial circulation excessive trauma to the vasculature (potentially leading to trauma to the vasculature (potentially leading to vasospasm vessel dissection perforation or vasospasm vessel dissection perforation or rupture) rupture)
fragmented thrombus causing distal embolization fragmented thrombus causing distal embolization into previously unaffected territories into previously unaffected territories
Nevertheless the advantages of mechanical stroke Nevertheless the advantages of mechanical stroke therapy appear to significantly outweigh its therapy appear to significantly outweigh its disadvantages and risksdisadvantages and risks
Contraindications to Thrombolytic Contraindications to Thrombolytic agents agents
Recent thoracic abdominal or Recent thoracic abdominal or intracranial surgeryintracranial surgery
Recent haemorrhagic CVA Head injury Recent haemorrhagic CVA Head injury or neoplasmor neoplasm
Bleeding ulcerBleeding ulcer Anticipated invasive procedures (arterial Anticipated invasive procedures (arterial
punctures biopsies)punctures biopsies) Concurrent hemostatic dysfunctionConcurrent hemostatic dysfunction
Monitoring of thrombolytic Monitoring of thrombolytic therapytherapy
Thrombin time Measures the availability of functional
fibrinogen Normal thrombin time is 10-14 sec Prolonged when fibrinogen level is below
75-100 mgdl
Half Life of ThrombolyticsHalf Life of ThrombolyticsAgent Administration Half Life
Streptokinase IA 60-80min
Urokinase IAIV 9-12min
rTPA IAIV 6min
Abciximab(Reopro) IAIV 12hour
Aspirin POIV 15-20min
Heparin IVSC 60min
Coumadin PO 15-25 days
Anti Platelet DrugsAnti Platelet DrugsDrug Drug Mechanism Mechanism UsesUsesAspirinAspirin Permanently inhibits Permanently inhibits
COX-1 and COX-2COX-1 and COX-2CADCAD
Stroke-TIAsStroke-TIAs
NSAIDsNSAIDs Reversibly inhibits Reversibly inhibits COX-1COX-1
LimitedLimited
DipyridamoleDipyridamole Inhibits PDE increases Inhibits PDE increases cAMPcAMP
TIAsTIAs
ThenopyridinesThenopyridines
(Ticlopidine(Ticlopidine
ClopidrgrelClopidrgrel))
Inhibits ADP Inhibits ADP
PlatAg PlatAg
TIAsStrokeTIAsStroke
CAD PVDCAD PVD
Abciximab (ReoPro)Abciximab (ReoPro)
Eptifibatide (Integrilin)Eptifibatide (Integrilin)
TirofibanTirofiban
GP IIBIIIA InhibitorsGP IIBIIIA Inhibitors
Stroke- TIAs Stroke- TIAs
MonitoringMonitoring
Bleeding timeBleeding time
Optical aggregometryOptical aggregometry
Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay
Bleeding timeBleeding time
Requires a skin incision (usually made on the ear lobe or Requires a skin incision (usually made on the ear lobe or forearm offorearm of
a depth that results in disruption of capillary loops and a depth that results in disruption of capillary loops and small vessels)small vessels)
AdvantagesAdvantages Universally availableUniversally available Relatively simple techniquesRelatively simple techniques Can be performed bedsideCan be performed bedside
DisadvantagesDisadvantages Insensitive inaccurate non-specific techniqueInsensitive inaccurate non-specific technique
Poorly reproducible (as depends on multiple variables)Poorly reproducible (as depends on multiple variables)
Optical aggregometryOptical aggregometry
Gold standard assay for platelet functionGold standard assay for platelet function Agonist induced aggregation is measuredAgonist induced aggregation is measured Different agonist are available for different Different agonist are available for different
agentsagents However require unique expertise and are not However require unique expertise and are not
universally availableuniversally available Aspirin measured with ADP or AA(gt70 Aspirin measured with ADP or AA(gt70
aggregation so resistance)aggregation so resistance) Clopidogrel( ADP gt 90 aggregation means Clopidogrel( ADP gt 90 aggregation means
resistance) resistance)
Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay
Can be performed bed sideCan be performed bed side Different assay devices with different Different assay devices with different
agonist are used for each of different agonist are used for each of different antiplatelet agents antiplatelet agents
For Aspirin AA is used (result is reported as aspirin For Aspirin AA is used (result is reported as aspirin reaction units [ARU] ARUgt 550 indicates non-reaction units [ARU] ARUgt 550 indicates non-responsiveness)responsiveness)
Verify IIbIIIa assay device uses TRAP as agonist for Verify IIbIIIa assay device uses TRAP as agonist for Abciximab and TirofibanAbciximab and Tirofiban
Practical Applications Practical Applications related to specific related to specific
Neurovascular Neurovascular interventionsinterventions
Acute ischemic StrokeAcute ischemic Stroke When an artery occludes neurons are affected When an artery occludes neurons are affected
differently depending upon the amount of residual blood differently depending upon the amount of residual blood flowflow
Normal cerebral blood flow is greater than 50 mL100 Normal cerebral blood flow is greater than 50 mL100 mgminmgmin
Once blood flow decreases to less than 20 mL100 Once blood flow decreases to less than 20 mL100 mgmin infarction occursmgmin infarction occurs
If blood flow decreases to less than 10 mL100 mgmin If blood flow decreases to less than 10 mL100 mgmin irreversible neuronal death occurs rapidly irreversible neuronal death occurs rapidly
Blood flow between 11 and 20 mL100 mgmin is thought Blood flow between 11 and 20 mL100 mgmin is thought to represent the ischemic penumbra an area where the to represent the ischemic penumbra an area where the cells are functionally silent because of ischemia but are cells are functionally silent because of ischemia but are still able to recover if blood flow is restored still able to recover if blood flow is restored
Many acute stroke therapies are targeted toward Many acute stroke therapies are targeted toward restoring flow or function to the ischemic penumbrarestoring flow or function to the ischemic penumbra
Therapeutic window in Therapeutic window in management of acute Ischemic management of acute Ischemic
StrokeStrokeThe early diagnosis of ischemic stroke is critical to the The early diagnosis of ischemic stroke is critical to the
with only a narrow therapeutic window in the first few with only a narrow therapeutic window in the first few hours following stroke ictushours following stroke ictus
Diagnosis in the first 3 hours postictus provides the Diagnosis in the first 3 hours postictus provides the opportunity for intravenous or intraarterial thrombolysis opportunity for intravenous or intraarterial thrombolysis and intra-arterial clot mechanical treatment which and intra-arterial clot mechanical treatment which improve the outcome improve the outcome
Diagnosis in the time period between 3 and 6 hours Diagnosis in the time period between 3 and 6 hours provides an opportunity for intra-arterial thrombolysis provides an opportunity for intra-arterial thrombolysis and mechanical treatment and mechanical treatment
Involvement of the posterior circulation especially the Involvement of the posterior circulation especially the basilar artery is treated by some regardless of time of basilar artery is treated by some regardless of time of onset or up until 12 to 24 hours in some practices This is onset or up until 12 to 24 hours in some practices This is related to the potentially high mortality and morbidity related to the potentially high mortality and morbidity associated with basilar artery thrombosisassociated with basilar artery thrombosis
Infarct evaluation on angiographyInfarct evaluation on angiography(CT angiography and catheter (CT angiography and catheter
angiography)angiography)CTA is an excellent first-line examination for CTA is an excellent first-line examination for
evaluation of the head and neck arteries evaluation of the head and neck arteries In comparison with catheter angiography In comparison with catheter angiography
what it gives up in resolution and dynamic what it gives up in resolution and dynamic properties it makes up for with rapid properties it makes up for with rapid acquisition of a 3-D dataset and the potential acquisition of a 3-D dataset and the potential for assessment of whole-brain perfusion and for assessment of whole-brain perfusion and better parenchymal evaluationbetter parenchymal evaluation
Moreover CTA illustrates not only arterial Moreover CTA illustrates not only arterial stenosis or occlusion but also the vessel wall stenosis or occlusion but also the vessel wall This factor is most important for evaluation of This factor is most important for evaluation of intramural dissection and thrombosed intramural dissection and thrombosed aneurysms which may both complicate aneurysms which may both complicate evaluation of stroke patientsevaluation of stroke patients
Early angiographic signs of strokes Early angiographic signs of strokes both CTA both CTA and DSA and DSA
Vessel occlusion or cutoff related to Vessel occlusion or cutoff related to thromboembolithromboemboli
aneurysms aneurysms arterial dissection arterial dissection Meniscus or flattened shape to clot Meniscus or flattened shape to clot
(recent) versus reverse meniscus (older)(recent) versus reverse meniscus (older) tram track (nonocclusive or recanalized tram track (nonocclusive or recanalized
clot) clot) delayed (antegrade) flow (manifest as delayed (antegrade) flow (manifest as
decreased whole-brain perfusion on CTA)decreased whole-brain perfusion on CTA) retrograde collateral flowretrograde collateral flow
Non-occlusive left MCA thrombus on 3-D imaging performed from CTA source data and was confirmed at catheter angiography
Therapy to be started within a 6-hr Therapy to be started within a 6-hr time to treatment (TTT) window time to treatment (TTT) window (while in case of IV thrombolysis (while in case of IV thrombolysis therapy to be started with in 3hrs)therapy to be started with in 3hrs)
Exclusion criteria Exclusion criteria Rapidly improving neurologic deficit or Rapidly improving neurologic deficit or Sustained blood pressure of gt180100 Sustained blood pressure of gt180100 Hemorrhage is detected on CTHemorrhage is detected on CT Infarct involving gt more than 13 rd Infarct involving gt more than 13 rd
territory of MCAterritory of MCA MRADWI-Perfusion mismatchlt 20MRADWI-Perfusion mismatchlt 20 Definite hypodensity on CTDefinite hypodensity on CT
Intra-arterial Thrombolysis
Fibrinolytics + AntiplateletsFibrinolytics + Antiplatelets
PlasminogenPlasminogen activators through fibrinolysis exposes activators through fibrinolysis exposes free thrombin and paradoxically stimulatesfree thrombin and paradoxically stimulates platelet platelet aggregation which leads to formation of aaggregation which leads to formation of a platelet platelet thrombus (white clot) thrombus (white clot)
This new thrombus is relatively resistant to This new thrombus is relatively resistant to fibrinolyticsfibrinolytics
So new regimen in case of acute stroke isSo new regimen in case of acute stroke is fibrinolytics + antiplatelet drugsfibrinolytics + antiplatelet drugs
rtPA + IIbIIIa inhibitors( tirofiban rtPA + IIbIIIa inhibitors( tirofiban abciximab) orabciximab) or
Urokinase + IIbIIIa Urokinase + IIbIIIa inhibitors( tirofiban abciximab)inhibitors( tirofiban abciximab)
Intra-arterial Thrombolysis Tirofiban (04 microgkgmin bolus for 3 min followed by Tirofiban (04 microgkgmin bolus for 3 min followed by
0125 ugkgmin)0125 ugkgmin)
++
Heparin (2000ndash3000 IU bolus followed by Heparin (2000ndash3000 IU bolus followed by 1000 IUhour infusion 1000 IUhour infusion
with ACT maintained bw 200-300) throughout the with ACT maintained bw 200-300) throughout the interventional procedure and for 24ndash48 hours thereafter when interventional procedure and for 24ndash48 hours thereafter when there is neither intraprocedural bleeding nor suspicion of there is neither intraprocedural bleeding nor suspicion of increased risk of bleeding increased risk of bleeding
Maximum dose of Urokinase Maximum dose of Urokinase Anterior circulation stroke - 500000 IU (mean 400000 Anterior circulation stroke - 500000 IU (mean 400000
IU range 300000ndash500000 IU)IU range 300000ndash500000 IU) Posterior circulation stroke -1000000 IU (mean 837000 Posterior circulation stroke -1000000 IU (mean 837000
IU range 300000ndash1000000 IU)IU range 300000ndash1000000 IU)American Journal of NeuroradiologyAmerican Journal of Neuroradiology 262595-2601 2005262595-2601 2005
Intravenous ThrombolysisIntravenous Thrombolysis
The first method to restore cerebral The first method to restore cerebral perfusion is clot lysis with the goal perfusion is clot lysis with the goal of re-establishing blood flow to the of re-establishing blood flow to the affected tissue affected tissue
IV thrombolysis rt-PA is the only IV thrombolysis rt-PA is the only FDA- approved treatment for AIS FDA- approved treatment for AIS
Fibrinolysis is enhanced powerfully Fibrinolysis is enhanced powerfully by rt-PAby rt-PA
Intravenous rTPA Intravenous rTPA administration administration protocolprotocol
Total dose of rt-PA 09 mgkg (maximum dose Total dose of rt-PA 09 mgkg (maximum dose 90 mg)90 mg)
Give 10 as initial IV bolusGive 10 as initial IV bolus Infuse remainder over 1 hourInfuse remainder over 1 hour Admit patient to an ICU or stroke unit for Admit patient to an ICU or stroke unit for
monitoringmonitoring Neurologic assessments every 15 minutes Neurologic assessments every 15 minutes
during infusion then every 30 minutes for next during infusion then every 30 minutes for next 6 hours then every hour until 24hours after 6 hours then every hour until 24hours after treatmenttreatment
Favorable Outcome vs Treatment Time Favorable Outcome vs Treatment Time with IV rTPAwith IV rTPA
Protocol limit = 3 hrs
Benefit ~ 45 hrs
Thromboembolism During coilingThromboembolism During coiling Most feared and frequent complication Most feared and frequent complication Reported incidence - Approx 7 Reported incidence - Approx 7 SourcesSources of Thromboembolism are of Thromboembolism are
- Clots at the aneurysmal neck during or immediately- Clots at the aneurysmal neck during or immediately after after embolization embolization
- Thrombus forming on catheters during- Thrombus forming on catheters during proceduresprocedures
- Stenosis of an adjacent artery dt coil mass- Stenosis of an adjacent artery dt coil mass or herniationor herniation
- Migration of intraaneurysmal- Migration of intraaneurysmal thrombus during coil thrombus during coil placement placement
- Slow flow dt vasospasm - Slow flow dt vasospasm
- Rare and unlikely causes are hypercoagulable- Rare and unlikely causes are hypercoagulable state such state such as antiphospholipid antibody syndrome or due to HITas antiphospholipid antibody syndrome or due to HIT
Occur more often with wide-necked aneurysms (dt Occur more often with wide-necked aneurysms (dt increased exposed surface area of thrombogenic coil increased exposed surface area of thrombogenic coil material)material)
Current regimen of endovascular Current regimen of endovascular managementmanagement
The The glycoprotein IIbIIIa antagonist tirofiban glycoprotein IIbIIIa antagonist tirofiban (04 (04 microgkgmin bolus for 30 minutes followed by infusion of microgkgmin bolus for 30 minutes followed by infusion of 0125 ugkgmin until the thrombus dissolved) 0125 ugkgmin until the thrombus dissolved)
Intraarterial thrombolysis with Intraarterial thrombolysis with urokinase or r- TPA urokinase or r- TPA increase of intravenous (IV) heparin (measured by increase of intravenous (IV) heparin (measured by
ACT) ACT) Intravenous aspirin Intravenous aspirin
Coil-related platelet aggregation (white clot) is Coil-related platelet aggregation (white clot) is unlikely to respond to fibrinolytics but has a high risk unlikely to respond to fibrinolytics but has a high risk of hemorrhage (In ISAT) all 5 patients who had of hemorrhage (In ISAT) all 5 patients who had received thrombolytic therapy with tPA to treat a received thrombolytic therapy with tPA to treat a thromboembolic complication after endovascular thromboembolic complication after endovascular treatment rebleed and all of these patients died)treatment rebleed and all of these patients died)
IntracranialIntracranial Stenting Stenting Metallic foreign body such as stent will accumulate Metallic foreign body such as stent will accumulate
thrombus in the absence of platelet inhibitionthrombus in the absence of platelet inhibition Antiplatelet drugs are important to prevent peri or Antiplatelet drugs are important to prevent peri or
post-interventional thromboembolic eventspost-interventional thromboembolic events Optimal treatment regimens has not been determined Optimal treatment regimens has not been determined
but usually but usually Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-
procedureprocedureOrOr
Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on
morning of proceduremorning of procedure
If need to use stent is not pre-planned thanIf need to use stent is not pre-planned than
Abciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkgAbciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkg IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)
Glycoprotein IIbIIIa inhibitor are not used routinely during elective Glycoprotein IIbIIIa inhibitor are not used routinely during elective stenting procedure dt increased risk of ICH stenting procedure dt increased risk of ICH
Carotid StentingCarotid Stenting
Pre-procedurePre-procedure
Double Antiplatelet therapy is routinely given Double Antiplatelet therapy is routinely given beginning at least 3beginning at least 3
days before the proceduredays before the procedure
Aspirin 325mgd+Clopidogrel 75mgdAspirin 325mgd+Clopidogrel 75mgd During procedureDuring procedure
Heparin is given with target clotting time of 250-Heparin is given with target clotting time of 250-300sec300sec
Post-procedure Post-procedure
Aspirin 325mg is continued indefinitely and Aspirin 325mg is continued indefinitely and
Clopidogrel 75mgd for at least 6 weeks Clopidogrel 75mgd for at least 6 weeks
Inclusion criteria for Local ThrombolysisInclusion criteria for Local Thrombolysis a)a) Patients in severe clinical grade on admission Patients in severe clinical grade on admission
with evidence of dural venous sinus with evidence of dural venous sinus thrombosis and restrictive venous outflow on thrombosis and restrictive venous outflow on cerebral angiogramcerebral angiogram
b)b) Patients in clinical grade 3 worsening on Patients in clinical grade 3 worsening on heparin therapy Restriction to venous heparin therapy Restriction to venous outflow was defined as an increase in brain outflow was defined as an increase in brain circulation time gt 12 s delay in the drainage circulation time gt 12 s delay in the drainage of cortical veins with cortical veins hanging of cortical veins with cortical veins hanging in spacein space
Treatment Options for Venous Thrombosis
CT Grading for Venous ThrombosisCT Grading for Venous Thrombosis Grade I no parenchymal change Grade I no parenchymal change
(hyperdense (hyperdense sinuses cortical veins empty sinuses cortical veins empty delta sign)delta sign)
Grade II non hemorrhagic venous infarct Grade II non hemorrhagic venous infarct without mass effect without mass effect
Grade III non-hemorrhagic infarct with Grade III non-hemorrhagic infarct with mass effectmass effect
Grade IV hemorrhagic venous infarct (max Grade IV hemorrhagic venous infarct (max diameter lt 3 cm) with no mass effectdiameter lt 3 cm) with no mass effect
Grade V hemorrhagic venous infarct (max Grade V hemorrhagic venous infarct (max diameter gt 3 cm) with mass effect diameter gt 3 cm) with mass effect
Local ThrombolysisLocal Thrombolysis
Femoral Jugular access was secured and a guiding Femoral Jugular access was secured and a guiding catheter was placed in the jugular bulb catheter was placed in the jugular bulb Mechanical Mechanical clot maceration clot maceration was done with the guidewire was done with the guidewire following which a microcatheter (was navigated and following which a microcatheter (was navigated and placed in the thrombosed segment of sinus confirmed placed in the thrombosed segment of sinus confirmed on a selective venogram on a selective venogram
Urokinase infusion Bolus dose of 2-6 lacs followed Urokinase infusion Bolus dose of 2-6 lacs followed by 60000 to 100000 units per hour along with by 60000 to 100000 units per hour along with periodic check venogram Along with maintenance periodic check venogram Along with maintenance systemic infusion of Heparinsystemic infusion of Heparin Other agents such as Other agents such as streptokinase altepase or rTPAstreptokinase altepase or rTPA can be also used can be also used
After thrombolysis patient should subjected to oral After thrombolysis patient should subjected to oral anticoagulation for six monthsanticoagulation for six months
Low-molecular-weight Low-molecular-weight heparinheparin
PharmacologyPharmacologyLMWH as its name suggests is a glycosaminoglycan that is approximatelyLMWH as its name suggests is a glycosaminoglycan that is approximately
one third the molecular weight of UFH It is derived from UFH through one third the molecular weight of UFH It is derived from UFH through variousvarious
depolymerization processes LMWH binds to antithrombin which in turn depolymerization processes LMWH binds to antithrombin which in turn
Neutralizes actors Xa and IIa Because LMWH lacks many of the longer Neutralizes actors Xa and IIa Because LMWH lacks many of the longer chains chains
required for binding to thrombin it has less ability to neutralize thrombin required for binding to thrombin it has less ability to neutralize thrombin
relativeto its ability to neutralize factor Xa LMWH also has less relativeto its ability to neutralize factor Xa LMWH also has less nonspecific nonspecific
binding to other proteins There is greater bioavailability with more binding to other proteins There is greater bioavailability with more predictable predictable
pharmacokinetics that eliminates the need for monitoring The smaller pharmacokinetics that eliminates the need for monitoring The smaller size also size also
allows for enhanced subcutaneous absorption when compared with UFHallows for enhanced subcutaneous absorption when compared with UFH
Three LMWH preparations are Three LMWH preparations are currently approved for use in the currently approved for use in the United States (1) enoxaparin (2) United States (1) enoxaparin (2) dalteparin and (3) tinzaparin dalteparin and (3) tinzaparin
They are all administered They are all administered subcutaneously at intervals of either subcutaneously at intervals of either once or twice daily for both once or twice daily for both prophylaxis and treatment dosesprophylaxis and treatment doses
Few Experiences of Few Experiences of ThrombolysisThrombolysis
Vickey 25 Yrs male patient presented Vickey 25 Yrs male patient presented with 12with 12thth day HO severe headache with day HO severe headache with right sided hemiplegiaright sided hemiplegia
MRI shows thrombosis of the superior MRI shows thrombosis of the superior sagittal left transverse left sigmoid sagittal left transverse left sigmoid sinuses and cortical veins in the fronto-sinuses and cortical veins in the fronto-parietal regions with eo haemorrhagic parietal regions with eo haemorrhagic infarct in the left cerebral hemisphere infarct in the left cerebral hemisphere with mass effect( Grade ndashV)with mass effect( Grade ndashV)
Sashi Srivastava 64 yrs FSashi Srivastava 64 yrs F In a follow up case of MRD with infra-renal In a follow up case of MRD with infra-renal
aortic abdominal and bilateral renal artery aortic abdominal and bilateral renal artery thrombosis renal angiogram shows filling thrombosis renal angiogram shows filling defects in the right Renal artery defects in the right Renal artery
Initially Renal angioplasty was done Initially Renal angioplasty was done Following angioplasty few thrombi are seem Following angioplasty few thrombi are seem to extends into the segmental branches and to extends into the segmental branches and causing blockage So Thrombolysis was causing blockage So Thrombolysis was plane to dissolve the run-out thrombi with plane to dissolve the run-out thrombi with urokinase urokinase
Rakesh 34yrsMRakesh 34yrsM Left SFA pseudoaneurysm with Left SFA pseudoaneurysm with
Covered stent placementCovered stent placement Pre operative antiplatelets with post Pre operative antiplatelets with post
procedure heparin Tirofiban procedure heparin Tirofiban followed by aspirin and clopidogrel followed by aspirin and clopidogrel were usedwere used
IAT may be a treatment option for selected patients IAT may be a treatment option for selected patients Possible selection criteria include Possible selection criteria include
presentation between 3 and 6 hours from symptom onsetpresentation between 3 and 6 hours from symptom onset major cerebral artery occlusion major cerebral artery occlusion severe neurologic deficits severe neurologic deficits high risk of systemic hemorrhage with IV rt-PA (eg recent high risk of systemic hemorrhage with IV rt-PA (eg recent
surgery) surgery) The MERCI (Mechanical Embolus Removal in Cerebral The MERCI (Mechanical Embolus Removal in Cerebral
Ischemia) retrievalIschemia) retrieval system system
Has been FDA-approved for recanalizing acutely occluded Has been FDA-approved for recanalizing acutely occluded cerebral arteries cerebral arteries
In the Multi-MERCI study patients who did not improve In the Multi-MERCI study patients who did not improve immediately after IV rt-PA underwent mechanical immediately after IV rt-PA underwent mechanical embolectomy within 8 hours of symptom onset embolectomy within 8 hours of symptom onset
Partial or complete recanalization occurred in 74 of Partial or complete recanalization occurred in 74 of patientspatients
with a symptomatic intracerebral hemorrhage (sICH) rate of with a symptomatic intracerebral hemorrhage (sICH) rate of 67 67
Mechanical embolectomy with the MERCI retriever may be a Mechanical embolectomy with the MERCI retriever may be a feasible and safe option for patients after IV rt-PAfeasible and safe option for patients after IV rt-PA
Penumbra stroke systemPenumbra stroke system This device combines two methods of clot This device combines two methods of clot
extraction aspiration and mechanical extraction aspiration and mechanical extraction extraction
First the clot is aspirated then a thrombus First the clot is aspirated then a thrombus removal ring can be used if necessary to removal ring can be used if necessary to remove remaining clot remove remaining clot
successful recanalizing 82successful recanalizing 82 Bridging therapyBridging therapy
06 mgkg IV rt-PA followed by IAT with IA rt-06 mgkg IV rt-PA followed by IAT with IA rt-PA (up to 20 mg)PA (up to 20 mg)
achieved a higher recanalization rateachieved a higher recanalization rate
Criteria for thrombolysis with rTPACriteria for thrombolysis with rTPA
Inclusion criteriaInclusion criteria Clinical signs and symptoms consistent with ischemic Clinical signs and symptoms consistent with ischemic
strokestroke Patient last seen normal within 3 hoursPatient last seen normal within 3 hours Measurable neurologic deficitMeasurable neurologic deficit
Exclusion criteriaExclusion criteria Any hemorrhage on neuroimaging (CT or MRI)Any hemorrhage on neuroimaging (CT or MRI) Symptoms suggestive of subarachnoid hemorrhageSymptoms suggestive of subarachnoid hemorrhage Seizure at stroke onset that is thought to contribute to Seizure at stroke onset that is thought to contribute to
neurologic deficitneurologic deficit Hypodensity greater than one third cerebral hemisphere Hypodensity greater than one third cerebral hemisphere
on CTon CT SBP greater than 185 mm Hg or DBP greater than 110 SBP greater than 185 mm Hg or DBP greater than 110
mm Hgmm Hg International normalized ratio (INR) greater than 17International normalized ratio (INR) greater than 17
Ischemic Stroke Ischemic Stroke Treatment ndash 2006Treatment ndash 2006
IV tissue plasminogen activator (tPA)IV tissue plasminogen activator (tPA) ndash ndash Only FDA-approved acute stroke drugOnly FDA-approved acute stroke drug ndash ndash 3 hour treatment window3 hour treatment window
MERCI - Concentric clot retrieval MERCI - Concentric clot retrieval devicedevice ndash ndash Rescue therapy - approved 2004Rescue therapy - approved 2004 ndash ndash Device approval (not outcomes-based)Device approval (not outcomes-based)
Off label approachesOff label approaches ndash ndash IV tPA after 3 hoursIV tPA after 3 hours ndash ndash IV-IA tPA sequential strategiesIV-IA tPA sequential strategies ndash ndash IA tPA clot angioplasty fragmentationIA tPA clot angioplasty fragmentation ndash ndash Ultrasound-assisted tPA lysisUltrasound-assisted tPA lysis
rt-PA Trials NINDSrt-PA Trials NINDS
Acute stroke - 624 patientsAcute stroke - 624 patients Treat within 3 hrsTreat within 3 hrs Intravenous 09 mgkg rt-PA vs placeboIntravenous 09 mgkg rt-PA vs placebo Hemorrhage 64 tPA 06 placeboHemorrhage 64 tPA 06 placebo Neurologic recovery better with tPA 30 Neurologic recovery better with tPA 30
more like to have minimal or no disabilitymore like to have minimal or no disability
First proven approved treatment for First proven approved treatment for strokestroke
Limitations of tPALimitations of tPA Only 4 of acute strokes receive tPAOnly 4 of acute strokes receive tPA (Kleindorfer et al Stroke 2004 35 e27-e29)(Kleindorfer et al Stroke 2004 35 e27-e29)
Only 22 of patients present within 3 hoursOnly 22 of patients present within 3 hours1048707 1048707 51 of these ineligible due to51 of these ineligible due to
bull bull Mild severityMild severity bull bull Medical or surgical historyMedical or surgical history bull bull Blood testsBlood tests
Sustained recanalization only 13Sustained recanalization only 13 (Alexandrov et al NEJM 2004 351 2170-8)(Alexandrov et al NEJM 2004 351 2170-8)
Concern for hemorrhageConcern for hemorrhage tPA potentiates apoptotic injury tPA potentiates apoptotic injury (Liu et al Nature Med 2004 101379-83)(Liu et al Nature Med 2004 101379-83)
PROACT II IA Lysis TrialPROACT II IA Lysis Trial Baseline 24 hours 8 days
Baseline 60 minutes 120 minutes
9mg IAProurokinase
Desmoteplase Trials DEDAS Desmoteplase Trials DEDAS DIASDIAS
Trial OverviewTrial Overview Double blind randomized placebo Double blind randomized placebo
controlled trialscontrolled trials IV delivery 3-9 hour time windowIV delivery 3-9 hour time window Plasminogen activator ndash from Plasminogen activator ndash from vampire bat vampire bat
salivasaliva Selection based on PWI-DWI MismatchSelection based on PWI-DWI Mismatch
MRI InclusionMRI Inclusion PWI defect at least 2 cm AND ~20 larger PWI defect at least 2 cm AND ~20 larger
than DWIthan DWI PWI should be obvious even visible on PWI should be obvious even visible on
raw imagesraw imagesMRI ExclusionMRI Exclusion
DWI gt 13 MCADWI gt 13 MCA MRA ICA occlusionMRA ICA occlusion
Desmoteplase ndash DIAS Desmoteplase ndash DIAS ResultsResults
Mechanical Thrombolysis Mechanical Thrombolysis devicesdevices
mechanical thrombolysis potentially extends the treatment mechanical thrombolysis potentially extends the treatment window because they act promptly at the site of the thrombuswindow because they act promptly at the site of the thrombus
The devices can retrieve large clots that pharmaceutical agents The devices can retrieve large clots that pharmaceutical agents may not successfully lysemay not successfully lyse
Patients treated with IV tPA may be considered for treatment of Patients treated with IV tPA may be considered for treatment of residual clot with some of these devicesresidual clot with some of these devices
suction-creating saline jets suction-creating saline jets laser energy ultrasound laser energy ultrasound a corkscrew apparatus to treat strokesa corkscrew apparatus to treat strokes The AngioJet systemThe AngioJet system uses saline jets that are directed back into the catheter to uses saline jets that are directed back into the catheter to
create a low-pressure zone around the catheter tip inducing create a low-pressure zone around the catheter tip inducing suction suction
The clot is pulled into the exhaust lumen and removed from the The clot is pulled into the exhaust lumen and removed from the vessel Although US Food and Drug Administration (FDA) has vessel Although US Food and Drug Administration (FDA) has approved this device for use in arteriovenous dialysis grafts and approved this device for use in arteriovenous dialysis grafts and fistulae and for the treatment of coronary arteries saphenous fistulae and for the treatment of coronary arteries saphenous vein grafts and peripheral vessels clinical trials for the vein grafts and peripheral vessels clinical trials for the treatment of acute stroke are no longer in progress treatment of acute stroke are no longer in progress
Most devices are used in cerebral vessels that 2-5 mm
The Latis laser device The Latis laser device used laser energy to ablate clots used laser energy to ablate clots Arteries 2-5 mm in diameter could be Arteries 2-5 mm in diameter could be
treated including the ICA M1 or M2 treated including the ICA M1 or M2 branch of the MCA A1 branch of the branch of the MCA A1 branch of the anterior cerebral artery (ACA) basilar anterior cerebral artery (ACA) basilar artery posterior cerebral artery (PCA) artery posterior cerebral artery (PCA) and vertebral and vertebral
Patients could receive treatment as late Patients could receive treatment as late as 8 hours after symptom onset in the as 8 hours after symptom onset in the anterior circulation and within 24 hours in anterior circulation and within 24 hours in the posterior circulation the posterior circulation
Endovascular Photo Acoustic Endovascular Photo Acoustic Recanalization (EPAR) Recanalization (EPAR)
A laser power source generated energy for the A laser power source generated energy for the systemsystem
The energy was delivered by means of The energy was delivered by means of fiberoptics to the tip of the catheter at the fiberoptics to the tip of the catheter at the treatment sitetreatment site
Absorption of laser light by darkly pigmented Absorption of laser light by darkly pigmented materials (ie the clot) occurred inside the 1-mm materials (ie the clot) occurred inside the 1-mm catheter tipcatheter tip
the system was designed to minimize scattering the system was designed to minimize scattering of laser light of laser light
Absorption converted photo energy to acoustic Absorption converted photo energy to acoustic energy which then emulsified the clot inside the energy which then emulsified the clot inside the catheter tip catheter tip
EKOS ultrasound( the EKOS ultrasound( the Ultrasound Thrombolytic Ultrasound Thrombolytic
Infusion Catheter) Infusion Catheter) combines the use of a distal ultrasound transducer with combines the use of a distal ultrasound transducer with
infusion of a thrombolytic agent through the infusion of a thrombolytic agent through the microcathetermicrocatheter
Ultrasound changes the structure of the clot to Ultrasound changes the structure of the clot to temporarily increase its permeability while providing an temporarily increase its permeability while providing an acoustic pressure gradient to move the drug into the clot acoustic pressure gradient to move the drug into the clot to speed its dissolution to speed its dissolution
The EKOS catheter is placed in the proximal portion of the The EKOS catheter is placed in the proximal portion of the clot clot
After a 2-mg bolus of tPA was injected through the After a 2-mg bolus of tPA was injected through the catheter catheter
the patient received a continuous infusion of IA tPA 03 the patient received a continuous infusion of IA tPA 03 mgmin to a maximum of 20 mg and simultaneous mgmin to a maximum of 20 mg and simultaneous ultrasound transmission for as long as 60 minutes ultrasound transmission for as long as 60 minutes
One patient was treated with a total of 4 units of One patient was treated with a total of 4 units of recombinant reteplase (Retavase) hand-injected over 60 recombinant reteplase (Retavase) hand-injected over 60 minutes minutes
Penumbra system Penumbra system The Penumbra system (Penumbra Inc) provides a dual The Penumbra system (Penumbra Inc) provides a dual
approach to clot extraction using aspiration followed by approach to clot extraction using aspiration followed by clot retrieval with a ring device if needed clot retrieval with a ring device if needed
Mechanical Embolus Removal in Cerebral Ischemia Mechanical Embolus Removal in Cerebral Ischemia (MERCI)(MERCI)
a corkscrew-like apparatus to remove blood clots from a corkscrew-like apparatus to remove blood clots from the brain in patients experiencing an ischemic stroke the brain in patients experiencing an ischemic stroke
The corkscrew itself resides in the catheter tip which The corkscrew itself resides in the catheter tip which shields it from the wall of the vessel until it is ready to be shields it from the wall of the vessel until it is ready to be burrowed into the clot Once lodged in the clot the device burrowed into the clot Once lodged in the clot the device and clot are withdrawn from the vessel and clot are withdrawn from the vessel
Snarelike devicesSnarelike devices Snares such as the Neuronet snare (Guidant Snares such as the Neuronet snare (Guidant
Endovascular Santa Clara CA) have been developed Endovascular Santa Clara CA) have been developed specifically for use in the treatment of strokes specifically for use in the treatment of strokes
These devices are simple in design and do not require the These devices are simple in design and do not require the clot to be amenable to emulsification clot to be amenable to emulsification
X-Sizer deviceX-Sizer device a device with small moving blades at the a device with small moving blades at the
catheter tip catheter tip This device the X-Sizer device (EndiCor Medical This device the X-Sizer device (EndiCor Medical
San Clemente CA) can be used to excise the San Clemente CA) can be used to excise the thrombus and aspirate it thrombus and aspirate it
The device was being evaluated in randomized The device was being evaluated in randomized studies of coronary vessels and in a registry of studies of coronary vessels and in a registry of patients with acute myocardial infarctionpatients with acute myocardial infarction
Although the manufacturer had modified the Although the manufacturer had modified the device for use in cerebral vessels a safety and device for use in cerebral vessels a safety and feasibility study was indefinitely suspended after feasibility study was indefinitely suspended after only 1 patient was treated with the device in only 1 patient was treated with the device in Europe Europe
Suction thrombectomySuction thrombectomy This method of mechanical thrombolysis is one of the This method of mechanical thrombolysis is one of the
simplestsimplest In this readily available technique suction is applied with In this readily available technique suction is applied with
a syringe to remove thrombus in the ICA a syringe to remove thrombus in the ICA It requires no other devicesIt requires no other devices A catheter with a large inner diameter (Brite Tip Cordis A catheter with a large inner diameter (Brite Tip Cordis
Corporation Miami FL) was placed in the symptomatic Corporation Miami FL) was placed in the symptomatic vessel and navigated over a guidewire into the thrombusvessel and navigated over a guidewire into the thrombus
A 60-mL syringe was used to aspirate the thrombus A 60-mL syringe was used to aspirate the thrombus Each patient required angioplasty and stenting of carotid Each patient required angioplasty and stenting of carotid
bifurcation stenosis and received daily aspirin and bifurcation stenosis and received daily aspirin and ticlopidine after the procedure No complications ticlopidine after the procedure No complications occurred occurred
Summary Acute Stroke Summary Acute Stroke ImagingImaging
PhysiologyPhysiology importance collaterals importance collaterals
ndash ndashGrowing role for perfusion Growing role for perfusion assessmentassessment
tPAtPA guidelines amp limitations guidelines amp limitations Signs on CT amp MRSigns on CT amp MR follow physiology follow physiology Stroke trialsStroke trials PWI-DWI mismatch PWI-DWI mismatch
ndash ndashTreat based on physiology not timeTreat based on physiology not time ProtocolsProtocols should be fast and should be fast and
comprehensivecomprehensive
Rationale for anticoagulant Rationale for anticoagulant therapytherapy
PHARMACOLOGICAL PHARMACOLOGICAL AGENTSAGENTS
Pharmacologic AgentsPharmacologic Agents
AnticoagulantsAnticoagulants
Fibrinolytics (Agents for pharmacological Fibrinolytics (Agents for pharmacological recanalization)recanalization)
Anti platelet drugsAnti platelet drugs
Thrombin inhibitorThrombin inhibitor
ANTICOAGULANTSANTICOAGULANTS
Heparin and Low Molecular Weight Heparins Heparin and Low Molecular Weight Heparins ((eg enoxaparin dalteparin)eg enoxaparin dalteparin)
Oral anticoagulantsOral anticoagulants Coumarin Derivatves Coumarin Derivatves eg Warfarin eg Warfarin
AcenocoumarolAcenocoumarol Indandione Derivatves Indandione Derivatves eg Phenindione eg Phenindione
AnisindioneAnisindione
ThrombolyticsThrombolytics
Plasminogen activators
Fibrinolytics
Anti Platelet DrugsAnti Platelet DrugsDrug Mechanism UsesDrug Mechanism UsesAspirinAspirin Permanently inhibits Permanently inhibits
COX-1 and COX-2COX-1 and COX-2CADCAD
Stroke-TIAsStroke-TIAs
NSAIDsNSAIDs Reversibly inhibits Reversibly inhibits COX-1COX-1
LimitedLimited
DipyridamoleDipyridamole Inhibits PDE Inhibits PDE increases cAMPincreases cAMP
TIAsTIAs
ThenopyridinesThenopyridines
(Ticlopidine(Ticlopidine
Clopidegrel)Clopidegrel)
Inhibits ADP Inhibits ADP
PlatAg PlatAg
TIAsStrokeTIAsStroke
CAD PVDCAD PVD
Abciximab (ReoPro)Abciximab (ReoPro)
Eptifibatide Eptifibatide (Integrilin)(Integrilin)
TirofibaTirofibann
GP IIBIIIA InhibitorsGP IIBIIIA Inhibitors
Stroke- TIAs Stroke- TIAs
Maintainance of patency Maintainance of patency of vascular of vascular grafts catheters shunts bypassesgrafts catheters shunts bypasses
Arterial thromboembolic diseaseArterial thromboembolic diseasebull Transient ischemic attacksTransient ischemic attacksbull Stroke in evolutionStroke in evolution
Ischemic events occurs in Ischemic events occurs in 1313 of of conventional neuroangiographic conventional neuroangiographic procedures without Endovascular surgeryprocedures without Endovascular surgery
Indications for Antithrombotic Therapy in Indications for Antithrombotic Therapy in Diagnostics and Interventional ProceduresDiagnostics and Interventional Procedures
WHY TO MONITOR ANTICOAGULANT THERAPYWHY TO MONITOR ANTICOAGULANT THERAPY
Narrow therapeutic rangeNarrow therapeutic range
Can increase risk of bleedingCan increase risk of bleeding
Coagulation TestingCoagulation Testing
Monitoring therapyMonitoring therapy
Intrinsic Pathway
Extrinsic Pathway
Common Pathway
CLOT
Heparin Coumadin
Monitor with
ACT aPTT
Monitor with PTINR
Thrombolytics
Monitor with TT Fibrinogen
Monitoring of Monitoring of Anti platelet drugsAnti platelet drugs
Bleeding timeBleeding time
Optical aggregometryOptical aggregometry
Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay
HeparinHeparin
Heterogeneous 3000-30000 dalton in Heterogeneous 3000-30000 dalton in molecular weight molecular weight
Average=15000 d (~45monosaccharide Average=15000 d (~45monosaccharide chains)chains)
About About 13 of dose binds to AT III and forms 13 of dose binds to AT III and forms the AT IIIHeparinClotting Factor Complexthe AT IIIHeparinClotting Factor Complex
Complex binds to clotting factors of the Complex binds to clotting factors of the intrinsic and common pathway (Xa IIa IXa intrinsic and common pathway (Xa IIa IXa XIa XIIa XIIIa) and inactivates themXIa XIIa XIIIa) and inactivates them
Anticoagulant of choice in pregnancy (not Anticoagulant of choice in pregnancy (not crosses placenta)crosses placenta)
Heparin and Low molecular weight heparinsHeparin and Low molecular weight heparins
Structure and sequence
O
OH
OH
O
COO
O
O
CH2OH
NHSO3
OH
_
_
O
O
CH2OSO3
NHSO3
OH
_
_
O
OH
OH
O
COOO
O
CH2OSO3
NHSO3
OH
_
_
O
OSO3
OHO
COOO
O
CH2OSO3
NHCOCH3
OH
_
_ _
_
_
O
OH
OH
O
COO
1
23
4
5
6
-D-glucosamine -L-iduronic acid -D-glucuronic acid
O
O
CH2OH
NH2
OH 12
3
4
5
6
O
OH
OHO
COO_
1
23
4
5
6
polymeric structure of heparin
Anticoagulant Properties of Anticoagulant Properties of HeparinHeparin
11 Inhibits the thrombin-mediated conversion of Inhibits the thrombin-mediated conversion of fibrinogen to fibrinfibrinogen to fibrin
22 Inhibits the aggregation of platelets by thrombin Inhibits the aggregation of platelets by thrombin (prolongs bleeding time)(prolongs bleeding time)
33 Inhibits activation of fibrin stabilizing enzymeInhibits activation of fibrin stabilizing enzyme
44 Inhibits activated factors XII XI IX X and IIInhibits activated factors XII XI IX X and II All available forms of heparin must be All available forms of heparin must be
administered administered parenterally since they are parenterally since they are highly charged and rapidlyhighly charged and rapidly hydrolyzed in the hydrolyzed in the GI tractGI tract
Heparin antagonist Protamine sulfate (Heparin antagonist Protamine sulfate (10mg for 10mg for 1000 unit of heparin)1000 unit of heparin)
Monitoring of heparin Monitoring of heparin
Subcutenous Subcutenous no monitoring requiredno monitoring required Intravenous Intravenous
Partial thromboplastin time (PTT normal value Partial thromboplastin time (PTT normal value ~30sec) ~30sec)
Activated clotting time ( ACT normal value ~90-Activated clotting time ( ACT normal value ~90-120sec)120sec)
Daily or more frequent if PTT ACT variesDaily or more frequent if PTT ACT varies
Mechanism Mechanism ndash measures intrinsic pathwayndash measures intrinsic pathway Therapeutic goal Therapeutic goal 2-25 times normal control value 2-25 times normal control value
ACT or aPTTACT or aPTT
Determine when to pull the femoral sheath Determine when to pull the femoral sheath Premature sheath pull can lead to bleedingPremature sheath pull can lead to bleeding Delayed removal can increase time in ICUDelayed removal can increase time in ICU Target set Target set at each siteat each site
ACT targets range from 150 ndash 220 ACT targets range from 150 ndash 220 secondsseconds
aPTT targets range from 40 ndash 70 seconds aPTT targets range from 40 ndash 70 seconds
During neuroangiography-During neuroangiography- Recommended therapeutic range of heparin in Recommended therapeutic range of heparin in
plasma is 02-08 uml ( corresponding to aPTT plasma is 02-08 uml ( corresponding to aPTT ACT values 15-25 times the baseline values)ACT values 15-25 times the baseline values)
Dose In diagnostic angiography bolus dose of Dose In diagnostic angiography bolus dose of 2500 iu is used followed by 1000 iu hour2500 iu is used followed by 1000 iu hour
Bolus dose is Bolus dose is 60 ukg to maintain the therapeutic 60 ukg to maintain the therapeutic range range If procedure continues for more than 75 If procedure continues for more than 75 minutes additional dose is required ( half of the minutes additional dose is required ( half of the initial dose for another 75 minutes) initial dose for another 75 minutes)
(AJNR 199415 51-54)
Mechanisms of HIT( Mechanisms of HIT( Heparin Heparin induced Thrombocytopeniainduced Thrombocytopenia))
Type 1Type 1 Fall in platelet count occurs within the first two Fall in platelet count occurs within the first two
days after heparin initiation often returns to days after heparin initiation often returns to normal with continued heparin administration normal with continued heparin administration and is of no clinical consequence and is of no clinical consequence
The mechanism of the thrombocytopenia is non-The mechanism of the thrombocytopenia is non-immune and appears to be due to a direct effect of immune and appears to be due to a direct effect of heparin on platelet activationheparin on platelet activation
Type 2Type 2 Approximately 03 to 3 percent of patients Approximately 03 to 3 percent of patients
receiving heparin develop an immune receiving heparin develop an immune thrombocytopenia mediated by antibodies to a thrombocytopenia mediated by antibodies to a heparin-platelet factor 4 complex heparin-platelet factor 4 complex
(AJNR 28155-158 2007)
Treatment of heparin-induced Treatment of heparin-induced thrombocytopeniathrombocytopenia
When HIT is diagnosed it is important to When HIT is diagnosed it is important to stop heparin mainly in type 2 and to avoid stop heparin mainly in type 2 and to avoid the use of LMWH the use of LMWH
Because of the increased risk of thrombosis Because of the increased risk of thrombosis however continuation of an anticoagulant however continuation of an anticoagulant must be considered must be considered
The drugs currently approved for the The drugs currently approved for the treatment of HIT in the United States are treatment of HIT in the United States are direct thrombin inhibitors argatroban and direct thrombin inhibitors argatroban and lepirudinlepirudin
WARFARIN MECHANISM OF ACTIONWARFARIN MECHANISM OF ACTION
Inactive factors II VII IX and X
Proteins S and C
Active factors II VII IX and X
Proteins S and C
Vitamin K epoxide
Vitamin K reduced
WA
RF
AR
IN
Prevents the reduction of vitamin K which is essential for Prevents the reduction of vitamin K which is essential for activation of certain factorsactivation of certain factors
Has no effect on previously formed thrombusHas no effect on previously formed thrombus
Antagonist is Vit KAntagonist is Vit K
OPTIMIZING WARFARIN THERAPYOPTIMIZING WARFARIN THERAPY
Use of large loading dose may lead to hemorrhage and Use of large loading dose may lead to hemorrhage and other complicationsother complications
Initial dose 2-5 mg once dailyInitial dose 2-5 mg once daily Maintenance dose 2-10 mg once dailyMaintenance dose 2-10 mg once daily If Immediate anticoagulation is requiredIf Immediate anticoagulation is required Heparin IS Heparin IS
started along with loading dose of warfarin 10 mg started along with loading dose of warfarin 10 mg Heparin is usually discontinued after 4-5 days Heparin is usually discontinued after 4-5 days Before Before discontinuing INR should be in therapeutic range for 2 discontinuing INR should be in therapeutic range for 2 consecutive daysconsecutive days
Daily monitoring of INR until INR is in therapeutic Daily monitoring of INR until INR is in therapeutic range then 3 times weekly for 1-2 weeks then less often range then 3 times weekly for 1-2 weeks then less often (every 4 to 6 weeks)(every 4 to 6 weeks)
OPTIMAL THERAPEUTIC RANGEOPTIMAL THERAPEUTIC RANGE
IndicationIndication INRINR
Prophylaxis of venous Prophylaxis of venous thromboembolismthromboembolism
20-3020-30
Treatment of venous Treatment of venous thromboembolismthromboembolism
20-3020-30
Atrial fibrillationAtrial fibrillation 20-3020-30
Mitral valve stenosisMitral valve stenosis 20-3020-30
Heart valve replacementHeart valve replacement
Bioprosthetic valveBioprosthetic valve
Mechanical valveMechanical valve
20-3020-30
25-3525-35
Myocardial infarctionMyocardial infarction 20-3020-30
25-35 25-35 (high risk patients)(high risk patients)
FACTORS INFLUENCING DOSE RESPONSEFACTORS INFLUENCING DOSE RESPONSE
Poor patient compliancePoor patient compliance Concomitant medicationsConcomitant medications Levels of dietary vitamin KLevels of dietary vitamin K Alcohol Inaccurate lab testingAlcohol Inaccurate lab testing Inaccurate lab testingInaccurate lab testing Hepatic dysfunctionHepatic dysfunction FeverFever
Contraindication for WarfarinContraindication for Warfarin
Hypersensitivity to warfarinHypersensitivity to warfarin Hemorrhagic tendencyHemorrhagic tendency Condition with risk of hemorrhageCondition with risk of hemorrhage Inadequate laboratory techniquesInadequate laboratory techniques Protein C amp S deficiencyProtein C amp S deficiency Vitamin K deficiencyVitamin K deficiency
SIDE EFFECTSSIDE EFFECTS
Hemorrhage Hemorrhage Skin necrosisSkin necrosis Purple toe syndromePurple toe syndrome Microembolization Microembolization TeratogenecityTeratogenecity Agranulocytosis leukopenia Agranulocytosis leukopenia Diarrhoeanausea anorexiaDiarrhoeanausea anorexia
MONITORING OF WARFARIN THERAPYMONITORING OF WARFARIN THERAPY
Prothrombin timeProthrombin time PT ratioPT ratio INR (International Normalized Ratio)INR (International Normalized Ratio)
PROTHROMBIN TIME (PT)PROTHROMBIN TIME (PT)
Time required for blood to coagulate Time required for blood to coagulate is called PT ( normal value ~10sec)is called PT ( normal value ~10sec)
Performed by adding a mixture of Performed by adding a mixture of calcium and thromboplastin to calcium and thromboplastin to citrated plasmacitrated plasma
As a control a normal blood sample is As a control a normal blood sample is tested continuouslytested continuously
PT ratio (PTR) = PT ratio (PTR) = Patientrsquos PTPatientrsquos PT Control PTControl PT
PROBLEMS WITH PTPTRPROBLEMS WITH PTPTR
Thromboplastins are extracts from Thromboplastins are extracts from brain lung or placenta of animalsbrain lung or placenta of animals
Thromboplastins from various Thromboplastins from various manufacturers differ in their manufacturers differ in their sensitivity to prolong PTsensitivity to prolong PT
May result in false control of May result in false control of anticoagulant therapyanticoagulant therapy
INTERNATIONAL NORMALISED RATIO (INR)INTERNATIONAL NORMALISED RATIO (INR)
International Normalized Ratio (INR) International Normalized Ratio (INR) a PT test with a a PT test with a formula based ratio to normalize the often variable source formula based ratio to normalize the often variable source of tissue factor (human rabbit recombinant)of tissue factor (human rabbit recombinant)
INR = [PTINR = [PTptpt] ] ISIISI
[PT[PTRefRef]]
PTPTpt pt ndash prothrombin time of patientndash prothrombin time of patient
PTPTRef Ref ndash prothrombin time of normal pooled samplendash prothrombin time of normal pooled sample
ISI ndash International Sensitivity IndexISI ndash International Sensitivity Index
Warfarin is given orally and titrated to achieve an INR of Warfarin is given orally and titrated to achieve an INR of typically 20 ndash 30typically 20 ndash 30
Heparin versus WarfarinHeparin versus Warfarin
Drug ActionMechan-ism
Moni-toring
Effective
HeparinDirect
Inhibition ofThrombin
ATIIIcofactor
APTTACT
Immediate
WarfarinDecreasesProductionof factors
Vitamin K PTDelay
3-5 days
INR
Recanalization or Antegrade Recanalization or Antegrade Reperfusion StrategiesReperfusion Strategies
Recanalization strategies focus on removing Recanalization strategies focus on removing andor dissolving the occlusive thrombus to re-andor dissolving the occlusive thrombus to re-establish antegrade flow Strategies may be establish antegrade flow Strategies may be classified into 7 different categories on the classified into 7 different categories on the basis of their primary mechanism of action basis of their primary mechanism of action 1) 1) IV andor intraarterial thrombolysis (IAT) IV andor intraarterial thrombolysis (IAT) 2) endovascular thrombectomy2) endovascular thrombectomy3) endovascular thromboaspiration 3) endovascular thromboaspiration 4) endovascular mechanical thrombus disruption or 4) endovascular mechanical thrombus disruption or
thromborrhexisthromborrhexis5) 5) transcranial or endovascular augmented transcranial or endovascular augmented
fibrinolysis fibrinolysis 6) endovascular thrombus entrapment and 6) endovascular thrombus entrapment and 7) temporary endovascular bypass7) temporary endovascular bypass
IAT in Acute Ischemic StrokeIAT in Acute Ischemic Stroke
IAT advantages over IV thrombolysisIAT advantages over IV thrombolysis Coaxial microcatheter techniques the occluded intracranial Coaxial microcatheter techniques the occluded intracranial
vessel is directly accessible and the fibrinolytic agent can be vessel is directly accessible and the fibrinolytic agent can be infused directly into the thrombusinfused directly into the thrombus
This permits a smaller dose of fibrinolytic agent to reach a This permits a smaller dose of fibrinolytic agent to reach a higher local concentration than that reached by systemic higher local concentration than that reached by systemic infusioninfusion
Allows more complete recanalization with lower total doses of Allows more complete recanalization with lower total doses of thrombolytic thrombolytic
With the smaller dose complications from systemic fibrinolytic With the smaller dose complications from systemic fibrinolytic effects including intracranial hemorrhage (ICH) can effects including intracranial hemorrhage (ICH) can theoretically be reduced theoretically be reduced
Treatment window for endovascular techniques can be Treatment window for endovascular techniques can be extended beyond the typical IV window of 3 hours extended beyond the typical IV window of 3 hours
IA techniques have led to higher recanalization rates than IV IA techniques have led to higher recanalization rates than IV thrombolysisthrombolysis
Major disadvantagesMajor disadvantages Relative complexity of the procedure the level Relative complexity of the procedure the level
of required technical expertise and its of required technical expertise and its relatively low availability relatively low availability
Delays in initiating treatmentDelays in initiating treatment InvasiveInvasive
ThrombolyticsThrombolytics
Plasminogen activators
Fibrinolytics
1 Plasminogen Activators 1 Plasminogen Activators drugs act by converting the inactive proenzyme drugs act by converting the inactive proenzyme plasminogen into the active enzyme plasmin Plasmin plasminogen into the active enzyme plasmin Plasmin digests fibrinogen fibrin monomers and cross-linked digests fibrinogen fibrin monomers and cross-linked fibrin (as found in a thrombus) into fibrin degradation fibrin (as found in a thrombus) into fibrin degradation productsproducts
First-Generation Agents First-Generation Agents StreptokinaseStreptokinase a protein derived from group C a protein derived from group C
szlig-hemolytic streptococci has a half-life of 16ndashszlig-hemolytic streptococci has a half-life of 16ndash90 minutes and low fibrin specificity This drug 90 minutes and low fibrin specificity This drug proved to have a very narrow therapeutic proved to have a very narrow therapeutic window and significant rates of ICH and window and significant rates of ICH and systemic hemorrhage18systemic hemorrhage18
UrokinaseUrokinase is a serine protease with a plasma is a serine protease with a plasma half life of 14 minutes and low fibrin specificity half life of 14 minutes and low fibrin specificity
The urokinase dose used in cerebral IAT has The urokinase dose used in cerebral IAT has ranged from 002 to 2 X106unitsranged from 002 to 2 X106units
Second-Generation Agents Second-Generation Agents Alteplase (rtPA) Alteplase (rtPA)
is a serine is a serine protease with a plasma half-life of 35 protease with a plasma half-life of 35 minutes and a high degree of fibrin affinity and minutes and a high degree of fibrin affinity and specificity specificity
Dose used in cerebral IAT has ranged between 20 Dose used in cerebral IAT has ranged between 20 and 60 mgand 60 mg
Disadvantages of alteplase include its relatively short Disadvantages of alteplase include its relatively short halflife and limited penetration into the clot matrix halflife and limited penetration into the clot matrix because of strong binding with surface fibrin which because of strong binding with surface fibrin which could delay recanalization and increase the risk of could delay recanalization and increase the risk of recurrent occlusion recurrent occlusion
Prourokinase (r-prourokinase) Prourokinase (r-prourokinase) is the proenzyme precursor of urokinase is the proenzyme precursor of urokinase T12 of 7 minutes and high fibrin specificity T12 of 7 minutes and high fibrin specificity
Third-Generation AgentsThird-Generation Agents
ReteplaseReteplase is a structurally modified is a structurally modified form of alteplase form of alteplase
with a longer half-life (15ndash18 minutes) In with a longer half-life (15ndash18 minutes) In addition it does not bind as highly to fibrin addition it does not bind as highly to fibrin unbound reteplase can thus theoretically better unbound reteplase can thus theoretically better penetrate the clot and potentially penetrate the clot and potentially improve in improve in vivo fibrinolytic activity vivo fibrinolytic activity
TenecteplaseTenecteplase is another modified form of rtPA with a longer is another modified form of rtPA with a longer
half-life (17 minutes)half-life (17 minutes) greater fibrin specificity and greater greater fibrin specificity and greater
resistance to plasminogen activator inhibitor-1 resistance to plasminogen activator inhibitor-1 IV tenecteplase in acute ischemic stroke IV tenecteplase in acute ischemic stroke
suggest that the drug is safe and promisingsuggest that the drug is safe and promising
Newer plasminogen activatorNewer plasminogen activator
DesmoteplaseDesmoteplase is a genetically engineered is a genetically engineered version of the clot-dissolving factor version of the clot-dissolving factor
found in the saliva found in the saliva of the vampire bat Desmodus rotundusof the vampire bat Desmodus rotundus moremore potent and more selective for fibrin-bound potent and more selective for fibrin-bound
plasminogen than any other known plasminogen plasminogen than any other known plasminogen activatoractivator
Unlike tissue plasminogen activator (tPA) desmoteplase Unlike tissue plasminogen activator (tPA) desmoteplase is not activated by fibrinogen or -amyloid proteins is not activated by fibrinogen or -amyloid proteins factors that may exacerbate the risk for ICH factors that may exacerbate the risk for ICH
The effect of IV administration of desmoteplase 3ndash9 The effect of IV administration of desmoteplase 3ndash9 hours after symptom onset in patients with stroke who hours after symptom onset in patients with stroke who present with mismatch on MR imaging or CT perfusion present with mismatch on MR imaging or CT perfusion
3 DefibrinogenatingFibrinogenolytic 3 DefibrinogenatingFibrinogenolytic Agents Agents
AncrodAncrod(Viprinex)(Viprinex) is is the purified fraction of the Malayan pit viper venomthe purified fraction of the Malayan pit viper venom It acts by directly cleaving and inactivating fibrinogen It acts by directly cleaving and inactivating fibrinogen
and thus indirectly promoting anticoagulation and thus indirectly promoting anticoagulation The reduction in the blood levels of fibrinogen also The reduction in the blood levels of fibrinogen also
leads to a reduced blood viscosity which may improve leads to a reduced blood viscosity which may improve blood flow to the affected areas of the brain blood flow to the affected areas of the brain
In the Stroke Treatment with Ancrod Trial 500 In the Stroke Treatment with Ancrod Trial 500 patients with stroke presenting within 3 hours of patients with stroke presenting within 3 hours of symptom onset were randomized to receive ancrod (symptom onset were randomized to receive ancrod (n n 248) or a placebo (n 252) Good outcome (Barthel 248) or a placebo (n 252) Good outcome (Barthel Index 95ndash100 at 3 months) was achieved in 4221 Index 95ndash100 at 3 months) was achieved in 4221 and 344 of the patients respectively and 344 of the patients respectively
2 Direct Fibrinolytics2 Direct Fibrinolytics
Microplasmin (Microplasmin (ThromboGenics Heverlee Belgium)ThromboGenics Heverlee Belgium) is a truncated form of plasmin that is more resistant to the effects is a truncated form of plasmin that is more resistant to the effects
of antiplasmin of antiplasmin microplasmin can be used upto 4ndash12 hours after stroke onset microplasmin can be used upto 4ndash12 hours after stroke onset There was no evidence of increased bleeding risk with There was no evidence of increased bleeding risk with
microplasminmicroplasmin
Alfimeprase (Nuvelo San Carlos Calif)Alfimeprase (Nuvelo San Carlos Calif) is a recombinant truncated form of fibrolase a fibrinolytic zinc metalloproteinase is a recombinant truncated form of fibrolase a fibrinolytic zinc metalloproteinase
isolated from the venom of the southern copperhead snake isolated from the venom of the southern copperhead snake It degrades fibrin directly and achieves thrombolysis independent It degrades fibrin directly and achieves thrombolysis independent
of plasmin formationof plasmin formation its thrombolytic activity appears to be localized to the site of its thrombolytic activity appears to be localized to the site of
delivery These properties should theoretically result in faster delivery These properties should theoretically result in faster recanalization and lower hemorrhagic conversion riskrecanalization and lower hemorrhagic conversion risk
Anti-fibrinolyticsAnti-fibrinolytics
to limit fibrinolytic activityto limit fibrinolytic activity -aminocaproic acid (EACA) -aminocaproic acid (EACA) competitively inhibitscompetitively inhibits plasminogen and plasminogen activators from plasminogen and plasminogen activators from
binding to fibrinbinding to fibrin
alpha2-antiplasminalpha2-antiplasmin a serine protease inhibitor that a serine protease inhibitor that neutralizes any free circulating plasminneutralizes any free circulating plasmin
Plasminogen activator inhibitor-1Plasminogen activator inhibitor-1 a serine protease a serine protease inhibitor that inhibits tissue-type plasminogen inhibitor that inhibits tissue-type plasminogen activatoractivator
Glycoprotein (GP) IIbIIIa antagonistsGlycoprotein (GP) IIbIIIa antagonists
such as ReoPro (abciximab) Integrilin such as ReoPro (abciximab) Integrilin (eptifibatide) or Aggrastat (tirofiban) in (eptifibatide) or Aggrastat (tirofiban) in ischemic stroke remains investigational ischemic stroke remains investigational Deshmukh et al38 reported 21 patients with Deshmukh et al38 reported 21 patients with large-vessel occlusion refractory to IAT with large-vessel occlusion refractory to IAT with rtPA who were treated with IV andor IA rtPA who were treated with IV andor IA abciximab eptifibatide or tirofiban abciximab eptifibatide or tirofiban
IA Mechanical Approaches in Acute Ischemic Stroke IA Mechanical Approaches in Acute Ischemic Stroke Mechanical strategies have several advantagesMechanical strategies have several advantages First they lessen and may even preclude the use of chemical First they lessen and may even preclude the use of chemical
thrombolytics in this manner very likely reducing the risk of ICHthrombolytics in this manner very likely reducing the risk of ICH Second by avoiding the use of chemical thrombolytics it is Second by avoiding the use of chemical thrombolytics it is
possible to extend the treatment window beyond the limit of 6ndash8 possible to extend the treatment window beyond the limit of 6ndash8 hours hours
Third mechanically fragmenting a clot increases the surface area Third mechanically fragmenting a clot increases the surface area accessible to fibrinolytic agents and allows inflow of fresh accessible to fibrinolytic agents and allows inflow of fresh plasminogen which in turn may increase the speed of plasminogen which in turn may increase the speed of thrombolysis thrombolysis
Finally clot-retrieval devices may provide faster recanalization Finally clot-retrieval devices may provide faster recanalization
The disadvantages of the mechanical The disadvantages of the mechanical approaches approaches technical difficulty of navigating mechanical technical difficulty of navigating mechanical
devices into the intracranial circulation excessive devices into the intracranial circulation excessive trauma to the vasculature (potentially leading to trauma to the vasculature (potentially leading to vasospasm vessel dissection perforation or vasospasm vessel dissection perforation or rupture) rupture)
fragmented thrombus causing distal embolization fragmented thrombus causing distal embolization into previously unaffected territories into previously unaffected territories
Nevertheless the advantages of mechanical stroke Nevertheless the advantages of mechanical stroke therapy appear to significantly outweigh its therapy appear to significantly outweigh its disadvantages and risksdisadvantages and risks
Contraindications to Thrombolytic Contraindications to Thrombolytic agents agents
Recent thoracic abdominal or Recent thoracic abdominal or intracranial surgeryintracranial surgery
Recent haemorrhagic CVA Head injury Recent haemorrhagic CVA Head injury or neoplasmor neoplasm
Bleeding ulcerBleeding ulcer Anticipated invasive procedures (arterial Anticipated invasive procedures (arterial
punctures biopsies)punctures biopsies) Concurrent hemostatic dysfunctionConcurrent hemostatic dysfunction
Monitoring of thrombolytic Monitoring of thrombolytic therapytherapy
Thrombin time Measures the availability of functional
fibrinogen Normal thrombin time is 10-14 sec Prolonged when fibrinogen level is below
75-100 mgdl
Half Life of ThrombolyticsHalf Life of ThrombolyticsAgent Administration Half Life
Streptokinase IA 60-80min
Urokinase IAIV 9-12min
rTPA IAIV 6min
Abciximab(Reopro) IAIV 12hour
Aspirin POIV 15-20min
Heparin IVSC 60min
Coumadin PO 15-25 days
Anti Platelet DrugsAnti Platelet DrugsDrug Drug Mechanism Mechanism UsesUsesAspirinAspirin Permanently inhibits Permanently inhibits
COX-1 and COX-2COX-1 and COX-2CADCAD
Stroke-TIAsStroke-TIAs
NSAIDsNSAIDs Reversibly inhibits Reversibly inhibits COX-1COX-1
LimitedLimited
DipyridamoleDipyridamole Inhibits PDE increases Inhibits PDE increases cAMPcAMP
TIAsTIAs
ThenopyridinesThenopyridines
(Ticlopidine(Ticlopidine
ClopidrgrelClopidrgrel))
Inhibits ADP Inhibits ADP
PlatAg PlatAg
TIAsStrokeTIAsStroke
CAD PVDCAD PVD
Abciximab (ReoPro)Abciximab (ReoPro)
Eptifibatide (Integrilin)Eptifibatide (Integrilin)
TirofibanTirofiban
GP IIBIIIA InhibitorsGP IIBIIIA Inhibitors
Stroke- TIAs Stroke- TIAs
MonitoringMonitoring
Bleeding timeBleeding time
Optical aggregometryOptical aggregometry
Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay
Bleeding timeBleeding time
Requires a skin incision (usually made on the ear lobe or Requires a skin incision (usually made on the ear lobe or forearm offorearm of
a depth that results in disruption of capillary loops and a depth that results in disruption of capillary loops and small vessels)small vessels)
AdvantagesAdvantages Universally availableUniversally available Relatively simple techniquesRelatively simple techniques Can be performed bedsideCan be performed bedside
DisadvantagesDisadvantages Insensitive inaccurate non-specific techniqueInsensitive inaccurate non-specific technique
Poorly reproducible (as depends on multiple variables)Poorly reproducible (as depends on multiple variables)
Optical aggregometryOptical aggregometry
Gold standard assay for platelet functionGold standard assay for platelet function Agonist induced aggregation is measuredAgonist induced aggregation is measured Different agonist are available for different Different agonist are available for different
agentsagents However require unique expertise and are not However require unique expertise and are not
universally availableuniversally available Aspirin measured with ADP or AA(gt70 Aspirin measured with ADP or AA(gt70
aggregation so resistance)aggregation so resistance) Clopidogrel( ADP gt 90 aggregation means Clopidogrel( ADP gt 90 aggregation means
resistance) resistance)
Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay
Can be performed bed sideCan be performed bed side Different assay devices with different Different assay devices with different
agonist are used for each of different agonist are used for each of different antiplatelet agents antiplatelet agents
For Aspirin AA is used (result is reported as aspirin For Aspirin AA is used (result is reported as aspirin reaction units [ARU] ARUgt 550 indicates non-reaction units [ARU] ARUgt 550 indicates non-responsiveness)responsiveness)
Verify IIbIIIa assay device uses TRAP as agonist for Verify IIbIIIa assay device uses TRAP as agonist for Abciximab and TirofibanAbciximab and Tirofiban
Practical Applications Practical Applications related to specific related to specific
Neurovascular Neurovascular interventionsinterventions
Acute ischemic StrokeAcute ischemic Stroke When an artery occludes neurons are affected When an artery occludes neurons are affected
differently depending upon the amount of residual blood differently depending upon the amount of residual blood flowflow
Normal cerebral blood flow is greater than 50 mL100 Normal cerebral blood flow is greater than 50 mL100 mgminmgmin
Once blood flow decreases to less than 20 mL100 Once blood flow decreases to less than 20 mL100 mgmin infarction occursmgmin infarction occurs
If blood flow decreases to less than 10 mL100 mgmin If blood flow decreases to less than 10 mL100 mgmin irreversible neuronal death occurs rapidly irreversible neuronal death occurs rapidly
Blood flow between 11 and 20 mL100 mgmin is thought Blood flow between 11 and 20 mL100 mgmin is thought to represent the ischemic penumbra an area where the to represent the ischemic penumbra an area where the cells are functionally silent because of ischemia but are cells are functionally silent because of ischemia but are still able to recover if blood flow is restored still able to recover if blood flow is restored
Many acute stroke therapies are targeted toward Many acute stroke therapies are targeted toward restoring flow or function to the ischemic penumbrarestoring flow or function to the ischemic penumbra
Therapeutic window in Therapeutic window in management of acute Ischemic management of acute Ischemic
StrokeStrokeThe early diagnosis of ischemic stroke is critical to the The early diagnosis of ischemic stroke is critical to the
with only a narrow therapeutic window in the first few with only a narrow therapeutic window in the first few hours following stroke ictushours following stroke ictus
Diagnosis in the first 3 hours postictus provides the Diagnosis in the first 3 hours postictus provides the opportunity for intravenous or intraarterial thrombolysis opportunity for intravenous or intraarterial thrombolysis and intra-arterial clot mechanical treatment which and intra-arterial clot mechanical treatment which improve the outcome improve the outcome
Diagnosis in the time period between 3 and 6 hours Diagnosis in the time period between 3 and 6 hours provides an opportunity for intra-arterial thrombolysis provides an opportunity for intra-arterial thrombolysis and mechanical treatment and mechanical treatment
Involvement of the posterior circulation especially the Involvement of the posterior circulation especially the basilar artery is treated by some regardless of time of basilar artery is treated by some regardless of time of onset or up until 12 to 24 hours in some practices This is onset or up until 12 to 24 hours in some practices This is related to the potentially high mortality and morbidity related to the potentially high mortality and morbidity associated with basilar artery thrombosisassociated with basilar artery thrombosis
Infarct evaluation on angiographyInfarct evaluation on angiography(CT angiography and catheter (CT angiography and catheter
angiography)angiography)CTA is an excellent first-line examination for CTA is an excellent first-line examination for
evaluation of the head and neck arteries evaluation of the head and neck arteries In comparison with catheter angiography In comparison with catheter angiography
what it gives up in resolution and dynamic what it gives up in resolution and dynamic properties it makes up for with rapid properties it makes up for with rapid acquisition of a 3-D dataset and the potential acquisition of a 3-D dataset and the potential for assessment of whole-brain perfusion and for assessment of whole-brain perfusion and better parenchymal evaluationbetter parenchymal evaluation
Moreover CTA illustrates not only arterial Moreover CTA illustrates not only arterial stenosis or occlusion but also the vessel wall stenosis or occlusion but also the vessel wall This factor is most important for evaluation of This factor is most important for evaluation of intramural dissection and thrombosed intramural dissection and thrombosed aneurysms which may both complicate aneurysms which may both complicate evaluation of stroke patientsevaluation of stroke patients
Early angiographic signs of strokes Early angiographic signs of strokes both CTA both CTA and DSA and DSA
Vessel occlusion or cutoff related to Vessel occlusion or cutoff related to thromboembolithromboemboli
aneurysms aneurysms arterial dissection arterial dissection Meniscus or flattened shape to clot Meniscus or flattened shape to clot
(recent) versus reverse meniscus (older)(recent) versus reverse meniscus (older) tram track (nonocclusive or recanalized tram track (nonocclusive or recanalized
clot) clot) delayed (antegrade) flow (manifest as delayed (antegrade) flow (manifest as
decreased whole-brain perfusion on CTA)decreased whole-brain perfusion on CTA) retrograde collateral flowretrograde collateral flow
Non-occlusive left MCA thrombus on 3-D imaging performed from CTA source data and was confirmed at catheter angiography
Therapy to be started within a 6-hr Therapy to be started within a 6-hr time to treatment (TTT) window time to treatment (TTT) window (while in case of IV thrombolysis (while in case of IV thrombolysis therapy to be started with in 3hrs)therapy to be started with in 3hrs)
Exclusion criteria Exclusion criteria Rapidly improving neurologic deficit or Rapidly improving neurologic deficit or Sustained blood pressure of gt180100 Sustained blood pressure of gt180100 Hemorrhage is detected on CTHemorrhage is detected on CT Infarct involving gt more than 13 rd Infarct involving gt more than 13 rd
territory of MCAterritory of MCA MRADWI-Perfusion mismatchlt 20MRADWI-Perfusion mismatchlt 20 Definite hypodensity on CTDefinite hypodensity on CT
Intra-arterial Thrombolysis
Fibrinolytics + AntiplateletsFibrinolytics + Antiplatelets
PlasminogenPlasminogen activators through fibrinolysis exposes activators through fibrinolysis exposes free thrombin and paradoxically stimulatesfree thrombin and paradoxically stimulates platelet platelet aggregation which leads to formation of aaggregation which leads to formation of a platelet platelet thrombus (white clot) thrombus (white clot)
This new thrombus is relatively resistant to This new thrombus is relatively resistant to fibrinolyticsfibrinolytics
So new regimen in case of acute stroke isSo new regimen in case of acute stroke is fibrinolytics + antiplatelet drugsfibrinolytics + antiplatelet drugs
rtPA + IIbIIIa inhibitors( tirofiban rtPA + IIbIIIa inhibitors( tirofiban abciximab) orabciximab) or
Urokinase + IIbIIIa Urokinase + IIbIIIa inhibitors( tirofiban abciximab)inhibitors( tirofiban abciximab)
Intra-arterial Thrombolysis Tirofiban (04 microgkgmin bolus for 3 min followed by Tirofiban (04 microgkgmin bolus for 3 min followed by
0125 ugkgmin)0125 ugkgmin)
++
Heparin (2000ndash3000 IU bolus followed by Heparin (2000ndash3000 IU bolus followed by 1000 IUhour infusion 1000 IUhour infusion
with ACT maintained bw 200-300) throughout the with ACT maintained bw 200-300) throughout the interventional procedure and for 24ndash48 hours thereafter when interventional procedure and for 24ndash48 hours thereafter when there is neither intraprocedural bleeding nor suspicion of there is neither intraprocedural bleeding nor suspicion of increased risk of bleeding increased risk of bleeding
Maximum dose of Urokinase Maximum dose of Urokinase Anterior circulation stroke - 500000 IU (mean 400000 Anterior circulation stroke - 500000 IU (mean 400000
IU range 300000ndash500000 IU)IU range 300000ndash500000 IU) Posterior circulation stroke -1000000 IU (mean 837000 Posterior circulation stroke -1000000 IU (mean 837000
IU range 300000ndash1000000 IU)IU range 300000ndash1000000 IU)American Journal of NeuroradiologyAmerican Journal of Neuroradiology 262595-2601 2005262595-2601 2005
Intravenous ThrombolysisIntravenous Thrombolysis
The first method to restore cerebral The first method to restore cerebral perfusion is clot lysis with the goal perfusion is clot lysis with the goal of re-establishing blood flow to the of re-establishing blood flow to the affected tissue affected tissue
IV thrombolysis rt-PA is the only IV thrombolysis rt-PA is the only FDA- approved treatment for AIS FDA- approved treatment for AIS
Fibrinolysis is enhanced powerfully Fibrinolysis is enhanced powerfully by rt-PAby rt-PA
Intravenous rTPA Intravenous rTPA administration administration protocolprotocol
Total dose of rt-PA 09 mgkg (maximum dose Total dose of rt-PA 09 mgkg (maximum dose 90 mg)90 mg)
Give 10 as initial IV bolusGive 10 as initial IV bolus Infuse remainder over 1 hourInfuse remainder over 1 hour Admit patient to an ICU or stroke unit for Admit patient to an ICU or stroke unit for
monitoringmonitoring Neurologic assessments every 15 minutes Neurologic assessments every 15 minutes
during infusion then every 30 minutes for next during infusion then every 30 minutes for next 6 hours then every hour until 24hours after 6 hours then every hour until 24hours after treatmenttreatment
Favorable Outcome vs Treatment Time Favorable Outcome vs Treatment Time with IV rTPAwith IV rTPA
Protocol limit = 3 hrs
Benefit ~ 45 hrs
Thromboembolism During coilingThromboembolism During coiling Most feared and frequent complication Most feared and frequent complication Reported incidence - Approx 7 Reported incidence - Approx 7 SourcesSources of Thromboembolism are of Thromboembolism are
- Clots at the aneurysmal neck during or immediately- Clots at the aneurysmal neck during or immediately after after embolization embolization
- Thrombus forming on catheters during- Thrombus forming on catheters during proceduresprocedures
- Stenosis of an adjacent artery dt coil mass- Stenosis of an adjacent artery dt coil mass or herniationor herniation
- Migration of intraaneurysmal- Migration of intraaneurysmal thrombus during coil thrombus during coil placement placement
- Slow flow dt vasospasm - Slow flow dt vasospasm
- Rare and unlikely causes are hypercoagulable- Rare and unlikely causes are hypercoagulable state such state such as antiphospholipid antibody syndrome or due to HITas antiphospholipid antibody syndrome or due to HIT
Occur more often with wide-necked aneurysms (dt Occur more often with wide-necked aneurysms (dt increased exposed surface area of thrombogenic coil increased exposed surface area of thrombogenic coil material)material)
Current regimen of endovascular Current regimen of endovascular managementmanagement
The The glycoprotein IIbIIIa antagonist tirofiban glycoprotein IIbIIIa antagonist tirofiban (04 (04 microgkgmin bolus for 30 minutes followed by infusion of microgkgmin bolus for 30 minutes followed by infusion of 0125 ugkgmin until the thrombus dissolved) 0125 ugkgmin until the thrombus dissolved)
Intraarterial thrombolysis with Intraarterial thrombolysis with urokinase or r- TPA urokinase or r- TPA increase of intravenous (IV) heparin (measured by increase of intravenous (IV) heparin (measured by
ACT) ACT) Intravenous aspirin Intravenous aspirin
Coil-related platelet aggregation (white clot) is Coil-related platelet aggregation (white clot) is unlikely to respond to fibrinolytics but has a high risk unlikely to respond to fibrinolytics but has a high risk of hemorrhage (In ISAT) all 5 patients who had of hemorrhage (In ISAT) all 5 patients who had received thrombolytic therapy with tPA to treat a received thrombolytic therapy with tPA to treat a thromboembolic complication after endovascular thromboembolic complication after endovascular treatment rebleed and all of these patients died)treatment rebleed and all of these patients died)
IntracranialIntracranial Stenting Stenting Metallic foreign body such as stent will accumulate Metallic foreign body such as stent will accumulate
thrombus in the absence of platelet inhibitionthrombus in the absence of platelet inhibition Antiplatelet drugs are important to prevent peri or Antiplatelet drugs are important to prevent peri or
post-interventional thromboembolic eventspost-interventional thromboembolic events Optimal treatment regimens has not been determined Optimal treatment regimens has not been determined
but usually but usually Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-
procedureprocedureOrOr
Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on
morning of proceduremorning of procedure
If need to use stent is not pre-planned thanIf need to use stent is not pre-planned than
Abciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkgAbciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkg IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)
Glycoprotein IIbIIIa inhibitor are not used routinely during elective Glycoprotein IIbIIIa inhibitor are not used routinely during elective stenting procedure dt increased risk of ICH stenting procedure dt increased risk of ICH
Carotid StentingCarotid Stenting
Pre-procedurePre-procedure
Double Antiplatelet therapy is routinely given Double Antiplatelet therapy is routinely given beginning at least 3beginning at least 3
days before the proceduredays before the procedure
Aspirin 325mgd+Clopidogrel 75mgdAspirin 325mgd+Clopidogrel 75mgd During procedureDuring procedure
Heparin is given with target clotting time of 250-Heparin is given with target clotting time of 250-300sec300sec
Post-procedure Post-procedure
Aspirin 325mg is continued indefinitely and Aspirin 325mg is continued indefinitely and
Clopidogrel 75mgd for at least 6 weeks Clopidogrel 75mgd for at least 6 weeks
Inclusion criteria for Local ThrombolysisInclusion criteria for Local Thrombolysis a)a) Patients in severe clinical grade on admission Patients in severe clinical grade on admission
with evidence of dural venous sinus with evidence of dural venous sinus thrombosis and restrictive venous outflow on thrombosis and restrictive venous outflow on cerebral angiogramcerebral angiogram
b)b) Patients in clinical grade 3 worsening on Patients in clinical grade 3 worsening on heparin therapy Restriction to venous heparin therapy Restriction to venous outflow was defined as an increase in brain outflow was defined as an increase in brain circulation time gt 12 s delay in the drainage circulation time gt 12 s delay in the drainage of cortical veins with cortical veins hanging of cortical veins with cortical veins hanging in spacein space
Treatment Options for Venous Thrombosis
CT Grading for Venous ThrombosisCT Grading for Venous Thrombosis Grade I no parenchymal change Grade I no parenchymal change
(hyperdense (hyperdense sinuses cortical veins empty sinuses cortical veins empty delta sign)delta sign)
Grade II non hemorrhagic venous infarct Grade II non hemorrhagic venous infarct without mass effect without mass effect
Grade III non-hemorrhagic infarct with Grade III non-hemorrhagic infarct with mass effectmass effect
Grade IV hemorrhagic venous infarct (max Grade IV hemorrhagic venous infarct (max diameter lt 3 cm) with no mass effectdiameter lt 3 cm) with no mass effect
Grade V hemorrhagic venous infarct (max Grade V hemorrhagic venous infarct (max diameter gt 3 cm) with mass effect diameter gt 3 cm) with mass effect
Local ThrombolysisLocal Thrombolysis
Femoral Jugular access was secured and a guiding Femoral Jugular access was secured and a guiding catheter was placed in the jugular bulb catheter was placed in the jugular bulb Mechanical Mechanical clot maceration clot maceration was done with the guidewire was done with the guidewire following which a microcatheter (was navigated and following which a microcatheter (was navigated and placed in the thrombosed segment of sinus confirmed placed in the thrombosed segment of sinus confirmed on a selective venogram on a selective venogram
Urokinase infusion Bolus dose of 2-6 lacs followed Urokinase infusion Bolus dose of 2-6 lacs followed by 60000 to 100000 units per hour along with by 60000 to 100000 units per hour along with periodic check venogram Along with maintenance periodic check venogram Along with maintenance systemic infusion of Heparinsystemic infusion of Heparin Other agents such as Other agents such as streptokinase altepase or rTPAstreptokinase altepase or rTPA can be also used can be also used
After thrombolysis patient should subjected to oral After thrombolysis patient should subjected to oral anticoagulation for six monthsanticoagulation for six months
Low-molecular-weight Low-molecular-weight heparinheparin
PharmacologyPharmacologyLMWH as its name suggests is a glycosaminoglycan that is approximatelyLMWH as its name suggests is a glycosaminoglycan that is approximately
one third the molecular weight of UFH It is derived from UFH through one third the molecular weight of UFH It is derived from UFH through variousvarious
depolymerization processes LMWH binds to antithrombin which in turn depolymerization processes LMWH binds to antithrombin which in turn
Neutralizes actors Xa and IIa Because LMWH lacks many of the longer Neutralizes actors Xa and IIa Because LMWH lacks many of the longer chains chains
required for binding to thrombin it has less ability to neutralize thrombin required for binding to thrombin it has less ability to neutralize thrombin
relativeto its ability to neutralize factor Xa LMWH also has less relativeto its ability to neutralize factor Xa LMWH also has less nonspecific nonspecific
binding to other proteins There is greater bioavailability with more binding to other proteins There is greater bioavailability with more predictable predictable
pharmacokinetics that eliminates the need for monitoring The smaller pharmacokinetics that eliminates the need for monitoring The smaller size also size also
allows for enhanced subcutaneous absorption when compared with UFHallows for enhanced subcutaneous absorption when compared with UFH
Three LMWH preparations are Three LMWH preparations are currently approved for use in the currently approved for use in the United States (1) enoxaparin (2) United States (1) enoxaparin (2) dalteparin and (3) tinzaparin dalteparin and (3) tinzaparin
They are all administered They are all administered subcutaneously at intervals of either subcutaneously at intervals of either once or twice daily for both once or twice daily for both prophylaxis and treatment dosesprophylaxis and treatment doses
Few Experiences of Few Experiences of ThrombolysisThrombolysis
Vickey 25 Yrs male patient presented Vickey 25 Yrs male patient presented with 12with 12thth day HO severe headache with day HO severe headache with right sided hemiplegiaright sided hemiplegia
MRI shows thrombosis of the superior MRI shows thrombosis of the superior sagittal left transverse left sigmoid sagittal left transverse left sigmoid sinuses and cortical veins in the fronto-sinuses and cortical veins in the fronto-parietal regions with eo haemorrhagic parietal regions with eo haemorrhagic infarct in the left cerebral hemisphere infarct in the left cerebral hemisphere with mass effect( Grade ndashV)with mass effect( Grade ndashV)
Sashi Srivastava 64 yrs FSashi Srivastava 64 yrs F In a follow up case of MRD with infra-renal In a follow up case of MRD with infra-renal
aortic abdominal and bilateral renal artery aortic abdominal and bilateral renal artery thrombosis renal angiogram shows filling thrombosis renal angiogram shows filling defects in the right Renal artery defects in the right Renal artery
Initially Renal angioplasty was done Initially Renal angioplasty was done Following angioplasty few thrombi are seem Following angioplasty few thrombi are seem to extends into the segmental branches and to extends into the segmental branches and causing blockage So Thrombolysis was causing blockage So Thrombolysis was plane to dissolve the run-out thrombi with plane to dissolve the run-out thrombi with urokinase urokinase
Rakesh 34yrsMRakesh 34yrsM Left SFA pseudoaneurysm with Left SFA pseudoaneurysm with
Covered stent placementCovered stent placement Pre operative antiplatelets with post Pre operative antiplatelets with post
procedure heparin Tirofiban procedure heparin Tirofiban followed by aspirin and clopidogrel followed by aspirin and clopidogrel were usedwere used
IAT may be a treatment option for selected patients IAT may be a treatment option for selected patients Possible selection criteria include Possible selection criteria include
presentation between 3 and 6 hours from symptom onsetpresentation between 3 and 6 hours from symptom onset major cerebral artery occlusion major cerebral artery occlusion severe neurologic deficits severe neurologic deficits high risk of systemic hemorrhage with IV rt-PA (eg recent high risk of systemic hemorrhage with IV rt-PA (eg recent
surgery) surgery) The MERCI (Mechanical Embolus Removal in Cerebral The MERCI (Mechanical Embolus Removal in Cerebral
Ischemia) retrievalIschemia) retrieval system system
Has been FDA-approved for recanalizing acutely occluded Has been FDA-approved for recanalizing acutely occluded cerebral arteries cerebral arteries
In the Multi-MERCI study patients who did not improve In the Multi-MERCI study patients who did not improve immediately after IV rt-PA underwent mechanical immediately after IV rt-PA underwent mechanical embolectomy within 8 hours of symptom onset embolectomy within 8 hours of symptom onset
Partial or complete recanalization occurred in 74 of Partial or complete recanalization occurred in 74 of patientspatients
with a symptomatic intracerebral hemorrhage (sICH) rate of with a symptomatic intracerebral hemorrhage (sICH) rate of 67 67
Mechanical embolectomy with the MERCI retriever may be a Mechanical embolectomy with the MERCI retriever may be a feasible and safe option for patients after IV rt-PAfeasible and safe option for patients after IV rt-PA
Penumbra stroke systemPenumbra stroke system This device combines two methods of clot This device combines two methods of clot
extraction aspiration and mechanical extraction aspiration and mechanical extraction extraction
First the clot is aspirated then a thrombus First the clot is aspirated then a thrombus removal ring can be used if necessary to removal ring can be used if necessary to remove remaining clot remove remaining clot
successful recanalizing 82successful recanalizing 82 Bridging therapyBridging therapy
06 mgkg IV rt-PA followed by IAT with IA rt-06 mgkg IV rt-PA followed by IAT with IA rt-PA (up to 20 mg)PA (up to 20 mg)
achieved a higher recanalization rateachieved a higher recanalization rate
Criteria for thrombolysis with rTPACriteria for thrombolysis with rTPA
Inclusion criteriaInclusion criteria Clinical signs and symptoms consistent with ischemic Clinical signs and symptoms consistent with ischemic
strokestroke Patient last seen normal within 3 hoursPatient last seen normal within 3 hours Measurable neurologic deficitMeasurable neurologic deficit
Exclusion criteriaExclusion criteria Any hemorrhage on neuroimaging (CT or MRI)Any hemorrhage on neuroimaging (CT or MRI) Symptoms suggestive of subarachnoid hemorrhageSymptoms suggestive of subarachnoid hemorrhage Seizure at stroke onset that is thought to contribute to Seizure at stroke onset that is thought to contribute to
neurologic deficitneurologic deficit Hypodensity greater than one third cerebral hemisphere Hypodensity greater than one third cerebral hemisphere
on CTon CT SBP greater than 185 mm Hg or DBP greater than 110 SBP greater than 185 mm Hg or DBP greater than 110
mm Hgmm Hg International normalized ratio (INR) greater than 17International normalized ratio (INR) greater than 17
Ischemic Stroke Ischemic Stroke Treatment ndash 2006Treatment ndash 2006
IV tissue plasminogen activator (tPA)IV tissue plasminogen activator (tPA) ndash ndash Only FDA-approved acute stroke drugOnly FDA-approved acute stroke drug ndash ndash 3 hour treatment window3 hour treatment window
MERCI - Concentric clot retrieval MERCI - Concentric clot retrieval devicedevice ndash ndash Rescue therapy - approved 2004Rescue therapy - approved 2004 ndash ndash Device approval (not outcomes-based)Device approval (not outcomes-based)
Off label approachesOff label approaches ndash ndash IV tPA after 3 hoursIV tPA after 3 hours ndash ndash IV-IA tPA sequential strategiesIV-IA tPA sequential strategies ndash ndash IA tPA clot angioplasty fragmentationIA tPA clot angioplasty fragmentation ndash ndash Ultrasound-assisted tPA lysisUltrasound-assisted tPA lysis
rt-PA Trials NINDSrt-PA Trials NINDS
Acute stroke - 624 patientsAcute stroke - 624 patients Treat within 3 hrsTreat within 3 hrs Intravenous 09 mgkg rt-PA vs placeboIntravenous 09 mgkg rt-PA vs placebo Hemorrhage 64 tPA 06 placeboHemorrhage 64 tPA 06 placebo Neurologic recovery better with tPA 30 Neurologic recovery better with tPA 30
more like to have minimal or no disabilitymore like to have minimal or no disability
First proven approved treatment for First proven approved treatment for strokestroke
Limitations of tPALimitations of tPA Only 4 of acute strokes receive tPAOnly 4 of acute strokes receive tPA (Kleindorfer et al Stroke 2004 35 e27-e29)(Kleindorfer et al Stroke 2004 35 e27-e29)
Only 22 of patients present within 3 hoursOnly 22 of patients present within 3 hours1048707 1048707 51 of these ineligible due to51 of these ineligible due to
bull bull Mild severityMild severity bull bull Medical or surgical historyMedical or surgical history bull bull Blood testsBlood tests
Sustained recanalization only 13Sustained recanalization only 13 (Alexandrov et al NEJM 2004 351 2170-8)(Alexandrov et al NEJM 2004 351 2170-8)
Concern for hemorrhageConcern for hemorrhage tPA potentiates apoptotic injury tPA potentiates apoptotic injury (Liu et al Nature Med 2004 101379-83)(Liu et al Nature Med 2004 101379-83)
PROACT II IA Lysis TrialPROACT II IA Lysis Trial Baseline 24 hours 8 days
Baseline 60 minutes 120 minutes
9mg IAProurokinase
Desmoteplase Trials DEDAS Desmoteplase Trials DEDAS DIASDIAS
Trial OverviewTrial Overview Double blind randomized placebo Double blind randomized placebo
controlled trialscontrolled trials IV delivery 3-9 hour time windowIV delivery 3-9 hour time window Plasminogen activator ndash from Plasminogen activator ndash from vampire bat vampire bat
salivasaliva Selection based on PWI-DWI MismatchSelection based on PWI-DWI Mismatch
MRI InclusionMRI Inclusion PWI defect at least 2 cm AND ~20 larger PWI defect at least 2 cm AND ~20 larger
than DWIthan DWI PWI should be obvious even visible on PWI should be obvious even visible on
raw imagesraw imagesMRI ExclusionMRI Exclusion
DWI gt 13 MCADWI gt 13 MCA MRA ICA occlusionMRA ICA occlusion
Desmoteplase ndash DIAS Desmoteplase ndash DIAS ResultsResults
Mechanical Thrombolysis Mechanical Thrombolysis devicesdevices
mechanical thrombolysis potentially extends the treatment mechanical thrombolysis potentially extends the treatment window because they act promptly at the site of the thrombuswindow because they act promptly at the site of the thrombus
The devices can retrieve large clots that pharmaceutical agents The devices can retrieve large clots that pharmaceutical agents may not successfully lysemay not successfully lyse
Patients treated with IV tPA may be considered for treatment of Patients treated with IV tPA may be considered for treatment of residual clot with some of these devicesresidual clot with some of these devices
suction-creating saline jets suction-creating saline jets laser energy ultrasound laser energy ultrasound a corkscrew apparatus to treat strokesa corkscrew apparatus to treat strokes The AngioJet systemThe AngioJet system uses saline jets that are directed back into the catheter to uses saline jets that are directed back into the catheter to
create a low-pressure zone around the catheter tip inducing create a low-pressure zone around the catheter tip inducing suction suction
The clot is pulled into the exhaust lumen and removed from the The clot is pulled into the exhaust lumen and removed from the vessel Although US Food and Drug Administration (FDA) has vessel Although US Food and Drug Administration (FDA) has approved this device for use in arteriovenous dialysis grafts and approved this device for use in arteriovenous dialysis grafts and fistulae and for the treatment of coronary arteries saphenous fistulae and for the treatment of coronary arteries saphenous vein grafts and peripheral vessels clinical trials for the vein grafts and peripheral vessels clinical trials for the treatment of acute stroke are no longer in progress treatment of acute stroke are no longer in progress
Most devices are used in cerebral vessels that 2-5 mm
The Latis laser device The Latis laser device used laser energy to ablate clots used laser energy to ablate clots Arteries 2-5 mm in diameter could be Arteries 2-5 mm in diameter could be
treated including the ICA M1 or M2 treated including the ICA M1 or M2 branch of the MCA A1 branch of the branch of the MCA A1 branch of the anterior cerebral artery (ACA) basilar anterior cerebral artery (ACA) basilar artery posterior cerebral artery (PCA) artery posterior cerebral artery (PCA) and vertebral and vertebral
Patients could receive treatment as late Patients could receive treatment as late as 8 hours after symptom onset in the as 8 hours after symptom onset in the anterior circulation and within 24 hours in anterior circulation and within 24 hours in the posterior circulation the posterior circulation
Endovascular Photo Acoustic Endovascular Photo Acoustic Recanalization (EPAR) Recanalization (EPAR)
A laser power source generated energy for the A laser power source generated energy for the systemsystem
The energy was delivered by means of The energy was delivered by means of fiberoptics to the tip of the catheter at the fiberoptics to the tip of the catheter at the treatment sitetreatment site
Absorption of laser light by darkly pigmented Absorption of laser light by darkly pigmented materials (ie the clot) occurred inside the 1-mm materials (ie the clot) occurred inside the 1-mm catheter tipcatheter tip
the system was designed to minimize scattering the system was designed to minimize scattering of laser light of laser light
Absorption converted photo energy to acoustic Absorption converted photo energy to acoustic energy which then emulsified the clot inside the energy which then emulsified the clot inside the catheter tip catheter tip
EKOS ultrasound( the EKOS ultrasound( the Ultrasound Thrombolytic Ultrasound Thrombolytic
Infusion Catheter) Infusion Catheter) combines the use of a distal ultrasound transducer with combines the use of a distal ultrasound transducer with
infusion of a thrombolytic agent through the infusion of a thrombolytic agent through the microcathetermicrocatheter
Ultrasound changes the structure of the clot to Ultrasound changes the structure of the clot to temporarily increase its permeability while providing an temporarily increase its permeability while providing an acoustic pressure gradient to move the drug into the clot acoustic pressure gradient to move the drug into the clot to speed its dissolution to speed its dissolution
The EKOS catheter is placed in the proximal portion of the The EKOS catheter is placed in the proximal portion of the clot clot
After a 2-mg bolus of tPA was injected through the After a 2-mg bolus of tPA was injected through the catheter catheter
the patient received a continuous infusion of IA tPA 03 the patient received a continuous infusion of IA tPA 03 mgmin to a maximum of 20 mg and simultaneous mgmin to a maximum of 20 mg and simultaneous ultrasound transmission for as long as 60 minutes ultrasound transmission for as long as 60 minutes
One patient was treated with a total of 4 units of One patient was treated with a total of 4 units of recombinant reteplase (Retavase) hand-injected over 60 recombinant reteplase (Retavase) hand-injected over 60 minutes minutes
Penumbra system Penumbra system The Penumbra system (Penumbra Inc) provides a dual The Penumbra system (Penumbra Inc) provides a dual
approach to clot extraction using aspiration followed by approach to clot extraction using aspiration followed by clot retrieval with a ring device if needed clot retrieval with a ring device if needed
Mechanical Embolus Removal in Cerebral Ischemia Mechanical Embolus Removal in Cerebral Ischemia (MERCI)(MERCI)
a corkscrew-like apparatus to remove blood clots from a corkscrew-like apparatus to remove blood clots from the brain in patients experiencing an ischemic stroke the brain in patients experiencing an ischemic stroke
The corkscrew itself resides in the catheter tip which The corkscrew itself resides in the catheter tip which shields it from the wall of the vessel until it is ready to be shields it from the wall of the vessel until it is ready to be burrowed into the clot Once lodged in the clot the device burrowed into the clot Once lodged in the clot the device and clot are withdrawn from the vessel and clot are withdrawn from the vessel
Snarelike devicesSnarelike devices Snares such as the Neuronet snare (Guidant Snares such as the Neuronet snare (Guidant
Endovascular Santa Clara CA) have been developed Endovascular Santa Clara CA) have been developed specifically for use in the treatment of strokes specifically for use in the treatment of strokes
These devices are simple in design and do not require the These devices are simple in design and do not require the clot to be amenable to emulsification clot to be amenable to emulsification
X-Sizer deviceX-Sizer device a device with small moving blades at the a device with small moving blades at the
catheter tip catheter tip This device the X-Sizer device (EndiCor Medical This device the X-Sizer device (EndiCor Medical
San Clemente CA) can be used to excise the San Clemente CA) can be used to excise the thrombus and aspirate it thrombus and aspirate it
The device was being evaluated in randomized The device was being evaluated in randomized studies of coronary vessels and in a registry of studies of coronary vessels and in a registry of patients with acute myocardial infarctionpatients with acute myocardial infarction
Although the manufacturer had modified the Although the manufacturer had modified the device for use in cerebral vessels a safety and device for use in cerebral vessels a safety and feasibility study was indefinitely suspended after feasibility study was indefinitely suspended after only 1 patient was treated with the device in only 1 patient was treated with the device in Europe Europe
Suction thrombectomySuction thrombectomy This method of mechanical thrombolysis is one of the This method of mechanical thrombolysis is one of the
simplestsimplest In this readily available technique suction is applied with In this readily available technique suction is applied with
a syringe to remove thrombus in the ICA a syringe to remove thrombus in the ICA It requires no other devicesIt requires no other devices A catheter with a large inner diameter (Brite Tip Cordis A catheter with a large inner diameter (Brite Tip Cordis
Corporation Miami FL) was placed in the symptomatic Corporation Miami FL) was placed in the symptomatic vessel and navigated over a guidewire into the thrombusvessel and navigated over a guidewire into the thrombus
A 60-mL syringe was used to aspirate the thrombus A 60-mL syringe was used to aspirate the thrombus Each patient required angioplasty and stenting of carotid Each patient required angioplasty and stenting of carotid
bifurcation stenosis and received daily aspirin and bifurcation stenosis and received daily aspirin and ticlopidine after the procedure No complications ticlopidine after the procedure No complications occurred occurred
Summary Acute Stroke Summary Acute Stroke ImagingImaging
PhysiologyPhysiology importance collaterals importance collaterals
ndash ndashGrowing role for perfusion Growing role for perfusion assessmentassessment
tPAtPA guidelines amp limitations guidelines amp limitations Signs on CT amp MRSigns on CT amp MR follow physiology follow physiology Stroke trialsStroke trials PWI-DWI mismatch PWI-DWI mismatch
ndash ndashTreat based on physiology not timeTreat based on physiology not time ProtocolsProtocols should be fast and should be fast and
comprehensivecomprehensive
PHARMACOLOGICAL PHARMACOLOGICAL AGENTSAGENTS
Pharmacologic AgentsPharmacologic Agents
AnticoagulantsAnticoagulants
Fibrinolytics (Agents for pharmacological Fibrinolytics (Agents for pharmacological recanalization)recanalization)
Anti platelet drugsAnti platelet drugs
Thrombin inhibitorThrombin inhibitor
ANTICOAGULANTSANTICOAGULANTS
Heparin and Low Molecular Weight Heparins Heparin and Low Molecular Weight Heparins ((eg enoxaparin dalteparin)eg enoxaparin dalteparin)
Oral anticoagulantsOral anticoagulants Coumarin Derivatves Coumarin Derivatves eg Warfarin eg Warfarin
AcenocoumarolAcenocoumarol Indandione Derivatves Indandione Derivatves eg Phenindione eg Phenindione
AnisindioneAnisindione
ThrombolyticsThrombolytics
Plasminogen activators
Fibrinolytics
Anti Platelet DrugsAnti Platelet DrugsDrug Mechanism UsesDrug Mechanism UsesAspirinAspirin Permanently inhibits Permanently inhibits
COX-1 and COX-2COX-1 and COX-2CADCAD
Stroke-TIAsStroke-TIAs
NSAIDsNSAIDs Reversibly inhibits Reversibly inhibits COX-1COX-1
LimitedLimited
DipyridamoleDipyridamole Inhibits PDE Inhibits PDE increases cAMPincreases cAMP
TIAsTIAs
ThenopyridinesThenopyridines
(Ticlopidine(Ticlopidine
Clopidegrel)Clopidegrel)
Inhibits ADP Inhibits ADP
PlatAg PlatAg
TIAsStrokeTIAsStroke
CAD PVDCAD PVD
Abciximab (ReoPro)Abciximab (ReoPro)
Eptifibatide Eptifibatide (Integrilin)(Integrilin)
TirofibaTirofibann
GP IIBIIIA InhibitorsGP IIBIIIA Inhibitors
Stroke- TIAs Stroke- TIAs
Maintainance of patency Maintainance of patency of vascular of vascular grafts catheters shunts bypassesgrafts catheters shunts bypasses
Arterial thromboembolic diseaseArterial thromboembolic diseasebull Transient ischemic attacksTransient ischemic attacksbull Stroke in evolutionStroke in evolution
Ischemic events occurs in Ischemic events occurs in 1313 of of conventional neuroangiographic conventional neuroangiographic procedures without Endovascular surgeryprocedures without Endovascular surgery
Indications for Antithrombotic Therapy in Indications for Antithrombotic Therapy in Diagnostics and Interventional ProceduresDiagnostics and Interventional Procedures
WHY TO MONITOR ANTICOAGULANT THERAPYWHY TO MONITOR ANTICOAGULANT THERAPY
Narrow therapeutic rangeNarrow therapeutic range
Can increase risk of bleedingCan increase risk of bleeding
Coagulation TestingCoagulation Testing
Monitoring therapyMonitoring therapy
Intrinsic Pathway
Extrinsic Pathway
Common Pathway
CLOT
Heparin Coumadin
Monitor with
ACT aPTT
Monitor with PTINR
Thrombolytics
Monitor with TT Fibrinogen
Monitoring of Monitoring of Anti platelet drugsAnti platelet drugs
Bleeding timeBleeding time
Optical aggregometryOptical aggregometry
Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay
HeparinHeparin
Heterogeneous 3000-30000 dalton in Heterogeneous 3000-30000 dalton in molecular weight molecular weight
Average=15000 d (~45monosaccharide Average=15000 d (~45monosaccharide chains)chains)
About About 13 of dose binds to AT III and forms 13 of dose binds to AT III and forms the AT IIIHeparinClotting Factor Complexthe AT IIIHeparinClotting Factor Complex
Complex binds to clotting factors of the Complex binds to clotting factors of the intrinsic and common pathway (Xa IIa IXa intrinsic and common pathway (Xa IIa IXa XIa XIIa XIIIa) and inactivates themXIa XIIa XIIIa) and inactivates them
Anticoagulant of choice in pregnancy (not Anticoagulant of choice in pregnancy (not crosses placenta)crosses placenta)
Heparin and Low molecular weight heparinsHeparin and Low molecular weight heparins
Structure and sequence
O
OH
OH
O
COO
O
O
CH2OH
NHSO3
OH
_
_
O
O
CH2OSO3
NHSO3
OH
_
_
O
OH
OH
O
COOO
O
CH2OSO3
NHSO3
OH
_
_
O
OSO3
OHO
COOO
O
CH2OSO3
NHCOCH3
OH
_
_ _
_
_
O
OH
OH
O
COO
1
23
4
5
6
-D-glucosamine -L-iduronic acid -D-glucuronic acid
O
O
CH2OH
NH2
OH 12
3
4
5
6
O
OH
OHO
COO_
1
23
4
5
6
polymeric structure of heparin
Anticoagulant Properties of Anticoagulant Properties of HeparinHeparin
11 Inhibits the thrombin-mediated conversion of Inhibits the thrombin-mediated conversion of fibrinogen to fibrinfibrinogen to fibrin
22 Inhibits the aggregation of platelets by thrombin Inhibits the aggregation of platelets by thrombin (prolongs bleeding time)(prolongs bleeding time)
33 Inhibits activation of fibrin stabilizing enzymeInhibits activation of fibrin stabilizing enzyme
44 Inhibits activated factors XII XI IX X and IIInhibits activated factors XII XI IX X and II All available forms of heparin must be All available forms of heparin must be
administered administered parenterally since they are parenterally since they are highly charged and rapidlyhighly charged and rapidly hydrolyzed in the hydrolyzed in the GI tractGI tract
Heparin antagonist Protamine sulfate (Heparin antagonist Protamine sulfate (10mg for 10mg for 1000 unit of heparin)1000 unit of heparin)
Monitoring of heparin Monitoring of heparin
Subcutenous Subcutenous no monitoring requiredno monitoring required Intravenous Intravenous
Partial thromboplastin time (PTT normal value Partial thromboplastin time (PTT normal value ~30sec) ~30sec)
Activated clotting time ( ACT normal value ~90-Activated clotting time ( ACT normal value ~90-120sec)120sec)
Daily or more frequent if PTT ACT variesDaily or more frequent if PTT ACT varies
Mechanism Mechanism ndash measures intrinsic pathwayndash measures intrinsic pathway Therapeutic goal Therapeutic goal 2-25 times normal control value 2-25 times normal control value
ACT or aPTTACT or aPTT
Determine when to pull the femoral sheath Determine when to pull the femoral sheath Premature sheath pull can lead to bleedingPremature sheath pull can lead to bleeding Delayed removal can increase time in ICUDelayed removal can increase time in ICU Target set Target set at each siteat each site
ACT targets range from 150 ndash 220 ACT targets range from 150 ndash 220 secondsseconds
aPTT targets range from 40 ndash 70 seconds aPTT targets range from 40 ndash 70 seconds
During neuroangiography-During neuroangiography- Recommended therapeutic range of heparin in Recommended therapeutic range of heparin in
plasma is 02-08 uml ( corresponding to aPTT plasma is 02-08 uml ( corresponding to aPTT ACT values 15-25 times the baseline values)ACT values 15-25 times the baseline values)
Dose In diagnostic angiography bolus dose of Dose In diagnostic angiography bolus dose of 2500 iu is used followed by 1000 iu hour2500 iu is used followed by 1000 iu hour
Bolus dose is Bolus dose is 60 ukg to maintain the therapeutic 60 ukg to maintain the therapeutic range range If procedure continues for more than 75 If procedure continues for more than 75 minutes additional dose is required ( half of the minutes additional dose is required ( half of the initial dose for another 75 minutes) initial dose for another 75 minutes)
(AJNR 199415 51-54)
Mechanisms of HIT( Mechanisms of HIT( Heparin Heparin induced Thrombocytopeniainduced Thrombocytopenia))
Type 1Type 1 Fall in platelet count occurs within the first two Fall in platelet count occurs within the first two
days after heparin initiation often returns to days after heparin initiation often returns to normal with continued heparin administration normal with continued heparin administration and is of no clinical consequence and is of no clinical consequence
The mechanism of the thrombocytopenia is non-The mechanism of the thrombocytopenia is non-immune and appears to be due to a direct effect of immune and appears to be due to a direct effect of heparin on platelet activationheparin on platelet activation
Type 2Type 2 Approximately 03 to 3 percent of patients Approximately 03 to 3 percent of patients
receiving heparin develop an immune receiving heparin develop an immune thrombocytopenia mediated by antibodies to a thrombocytopenia mediated by antibodies to a heparin-platelet factor 4 complex heparin-platelet factor 4 complex
(AJNR 28155-158 2007)
Treatment of heparin-induced Treatment of heparin-induced thrombocytopeniathrombocytopenia
When HIT is diagnosed it is important to When HIT is diagnosed it is important to stop heparin mainly in type 2 and to avoid stop heparin mainly in type 2 and to avoid the use of LMWH the use of LMWH
Because of the increased risk of thrombosis Because of the increased risk of thrombosis however continuation of an anticoagulant however continuation of an anticoagulant must be considered must be considered
The drugs currently approved for the The drugs currently approved for the treatment of HIT in the United States are treatment of HIT in the United States are direct thrombin inhibitors argatroban and direct thrombin inhibitors argatroban and lepirudinlepirudin
WARFARIN MECHANISM OF ACTIONWARFARIN MECHANISM OF ACTION
Inactive factors II VII IX and X
Proteins S and C
Active factors II VII IX and X
Proteins S and C
Vitamin K epoxide
Vitamin K reduced
WA
RF
AR
IN
Prevents the reduction of vitamin K which is essential for Prevents the reduction of vitamin K which is essential for activation of certain factorsactivation of certain factors
Has no effect on previously formed thrombusHas no effect on previously formed thrombus
Antagonist is Vit KAntagonist is Vit K
OPTIMIZING WARFARIN THERAPYOPTIMIZING WARFARIN THERAPY
Use of large loading dose may lead to hemorrhage and Use of large loading dose may lead to hemorrhage and other complicationsother complications
Initial dose 2-5 mg once dailyInitial dose 2-5 mg once daily Maintenance dose 2-10 mg once dailyMaintenance dose 2-10 mg once daily If Immediate anticoagulation is requiredIf Immediate anticoagulation is required Heparin IS Heparin IS
started along with loading dose of warfarin 10 mg started along with loading dose of warfarin 10 mg Heparin is usually discontinued after 4-5 days Heparin is usually discontinued after 4-5 days Before Before discontinuing INR should be in therapeutic range for 2 discontinuing INR should be in therapeutic range for 2 consecutive daysconsecutive days
Daily monitoring of INR until INR is in therapeutic Daily monitoring of INR until INR is in therapeutic range then 3 times weekly for 1-2 weeks then less often range then 3 times weekly for 1-2 weeks then less often (every 4 to 6 weeks)(every 4 to 6 weeks)
OPTIMAL THERAPEUTIC RANGEOPTIMAL THERAPEUTIC RANGE
IndicationIndication INRINR
Prophylaxis of venous Prophylaxis of venous thromboembolismthromboembolism
20-3020-30
Treatment of venous Treatment of venous thromboembolismthromboembolism
20-3020-30
Atrial fibrillationAtrial fibrillation 20-3020-30
Mitral valve stenosisMitral valve stenosis 20-3020-30
Heart valve replacementHeart valve replacement
Bioprosthetic valveBioprosthetic valve
Mechanical valveMechanical valve
20-3020-30
25-3525-35
Myocardial infarctionMyocardial infarction 20-3020-30
25-35 25-35 (high risk patients)(high risk patients)
FACTORS INFLUENCING DOSE RESPONSEFACTORS INFLUENCING DOSE RESPONSE
Poor patient compliancePoor patient compliance Concomitant medicationsConcomitant medications Levels of dietary vitamin KLevels of dietary vitamin K Alcohol Inaccurate lab testingAlcohol Inaccurate lab testing Inaccurate lab testingInaccurate lab testing Hepatic dysfunctionHepatic dysfunction FeverFever
Contraindication for WarfarinContraindication for Warfarin
Hypersensitivity to warfarinHypersensitivity to warfarin Hemorrhagic tendencyHemorrhagic tendency Condition with risk of hemorrhageCondition with risk of hemorrhage Inadequate laboratory techniquesInadequate laboratory techniques Protein C amp S deficiencyProtein C amp S deficiency Vitamin K deficiencyVitamin K deficiency
SIDE EFFECTSSIDE EFFECTS
Hemorrhage Hemorrhage Skin necrosisSkin necrosis Purple toe syndromePurple toe syndrome Microembolization Microembolization TeratogenecityTeratogenecity Agranulocytosis leukopenia Agranulocytosis leukopenia Diarrhoeanausea anorexiaDiarrhoeanausea anorexia
MONITORING OF WARFARIN THERAPYMONITORING OF WARFARIN THERAPY
Prothrombin timeProthrombin time PT ratioPT ratio INR (International Normalized Ratio)INR (International Normalized Ratio)
PROTHROMBIN TIME (PT)PROTHROMBIN TIME (PT)
Time required for blood to coagulate Time required for blood to coagulate is called PT ( normal value ~10sec)is called PT ( normal value ~10sec)
Performed by adding a mixture of Performed by adding a mixture of calcium and thromboplastin to calcium and thromboplastin to citrated plasmacitrated plasma
As a control a normal blood sample is As a control a normal blood sample is tested continuouslytested continuously
PT ratio (PTR) = PT ratio (PTR) = Patientrsquos PTPatientrsquos PT Control PTControl PT
PROBLEMS WITH PTPTRPROBLEMS WITH PTPTR
Thromboplastins are extracts from Thromboplastins are extracts from brain lung or placenta of animalsbrain lung or placenta of animals
Thromboplastins from various Thromboplastins from various manufacturers differ in their manufacturers differ in their sensitivity to prolong PTsensitivity to prolong PT
May result in false control of May result in false control of anticoagulant therapyanticoagulant therapy
INTERNATIONAL NORMALISED RATIO (INR)INTERNATIONAL NORMALISED RATIO (INR)
International Normalized Ratio (INR) International Normalized Ratio (INR) a PT test with a a PT test with a formula based ratio to normalize the often variable source formula based ratio to normalize the often variable source of tissue factor (human rabbit recombinant)of tissue factor (human rabbit recombinant)
INR = [PTINR = [PTptpt] ] ISIISI
[PT[PTRefRef]]
PTPTpt pt ndash prothrombin time of patientndash prothrombin time of patient
PTPTRef Ref ndash prothrombin time of normal pooled samplendash prothrombin time of normal pooled sample
ISI ndash International Sensitivity IndexISI ndash International Sensitivity Index
Warfarin is given orally and titrated to achieve an INR of Warfarin is given orally and titrated to achieve an INR of typically 20 ndash 30typically 20 ndash 30
Heparin versus WarfarinHeparin versus Warfarin
Drug ActionMechan-ism
Moni-toring
Effective
HeparinDirect
Inhibition ofThrombin
ATIIIcofactor
APTTACT
Immediate
WarfarinDecreasesProductionof factors
Vitamin K PTDelay
3-5 days
INR
Recanalization or Antegrade Recanalization or Antegrade Reperfusion StrategiesReperfusion Strategies
Recanalization strategies focus on removing Recanalization strategies focus on removing andor dissolving the occlusive thrombus to re-andor dissolving the occlusive thrombus to re-establish antegrade flow Strategies may be establish antegrade flow Strategies may be classified into 7 different categories on the classified into 7 different categories on the basis of their primary mechanism of action basis of their primary mechanism of action 1) 1) IV andor intraarterial thrombolysis (IAT) IV andor intraarterial thrombolysis (IAT) 2) endovascular thrombectomy2) endovascular thrombectomy3) endovascular thromboaspiration 3) endovascular thromboaspiration 4) endovascular mechanical thrombus disruption or 4) endovascular mechanical thrombus disruption or
thromborrhexisthromborrhexis5) 5) transcranial or endovascular augmented transcranial or endovascular augmented
fibrinolysis fibrinolysis 6) endovascular thrombus entrapment and 6) endovascular thrombus entrapment and 7) temporary endovascular bypass7) temporary endovascular bypass
IAT in Acute Ischemic StrokeIAT in Acute Ischemic Stroke
IAT advantages over IV thrombolysisIAT advantages over IV thrombolysis Coaxial microcatheter techniques the occluded intracranial Coaxial microcatheter techniques the occluded intracranial
vessel is directly accessible and the fibrinolytic agent can be vessel is directly accessible and the fibrinolytic agent can be infused directly into the thrombusinfused directly into the thrombus
This permits a smaller dose of fibrinolytic agent to reach a This permits a smaller dose of fibrinolytic agent to reach a higher local concentration than that reached by systemic higher local concentration than that reached by systemic infusioninfusion
Allows more complete recanalization with lower total doses of Allows more complete recanalization with lower total doses of thrombolytic thrombolytic
With the smaller dose complications from systemic fibrinolytic With the smaller dose complications from systemic fibrinolytic effects including intracranial hemorrhage (ICH) can effects including intracranial hemorrhage (ICH) can theoretically be reduced theoretically be reduced
Treatment window for endovascular techniques can be Treatment window for endovascular techniques can be extended beyond the typical IV window of 3 hours extended beyond the typical IV window of 3 hours
IA techniques have led to higher recanalization rates than IV IA techniques have led to higher recanalization rates than IV thrombolysisthrombolysis
Major disadvantagesMajor disadvantages Relative complexity of the procedure the level Relative complexity of the procedure the level
of required technical expertise and its of required technical expertise and its relatively low availability relatively low availability
Delays in initiating treatmentDelays in initiating treatment InvasiveInvasive
ThrombolyticsThrombolytics
Plasminogen activators
Fibrinolytics
1 Plasminogen Activators 1 Plasminogen Activators drugs act by converting the inactive proenzyme drugs act by converting the inactive proenzyme plasminogen into the active enzyme plasmin Plasmin plasminogen into the active enzyme plasmin Plasmin digests fibrinogen fibrin monomers and cross-linked digests fibrinogen fibrin monomers and cross-linked fibrin (as found in a thrombus) into fibrin degradation fibrin (as found in a thrombus) into fibrin degradation productsproducts
First-Generation Agents First-Generation Agents StreptokinaseStreptokinase a protein derived from group C a protein derived from group C
szlig-hemolytic streptococci has a half-life of 16ndashszlig-hemolytic streptococci has a half-life of 16ndash90 minutes and low fibrin specificity This drug 90 minutes and low fibrin specificity This drug proved to have a very narrow therapeutic proved to have a very narrow therapeutic window and significant rates of ICH and window and significant rates of ICH and systemic hemorrhage18systemic hemorrhage18
UrokinaseUrokinase is a serine protease with a plasma is a serine protease with a plasma half life of 14 minutes and low fibrin specificity half life of 14 minutes and low fibrin specificity
The urokinase dose used in cerebral IAT has The urokinase dose used in cerebral IAT has ranged from 002 to 2 X106unitsranged from 002 to 2 X106units
Second-Generation Agents Second-Generation Agents Alteplase (rtPA) Alteplase (rtPA)
is a serine is a serine protease with a plasma half-life of 35 protease with a plasma half-life of 35 minutes and a high degree of fibrin affinity and minutes and a high degree of fibrin affinity and specificity specificity
Dose used in cerebral IAT has ranged between 20 Dose used in cerebral IAT has ranged between 20 and 60 mgand 60 mg
Disadvantages of alteplase include its relatively short Disadvantages of alteplase include its relatively short halflife and limited penetration into the clot matrix halflife and limited penetration into the clot matrix because of strong binding with surface fibrin which because of strong binding with surface fibrin which could delay recanalization and increase the risk of could delay recanalization and increase the risk of recurrent occlusion recurrent occlusion
Prourokinase (r-prourokinase) Prourokinase (r-prourokinase) is the proenzyme precursor of urokinase is the proenzyme precursor of urokinase T12 of 7 minutes and high fibrin specificity T12 of 7 minutes and high fibrin specificity
Third-Generation AgentsThird-Generation Agents
ReteplaseReteplase is a structurally modified is a structurally modified form of alteplase form of alteplase
with a longer half-life (15ndash18 minutes) In with a longer half-life (15ndash18 minutes) In addition it does not bind as highly to fibrin addition it does not bind as highly to fibrin unbound reteplase can thus theoretically better unbound reteplase can thus theoretically better penetrate the clot and potentially penetrate the clot and potentially improve in improve in vivo fibrinolytic activity vivo fibrinolytic activity
TenecteplaseTenecteplase is another modified form of rtPA with a longer is another modified form of rtPA with a longer
half-life (17 minutes)half-life (17 minutes) greater fibrin specificity and greater greater fibrin specificity and greater
resistance to plasminogen activator inhibitor-1 resistance to plasminogen activator inhibitor-1 IV tenecteplase in acute ischemic stroke IV tenecteplase in acute ischemic stroke
suggest that the drug is safe and promisingsuggest that the drug is safe and promising
Newer plasminogen activatorNewer plasminogen activator
DesmoteplaseDesmoteplase is a genetically engineered is a genetically engineered version of the clot-dissolving factor version of the clot-dissolving factor
found in the saliva found in the saliva of the vampire bat Desmodus rotundusof the vampire bat Desmodus rotundus moremore potent and more selective for fibrin-bound potent and more selective for fibrin-bound
plasminogen than any other known plasminogen plasminogen than any other known plasminogen activatoractivator
Unlike tissue plasminogen activator (tPA) desmoteplase Unlike tissue plasminogen activator (tPA) desmoteplase is not activated by fibrinogen or -amyloid proteins is not activated by fibrinogen or -amyloid proteins factors that may exacerbate the risk for ICH factors that may exacerbate the risk for ICH
The effect of IV administration of desmoteplase 3ndash9 The effect of IV administration of desmoteplase 3ndash9 hours after symptom onset in patients with stroke who hours after symptom onset in patients with stroke who present with mismatch on MR imaging or CT perfusion present with mismatch on MR imaging or CT perfusion
3 DefibrinogenatingFibrinogenolytic 3 DefibrinogenatingFibrinogenolytic Agents Agents
AncrodAncrod(Viprinex)(Viprinex) is is the purified fraction of the Malayan pit viper venomthe purified fraction of the Malayan pit viper venom It acts by directly cleaving and inactivating fibrinogen It acts by directly cleaving and inactivating fibrinogen
and thus indirectly promoting anticoagulation and thus indirectly promoting anticoagulation The reduction in the blood levels of fibrinogen also The reduction in the blood levels of fibrinogen also
leads to a reduced blood viscosity which may improve leads to a reduced blood viscosity which may improve blood flow to the affected areas of the brain blood flow to the affected areas of the brain
In the Stroke Treatment with Ancrod Trial 500 In the Stroke Treatment with Ancrod Trial 500 patients with stroke presenting within 3 hours of patients with stroke presenting within 3 hours of symptom onset were randomized to receive ancrod (symptom onset were randomized to receive ancrod (n n 248) or a placebo (n 252) Good outcome (Barthel 248) or a placebo (n 252) Good outcome (Barthel Index 95ndash100 at 3 months) was achieved in 4221 Index 95ndash100 at 3 months) was achieved in 4221 and 344 of the patients respectively and 344 of the patients respectively
2 Direct Fibrinolytics2 Direct Fibrinolytics
Microplasmin (Microplasmin (ThromboGenics Heverlee Belgium)ThromboGenics Heverlee Belgium) is a truncated form of plasmin that is more resistant to the effects is a truncated form of plasmin that is more resistant to the effects
of antiplasmin of antiplasmin microplasmin can be used upto 4ndash12 hours after stroke onset microplasmin can be used upto 4ndash12 hours after stroke onset There was no evidence of increased bleeding risk with There was no evidence of increased bleeding risk with
microplasminmicroplasmin
Alfimeprase (Nuvelo San Carlos Calif)Alfimeprase (Nuvelo San Carlos Calif) is a recombinant truncated form of fibrolase a fibrinolytic zinc metalloproteinase is a recombinant truncated form of fibrolase a fibrinolytic zinc metalloproteinase
isolated from the venom of the southern copperhead snake isolated from the venom of the southern copperhead snake It degrades fibrin directly and achieves thrombolysis independent It degrades fibrin directly and achieves thrombolysis independent
of plasmin formationof plasmin formation its thrombolytic activity appears to be localized to the site of its thrombolytic activity appears to be localized to the site of
delivery These properties should theoretically result in faster delivery These properties should theoretically result in faster recanalization and lower hemorrhagic conversion riskrecanalization and lower hemorrhagic conversion risk
Anti-fibrinolyticsAnti-fibrinolytics
to limit fibrinolytic activityto limit fibrinolytic activity -aminocaproic acid (EACA) -aminocaproic acid (EACA) competitively inhibitscompetitively inhibits plasminogen and plasminogen activators from plasminogen and plasminogen activators from
binding to fibrinbinding to fibrin
alpha2-antiplasminalpha2-antiplasmin a serine protease inhibitor that a serine protease inhibitor that neutralizes any free circulating plasminneutralizes any free circulating plasmin
Plasminogen activator inhibitor-1Plasminogen activator inhibitor-1 a serine protease a serine protease inhibitor that inhibits tissue-type plasminogen inhibitor that inhibits tissue-type plasminogen activatoractivator
Glycoprotein (GP) IIbIIIa antagonistsGlycoprotein (GP) IIbIIIa antagonists
such as ReoPro (abciximab) Integrilin such as ReoPro (abciximab) Integrilin (eptifibatide) or Aggrastat (tirofiban) in (eptifibatide) or Aggrastat (tirofiban) in ischemic stroke remains investigational ischemic stroke remains investigational Deshmukh et al38 reported 21 patients with Deshmukh et al38 reported 21 patients with large-vessel occlusion refractory to IAT with large-vessel occlusion refractory to IAT with rtPA who were treated with IV andor IA rtPA who were treated with IV andor IA abciximab eptifibatide or tirofiban abciximab eptifibatide or tirofiban
IA Mechanical Approaches in Acute Ischemic Stroke IA Mechanical Approaches in Acute Ischemic Stroke Mechanical strategies have several advantagesMechanical strategies have several advantages First they lessen and may even preclude the use of chemical First they lessen and may even preclude the use of chemical
thrombolytics in this manner very likely reducing the risk of ICHthrombolytics in this manner very likely reducing the risk of ICH Second by avoiding the use of chemical thrombolytics it is Second by avoiding the use of chemical thrombolytics it is
possible to extend the treatment window beyond the limit of 6ndash8 possible to extend the treatment window beyond the limit of 6ndash8 hours hours
Third mechanically fragmenting a clot increases the surface area Third mechanically fragmenting a clot increases the surface area accessible to fibrinolytic agents and allows inflow of fresh accessible to fibrinolytic agents and allows inflow of fresh plasminogen which in turn may increase the speed of plasminogen which in turn may increase the speed of thrombolysis thrombolysis
Finally clot-retrieval devices may provide faster recanalization Finally clot-retrieval devices may provide faster recanalization
The disadvantages of the mechanical The disadvantages of the mechanical approaches approaches technical difficulty of navigating mechanical technical difficulty of navigating mechanical
devices into the intracranial circulation excessive devices into the intracranial circulation excessive trauma to the vasculature (potentially leading to trauma to the vasculature (potentially leading to vasospasm vessel dissection perforation or vasospasm vessel dissection perforation or rupture) rupture)
fragmented thrombus causing distal embolization fragmented thrombus causing distal embolization into previously unaffected territories into previously unaffected territories
Nevertheless the advantages of mechanical stroke Nevertheless the advantages of mechanical stroke therapy appear to significantly outweigh its therapy appear to significantly outweigh its disadvantages and risksdisadvantages and risks
Contraindications to Thrombolytic Contraindications to Thrombolytic agents agents
Recent thoracic abdominal or Recent thoracic abdominal or intracranial surgeryintracranial surgery
Recent haemorrhagic CVA Head injury Recent haemorrhagic CVA Head injury or neoplasmor neoplasm
Bleeding ulcerBleeding ulcer Anticipated invasive procedures (arterial Anticipated invasive procedures (arterial
punctures biopsies)punctures biopsies) Concurrent hemostatic dysfunctionConcurrent hemostatic dysfunction
Monitoring of thrombolytic Monitoring of thrombolytic therapytherapy
Thrombin time Measures the availability of functional
fibrinogen Normal thrombin time is 10-14 sec Prolonged when fibrinogen level is below
75-100 mgdl
Half Life of ThrombolyticsHalf Life of ThrombolyticsAgent Administration Half Life
Streptokinase IA 60-80min
Urokinase IAIV 9-12min
rTPA IAIV 6min
Abciximab(Reopro) IAIV 12hour
Aspirin POIV 15-20min
Heparin IVSC 60min
Coumadin PO 15-25 days
Anti Platelet DrugsAnti Platelet DrugsDrug Drug Mechanism Mechanism UsesUsesAspirinAspirin Permanently inhibits Permanently inhibits
COX-1 and COX-2COX-1 and COX-2CADCAD
Stroke-TIAsStroke-TIAs
NSAIDsNSAIDs Reversibly inhibits Reversibly inhibits COX-1COX-1
LimitedLimited
DipyridamoleDipyridamole Inhibits PDE increases Inhibits PDE increases cAMPcAMP
TIAsTIAs
ThenopyridinesThenopyridines
(Ticlopidine(Ticlopidine
ClopidrgrelClopidrgrel))
Inhibits ADP Inhibits ADP
PlatAg PlatAg
TIAsStrokeTIAsStroke
CAD PVDCAD PVD
Abciximab (ReoPro)Abciximab (ReoPro)
Eptifibatide (Integrilin)Eptifibatide (Integrilin)
TirofibanTirofiban
GP IIBIIIA InhibitorsGP IIBIIIA Inhibitors
Stroke- TIAs Stroke- TIAs
MonitoringMonitoring
Bleeding timeBleeding time
Optical aggregometryOptical aggregometry
Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay
Bleeding timeBleeding time
Requires a skin incision (usually made on the ear lobe or Requires a skin incision (usually made on the ear lobe or forearm offorearm of
a depth that results in disruption of capillary loops and a depth that results in disruption of capillary loops and small vessels)small vessels)
AdvantagesAdvantages Universally availableUniversally available Relatively simple techniquesRelatively simple techniques Can be performed bedsideCan be performed bedside
DisadvantagesDisadvantages Insensitive inaccurate non-specific techniqueInsensitive inaccurate non-specific technique
Poorly reproducible (as depends on multiple variables)Poorly reproducible (as depends on multiple variables)
Optical aggregometryOptical aggregometry
Gold standard assay for platelet functionGold standard assay for platelet function Agonist induced aggregation is measuredAgonist induced aggregation is measured Different agonist are available for different Different agonist are available for different
agentsagents However require unique expertise and are not However require unique expertise and are not
universally availableuniversally available Aspirin measured with ADP or AA(gt70 Aspirin measured with ADP or AA(gt70
aggregation so resistance)aggregation so resistance) Clopidogrel( ADP gt 90 aggregation means Clopidogrel( ADP gt 90 aggregation means
resistance) resistance)
Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay
Can be performed bed sideCan be performed bed side Different assay devices with different Different assay devices with different
agonist are used for each of different agonist are used for each of different antiplatelet agents antiplatelet agents
For Aspirin AA is used (result is reported as aspirin For Aspirin AA is used (result is reported as aspirin reaction units [ARU] ARUgt 550 indicates non-reaction units [ARU] ARUgt 550 indicates non-responsiveness)responsiveness)
Verify IIbIIIa assay device uses TRAP as agonist for Verify IIbIIIa assay device uses TRAP as agonist for Abciximab and TirofibanAbciximab and Tirofiban
Practical Applications Practical Applications related to specific related to specific
Neurovascular Neurovascular interventionsinterventions
Acute ischemic StrokeAcute ischemic Stroke When an artery occludes neurons are affected When an artery occludes neurons are affected
differently depending upon the amount of residual blood differently depending upon the amount of residual blood flowflow
Normal cerebral blood flow is greater than 50 mL100 Normal cerebral blood flow is greater than 50 mL100 mgminmgmin
Once blood flow decreases to less than 20 mL100 Once blood flow decreases to less than 20 mL100 mgmin infarction occursmgmin infarction occurs
If blood flow decreases to less than 10 mL100 mgmin If blood flow decreases to less than 10 mL100 mgmin irreversible neuronal death occurs rapidly irreversible neuronal death occurs rapidly
Blood flow between 11 and 20 mL100 mgmin is thought Blood flow between 11 and 20 mL100 mgmin is thought to represent the ischemic penumbra an area where the to represent the ischemic penumbra an area where the cells are functionally silent because of ischemia but are cells are functionally silent because of ischemia but are still able to recover if blood flow is restored still able to recover if blood flow is restored
Many acute stroke therapies are targeted toward Many acute stroke therapies are targeted toward restoring flow or function to the ischemic penumbrarestoring flow or function to the ischemic penumbra
Therapeutic window in Therapeutic window in management of acute Ischemic management of acute Ischemic
StrokeStrokeThe early diagnosis of ischemic stroke is critical to the The early diagnosis of ischemic stroke is critical to the
with only a narrow therapeutic window in the first few with only a narrow therapeutic window in the first few hours following stroke ictushours following stroke ictus
Diagnosis in the first 3 hours postictus provides the Diagnosis in the first 3 hours postictus provides the opportunity for intravenous or intraarterial thrombolysis opportunity for intravenous or intraarterial thrombolysis and intra-arterial clot mechanical treatment which and intra-arterial clot mechanical treatment which improve the outcome improve the outcome
Diagnosis in the time period between 3 and 6 hours Diagnosis in the time period between 3 and 6 hours provides an opportunity for intra-arterial thrombolysis provides an opportunity for intra-arterial thrombolysis and mechanical treatment and mechanical treatment
Involvement of the posterior circulation especially the Involvement of the posterior circulation especially the basilar artery is treated by some regardless of time of basilar artery is treated by some regardless of time of onset or up until 12 to 24 hours in some practices This is onset or up until 12 to 24 hours in some practices This is related to the potentially high mortality and morbidity related to the potentially high mortality and morbidity associated with basilar artery thrombosisassociated with basilar artery thrombosis
Infarct evaluation on angiographyInfarct evaluation on angiography(CT angiography and catheter (CT angiography and catheter
angiography)angiography)CTA is an excellent first-line examination for CTA is an excellent first-line examination for
evaluation of the head and neck arteries evaluation of the head and neck arteries In comparison with catheter angiography In comparison with catheter angiography
what it gives up in resolution and dynamic what it gives up in resolution and dynamic properties it makes up for with rapid properties it makes up for with rapid acquisition of a 3-D dataset and the potential acquisition of a 3-D dataset and the potential for assessment of whole-brain perfusion and for assessment of whole-brain perfusion and better parenchymal evaluationbetter parenchymal evaluation
Moreover CTA illustrates not only arterial Moreover CTA illustrates not only arterial stenosis or occlusion but also the vessel wall stenosis or occlusion but also the vessel wall This factor is most important for evaluation of This factor is most important for evaluation of intramural dissection and thrombosed intramural dissection and thrombosed aneurysms which may both complicate aneurysms which may both complicate evaluation of stroke patientsevaluation of stroke patients
Early angiographic signs of strokes Early angiographic signs of strokes both CTA both CTA and DSA and DSA
Vessel occlusion or cutoff related to Vessel occlusion or cutoff related to thromboembolithromboemboli
aneurysms aneurysms arterial dissection arterial dissection Meniscus or flattened shape to clot Meniscus or flattened shape to clot
(recent) versus reverse meniscus (older)(recent) versus reverse meniscus (older) tram track (nonocclusive or recanalized tram track (nonocclusive or recanalized
clot) clot) delayed (antegrade) flow (manifest as delayed (antegrade) flow (manifest as
decreased whole-brain perfusion on CTA)decreased whole-brain perfusion on CTA) retrograde collateral flowretrograde collateral flow
Non-occlusive left MCA thrombus on 3-D imaging performed from CTA source data and was confirmed at catheter angiography
Therapy to be started within a 6-hr Therapy to be started within a 6-hr time to treatment (TTT) window time to treatment (TTT) window (while in case of IV thrombolysis (while in case of IV thrombolysis therapy to be started with in 3hrs)therapy to be started with in 3hrs)
Exclusion criteria Exclusion criteria Rapidly improving neurologic deficit or Rapidly improving neurologic deficit or Sustained blood pressure of gt180100 Sustained blood pressure of gt180100 Hemorrhage is detected on CTHemorrhage is detected on CT Infarct involving gt more than 13 rd Infarct involving gt more than 13 rd
territory of MCAterritory of MCA MRADWI-Perfusion mismatchlt 20MRADWI-Perfusion mismatchlt 20 Definite hypodensity on CTDefinite hypodensity on CT
Intra-arterial Thrombolysis
Fibrinolytics + AntiplateletsFibrinolytics + Antiplatelets
PlasminogenPlasminogen activators through fibrinolysis exposes activators through fibrinolysis exposes free thrombin and paradoxically stimulatesfree thrombin and paradoxically stimulates platelet platelet aggregation which leads to formation of aaggregation which leads to formation of a platelet platelet thrombus (white clot) thrombus (white clot)
This new thrombus is relatively resistant to This new thrombus is relatively resistant to fibrinolyticsfibrinolytics
So new regimen in case of acute stroke isSo new regimen in case of acute stroke is fibrinolytics + antiplatelet drugsfibrinolytics + antiplatelet drugs
rtPA + IIbIIIa inhibitors( tirofiban rtPA + IIbIIIa inhibitors( tirofiban abciximab) orabciximab) or
Urokinase + IIbIIIa Urokinase + IIbIIIa inhibitors( tirofiban abciximab)inhibitors( tirofiban abciximab)
Intra-arterial Thrombolysis Tirofiban (04 microgkgmin bolus for 3 min followed by Tirofiban (04 microgkgmin bolus for 3 min followed by
0125 ugkgmin)0125 ugkgmin)
++
Heparin (2000ndash3000 IU bolus followed by Heparin (2000ndash3000 IU bolus followed by 1000 IUhour infusion 1000 IUhour infusion
with ACT maintained bw 200-300) throughout the with ACT maintained bw 200-300) throughout the interventional procedure and for 24ndash48 hours thereafter when interventional procedure and for 24ndash48 hours thereafter when there is neither intraprocedural bleeding nor suspicion of there is neither intraprocedural bleeding nor suspicion of increased risk of bleeding increased risk of bleeding
Maximum dose of Urokinase Maximum dose of Urokinase Anterior circulation stroke - 500000 IU (mean 400000 Anterior circulation stroke - 500000 IU (mean 400000
IU range 300000ndash500000 IU)IU range 300000ndash500000 IU) Posterior circulation stroke -1000000 IU (mean 837000 Posterior circulation stroke -1000000 IU (mean 837000
IU range 300000ndash1000000 IU)IU range 300000ndash1000000 IU)American Journal of NeuroradiologyAmerican Journal of Neuroradiology 262595-2601 2005262595-2601 2005
Intravenous ThrombolysisIntravenous Thrombolysis
The first method to restore cerebral The first method to restore cerebral perfusion is clot lysis with the goal perfusion is clot lysis with the goal of re-establishing blood flow to the of re-establishing blood flow to the affected tissue affected tissue
IV thrombolysis rt-PA is the only IV thrombolysis rt-PA is the only FDA- approved treatment for AIS FDA- approved treatment for AIS
Fibrinolysis is enhanced powerfully Fibrinolysis is enhanced powerfully by rt-PAby rt-PA
Intravenous rTPA Intravenous rTPA administration administration protocolprotocol
Total dose of rt-PA 09 mgkg (maximum dose Total dose of rt-PA 09 mgkg (maximum dose 90 mg)90 mg)
Give 10 as initial IV bolusGive 10 as initial IV bolus Infuse remainder over 1 hourInfuse remainder over 1 hour Admit patient to an ICU or stroke unit for Admit patient to an ICU or stroke unit for
monitoringmonitoring Neurologic assessments every 15 minutes Neurologic assessments every 15 minutes
during infusion then every 30 minutes for next during infusion then every 30 minutes for next 6 hours then every hour until 24hours after 6 hours then every hour until 24hours after treatmenttreatment
Favorable Outcome vs Treatment Time Favorable Outcome vs Treatment Time with IV rTPAwith IV rTPA
Protocol limit = 3 hrs
Benefit ~ 45 hrs
Thromboembolism During coilingThromboembolism During coiling Most feared and frequent complication Most feared and frequent complication Reported incidence - Approx 7 Reported incidence - Approx 7 SourcesSources of Thromboembolism are of Thromboembolism are
- Clots at the aneurysmal neck during or immediately- Clots at the aneurysmal neck during or immediately after after embolization embolization
- Thrombus forming on catheters during- Thrombus forming on catheters during proceduresprocedures
- Stenosis of an adjacent artery dt coil mass- Stenosis of an adjacent artery dt coil mass or herniationor herniation
- Migration of intraaneurysmal- Migration of intraaneurysmal thrombus during coil thrombus during coil placement placement
- Slow flow dt vasospasm - Slow flow dt vasospasm
- Rare and unlikely causes are hypercoagulable- Rare and unlikely causes are hypercoagulable state such state such as antiphospholipid antibody syndrome or due to HITas antiphospholipid antibody syndrome or due to HIT
Occur more often with wide-necked aneurysms (dt Occur more often with wide-necked aneurysms (dt increased exposed surface area of thrombogenic coil increased exposed surface area of thrombogenic coil material)material)
Current regimen of endovascular Current regimen of endovascular managementmanagement
The The glycoprotein IIbIIIa antagonist tirofiban glycoprotein IIbIIIa antagonist tirofiban (04 (04 microgkgmin bolus for 30 minutes followed by infusion of microgkgmin bolus for 30 minutes followed by infusion of 0125 ugkgmin until the thrombus dissolved) 0125 ugkgmin until the thrombus dissolved)
Intraarterial thrombolysis with Intraarterial thrombolysis with urokinase or r- TPA urokinase or r- TPA increase of intravenous (IV) heparin (measured by increase of intravenous (IV) heparin (measured by
ACT) ACT) Intravenous aspirin Intravenous aspirin
Coil-related platelet aggregation (white clot) is Coil-related platelet aggregation (white clot) is unlikely to respond to fibrinolytics but has a high risk unlikely to respond to fibrinolytics but has a high risk of hemorrhage (In ISAT) all 5 patients who had of hemorrhage (In ISAT) all 5 patients who had received thrombolytic therapy with tPA to treat a received thrombolytic therapy with tPA to treat a thromboembolic complication after endovascular thromboembolic complication after endovascular treatment rebleed and all of these patients died)treatment rebleed and all of these patients died)
IntracranialIntracranial Stenting Stenting Metallic foreign body such as stent will accumulate Metallic foreign body such as stent will accumulate
thrombus in the absence of platelet inhibitionthrombus in the absence of platelet inhibition Antiplatelet drugs are important to prevent peri or Antiplatelet drugs are important to prevent peri or
post-interventional thromboembolic eventspost-interventional thromboembolic events Optimal treatment regimens has not been determined Optimal treatment regimens has not been determined
but usually but usually Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-
procedureprocedureOrOr
Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on
morning of proceduremorning of procedure
If need to use stent is not pre-planned thanIf need to use stent is not pre-planned than
Abciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkgAbciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkg IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)
Glycoprotein IIbIIIa inhibitor are not used routinely during elective Glycoprotein IIbIIIa inhibitor are not used routinely during elective stenting procedure dt increased risk of ICH stenting procedure dt increased risk of ICH
Carotid StentingCarotid Stenting
Pre-procedurePre-procedure
Double Antiplatelet therapy is routinely given Double Antiplatelet therapy is routinely given beginning at least 3beginning at least 3
days before the proceduredays before the procedure
Aspirin 325mgd+Clopidogrel 75mgdAspirin 325mgd+Clopidogrel 75mgd During procedureDuring procedure
Heparin is given with target clotting time of 250-Heparin is given with target clotting time of 250-300sec300sec
Post-procedure Post-procedure
Aspirin 325mg is continued indefinitely and Aspirin 325mg is continued indefinitely and
Clopidogrel 75mgd for at least 6 weeks Clopidogrel 75mgd for at least 6 weeks
Inclusion criteria for Local ThrombolysisInclusion criteria for Local Thrombolysis a)a) Patients in severe clinical grade on admission Patients in severe clinical grade on admission
with evidence of dural venous sinus with evidence of dural venous sinus thrombosis and restrictive venous outflow on thrombosis and restrictive venous outflow on cerebral angiogramcerebral angiogram
b)b) Patients in clinical grade 3 worsening on Patients in clinical grade 3 worsening on heparin therapy Restriction to venous heparin therapy Restriction to venous outflow was defined as an increase in brain outflow was defined as an increase in brain circulation time gt 12 s delay in the drainage circulation time gt 12 s delay in the drainage of cortical veins with cortical veins hanging of cortical veins with cortical veins hanging in spacein space
Treatment Options for Venous Thrombosis
CT Grading for Venous ThrombosisCT Grading for Venous Thrombosis Grade I no parenchymal change Grade I no parenchymal change
(hyperdense (hyperdense sinuses cortical veins empty sinuses cortical veins empty delta sign)delta sign)
Grade II non hemorrhagic venous infarct Grade II non hemorrhagic venous infarct without mass effect without mass effect
Grade III non-hemorrhagic infarct with Grade III non-hemorrhagic infarct with mass effectmass effect
Grade IV hemorrhagic venous infarct (max Grade IV hemorrhagic venous infarct (max diameter lt 3 cm) with no mass effectdiameter lt 3 cm) with no mass effect
Grade V hemorrhagic venous infarct (max Grade V hemorrhagic venous infarct (max diameter gt 3 cm) with mass effect diameter gt 3 cm) with mass effect
Local ThrombolysisLocal Thrombolysis
Femoral Jugular access was secured and a guiding Femoral Jugular access was secured and a guiding catheter was placed in the jugular bulb catheter was placed in the jugular bulb Mechanical Mechanical clot maceration clot maceration was done with the guidewire was done with the guidewire following which a microcatheter (was navigated and following which a microcatheter (was navigated and placed in the thrombosed segment of sinus confirmed placed in the thrombosed segment of sinus confirmed on a selective venogram on a selective venogram
Urokinase infusion Bolus dose of 2-6 lacs followed Urokinase infusion Bolus dose of 2-6 lacs followed by 60000 to 100000 units per hour along with by 60000 to 100000 units per hour along with periodic check venogram Along with maintenance periodic check venogram Along with maintenance systemic infusion of Heparinsystemic infusion of Heparin Other agents such as Other agents such as streptokinase altepase or rTPAstreptokinase altepase or rTPA can be also used can be also used
After thrombolysis patient should subjected to oral After thrombolysis patient should subjected to oral anticoagulation for six monthsanticoagulation for six months
Low-molecular-weight Low-molecular-weight heparinheparin
PharmacologyPharmacologyLMWH as its name suggests is a glycosaminoglycan that is approximatelyLMWH as its name suggests is a glycosaminoglycan that is approximately
one third the molecular weight of UFH It is derived from UFH through one third the molecular weight of UFH It is derived from UFH through variousvarious
depolymerization processes LMWH binds to antithrombin which in turn depolymerization processes LMWH binds to antithrombin which in turn
Neutralizes actors Xa and IIa Because LMWH lacks many of the longer Neutralizes actors Xa and IIa Because LMWH lacks many of the longer chains chains
required for binding to thrombin it has less ability to neutralize thrombin required for binding to thrombin it has less ability to neutralize thrombin
relativeto its ability to neutralize factor Xa LMWH also has less relativeto its ability to neutralize factor Xa LMWH also has less nonspecific nonspecific
binding to other proteins There is greater bioavailability with more binding to other proteins There is greater bioavailability with more predictable predictable
pharmacokinetics that eliminates the need for monitoring The smaller pharmacokinetics that eliminates the need for monitoring The smaller size also size also
allows for enhanced subcutaneous absorption when compared with UFHallows for enhanced subcutaneous absorption when compared with UFH
Three LMWH preparations are Three LMWH preparations are currently approved for use in the currently approved for use in the United States (1) enoxaparin (2) United States (1) enoxaparin (2) dalteparin and (3) tinzaparin dalteparin and (3) tinzaparin
They are all administered They are all administered subcutaneously at intervals of either subcutaneously at intervals of either once or twice daily for both once or twice daily for both prophylaxis and treatment dosesprophylaxis and treatment doses
Few Experiences of Few Experiences of ThrombolysisThrombolysis
Vickey 25 Yrs male patient presented Vickey 25 Yrs male patient presented with 12with 12thth day HO severe headache with day HO severe headache with right sided hemiplegiaright sided hemiplegia
MRI shows thrombosis of the superior MRI shows thrombosis of the superior sagittal left transverse left sigmoid sagittal left transverse left sigmoid sinuses and cortical veins in the fronto-sinuses and cortical veins in the fronto-parietal regions with eo haemorrhagic parietal regions with eo haemorrhagic infarct in the left cerebral hemisphere infarct in the left cerebral hemisphere with mass effect( Grade ndashV)with mass effect( Grade ndashV)
Sashi Srivastava 64 yrs FSashi Srivastava 64 yrs F In a follow up case of MRD with infra-renal In a follow up case of MRD with infra-renal
aortic abdominal and bilateral renal artery aortic abdominal and bilateral renal artery thrombosis renal angiogram shows filling thrombosis renal angiogram shows filling defects in the right Renal artery defects in the right Renal artery
Initially Renal angioplasty was done Initially Renal angioplasty was done Following angioplasty few thrombi are seem Following angioplasty few thrombi are seem to extends into the segmental branches and to extends into the segmental branches and causing blockage So Thrombolysis was causing blockage So Thrombolysis was plane to dissolve the run-out thrombi with plane to dissolve the run-out thrombi with urokinase urokinase
Rakesh 34yrsMRakesh 34yrsM Left SFA pseudoaneurysm with Left SFA pseudoaneurysm with
Covered stent placementCovered stent placement Pre operative antiplatelets with post Pre operative antiplatelets with post
procedure heparin Tirofiban procedure heparin Tirofiban followed by aspirin and clopidogrel followed by aspirin and clopidogrel were usedwere used
IAT may be a treatment option for selected patients IAT may be a treatment option for selected patients Possible selection criteria include Possible selection criteria include
presentation between 3 and 6 hours from symptom onsetpresentation between 3 and 6 hours from symptom onset major cerebral artery occlusion major cerebral artery occlusion severe neurologic deficits severe neurologic deficits high risk of systemic hemorrhage with IV rt-PA (eg recent high risk of systemic hemorrhage with IV rt-PA (eg recent
surgery) surgery) The MERCI (Mechanical Embolus Removal in Cerebral The MERCI (Mechanical Embolus Removal in Cerebral
Ischemia) retrievalIschemia) retrieval system system
Has been FDA-approved for recanalizing acutely occluded Has been FDA-approved for recanalizing acutely occluded cerebral arteries cerebral arteries
In the Multi-MERCI study patients who did not improve In the Multi-MERCI study patients who did not improve immediately after IV rt-PA underwent mechanical immediately after IV rt-PA underwent mechanical embolectomy within 8 hours of symptom onset embolectomy within 8 hours of symptom onset
Partial or complete recanalization occurred in 74 of Partial or complete recanalization occurred in 74 of patientspatients
with a symptomatic intracerebral hemorrhage (sICH) rate of with a symptomatic intracerebral hemorrhage (sICH) rate of 67 67
Mechanical embolectomy with the MERCI retriever may be a Mechanical embolectomy with the MERCI retriever may be a feasible and safe option for patients after IV rt-PAfeasible and safe option for patients after IV rt-PA
Penumbra stroke systemPenumbra stroke system This device combines two methods of clot This device combines two methods of clot
extraction aspiration and mechanical extraction aspiration and mechanical extraction extraction
First the clot is aspirated then a thrombus First the clot is aspirated then a thrombus removal ring can be used if necessary to removal ring can be used if necessary to remove remaining clot remove remaining clot
successful recanalizing 82successful recanalizing 82 Bridging therapyBridging therapy
06 mgkg IV rt-PA followed by IAT with IA rt-06 mgkg IV rt-PA followed by IAT with IA rt-PA (up to 20 mg)PA (up to 20 mg)
achieved a higher recanalization rateachieved a higher recanalization rate
Criteria for thrombolysis with rTPACriteria for thrombolysis with rTPA
Inclusion criteriaInclusion criteria Clinical signs and symptoms consistent with ischemic Clinical signs and symptoms consistent with ischemic
strokestroke Patient last seen normal within 3 hoursPatient last seen normal within 3 hours Measurable neurologic deficitMeasurable neurologic deficit
Exclusion criteriaExclusion criteria Any hemorrhage on neuroimaging (CT or MRI)Any hemorrhage on neuroimaging (CT or MRI) Symptoms suggestive of subarachnoid hemorrhageSymptoms suggestive of subarachnoid hemorrhage Seizure at stroke onset that is thought to contribute to Seizure at stroke onset that is thought to contribute to
neurologic deficitneurologic deficit Hypodensity greater than one third cerebral hemisphere Hypodensity greater than one third cerebral hemisphere
on CTon CT SBP greater than 185 mm Hg or DBP greater than 110 SBP greater than 185 mm Hg or DBP greater than 110
mm Hgmm Hg International normalized ratio (INR) greater than 17International normalized ratio (INR) greater than 17
Ischemic Stroke Ischemic Stroke Treatment ndash 2006Treatment ndash 2006
IV tissue plasminogen activator (tPA)IV tissue plasminogen activator (tPA) ndash ndash Only FDA-approved acute stroke drugOnly FDA-approved acute stroke drug ndash ndash 3 hour treatment window3 hour treatment window
MERCI - Concentric clot retrieval MERCI - Concentric clot retrieval devicedevice ndash ndash Rescue therapy - approved 2004Rescue therapy - approved 2004 ndash ndash Device approval (not outcomes-based)Device approval (not outcomes-based)
Off label approachesOff label approaches ndash ndash IV tPA after 3 hoursIV tPA after 3 hours ndash ndash IV-IA tPA sequential strategiesIV-IA tPA sequential strategies ndash ndash IA tPA clot angioplasty fragmentationIA tPA clot angioplasty fragmentation ndash ndash Ultrasound-assisted tPA lysisUltrasound-assisted tPA lysis
rt-PA Trials NINDSrt-PA Trials NINDS
Acute stroke - 624 patientsAcute stroke - 624 patients Treat within 3 hrsTreat within 3 hrs Intravenous 09 mgkg rt-PA vs placeboIntravenous 09 mgkg rt-PA vs placebo Hemorrhage 64 tPA 06 placeboHemorrhage 64 tPA 06 placebo Neurologic recovery better with tPA 30 Neurologic recovery better with tPA 30
more like to have minimal or no disabilitymore like to have minimal or no disability
First proven approved treatment for First proven approved treatment for strokestroke
Limitations of tPALimitations of tPA Only 4 of acute strokes receive tPAOnly 4 of acute strokes receive tPA (Kleindorfer et al Stroke 2004 35 e27-e29)(Kleindorfer et al Stroke 2004 35 e27-e29)
Only 22 of patients present within 3 hoursOnly 22 of patients present within 3 hours1048707 1048707 51 of these ineligible due to51 of these ineligible due to
bull bull Mild severityMild severity bull bull Medical or surgical historyMedical or surgical history bull bull Blood testsBlood tests
Sustained recanalization only 13Sustained recanalization only 13 (Alexandrov et al NEJM 2004 351 2170-8)(Alexandrov et al NEJM 2004 351 2170-8)
Concern for hemorrhageConcern for hemorrhage tPA potentiates apoptotic injury tPA potentiates apoptotic injury (Liu et al Nature Med 2004 101379-83)(Liu et al Nature Med 2004 101379-83)
PROACT II IA Lysis TrialPROACT II IA Lysis Trial Baseline 24 hours 8 days
Baseline 60 minutes 120 minutes
9mg IAProurokinase
Desmoteplase Trials DEDAS Desmoteplase Trials DEDAS DIASDIAS
Trial OverviewTrial Overview Double blind randomized placebo Double blind randomized placebo
controlled trialscontrolled trials IV delivery 3-9 hour time windowIV delivery 3-9 hour time window Plasminogen activator ndash from Plasminogen activator ndash from vampire bat vampire bat
salivasaliva Selection based on PWI-DWI MismatchSelection based on PWI-DWI Mismatch
MRI InclusionMRI Inclusion PWI defect at least 2 cm AND ~20 larger PWI defect at least 2 cm AND ~20 larger
than DWIthan DWI PWI should be obvious even visible on PWI should be obvious even visible on
raw imagesraw imagesMRI ExclusionMRI Exclusion
DWI gt 13 MCADWI gt 13 MCA MRA ICA occlusionMRA ICA occlusion
Desmoteplase ndash DIAS Desmoteplase ndash DIAS ResultsResults
Mechanical Thrombolysis Mechanical Thrombolysis devicesdevices
mechanical thrombolysis potentially extends the treatment mechanical thrombolysis potentially extends the treatment window because they act promptly at the site of the thrombuswindow because they act promptly at the site of the thrombus
The devices can retrieve large clots that pharmaceutical agents The devices can retrieve large clots that pharmaceutical agents may not successfully lysemay not successfully lyse
Patients treated with IV tPA may be considered for treatment of Patients treated with IV tPA may be considered for treatment of residual clot with some of these devicesresidual clot with some of these devices
suction-creating saline jets suction-creating saline jets laser energy ultrasound laser energy ultrasound a corkscrew apparatus to treat strokesa corkscrew apparatus to treat strokes The AngioJet systemThe AngioJet system uses saline jets that are directed back into the catheter to uses saline jets that are directed back into the catheter to
create a low-pressure zone around the catheter tip inducing create a low-pressure zone around the catheter tip inducing suction suction
The clot is pulled into the exhaust lumen and removed from the The clot is pulled into the exhaust lumen and removed from the vessel Although US Food and Drug Administration (FDA) has vessel Although US Food and Drug Administration (FDA) has approved this device for use in arteriovenous dialysis grafts and approved this device for use in arteriovenous dialysis grafts and fistulae and for the treatment of coronary arteries saphenous fistulae and for the treatment of coronary arteries saphenous vein grafts and peripheral vessels clinical trials for the vein grafts and peripheral vessels clinical trials for the treatment of acute stroke are no longer in progress treatment of acute stroke are no longer in progress
Most devices are used in cerebral vessels that 2-5 mm
The Latis laser device The Latis laser device used laser energy to ablate clots used laser energy to ablate clots Arteries 2-5 mm in diameter could be Arteries 2-5 mm in diameter could be
treated including the ICA M1 or M2 treated including the ICA M1 or M2 branch of the MCA A1 branch of the branch of the MCA A1 branch of the anterior cerebral artery (ACA) basilar anterior cerebral artery (ACA) basilar artery posterior cerebral artery (PCA) artery posterior cerebral artery (PCA) and vertebral and vertebral
Patients could receive treatment as late Patients could receive treatment as late as 8 hours after symptom onset in the as 8 hours after symptom onset in the anterior circulation and within 24 hours in anterior circulation and within 24 hours in the posterior circulation the posterior circulation
Endovascular Photo Acoustic Endovascular Photo Acoustic Recanalization (EPAR) Recanalization (EPAR)
A laser power source generated energy for the A laser power source generated energy for the systemsystem
The energy was delivered by means of The energy was delivered by means of fiberoptics to the tip of the catheter at the fiberoptics to the tip of the catheter at the treatment sitetreatment site
Absorption of laser light by darkly pigmented Absorption of laser light by darkly pigmented materials (ie the clot) occurred inside the 1-mm materials (ie the clot) occurred inside the 1-mm catheter tipcatheter tip
the system was designed to minimize scattering the system was designed to minimize scattering of laser light of laser light
Absorption converted photo energy to acoustic Absorption converted photo energy to acoustic energy which then emulsified the clot inside the energy which then emulsified the clot inside the catheter tip catheter tip
EKOS ultrasound( the EKOS ultrasound( the Ultrasound Thrombolytic Ultrasound Thrombolytic
Infusion Catheter) Infusion Catheter) combines the use of a distal ultrasound transducer with combines the use of a distal ultrasound transducer with
infusion of a thrombolytic agent through the infusion of a thrombolytic agent through the microcathetermicrocatheter
Ultrasound changes the structure of the clot to Ultrasound changes the structure of the clot to temporarily increase its permeability while providing an temporarily increase its permeability while providing an acoustic pressure gradient to move the drug into the clot acoustic pressure gradient to move the drug into the clot to speed its dissolution to speed its dissolution
The EKOS catheter is placed in the proximal portion of the The EKOS catheter is placed in the proximal portion of the clot clot
After a 2-mg bolus of tPA was injected through the After a 2-mg bolus of tPA was injected through the catheter catheter
the patient received a continuous infusion of IA tPA 03 the patient received a continuous infusion of IA tPA 03 mgmin to a maximum of 20 mg and simultaneous mgmin to a maximum of 20 mg and simultaneous ultrasound transmission for as long as 60 minutes ultrasound transmission for as long as 60 minutes
One patient was treated with a total of 4 units of One patient was treated with a total of 4 units of recombinant reteplase (Retavase) hand-injected over 60 recombinant reteplase (Retavase) hand-injected over 60 minutes minutes
Penumbra system Penumbra system The Penumbra system (Penumbra Inc) provides a dual The Penumbra system (Penumbra Inc) provides a dual
approach to clot extraction using aspiration followed by approach to clot extraction using aspiration followed by clot retrieval with a ring device if needed clot retrieval with a ring device if needed
Mechanical Embolus Removal in Cerebral Ischemia Mechanical Embolus Removal in Cerebral Ischemia (MERCI)(MERCI)
a corkscrew-like apparatus to remove blood clots from a corkscrew-like apparatus to remove blood clots from the brain in patients experiencing an ischemic stroke the brain in patients experiencing an ischemic stroke
The corkscrew itself resides in the catheter tip which The corkscrew itself resides in the catheter tip which shields it from the wall of the vessel until it is ready to be shields it from the wall of the vessel until it is ready to be burrowed into the clot Once lodged in the clot the device burrowed into the clot Once lodged in the clot the device and clot are withdrawn from the vessel and clot are withdrawn from the vessel
Snarelike devicesSnarelike devices Snares such as the Neuronet snare (Guidant Snares such as the Neuronet snare (Guidant
Endovascular Santa Clara CA) have been developed Endovascular Santa Clara CA) have been developed specifically for use in the treatment of strokes specifically for use in the treatment of strokes
These devices are simple in design and do not require the These devices are simple in design and do not require the clot to be amenable to emulsification clot to be amenable to emulsification
X-Sizer deviceX-Sizer device a device with small moving blades at the a device with small moving blades at the
catheter tip catheter tip This device the X-Sizer device (EndiCor Medical This device the X-Sizer device (EndiCor Medical
San Clemente CA) can be used to excise the San Clemente CA) can be used to excise the thrombus and aspirate it thrombus and aspirate it
The device was being evaluated in randomized The device was being evaluated in randomized studies of coronary vessels and in a registry of studies of coronary vessels and in a registry of patients with acute myocardial infarctionpatients with acute myocardial infarction
Although the manufacturer had modified the Although the manufacturer had modified the device for use in cerebral vessels a safety and device for use in cerebral vessels a safety and feasibility study was indefinitely suspended after feasibility study was indefinitely suspended after only 1 patient was treated with the device in only 1 patient was treated with the device in Europe Europe
Suction thrombectomySuction thrombectomy This method of mechanical thrombolysis is one of the This method of mechanical thrombolysis is one of the
simplestsimplest In this readily available technique suction is applied with In this readily available technique suction is applied with
a syringe to remove thrombus in the ICA a syringe to remove thrombus in the ICA It requires no other devicesIt requires no other devices A catheter with a large inner diameter (Brite Tip Cordis A catheter with a large inner diameter (Brite Tip Cordis
Corporation Miami FL) was placed in the symptomatic Corporation Miami FL) was placed in the symptomatic vessel and navigated over a guidewire into the thrombusvessel and navigated over a guidewire into the thrombus
A 60-mL syringe was used to aspirate the thrombus A 60-mL syringe was used to aspirate the thrombus Each patient required angioplasty and stenting of carotid Each patient required angioplasty and stenting of carotid
bifurcation stenosis and received daily aspirin and bifurcation stenosis and received daily aspirin and ticlopidine after the procedure No complications ticlopidine after the procedure No complications occurred occurred
Summary Acute Stroke Summary Acute Stroke ImagingImaging
PhysiologyPhysiology importance collaterals importance collaterals
ndash ndashGrowing role for perfusion Growing role for perfusion assessmentassessment
tPAtPA guidelines amp limitations guidelines amp limitations Signs on CT amp MRSigns on CT amp MR follow physiology follow physiology Stroke trialsStroke trials PWI-DWI mismatch PWI-DWI mismatch
ndash ndashTreat based on physiology not timeTreat based on physiology not time ProtocolsProtocols should be fast and should be fast and
comprehensivecomprehensive
Pharmacologic AgentsPharmacologic Agents
AnticoagulantsAnticoagulants
Fibrinolytics (Agents for pharmacological Fibrinolytics (Agents for pharmacological recanalization)recanalization)
Anti platelet drugsAnti platelet drugs
Thrombin inhibitorThrombin inhibitor
ANTICOAGULANTSANTICOAGULANTS
Heparin and Low Molecular Weight Heparins Heparin and Low Molecular Weight Heparins ((eg enoxaparin dalteparin)eg enoxaparin dalteparin)
Oral anticoagulantsOral anticoagulants Coumarin Derivatves Coumarin Derivatves eg Warfarin eg Warfarin
AcenocoumarolAcenocoumarol Indandione Derivatves Indandione Derivatves eg Phenindione eg Phenindione
AnisindioneAnisindione
ThrombolyticsThrombolytics
Plasminogen activators
Fibrinolytics
Anti Platelet DrugsAnti Platelet DrugsDrug Mechanism UsesDrug Mechanism UsesAspirinAspirin Permanently inhibits Permanently inhibits
COX-1 and COX-2COX-1 and COX-2CADCAD
Stroke-TIAsStroke-TIAs
NSAIDsNSAIDs Reversibly inhibits Reversibly inhibits COX-1COX-1
LimitedLimited
DipyridamoleDipyridamole Inhibits PDE Inhibits PDE increases cAMPincreases cAMP
TIAsTIAs
ThenopyridinesThenopyridines
(Ticlopidine(Ticlopidine
Clopidegrel)Clopidegrel)
Inhibits ADP Inhibits ADP
PlatAg PlatAg
TIAsStrokeTIAsStroke
CAD PVDCAD PVD
Abciximab (ReoPro)Abciximab (ReoPro)
Eptifibatide Eptifibatide (Integrilin)(Integrilin)
TirofibaTirofibann
GP IIBIIIA InhibitorsGP IIBIIIA Inhibitors
Stroke- TIAs Stroke- TIAs
Maintainance of patency Maintainance of patency of vascular of vascular grafts catheters shunts bypassesgrafts catheters shunts bypasses
Arterial thromboembolic diseaseArterial thromboembolic diseasebull Transient ischemic attacksTransient ischemic attacksbull Stroke in evolutionStroke in evolution
Ischemic events occurs in Ischemic events occurs in 1313 of of conventional neuroangiographic conventional neuroangiographic procedures without Endovascular surgeryprocedures without Endovascular surgery
Indications for Antithrombotic Therapy in Indications for Antithrombotic Therapy in Diagnostics and Interventional ProceduresDiagnostics and Interventional Procedures
WHY TO MONITOR ANTICOAGULANT THERAPYWHY TO MONITOR ANTICOAGULANT THERAPY
Narrow therapeutic rangeNarrow therapeutic range
Can increase risk of bleedingCan increase risk of bleeding
Coagulation TestingCoagulation Testing
Monitoring therapyMonitoring therapy
Intrinsic Pathway
Extrinsic Pathway
Common Pathway
CLOT
Heparin Coumadin
Monitor with
ACT aPTT
Monitor with PTINR
Thrombolytics
Monitor with TT Fibrinogen
Monitoring of Monitoring of Anti platelet drugsAnti platelet drugs
Bleeding timeBleeding time
Optical aggregometryOptical aggregometry
Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay
HeparinHeparin
Heterogeneous 3000-30000 dalton in Heterogeneous 3000-30000 dalton in molecular weight molecular weight
Average=15000 d (~45monosaccharide Average=15000 d (~45monosaccharide chains)chains)
About About 13 of dose binds to AT III and forms 13 of dose binds to AT III and forms the AT IIIHeparinClotting Factor Complexthe AT IIIHeparinClotting Factor Complex
Complex binds to clotting factors of the Complex binds to clotting factors of the intrinsic and common pathway (Xa IIa IXa intrinsic and common pathway (Xa IIa IXa XIa XIIa XIIIa) and inactivates themXIa XIIa XIIIa) and inactivates them
Anticoagulant of choice in pregnancy (not Anticoagulant of choice in pregnancy (not crosses placenta)crosses placenta)
Heparin and Low molecular weight heparinsHeparin and Low molecular weight heparins
Structure and sequence
O
OH
OH
O
COO
O
O
CH2OH
NHSO3
OH
_
_
O
O
CH2OSO3
NHSO3
OH
_
_
O
OH
OH
O
COOO
O
CH2OSO3
NHSO3
OH
_
_
O
OSO3
OHO
COOO
O
CH2OSO3
NHCOCH3
OH
_
_ _
_
_
O
OH
OH
O
COO
1
23
4
5
6
-D-glucosamine -L-iduronic acid -D-glucuronic acid
O
O
CH2OH
NH2
OH 12
3
4
5
6
O
OH
OHO
COO_
1
23
4
5
6
polymeric structure of heparin
Anticoagulant Properties of Anticoagulant Properties of HeparinHeparin
11 Inhibits the thrombin-mediated conversion of Inhibits the thrombin-mediated conversion of fibrinogen to fibrinfibrinogen to fibrin
22 Inhibits the aggregation of platelets by thrombin Inhibits the aggregation of platelets by thrombin (prolongs bleeding time)(prolongs bleeding time)
33 Inhibits activation of fibrin stabilizing enzymeInhibits activation of fibrin stabilizing enzyme
44 Inhibits activated factors XII XI IX X and IIInhibits activated factors XII XI IX X and II All available forms of heparin must be All available forms of heparin must be
administered administered parenterally since they are parenterally since they are highly charged and rapidlyhighly charged and rapidly hydrolyzed in the hydrolyzed in the GI tractGI tract
Heparin antagonist Protamine sulfate (Heparin antagonist Protamine sulfate (10mg for 10mg for 1000 unit of heparin)1000 unit of heparin)
Monitoring of heparin Monitoring of heparin
Subcutenous Subcutenous no monitoring requiredno monitoring required Intravenous Intravenous
Partial thromboplastin time (PTT normal value Partial thromboplastin time (PTT normal value ~30sec) ~30sec)
Activated clotting time ( ACT normal value ~90-Activated clotting time ( ACT normal value ~90-120sec)120sec)
Daily or more frequent if PTT ACT variesDaily or more frequent if PTT ACT varies
Mechanism Mechanism ndash measures intrinsic pathwayndash measures intrinsic pathway Therapeutic goal Therapeutic goal 2-25 times normal control value 2-25 times normal control value
ACT or aPTTACT or aPTT
Determine when to pull the femoral sheath Determine when to pull the femoral sheath Premature sheath pull can lead to bleedingPremature sheath pull can lead to bleeding Delayed removal can increase time in ICUDelayed removal can increase time in ICU Target set Target set at each siteat each site
ACT targets range from 150 ndash 220 ACT targets range from 150 ndash 220 secondsseconds
aPTT targets range from 40 ndash 70 seconds aPTT targets range from 40 ndash 70 seconds
During neuroangiography-During neuroangiography- Recommended therapeutic range of heparin in Recommended therapeutic range of heparin in
plasma is 02-08 uml ( corresponding to aPTT plasma is 02-08 uml ( corresponding to aPTT ACT values 15-25 times the baseline values)ACT values 15-25 times the baseline values)
Dose In diagnostic angiography bolus dose of Dose In diagnostic angiography bolus dose of 2500 iu is used followed by 1000 iu hour2500 iu is used followed by 1000 iu hour
Bolus dose is Bolus dose is 60 ukg to maintain the therapeutic 60 ukg to maintain the therapeutic range range If procedure continues for more than 75 If procedure continues for more than 75 minutes additional dose is required ( half of the minutes additional dose is required ( half of the initial dose for another 75 minutes) initial dose for another 75 minutes)
(AJNR 199415 51-54)
Mechanisms of HIT( Mechanisms of HIT( Heparin Heparin induced Thrombocytopeniainduced Thrombocytopenia))
Type 1Type 1 Fall in platelet count occurs within the first two Fall in platelet count occurs within the first two
days after heparin initiation often returns to days after heparin initiation often returns to normal with continued heparin administration normal with continued heparin administration and is of no clinical consequence and is of no clinical consequence
The mechanism of the thrombocytopenia is non-The mechanism of the thrombocytopenia is non-immune and appears to be due to a direct effect of immune and appears to be due to a direct effect of heparin on platelet activationheparin on platelet activation
Type 2Type 2 Approximately 03 to 3 percent of patients Approximately 03 to 3 percent of patients
receiving heparin develop an immune receiving heparin develop an immune thrombocytopenia mediated by antibodies to a thrombocytopenia mediated by antibodies to a heparin-platelet factor 4 complex heparin-platelet factor 4 complex
(AJNR 28155-158 2007)
Treatment of heparin-induced Treatment of heparin-induced thrombocytopeniathrombocytopenia
When HIT is diagnosed it is important to When HIT is diagnosed it is important to stop heparin mainly in type 2 and to avoid stop heparin mainly in type 2 and to avoid the use of LMWH the use of LMWH
Because of the increased risk of thrombosis Because of the increased risk of thrombosis however continuation of an anticoagulant however continuation of an anticoagulant must be considered must be considered
The drugs currently approved for the The drugs currently approved for the treatment of HIT in the United States are treatment of HIT in the United States are direct thrombin inhibitors argatroban and direct thrombin inhibitors argatroban and lepirudinlepirudin
WARFARIN MECHANISM OF ACTIONWARFARIN MECHANISM OF ACTION
Inactive factors II VII IX and X
Proteins S and C
Active factors II VII IX and X
Proteins S and C
Vitamin K epoxide
Vitamin K reduced
WA
RF
AR
IN
Prevents the reduction of vitamin K which is essential for Prevents the reduction of vitamin K which is essential for activation of certain factorsactivation of certain factors
Has no effect on previously formed thrombusHas no effect on previously formed thrombus
Antagonist is Vit KAntagonist is Vit K
OPTIMIZING WARFARIN THERAPYOPTIMIZING WARFARIN THERAPY
Use of large loading dose may lead to hemorrhage and Use of large loading dose may lead to hemorrhage and other complicationsother complications
Initial dose 2-5 mg once dailyInitial dose 2-5 mg once daily Maintenance dose 2-10 mg once dailyMaintenance dose 2-10 mg once daily If Immediate anticoagulation is requiredIf Immediate anticoagulation is required Heparin IS Heparin IS
started along with loading dose of warfarin 10 mg started along with loading dose of warfarin 10 mg Heparin is usually discontinued after 4-5 days Heparin is usually discontinued after 4-5 days Before Before discontinuing INR should be in therapeutic range for 2 discontinuing INR should be in therapeutic range for 2 consecutive daysconsecutive days
Daily monitoring of INR until INR is in therapeutic Daily monitoring of INR until INR is in therapeutic range then 3 times weekly for 1-2 weeks then less often range then 3 times weekly for 1-2 weeks then less often (every 4 to 6 weeks)(every 4 to 6 weeks)
OPTIMAL THERAPEUTIC RANGEOPTIMAL THERAPEUTIC RANGE
IndicationIndication INRINR
Prophylaxis of venous Prophylaxis of venous thromboembolismthromboembolism
20-3020-30
Treatment of venous Treatment of venous thromboembolismthromboembolism
20-3020-30
Atrial fibrillationAtrial fibrillation 20-3020-30
Mitral valve stenosisMitral valve stenosis 20-3020-30
Heart valve replacementHeart valve replacement
Bioprosthetic valveBioprosthetic valve
Mechanical valveMechanical valve
20-3020-30
25-3525-35
Myocardial infarctionMyocardial infarction 20-3020-30
25-35 25-35 (high risk patients)(high risk patients)
FACTORS INFLUENCING DOSE RESPONSEFACTORS INFLUENCING DOSE RESPONSE
Poor patient compliancePoor patient compliance Concomitant medicationsConcomitant medications Levels of dietary vitamin KLevels of dietary vitamin K Alcohol Inaccurate lab testingAlcohol Inaccurate lab testing Inaccurate lab testingInaccurate lab testing Hepatic dysfunctionHepatic dysfunction FeverFever
Contraindication for WarfarinContraindication for Warfarin
Hypersensitivity to warfarinHypersensitivity to warfarin Hemorrhagic tendencyHemorrhagic tendency Condition with risk of hemorrhageCondition with risk of hemorrhage Inadequate laboratory techniquesInadequate laboratory techniques Protein C amp S deficiencyProtein C amp S deficiency Vitamin K deficiencyVitamin K deficiency
SIDE EFFECTSSIDE EFFECTS
Hemorrhage Hemorrhage Skin necrosisSkin necrosis Purple toe syndromePurple toe syndrome Microembolization Microembolization TeratogenecityTeratogenecity Agranulocytosis leukopenia Agranulocytosis leukopenia Diarrhoeanausea anorexiaDiarrhoeanausea anorexia
MONITORING OF WARFARIN THERAPYMONITORING OF WARFARIN THERAPY
Prothrombin timeProthrombin time PT ratioPT ratio INR (International Normalized Ratio)INR (International Normalized Ratio)
PROTHROMBIN TIME (PT)PROTHROMBIN TIME (PT)
Time required for blood to coagulate Time required for blood to coagulate is called PT ( normal value ~10sec)is called PT ( normal value ~10sec)
Performed by adding a mixture of Performed by adding a mixture of calcium and thromboplastin to calcium and thromboplastin to citrated plasmacitrated plasma
As a control a normal blood sample is As a control a normal blood sample is tested continuouslytested continuously
PT ratio (PTR) = PT ratio (PTR) = Patientrsquos PTPatientrsquos PT Control PTControl PT
PROBLEMS WITH PTPTRPROBLEMS WITH PTPTR
Thromboplastins are extracts from Thromboplastins are extracts from brain lung or placenta of animalsbrain lung or placenta of animals
Thromboplastins from various Thromboplastins from various manufacturers differ in their manufacturers differ in their sensitivity to prolong PTsensitivity to prolong PT
May result in false control of May result in false control of anticoagulant therapyanticoagulant therapy
INTERNATIONAL NORMALISED RATIO (INR)INTERNATIONAL NORMALISED RATIO (INR)
International Normalized Ratio (INR) International Normalized Ratio (INR) a PT test with a a PT test with a formula based ratio to normalize the often variable source formula based ratio to normalize the often variable source of tissue factor (human rabbit recombinant)of tissue factor (human rabbit recombinant)
INR = [PTINR = [PTptpt] ] ISIISI
[PT[PTRefRef]]
PTPTpt pt ndash prothrombin time of patientndash prothrombin time of patient
PTPTRef Ref ndash prothrombin time of normal pooled samplendash prothrombin time of normal pooled sample
ISI ndash International Sensitivity IndexISI ndash International Sensitivity Index
Warfarin is given orally and titrated to achieve an INR of Warfarin is given orally and titrated to achieve an INR of typically 20 ndash 30typically 20 ndash 30
Heparin versus WarfarinHeparin versus Warfarin
Drug ActionMechan-ism
Moni-toring
Effective
HeparinDirect
Inhibition ofThrombin
ATIIIcofactor
APTTACT
Immediate
WarfarinDecreasesProductionof factors
Vitamin K PTDelay
3-5 days
INR
Recanalization or Antegrade Recanalization or Antegrade Reperfusion StrategiesReperfusion Strategies
Recanalization strategies focus on removing Recanalization strategies focus on removing andor dissolving the occlusive thrombus to re-andor dissolving the occlusive thrombus to re-establish antegrade flow Strategies may be establish antegrade flow Strategies may be classified into 7 different categories on the classified into 7 different categories on the basis of their primary mechanism of action basis of their primary mechanism of action 1) 1) IV andor intraarterial thrombolysis (IAT) IV andor intraarterial thrombolysis (IAT) 2) endovascular thrombectomy2) endovascular thrombectomy3) endovascular thromboaspiration 3) endovascular thromboaspiration 4) endovascular mechanical thrombus disruption or 4) endovascular mechanical thrombus disruption or
thromborrhexisthromborrhexis5) 5) transcranial or endovascular augmented transcranial or endovascular augmented
fibrinolysis fibrinolysis 6) endovascular thrombus entrapment and 6) endovascular thrombus entrapment and 7) temporary endovascular bypass7) temporary endovascular bypass
IAT in Acute Ischemic StrokeIAT in Acute Ischemic Stroke
IAT advantages over IV thrombolysisIAT advantages over IV thrombolysis Coaxial microcatheter techniques the occluded intracranial Coaxial microcatheter techniques the occluded intracranial
vessel is directly accessible and the fibrinolytic agent can be vessel is directly accessible and the fibrinolytic agent can be infused directly into the thrombusinfused directly into the thrombus
This permits a smaller dose of fibrinolytic agent to reach a This permits a smaller dose of fibrinolytic agent to reach a higher local concentration than that reached by systemic higher local concentration than that reached by systemic infusioninfusion
Allows more complete recanalization with lower total doses of Allows more complete recanalization with lower total doses of thrombolytic thrombolytic
With the smaller dose complications from systemic fibrinolytic With the smaller dose complications from systemic fibrinolytic effects including intracranial hemorrhage (ICH) can effects including intracranial hemorrhage (ICH) can theoretically be reduced theoretically be reduced
Treatment window for endovascular techniques can be Treatment window for endovascular techniques can be extended beyond the typical IV window of 3 hours extended beyond the typical IV window of 3 hours
IA techniques have led to higher recanalization rates than IV IA techniques have led to higher recanalization rates than IV thrombolysisthrombolysis
Major disadvantagesMajor disadvantages Relative complexity of the procedure the level Relative complexity of the procedure the level
of required technical expertise and its of required technical expertise and its relatively low availability relatively low availability
Delays in initiating treatmentDelays in initiating treatment InvasiveInvasive
ThrombolyticsThrombolytics
Plasminogen activators
Fibrinolytics
1 Plasminogen Activators 1 Plasminogen Activators drugs act by converting the inactive proenzyme drugs act by converting the inactive proenzyme plasminogen into the active enzyme plasmin Plasmin plasminogen into the active enzyme plasmin Plasmin digests fibrinogen fibrin monomers and cross-linked digests fibrinogen fibrin monomers and cross-linked fibrin (as found in a thrombus) into fibrin degradation fibrin (as found in a thrombus) into fibrin degradation productsproducts
First-Generation Agents First-Generation Agents StreptokinaseStreptokinase a protein derived from group C a protein derived from group C
szlig-hemolytic streptococci has a half-life of 16ndashszlig-hemolytic streptococci has a half-life of 16ndash90 minutes and low fibrin specificity This drug 90 minutes and low fibrin specificity This drug proved to have a very narrow therapeutic proved to have a very narrow therapeutic window and significant rates of ICH and window and significant rates of ICH and systemic hemorrhage18systemic hemorrhage18
UrokinaseUrokinase is a serine protease with a plasma is a serine protease with a plasma half life of 14 minutes and low fibrin specificity half life of 14 minutes and low fibrin specificity
The urokinase dose used in cerebral IAT has The urokinase dose used in cerebral IAT has ranged from 002 to 2 X106unitsranged from 002 to 2 X106units
Second-Generation Agents Second-Generation Agents Alteplase (rtPA) Alteplase (rtPA)
is a serine is a serine protease with a plasma half-life of 35 protease with a plasma half-life of 35 minutes and a high degree of fibrin affinity and minutes and a high degree of fibrin affinity and specificity specificity
Dose used in cerebral IAT has ranged between 20 Dose used in cerebral IAT has ranged between 20 and 60 mgand 60 mg
Disadvantages of alteplase include its relatively short Disadvantages of alteplase include its relatively short halflife and limited penetration into the clot matrix halflife and limited penetration into the clot matrix because of strong binding with surface fibrin which because of strong binding with surface fibrin which could delay recanalization and increase the risk of could delay recanalization and increase the risk of recurrent occlusion recurrent occlusion
Prourokinase (r-prourokinase) Prourokinase (r-prourokinase) is the proenzyme precursor of urokinase is the proenzyme precursor of urokinase T12 of 7 minutes and high fibrin specificity T12 of 7 minutes and high fibrin specificity
Third-Generation AgentsThird-Generation Agents
ReteplaseReteplase is a structurally modified is a structurally modified form of alteplase form of alteplase
with a longer half-life (15ndash18 minutes) In with a longer half-life (15ndash18 minutes) In addition it does not bind as highly to fibrin addition it does not bind as highly to fibrin unbound reteplase can thus theoretically better unbound reteplase can thus theoretically better penetrate the clot and potentially penetrate the clot and potentially improve in improve in vivo fibrinolytic activity vivo fibrinolytic activity
TenecteplaseTenecteplase is another modified form of rtPA with a longer is another modified form of rtPA with a longer
half-life (17 minutes)half-life (17 minutes) greater fibrin specificity and greater greater fibrin specificity and greater
resistance to plasminogen activator inhibitor-1 resistance to plasminogen activator inhibitor-1 IV tenecteplase in acute ischemic stroke IV tenecteplase in acute ischemic stroke
suggest that the drug is safe and promisingsuggest that the drug is safe and promising
Newer plasminogen activatorNewer plasminogen activator
DesmoteplaseDesmoteplase is a genetically engineered is a genetically engineered version of the clot-dissolving factor version of the clot-dissolving factor
found in the saliva found in the saliva of the vampire bat Desmodus rotundusof the vampire bat Desmodus rotundus moremore potent and more selective for fibrin-bound potent and more selective for fibrin-bound
plasminogen than any other known plasminogen plasminogen than any other known plasminogen activatoractivator
Unlike tissue plasminogen activator (tPA) desmoteplase Unlike tissue plasminogen activator (tPA) desmoteplase is not activated by fibrinogen or -amyloid proteins is not activated by fibrinogen or -amyloid proteins factors that may exacerbate the risk for ICH factors that may exacerbate the risk for ICH
The effect of IV administration of desmoteplase 3ndash9 The effect of IV administration of desmoteplase 3ndash9 hours after symptom onset in patients with stroke who hours after symptom onset in patients with stroke who present with mismatch on MR imaging or CT perfusion present with mismatch on MR imaging or CT perfusion
3 DefibrinogenatingFibrinogenolytic 3 DefibrinogenatingFibrinogenolytic Agents Agents
AncrodAncrod(Viprinex)(Viprinex) is is the purified fraction of the Malayan pit viper venomthe purified fraction of the Malayan pit viper venom It acts by directly cleaving and inactivating fibrinogen It acts by directly cleaving and inactivating fibrinogen
and thus indirectly promoting anticoagulation and thus indirectly promoting anticoagulation The reduction in the blood levels of fibrinogen also The reduction in the blood levels of fibrinogen also
leads to a reduced blood viscosity which may improve leads to a reduced blood viscosity which may improve blood flow to the affected areas of the brain blood flow to the affected areas of the brain
In the Stroke Treatment with Ancrod Trial 500 In the Stroke Treatment with Ancrod Trial 500 patients with stroke presenting within 3 hours of patients with stroke presenting within 3 hours of symptom onset were randomized to receive ancrod (symptom onset were randomized to receive ancrod (n n 248) or a placebo (n 252) Good outcome (Barthel 248) or a placebo (n 252) Good outcome (Barthel Index 95ndash100 at 3 months) was achieved in 4221 Index 95ndash100 at 3 months) was achieved in 4221 and 344 of the patients respectively and 344 of the patients respectively
2 Direct Fibrinolytics2 Direct Fibrinolytics
Microplasmin (Microplasmin (ThromboGenics Heverlee Belgium)ThromboGenics Heverlee Belgium) is a truncated form of plasmin that is more resistant to the effects is a truncated form of plasmin that is more resistant to the effects
of antiplasmin of antiplasmin microplasmin can be used upto 4ndash12 hours after stroke onset microplasmin can be used upto 4ndash12 hours after stroke onset There was no evidence of increased bleeding risk with There was no evidence of increased bleeding risk with
microplasminmicroplasmin
Alfimeprase (Nuvelo San Carlos Calif)Alfimeprase (Nuvelo San Carlos Calif) is a recombinant truncated form of fibrolase a fibrinolytic zinc metalloproteinase is a recombinant truncated form of fibrolase a fibrinolytic zinc metalloproteinase
isolated from the venom of the southern copperhead snake isolated from the venom of the southern copperhead snake It degrades fibrin directly and achieves thrombolysis independent It degrades fibrin directly and achieves thrombolysis independent
of plasmin formationof plasmin formation its thrombolytic activity appears to be localized to the site of its thrombolytic activity appears to be localized to the site of
delivery These properties should theoretically result in faster delivery These properties should theoretically result in faster recanalization and lower hemorrhagic conversion riskrecanalization and lower hemorrhagic conversion risk
Anti-fibrinolyticsAnti-fibrinolytics
to limit fibrinolytic activityto limit fibrinolytic activity -aminocaproic acid (EACA) -aminocaproic acid (EACA) competitively inhibitscompetitively inhibits plasminogen and plasminogen activators from plasminogen and plasminogen activators from
binding to fibrinbinding to fibrin
alpha2-antiplasminalpha2-antiplasmin a serine protease inhibitor that a serine protease inhibitor that neutralizes any free circulating plasminneutralizes any free circulating plasmin
Plasminogen activator inhibitor-1Plasminogen activator inhibitor-1 a serine protease a serine protease inhibitor that inhibits tissue-type plasminogen inhibitor that inhibits tissue-type plasminogen activatoractivator
Glycoprotein (GP) IIbIIIa antagonistsGlycoprotein (GP) IIbIIIa antagonists
such as ReoPro (abciximab) Integrilin such as ReoPro (abciximab) Integrilin (eptifibatide) or Aggrastat (tirofiban) in (eptifibatide) or Aggrastat (tirofiban) in ischemic stroke remains investigational ischemic stroke remains investigational Deshmukh et al38 reported 21 patients with Deshmukh et al38 reported 21 patients with large-vessel occlusion refractory to IAT with large-vessel occlusion refractory to IAT with rtPA who were treated with IV andor IA rtPA who were treated with IV andor IA abciximab eptifibatide or tirofiban abciximab eptifibatide or tirofiban
IA Mechanical Approaches in Acute Ischemic Stroke IA Mechanical Approaches in Acute Ischemic Stroke Mechanical strategies have several advantagesMechanical strategies have several advantages First they lessen and may even preclude the use of chemical First they lessen and may even preclude the use of chemical
thrombolytics in this manner very likely reducing the risk of ICHthrombolytics in this manner very likely reducing the risk of ICH Second by avoiding the use of chemical thrombolytics it is Second by avoiding the use of chemical thrombolytics it is
possible to extend the treatment window beyond the limit of 6ndash8 possible to extend the treatment window beyond the limit of 6ndash8 hours hours
Third mechanically fragmenting a clot increases the surface area Third mechanically fragmenting a clot increases the surface area accessible to fibrinolytic agents and allows inflow of fresh accessible to fibrinolytic agents and allows inflow of fresh plasminogen which in turn may increase the speed of plasminogen which in turn may increase the speed of thrombolysis thrombolysis
Finally clot-retrieval devices may provide faster recanalization Finally clot-retrieval devices may provide faster recanalization
The disadvantages of the mechanical The disadvantages of the mechanical approaches approaches technical difficulty of navigating mechanical technical difficulty of navigating mechanical
devices into the intracranial circulation excessive devices into the intracranial circulation excessive trauma to the vasculature (potentially leading to trauma to the vasculature (potentially leading to vasospasm vessel dissection perforation or vasospasm vessel dissection perforation or rupture) rupture)
fragmented thrombus causing distal embolization fragmented thrombus causing distal embolization into previously unaffected territories into previously unaffected territories
Nevertheless the advantages of mechanical stroke Nevertheless the advantages of mechanical stroke therapy appear to significantly outweigh its therapy appear to significantly outweigh its disadvantages and risksdisadvantages and risks
Contraindications to Thrombolytic Contraindications to Thrombolytic agents agents
Recent thoracic abdominal or Recent thoracic abdominal or intracranial surgeryintracranial surgery
Recent haemorrhagic CVA Head injury Recent haemorrhagic CVA Head injury or neoplasmor neoplasm
Bleeding ulcerBleeding ulcer Anticipated invasive procedures (arterial Anticipated invasive procedures (arterial
punctures biopsies)punctures biopsies) Concurrent hemostatic dysfunctionConcurrent hemostatic dysfunction
Monitoring of thrombolytic Monitoring of thrombolytic therapytherapy
Thrombin time Measures the availability of functional
fibrinogen Normal thrombin time is 10-14 sec Prolonged when fibrinogen level is below
75-100 mgdl
Half Life of ThrombolyticsHalf Life of ThrombolyticsAgent Administration Half Life
Streptokinase IA 60-80min
Urokinase IAIV 9-12min
rTPA IAIV 6min
Abciximab(Reopro) IAIV 12hour
Aspirin POIV 15-20min
Heparin IVSC 60min
Coumadin PO 15-25 days
Anti Platelet DrugsAnti Platelet DrugsDrug Drug Mechanism Mechanism UsesUsesAspirinAspirin Permanently inhibits Permanently inhibits
COX-1 and COX-2COX-1 and COX-2CADCAD
Stroke-TIAsStroke-TIAs
NSAIDsNSAIDs Reversibly inhibits Reversibly inhibits COX-1COX-1
LimitedLimited
DipyridamoleDipyridamole Inhibits PDE increases Inhibits PDE increases cAMPcAMP
TIAsTIAs
ThenopyridinesThenopyridines
(Ticlopidine(Ticlopidine
ClopidrgrelClopidrgrel))
Inhibits ADP Inhibits ADP
PlatAg PlatAg
TIAsStrokeTIAsStroke
CAD PVDCAD PVD
Abciximab (ReoPro)Abciximab (ReoPro)
Eptifibatide (Integrilin)Eptifibatide (Integrilin)
TirofibanTirofiban
GP IIBIIIA InhibitorsGP IIBIIIA Inhibitors
Stroke- TIAs Stroke- TIAs
MonitoringMonitoring
Bleeding timeBleeding time
Optical aggregometryOptical aggregometry
Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay
Bleeding timeBleeding time
Requires a skin incision (usually made on the ear lobe or Requires a skin incision (usually made on the ear lobe or forearm offorearm of
a depth that results in disruption of capillary loops and a depth that results in disruption of capillary loops and small vessels)small vessels)
AdvantagesAdvantages Universally availableUniversally available Relatively simple techniquesRelatively simple techniques Can be performed bedsideCan be performed bedside
DisadvantagesDisadvantages Insensitive inaccurate non-specific techniqueInsensitive inaccurate non-specific technique
Poorly reproducible (as depends on multiple variables)Poorly reproducible (as depends on multiple variables)
Optical aggregometryOptical aggregometry
Gold standard assay for platelet functionGold standard assay for platelet function Agonist induced aggregation is measuredAgonist induced aggregation is measured Different agonist are available for different Different agonist are available for different
agentsagents However require unique expertise and are not However require unique expertise and are not
universally availableuniversally available Aspirin measured with ADP or AA(gt70 Aspirin measured with ADP or AA(gt70
aggregation so resistance)aggregation so resistance) Clopidogrel( ADP gt 90 aggregation means Clopidogrel( ADP gt 90 aggregation means
resistance) resistance)
Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay
Can be performed bed sideCan be performed bed side Different assay devices with different Different assay devices with different
agonist are used for each of different agonist are used for each of different antiplatelet agents antiplatelet agents
For Aspirin AA is used (result is reported as aspirin For Aspirin AA is used (result is reported as aspirin reaction units [ARU] ARUgt 550 indicates non-reaction units [ARU] ARUgt 550 indicates non-responsiveness)responsiveness)
Verify IIbIIIa assay device uses TRAP as agonist for Verify IIbIIIa assay device uses TRAP as agonist for Abciximab and TirofibanAbciximab and Tirofiban
Practical Applications Practical Applications related to specific related to specific
Neurovascular Neurovascular interventionsinterventions
Acute ischemic StrokeAcute ischemic Stroke When an artery occludes neurons are affected When an artery occludes neurons are affected
differently depending upon the amount of residual blood differently depending upon the amount of residual blood flowflow
Normal cerebral blood flow is greater than 50 mL100 Normal cerebral blood flow is greater than 50 mL100 mgminmgmin
Once blood flow decreases to less than 20 mL100 Once blood flow decreases to less than 20 mL100 mgmin infarction occursmgmin infarction occurs
If blood flow decreases to less than 10 mL100 mgmin If blood flow decreases to less than 10 mL100 mgmin irreversible neuronal death occurs rapidly irreversible neuronal death occurs rapidly
Blood flow between 11 and 20 mL100 mgmin is thought Blood flow between 11 and 20 mL100 mgmin is thought to represent the ischemic penumbra an area where the to represent the ischemic penumbra an area where the cells are functionally silent because of ischemia but are cells are functionally silent because of ischemia but are still able to recover if blood flow is restored still able to recover if blood flow is restored
Many acute stroke therapies are targeted toward Many acute stroke therapies are targeted toward restoring flow or function to the ischemic penumbrarestoring flow or function to the ischemic penumbra
Therapeutic window in Therapeutic window in management of acute Ischemic management of acute Ischemic
StrokeStrokeThe early diagnosis of ischemic stroke is critical to the The early diagnosis of ischemic stroke is critical to the
with only a narrow therapeutic window in the first few with only a narrow therapeutic window in the first few hours following stroke ictushours following stroke ictus
Diagnosis in the first 3 hours postictus provides the Diagnosis in the first 3 hours postictus provides the opportunity for intravenous or intraarterial thrombolysis opportunity for intravenous or intraarterial thrombolysis and intra-arterial clot mechanical treatment which and intra-arterial clot mechanical treatment which improve the outcome improve the outcome
Diagnosis in the time period between 3 and 6 hours Diagnosis in the time period between 3 and 6 hours provides an opportunity for intra-arterial thrombolysis provides an opportunity for intra-arterial thrombolysis and mechanical treatment and mechanical treatment
Involvement of the posterior circulation especially the Involvement of the posterior circulation especially the basilar artery is treated by some regardless of time of basilar artery is treated by some regardless of time of onset or up until 12 to 24 hours in some practices This is onset or up until 12 to 24 hours in some practices This is related to the potentially high mortality and morbidity related to the potentially high mortality and morbidity associated with basilar artery thrombosisassociated with basilar artery thrombosis
Infarct evaluation on angiographyInfarct evaluation on angiography(CT angiography and catheter (CT angiography and catheter
angiography)angiography)CTA is an excellent first-line examination for CTA is an excellent first-line examination for
evaluation of the head and neck arteries evaluation of the head and neck arteries In comparison with catheter angiography In comparison with catheter angiography
what it gives up in resolution and dynamic what it gives up in resolution and dynamic properties it makes up for with rapid properties it makes up for with rapid acquisition of a 3-D dataset and the potential acquisition of a 3-D dataset and the potential for assessment of whole-brain perfusion and for assessment of whole-brain perfusion and better parenchymal evaluationbetter parenchymal evaluation
Moreover CTA illustrates not only arterial Moreover CTA illustrates not only arterial stenosis or occlusion but also the vessel wall stenosis or occlusion but also the vessel wall This factor is most important for evaluation of This factor is most important for evaluation of intramural dissection and thrombosed intramural dissection and thrombosed aneurysms which may both complicate aneurysms which may both complicate evaluation of stroke patientsevaluation of stroke patients
Early angiographic signs of strokes Early angiographic signs of strokes both CTA both CTA and DSA and DSA
Vessel occlusion or cutoff related to Vessel occlusion or cutoff related to thromboembolithromboemboli
aneurysms aneurysms arterial dissection arterial dissection Meniscus or flattened shape to clot Meniscus or flattened shape to clot
(recent) versus reverse meniscus (older)(recent) versus reverse meniscus (older) tram track (nonocclusive or recanalized tram track (nonocclusive or recanalized
clot) clot) delayed (antegrade) flow (manifest as delayed (antegrade) flow (manifest as
decreased whole-brain perfusion on CTA)decreased whole-brain perfusion on CTA) retrograde collateral flowretrograde collateral flow
Non-occlusive left MCA thrombus on 3-D imaging performed from CTA source data and was confirmed at catheter angiography
Therapy to be started within a 6-hr Therapy to be started within a 6-hr time to treatment (TTT) window time to treatment (TTT) window (while in case of IV thrombolysis (while in case of IV thrombolysis therapy to be started with in 3hrs)therapy to be started with in 3hrs)
Exclusion criteria Exclusion criteria Rapidly improving neurologic deficit or Rapidly improving neurologic deficit or Sustained blood pressure of gt180100 Sustained blood pressure of gt180100 Hemorrhage is detected on CTHemorrhage is detected on CT Infarct involving gt more than 13 rd Infarct involving gt more than 13 rd
territory of MCAterritory of MCA MRADWI-Perfusion mismatchlt 20MRADWI-Perfusion mismatchlt 20 Definite hypodensity on CTDefinite hypodensity on CT
Intra-arterial Thrombolysis
Fibrinolytics + AntiplateletsFibrinolytics + Antiplatelets
PlasminogenPlasminogen activators through fibrinolysis exposes activators through fibrinolysis exposes free thrombin and paradoxically stimulatesfree thrombin and paradoxically stimulates platelet platelet aggregation which leads to formation of aaggregation which leads to formation of a platelet platelet thrombus (white clot) thrombus (white clot)
This new thrombus is relatively resistant to This new thrombus is relatively resistant to fibrinolyticsfibrinolytics
So new regimen in case of acute stroke isSo new regimen in case of acute stroke is fibrinolytics + antiplatelet drugsfibrinolytics + antiplatelet drugs
rtPA + IIbIIIa inhibitors( tirofiban rtPA + IIbIIIa inhibitors( tirofiban abciximab) orabciximab) or
Urokinase + IIbIIIa Urokinase + IIbIIIa inhibitors( tirofiban abciximab)inhibitors( tirofiban abciximab)
Intra-arterial Thrombolysis Tirofiban (04 microgkgmin bolus for 3 min followed by Tirofiban (04 microgkgmin bolus for 3 min followed by
0125 ugkgmin)0125 ugkgmin)
++
Heparin (2000ndash3000 IU bolus followed by Heparin (2000ndash3000 IU bolus followed by 1000 IUhour infusion 1000 IUhour infusion
with ACT maintained bw 200-300) throughout the with ACT maintained bw 200-300) throughout the interventional procedure and for 24ndash48 hours thereafter when interventional procedure and for 24ndash48 hours thereafter when there is neither intraprocedural bleeding nor suspicion of there is neither intraprocedural bleeding nor suspicion of increased risk of bleeding increased risk of bleeding
Maximum dose of Urokinase Maximum dose of Urokinase Anterior circulation stroke - 500000 IU (mean 400000 Anterior circulation stroke - 500000 IU (mean 400000
IU range 300000ndash500000 IU)IU range 300000ndash500000 IU) Posterior circulation stroke -1000000 IU (mean 837000 Posterior circulation stroke -1000000 IU (mean 837000
IU range 300000ndash1000000 IU)IU range 300000ndash1000000 IU)American Journal of NeuroradiologyAmerican Journal of Neuroradiology 262595-2601 2005262595-2601 2005
Intravenous ThrombolysisIntravenous Thrombolysis
The first method to restore cerebral The first method to restore cerebral perfusion is clot lysis with the goal perfusion is clot lysis with the goal of re-establishing blood flow to the of re-establishing blood flow to the affected tissue affected tissue
IV thrombolysis rt-PA is the only IV thrombolysis rt-PA is the only FDA- approved treatment for AIS FDA- approved treatment for AIS
Fibrinolysis is enhanced powerfully Fibrinolysis is enhanced powerfully by rt-PAby rt-PA
Intravenous rTPA Intravenous rTPA administration administration protocolprotocol
Total dose of rt-PA 09 mgkg (maximum dose Total dose of rt-PA 09 mgkg (maximum dose 90 mg)90 mg)
Give 10 as initial IV bolusGive 10 as initial IV bolus Infuse remainder over 1 hourInfuse remainder over 1 hour Admit patient to an ICU or stroke unit for Admit patient to an ICU or stroke unit for
monitoringmonitoring Neurologic assessments every 15 minutes Neurologic assessments every 15 minutes
during infusion then every 30 minutes for next during infusion then every 30 minutes for next 6 hours then every hour until 24hours after 6 hours then every hour until 24hours after treatmenttreatment
Favorable Outcome vs Treatment Time Favorable Outcome vs Treatment Time with IV rTPAwith IV rTPA
Protocol limit = 3 hrs
Benefit ~ 45 hrs
Thromboembolism During coilingThromboembolism During coiling Most feared and frequent complication Most feared and frequent complication Reported incidence - Approx 7 Reported incidence - Approx 7 SourcesSources of Thromboembolism are of Thromboembolism are
- Clots at the aneurysmal neck during or immediately- Clots at the aneurysmal neck during or immediately after after embolization embolization
- Thrombus forming on catheters during- Thrombus forming on catheters during proceduresprocedures
- Stenosis of an adjacent artery dt coil mass- Stenosis of an adjacent artery dt coil mass or herniationor herniation
- Migration of intraaneurysmal- Migration of intraaneurysmal thrombus during coil thrombus during coil placement placement
- Slow flow dt vasospasm - Slow flow dt vasospasm
- Rare and unlikely causes are hypercoagulable- Rare and unlikely causes are hypercoagulable state such state such as antiphospholipid antibody syndrome or due to HITas antiphospholipid antibody syndrome or due to HIT
Occur more often with wide-necked aneurysms (dt Occur more often with wide-necked aneurysms (dt increased exposed surface area of thrombogenic coil increased exposed surface area of thrombogenic coil material)material)
Current regimen of endovascular Current regimen of endovascular managementmanagement
The The glycoprotein IIbIIIa antagonist tirofiban glycoprotein IIbIIIa antagonist tirofiban (04 (04 microgkgmin bolus for 30 minutes followed by infusion of microgkgmin bolus for 30 minutes followed by infusion of 0125 ugkgmin until the thrombus dissolved) 0125 ugkgmin until the thrombus dissolved)
Intraarterial thrombolysis with Intraarterial thrombolysis with urokinase or r- TPA urokinase or r- TPA increase of intravenous (IV) heparin (measured by increase of intravenous (IV) heparin (measured by
ACT) ACT) Intravenous aspirin Intravenous aspirin
Coil-related platelet aggregation (white clot) is Coil-related platelet aggregation (white clot) is unlikely to respond to fibrinolytics but has a high risk unlikely to respond to fibrinolytics but has a high risk of hemorrhage (In ISAT) all 5 patients who had of hemorrhage (In ISAT) all 5 patients who had received thrombolytic therapy with tPA to treat a received thrombolytic therapy with tPA to treat a thromboembolic complication after endovascular thromboembolic complication after endovascular treatment rebleed and all of these patients died)treatment rebleed and all of these patients died)
IntracranialIntracranial Stenting Stenting Metallic foreign body such as stent will accumulate Metallic foreign body such as stent will accumulate
thrombus in the absence of platelet inhibitionthrombus in the absence of platelet inhibition Antiplatelet drugs are important to prevent peri or Antiplatelet drugs are important to prevent peri or
post-interventional thromboembolic eventspost-interventional thromboembolic events Optimal treatment regimens has not been determined Optimal treatment regimens has not been determined
but usually but usually Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-
procedureprocedureOrOr
Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on
morning of proceduremorning of procedure
If need to use stent is not pre-planned thanIf need to use stent is not pre-planned than
Abciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkgAbciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkg IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)
Glycoprotein IIbIIIa inhibitor are not used routinely during elective Glycoprotein IIbIIIa inhibitor are not used routinely during elective stenting procedure dt increased risk of ICH stenting procedure dt increased risk of ICH
Carotid StentingCarotid Stenting
Pre-procedurePre-procedure
Double Antiplatelet therapy is routinely given Double Antiplatelet therapy is routinely given beginning at least 3beginning at least 3
days before the proceduredays before the procedure
Aspirin 325mgd+Clopidogrel 75mgdAspirin 325mgd+Clopidogrel 75mgd During procedureDuring procedure
Heparin is given with target clotting time of 250-Heparin is given with target clotting time of 250-300sec300sec
Post-procedure Post-procedure
Aspirin 325mg is continued indefinitely and Aspirin 325mg is continued indefinitely and
Clopidogrel 75mgd for at least 6 weeks Clopidogrel 75mgd for at least 6 weeks
Inclusion criteria for Local ThrombolysisInclusion criteria for Local Thrombolysis a)a) Patients in severe clinical grade on admission Patients in severe clinical grade on admission
with evidence of dural venous sinus with evidence of dural venous sinus thrombosis and restrictive venous outflow on thrombosis and restrictive venous outflow on cerebral angiogramcerebral angiogram
b)b) Patients in clinical grade 3 worsening on Patients in clinical grade 3 worsening on heparin therapy Restriction to venous heparin therapy Restriction to venous outflow was defined as an increase in brain outflow was defined as an increase in brain circulation time gt 12 s delay in the drainage circulation time gt 12 s delay in the drainage of cortical veins with cortical veins hanging of cortical veins with cortical veins hanging in spacein space
Treatment Options for Venous Thrombosis
CT Grading for Venous ThrombosisCT Grading for Venous Thrombosis Grade I no parenchymal change Grade I no parenchymal change
(hyperdense (hyperdense sinuses cortical veins empty sinuses cortical veins empty delta sign)delta sign)
Grade II non hemorrhagic venous infarct Grade II non hemorrhagic venous infarct without mass effect without mass effect
Grade III non-hemorrhagic infarct with Grade III non-hemorrhagic infarct with mass effectmass effect
Grade IV hemorrhagic venous infarct (max Grade IV hemorrhagic venous infarct (max diameter lt 3 cm) with no mass effectdiameter lt 3 cm) with no mass effect
Grade V hemorrhagic venous infarct (max Grade V hemorrhagic venous infarct (max diameter gt 3 cm) with mass effect diameter gt 3 cm) with mass effect
Local ThrombolysisLocal Thrombolysis
Femoral Jugular access was secured and a guiding Femoral Jugular access was secured and a guiding catheter was placed in the jugular bulb catheter was placed in the jugular bulb Mechanical Mechanical clot maceration clot maceration was done with the guidewire was done with the guidewire following which a microcatheter (was navigated and following which a microcatheter (was navigated and placed in the thrombosed segment of sinus confirmed placed in the thrombosed segment of sinus confirmed on a selective venogram on a selective venogram
Urokinase infusion Bolus dose of 2-6 lacs followed Urokinase infusion Bolus dose of 2-6 lacs followed by 60000 to 100000 units per hour along with by 60000 to 100000 units per hour along with periodic check venogram Along with maintenance periodic check venogram Along with maintenance systemic infusion of Heparinsystemic infusion of Heparin Other agents such as Other agents such as streptokinase altepase or rTPAstreptokinase altepase or rTPA can be also used can be also used
After thrombolysis patient should subjected to oral After thrombolysis patient should subjected to oral anticoagulation for six monthsanticoagulation for six months
Low-molecular-weight Low-molecular-weight heparinheparin
PharmacologyPharmacologyLMWH as its name suggests is a glycosaminoglycan that is approximatelyLMWH as its name suggests is a glycosaminoglycan that is approximately
one third the molecular weight of UFH It is derived from UFH through one third the molecular weight of UFH It is derived from UFH through variousvarious
depolymerization processes LMWH binds to antithrombin which in turn depolymerization processes LMWH binds to antithrombin which in turn
Neutralizes actors Xa and IIa Because LMWH lacks many of the longer Neutralizes actors Xa and IIa Because LMWH lacks many of the longer chains chains
required for binding to thrombin it has less ability to neutralize thrombin required for binding to thrombin it has less ability to neutralize thrombin
relativeto its ability to neutralize factor Xa LMWH also has less relativeto its ability to neutralize factor Xa LMWH also has less nonspecific nonspecific
binding to other proteins There is greater bioavailability with more binding to other proteins There is greater bioavailability with more predictable predictable
pharmacokinetics that eliminates the need for monitoring The smaller pharmacokinetics that eliminates the need for monitoring The smaller size also size also
allows for enhanced subcutaneous absorption when compared with UFHallows for enhanced subcutaneous absorption when compared with UFH
Three LMWH preparations are Three LMWH preparations are currently approved for use in the currently approved for use in the United States (1) enoxaparin (2) United States (1) enoxaparin (2) dalteparin and (3) tinzaparin dalteparin and (3) tinzaparin
They are all administered They are all administered subcutaneously at intervals of either subcutaneously at intervals of either once or twice daily for both once or twice daily for both prophylaxis and treatment dosesprophylaxis and treatment doses
Few Experiences of Few Experiences of ThrombolysisThrombolysis
Vickey 25 Yrs male patient presented Vickey 25 Yrs male patient presented with 12with 12thth day HO severe headache with day HO severe headache with right sided hemiplegiaright sided hemiplegia
MRI shows thrombosis of the superior MRI shows thrombosis of the superior sagittal left transverse left sigmoid sagittal left transverse left sigmoid sinuses and cortical veins in the fronto-sinuses and cortical veins in the fronto-parietal regions with eo haemorrhagic parietal regions with eo haemorrhagic infarct in the left cerebral hemisphere infarct in the left cerebral hemisphere with mass effect( Grade ndashV)with mass effect( Grade ndashV)
Sashi Srivastava 64 yrs FSashi Srivastava 64 yrs F In a follow up case of MRD with infra-renal In a follow up case of MRD with infra-renal
aortic abdominal and bilateral renal artery aortic abdominal and bilateral renal artery thrombosis renal angiogram shows filling thrombosis renal angiogram shows filling defects in the right Renal artery defects in the right Renal artery
Initially Renal angioplasty was done Initially Renal angioplasty was done Following angioplasty few thrombi are seem Following angioplasty few thrombi are seem to extends into the segmental branches and to extends into the segmental branches and causing blockage So Thrombolysis was causing blockage So Thrombolysis was plane to dissolve the run-out thrombi with plane to dissolve the run-out thrombi with urokinase urokinase
Rakesh 34yrsMRakesh 34yrsM Left SFA pseudoaneurysm with Left SFA pseudoaneurysm with
Covered stent placementCovered stent placement Pre operative antiplatelets with post Pre operative antiplatelets with post
procedure heparin Tirofiban procedure heparin Tirofiban followed by aspirin and clopidogrel followed by aspirin and clopidogrel were usedwere used
IAT may be a treatment option for selected patients IAT may be a treatment option for selected patients Possible selection criteria include Possible selection criteria include
presentation between 3 and 6 hours from symptom onsetpresentation between 3 and 6 hours from symptom onset major cerebral artery occlusion major cerebral artery occlusion severe neurologic deficits severe neurologic deficits high risk of systemic hemorrhage with IV rt-PA (eg recent high risk of systemic hemorrhage with IV rt-PA (eg recent
surgery) surgery) The MERCI (Mechanical Embolus Removal in Cerebral The MERCI (Mechanical Embolus Removal in Cerebral
Ischemia) retrievalIschemia) retrieval system system
Has been FDA-approved for recanalizing acutely occluded Has been FDA-approved for recanalizing acutely occluded cerebral arteries cerebral arteries
In the Multi-MERCI study patients who did not improve In the Multi-MERCI study patients who did not improve immediately after IV rt-PA underwent mechanical immediately after IV rt-PA underwent mechanical embolectomy within 8 hours of symptom onset embolectomy within 8 hours of symptom onset
Partial or complete recanalization occurred in 74 of Partial or complete recanalization occurred in 74 of patientspatients
with a symptomatic intracerebral hemorrhage (sICH) rate of with a symptomatic intracerebral hemorrhage (sICH) rate of 67 67
Mechanical embolectomy with the MERCI retriever may be a Mechanical embolectomy with the MERCI retriever may be a feasible and safe option for patients after IV rt-PAfeasible and safe option for patients after IV rt-PA
Penumbra stroke systemPenumbra stroke system This device combines two methods of clot This device combines two methods of clot
extraction aspiration and mechanical extraction aspiration and mechanical extraction extraction
First the clot is aspirated then a thrombus First the clot is aspirated then a thrombus removal ring can be used if necessary to removal ring can be used if necessary to remove remaining clot remove remaining clot
successful recanalizing 82successful recanalizing 82 Bridging therapyBridging therapy
06 mgkg IV rt-PA followed by IAT with IA rt-06 mgkg IV rt-PA followed by IAT with IA rt-PA (up to 20 mg)PA (up to 20 mg)
achieved a higher recanalization rateachieved a higher recanalization rate
Criteria for thrombolysis with rTPACriteria for thrombolysis with rTPA
Inclusion criteriaInclusion criteria Clinical signs and symptoms consistent with ischemic Clinical signs and symptoms consistent with ischemic
strokestroke Patient last seen normal within 3 hoursPatient last seen normal within 3 hours Measurable neurologic deficitMeasurable neurologic deficit
Exclusion criteriaExclusion criteria Any hemorrhage on neuroimaging (CT or MRI)Any hemorrhage on neuroimaging (CT or MRI) Symptoms suggestive of subarachnoid hemorrhageSymptoms suggestive of subarachnoid hemorrhage Seizure at stroke onset that is thought to contribute to Seizure at stroke onset that is thought to contribute to
neurologic deficitneurologic deficit Hypodensity greater than one third cerebral hemisphere Hypodensity greater than one third cerebral hemisphere
on CTon CT SBP greater than 185 mm Hg or DBP greater than 110 SBP greater than 185 mm Hg or DBP greater than 110
mm Hgmm Hg International normalized ratio (INR) greater than 17International normalized ratio (INR) greater than 17
Ischemic Stroke Ischemic Stroke Treatment ndash 2006Treatment ndash 2006
IV tissue plasminogen activator (tPA)IV tissue plasminogen activator (tPA) ndash ndash Only FDA-approved acute stroke drugOnly FDA-approved acute stroke drug ndash ndash 3 hour treatment window3 hour treatment window
MERCI - Concentric clot retrieval MERCI - Concentric clot retrieval devicedevice ndash ndash Rescue therapy - approved 2004Rescue therapy - approved 2004 ndash ndash Device approval (not outcomes-based)Device approval (not outcomes-based)
Off label approachesOff label approaches ndash ndash IV tPA after 3 hoursIV tPA after 3 hours ndash ndash IV-IA tPA sequential strategiesIV-IA tPA sequential strategies ndash ndash IA tPA clot angioplasty fragmentationIA tPA clot angioplasty fragmentation ndash ndash Ultrasound-assisted tPA lysisUltrasound-assisted tPA lysis
rt-PA Trials NINDSrt-PA Trials NINDS
Acute stroke - 624 patientsAcute stroke - 624 patients Treat within 3 hrsTreat within 3 hrs Intravenous 09 mgkg rt-PA vs placeboIntravenous 09 mgkg rt-PA vs placebo Hemorrhage 64 tPA 06 placeboHemorrhage 64 tPA 06 placebo Neurologic recovery better with tPA 30 Neurologic recovery better with tPA 30
more like to have minimal or no disabilitymore like to have minimal or no disability
First proven approved treatment for First proven approved treatment for strokestroke
Limitations of tPALimitations of tPA Only 4 of acute strokes receive tPAOnly 4 of acute strokes receive tPA (Kleindorfer et al Stroke 2004 35 e27-e29)(Kleindorfer et al Stroke 2004 35 e27-e29)
Only 22 of patients present within 3 hoursOnly 22 of patients present within 3 hours1048707 1048707 51 of these ineligible due to51 of these ineligible due to
bull bull Mild severityMild severity bull bull Medical or surgical historyMedical or surgical history bull bull Blood testsBlood tests
Sustained recanalization only 13Sustained recanalization only 13 (Alexandrov et al NEJM 2004 351 2170-8)(Alexandrov et al NEJM 2004 351 2170-8)
Concern for hemorrhageConcern for hemorrhage tPA potentiates apoptotic injury tPA potentiates apoptotic injury (Liu et al Nature Med 2004 101379-83)(Liu et al Nature Med 2004 101379-83)
PROACT II IA Lysis TrialPROACT II IA Lysis Trial Baseline 24 hours 8 days
Baseline 60 minutes 120 minutes
9mg IAProurokinase
Desmoteplase Trials DEDAS Desmoteplase Trials DEDAS DIASDIAS
Trial OverviewTrial Overview Double blind randomized placebo Double blind randomized placebo
controlled trialscontrolled trials IV delivery 3-9 hour time windowIV delivery 3-9 hour time window Plasminogen activator ndash from Plasminogen activator ndash from vampire bat vampire bat
salivasaliva Selection based on PWI-DWI MismatchSelection based on PWI-DWI Mismatch
MRI InclusionMRI Inclusion PWI defect at least 2 cm AND ~20 larger PWI defect at least 2 cm AND ~20 larger
than DWIthan DWI PWI should be obvious even visible on PWI should be obvious even visible on
raw imagesraw imagesMRI ExclusionMRI Exclusion
DWI gt 13 MCADWI gt 13 MCA MRA ICA occlusionMRA ICA occlusion
Desmoteplase ndash DIAS Desmoteplase ndash DIAS ResultsResults
Mechanical Thrombolysis Mechanical Thrombolysis devicesdevices
mechanical thrombolysis potentially extends the treatment mechanical thrombolysis potentially extends the treatment window because they act promptly at the site of the thrombuswindow because they act promptly at the site of the thrombus
The devices can retrieve large clots that pharmaceutical agents The devices can retrieve large clots that pharmaceutical agents may not successfully lysemay not successfully lyse
Patients treated with IV tPA may be considered for treatment of Patients treated with IV tPA may be considered for treatment of residual clot with some of these devicesresidual clot with some of these devices
suction-creating saline jets suction-creating saline jets laser energy ultrasound laser energy ultrasound a corkscrew apparatus to treat strokesa corkscrew apparatus to treat strokes The AngioJet systemThe AngioJet system uses saline jets that are directed back into the catheter to uses saline jets that are directed back into the catheter to
create a low-pressure zone around the catheter tip inducing create a low-pressure zone around the catheter tip inducing suction suction
The clot is pulled into the exhaust lumen and removed from the The clot is pulled into the exhaust lumen and removed from the vessel Although US Food and Drug Administration (FDA) has vessel Although US Food and Drug Administration (FDA) has approved this device for use in arteriovenous dialysis grafts and approved this device for use in arteriovenous dialysis grafts and fistulae and for the treatment of coronary arteries saphenous fistulae and for the treatment of coronary arteries saphenous vein grafts and peripheral vessels clinical trials for the vein grafts and peripheral vessels clinical trials for the treatment of acute stroke are no longer in progress treatment of acute stroke are no longer in progress
Most devices are used in cerebral vessels that 2-5 mm
The Latis laser device The Latis laser device used laser energy to ablate clots used laser energy to ablate clots Arteries 2-5 mm in diameter could be Arteries 2-5 mm in diameter could be
treated including the ICA M1 or M2 treated including the ICA M1 or M2 branch of the MCA A1 branch of the branch of the MCA A1 branch of the anterior cerebral artery (ACA) basilar anterior cerebral artery (ACA) basilar artery posterior cerebral artery (PCA) artery posterior cerebral artery (PCA) and vertebral and vertebral
Patients could receive treatment as late Patients could receive treatment as late as 8 hours after symptom onset in the as 8 hours after symptom onset in the anterior circulation and within 24 hours in anterior circulation and within 24 hours in the posterior circulation the posterior circulation
Endovascular Photo Acoustic Endovascular Photo Acoustic Recanalization (EPAR) Recanalization (EPAR)
A laser power source generated energy for the A laser power source generated energy for the systemsystem
The energy was delivered by means of The energy was delivered by means of fiberoptics to the tip of the catheter at the fiberoptics to the tip of the catheter at the treatment sitetreatment site
Absorption of laser light by darkly pigmented Absorption of laser light by darkly pigmented materials (ie the clot) occurred inside the 1-mm materials (ie the clot) occurred inside the 1-mm catheter tipcatheter tip
the system was designed to minimize scattering the system was designed to minimize scattering of laser light of laser light
Absorption converted photo energy to acoustic Absorption converted photo energy to acoustic energy which then emulsified the clot inside the energy which then emulsified the clot inside the catheter tip catheter tip
EKOS ultrasound( the EKOS ultrasound( the Ultrasound Thrombolytic Ultrasound Thrombolytic
Infusion Catheter) Infusion Catheter) combines the use of a distal ultrasound transducer with combines the use of a distal ultrasound transducer with
infusion of a thrombolytic agent through the infusion of a thrombolytic agent through the microcathetermicrocatheter
Ultrasound changes the structure of the clot to Ultrasound changes the structure of the clot to temporarily increase its permeability while providing an temporarily increase its permeability while providing an acoustic pressure gradient to move the drug into the clot acoustic pressure gradient to move the drug into the clot to speed its dissolution to speed its dissolution
The EKOS catheter is placed in the proximal portion of the The EKOS catheter is placed in the proximal portion of the clot clot
After a 2-mg bolus of tPA was injected through the After a 2-mg bolus of tPA was injected through the catheter catheter
the patient received a continuous infusion of IA tPA 03 the patient received a continuous infusion of IA tPA 03 mgmin to a maximum of 20 mg and simultaneous mgmin to a maximum of 20 mg and simultaneous ultrasound transmission for as long as 60 minutes ultrasound transmission for as long as 60 minutes
One patient was treated with a total of 4 units of One patient was treated with a total of 4 units of recombinant reteplase (Retavase) hand-injected over 60 recombinant reteplase (Retavase) hand-injected over 60 minutes minutes
Penumbra system Penumbra system The Penumbra system (Penumbra Inc) provides a dual The Penumbra system (Penumbra Inc) provides a dual
approach to clot extraction using aspiration followed by approach to clot extraction using aspiration followed by clot retrieval with a ring device if needed clot retrieval with a ring device if needed
Mechanical Embolus Removal in Cerebral Ischemia Mechanical Embolus Removal in Cerebral Ischemia (MERCI)(MERCI)
a corkscrew-like apparatus to remove blood clots from a corkscrew-like apparatus to remove blood clots from the brain in patients experiencing an ischemic stroke the brain in patients experiencing an ischemic stroke
The corkscrew itself resides in the catheter tip which The corkscrew itself resides in the catheter tip which shields it from the wall of the vessel until it is ready to be shields it from the wall of the vessel until it is ready to be burrowed into the clot Once lodged in the clot the device burrowed into the clot Once lodged in the clot the device and clot are withdrawn from the vessel and clot are withdrawn from the vessel
Snarelike devicesSnarelike devices Snares such as the Neuronet snare (Guidant Snares such as the Neuronet snare (Guidant
Endovascular Santa Clara CA) have been developed Endovascular Santa Clara CA) have been developed specifically for use in the treatment of strokes specifically for use in the treatment of strokes
These devices are simple in design and do not require the These devices are simple in design and do not require the clot to be amenable to emulsification clot to be amenable to emulsification
X-Sizer deviceX-Sizer device a device with small moving blades at the a device with small moving blades at the
catheter tip catheter tip This device the X-Sizer device (EndiCor Medical This device the X-Sizer device (EndiCor Medical
San Clemente CA) can be used to excise the San Clemente CA) can be used to excise the thrombus and aspirate it thrombus and aspirate it
The device was being evaluated in randomized The device was being evaluated in randomized studies of coronary vessels and in a registry of studies of coronary vessels and in a registry of patients with acute myocardial infarctionpatients with acute myocardial infarction
Although the manufacturer had modified the Although the manufacturer had modified the device for use in cerebral vessels a safety and device for use in cerebral vessels a safety and feasibility study was indefinitely suspended after feasibility study was indefinitely suspended after only 1 patient was treated with the device in only 1 patient was treated with the device in Europe Europe
Suction thrombectomySuction thrombectomy This method of mechanical thrombolysis is one of the This method of mechanical thrombolysis is one of the
simplestsimplest In this readily available technique suction is applied with In this readily available technique suction is applied with
a syringe to remove thrombus in the ICA a syringe to remove thrombus in the ICA It requires no other devicesIt requires no other devices A catheter with a large inner diameter (Brite Tip Cordis A catheter with a large inner diameter (Brite Tip Cordis
Corporation Miami FL) was placed in the symptomatic Corporation Miami FL) was placed in the symptomatic vessel and navigated over a guidewire into the thrombusvessel and navigated over a guidewire into the thrombus
A 60-mL syringe was used to aspirate the thrombus A 60-mL syringe was used to aspirate the thrombus Each patient required angioplasty and stenting of carotid Each patient required angioplasty and stenting of carotid
bifurcation stenosis and received daily aspirin and bifurcation stenosis and received daily aspirin and ticlopidine after the procedure No complications ticlopidine after the procedure No complications occurred occurred
Summary Acute Stroke Summary Acute Stroke ImagingImaging
PhysiologyPhysiology importance collaterals importance collaterals
ndash ndashGrowing role for perfusion Growing role for perfusion assessmentassessment
tPAtPA guidelines amp limitations guidelines amp limitations Signs on CT amp MRSigns on CT amp MR follow physiology follow physiology Stroke trialsStroke trials PWI-DWI mismatch PWI-DWI mismatch
ndash ndashTreat based on physiology not timeTreat based on physiology not time ProtocolsProtocols should be fast and should be fast and
comprehensivecomprehensive
ANTICOAGULANTSANTICOAGULANTS
Heparin and Low Molecular Weight Heparins Heparin and Low Molecular Weight Heparins ((eg enoxaparin dalteparin)eg enoxaparin dalteparin)
Oral anticoagulantsOral anticoagulants Coumarin Derivatves Coumarin Derivatves eg Warfarin eg Warfarin
AcenocoumarolAcenocoumarol Indandione Derivatves Indandione Derivatves eg Phenindione eg Phenindione
AnisindioneAnisindione
ThrombolyticsThrombolytics
Plasminogen activators
Fibrinolytics
Anti Platelet DrugsAnti Platelet DrugsDrug Mechanism UsesDrug Mechanism UsesAspirinAspirin Permanently inhibits Permanently inhibits
COX-1 and COX-2COX-1 and COX-2CADCAD
Stroke-TIAsStroke-TIAs
NSAIDsNSAIDs Reversibly inhibits Reversibly inhibits COX-1COX-1
LimitedLimited
DipyridamoleDipyridamole Inhibits PDE Inhibits PDE increases cAMPincreases cAMP
TIAsTIAs
ThenopyridinesThenopyridines
(Ticlopidine(Ticlopidine
Clopidegrel)Clopidegrel)
Inhibits ADP Inhibits ADP
PlatAg PlatAg
TIAsStrokeTIAsStroke
CAD PVDCAD PVD
Abciximab (ReoPro)Abciximab (ReoPro)
Eptifibatide Eptifibatide (Integrilin)(Integrilin)
TirofibaTirofibann
GP IIBIIIA InhibitorsGP IIBIIIA Inhibitors
Stroke- TIAs Stroke- TIAs
Maintainance of patency Maintainance of patency of vascular of vascular grafts catheters shunts bypassesgrafts catheters shunts bypasses
Arterial thromboembolic diseaseArterial thromboembolic diseasebull Transient ischemic attacksTransient ischemic attacksbull Stroke in evolutionStroke in evolution
Ischemic events occurs in Ischemic events occurs in 1313 of of conventional neuroangiographic conventional neuroangiographic procedures without Endovascular surgeryprocedures without Endovascular surgery
Indications for Antithrombotic Therapy in Indications for Antithrombotic Therapy in Diagnostics and Interventional ProceduresDiagnostics and Interventional Procedures
WHY TO MONITOR ANTICOAGULANT THERAPYWHY TO MONITOR ANTICOAGULANT THERAPY
Narrow therapeutic rangeNarrow therapeutic range
Can increase risk of bleedingCan increase risk of bleeding
Coagulation TestingCoagulation Testing
Monitoring therapyMonitoring therapy
Intrinsic Pathway
Extrinsic Pathway
Common Pathway
CLOT
Heparin Coumadin
Monitor with
ACT aPTT
Monitor with PTINR
Thrombolytics
Monitor with TT Fibrinogen
Monitoring of Monitoring of Anti platelet drugsAnti platelet drugs
Bleeding timeBleeding time
Optical aggregometryOptical aggregometry
Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay
HeparinHeparin
Heterogeneous 3000-30000 dalton in Heterogeneous 3000-30000 dalton in molecular weight molecular weight
Average=15000 d (~45monosaccharide Average=15000 d (~45monosaccharide chains)chains)
About About 13 of dose binds to AT III and forms 13 of dose binds to AT III and forms the AT IIIHeparinClotting Factor Complexthe AT IIIHeparinClotting Factor Complex
Complex binds to clotting factors of the Complex binds to clotting factors of the intrinsic and common pathway (Xa IIa IXa intrinsic and common pathway (Xa IIa IXa XIa XIIa XIIIa) and inactivates themXIa XIIa XIIIa) and inactivates them
Anticoagulant of choice in pregnancy (not Anticoagulant of choice in pregnancy (not crosses placenta)crosses placenta)
Heparin and Low molecular weight heparinsHeparin and Low molecular weight heparins
Structure and sequence
O
OH
OH
O
COO
O
O
CH2OH
NHSO3
OH
_
_
O
O
CH2OSO3
NHSO3
OH
_
_
O
OH
OH
O
COOO
O
CH2OSO3
NHSO3
OH
_
_
O
OSO3
OHO
COOO
O
CH2OSO3
NHCOCH3
OH
_
_ _
_
_
O
OH
OH
O
COO
1
23
4
5
6
-D-glucosamine -L-iduronic acid -D-glucuronic acid
O
O
CH2OH
NH2
OH 12
3
4
5
6
O
OH
OHO
COO_
1
23
4
5
6
polymeric structure of heparin
Anticoagulant Properties of Anticoagulant Properties of HeparinHeparin
11 Inhibits the thrombin-mediated conversion of Inhibits the thrombin-mediated conversion of fibrinogen to fibrinfibrinogen to fibrin
22 Inhibits the aggregation of platelets by thrombin Inhibits the aggregation of platelets by thrombin (prolongs bleeding time)(prolongs bleeding time)
33 Inhibits activation of fibrin stabilizing enzymeInhibits activation of fibrin stabilizing enzyme
44 Inhibits activated factors XII XI IX X and IIInhibits activated factors XII XI IX X and II All available forms of heparin must be All available forms of heparin must be
administered administered parenterally since they are parenterally since they are highly charged and rapidlyhighly charged and rapidly hydrolyzed in the hydrolyzed in the GI tractGI tract
Heparin antagonist Protamine sulfate (Heparin antagonist Protamine sulfate (10mg for 10mg for 1000 unit of heparin)1000 unit of heparin)
Monitoring of heparin Monitoring of heparin
Subcutenous Subcutenous no monitoring requiredno monitoring required Intravenous Intravenous
Partial thromboplastin time (PTT normal value Partial thromboplastin time (PTT normal value ~30sec) ~30sec)
Activated clotting time ( ACT normal value ~90-Activated clotting time ( ACT normal value ~90-120sec)120sec)
Daily or more frequent if PTT ACT variesDaily or more frequent if PTT ACT varies
Mechanism Mechanism ndash measures intrinsic pathwayndash measures intrinsic pathway Therapeutic goal Therapeutic goal 2-25 times normal control value 2-25 times normal control value
ACT or aPTTACT or aPTT
Determine when to pull the femoral sheath Determine when to pull the femoral sheath Premature sheath pull can lead to bleedingPremature sheath pull can lead to bleeding Delayed removal can increase time in ICUDelayed removal can increase time in ICU Target set Target set at each siteat each site
ACT targets range from 150 ndash 220 ACT targets range from 150 ndash 220 secondsseconds
aPTT targets range from 40 ndash 70 seconds aPTT targets range from 40 ndash 70 seconds
During neuroangiography-During neuroangiography- Recommended therapeutic range of heparin in Recommended therapeutic range of heparin in
plasma is 02-08 uml ( corresponding to aPTT plasma is 02-08 uml ( corresponding to aPTT ACT values 15-25 times the baseline values)ACT values 15-25 times the baseline values)
Dose In diagnostic angiography bolus dose of Dose In diagnostic angiography bolus dose of 2500 iu is used followed by 1000 iu hour2500 iu is used followed by 1000 iu hour
Bolus dose is Bolus dose is 60 ukg to maintain the therapeutic 60 ukg to maintain the therapeutic range range If procedure continues for more than 75 If procedure continues for more than 75 minutes additional dose is required ( half of the minutes additional dose is required ( half of the initial dose for another 75 minutes) initial dose for another 75 minutes)
(AJNR 199415 51-54)
Mechanisms of HIT( Mechanisms of HIT( Heparin Heparin induced Thrombocytopeniainduced Thrombocytopenia))
Type 1Type 1 Fall in platelet count occurs within the first two Fall in platelet count occurs within the first two
days after heparin initiation often returns to days after heparin initiation often returns to normal with continued heparin administration normal with continued heparin administration and is of no clinical consequence and is of no clinical consequence
The mechanism of the thrombocytopenia is non-The mechanism of the thrombocytopenia is non-immune and appears to be due to a direct effect of immune and appears to be due to a direct effect of heparin on platelet activationheparin on platelet activation
Type 2Type 2 Approximately 03 to 3 percent of patients Approximately 03 to 3 percent of patients
receiving heparin develop an immune receiving heparin develop an immune thrombocytopenia mediated by antibodies to a thrombocytopenia mediated by antibodies to a heparin-platelet factor 4 complex heparin-platelet factor 4 complex
(AJNR 28155-158 2007)
Treatment of heparin-induced Treatment of heparin-induced thrombocytopeniathrombocytopenia
When HIT is diagnosed it is important to When HIT is diagnosed it is important to stop heparin mainly in type 2 and to avoid stop heparin mainly in type 2 and to avoid the use of LMWH the use of LMWH
Because of the increased risk of thrombosis Because of the increased risk of thrombosis however continuation of an anticoagulant however continuation of an anticoagulant must be considered must be considered
The drugs currently approved for the The drugs currently approved for the treatment of HIT in the United States are treatment of HIT in the United States are direct thrombin inhibitors argatroban and direct thrombin inhibitors argatroban and lepirudinlepirudin
WARFARIN MECHANISM OF ACTIONWARFARIN MECHANISM OF ACTION
Inactive factors II VII IX and X
Proteins S and C
Active factors II VII IX and X
Proteins S and C
Vitamin K epoxide
Vitamin K reduced
WA
RF
AR
IN
Prevents the reduction of vitamin K which is essential for Prevents the reduction of vitamin K which is essential for activation of certain factorsactivation of certain factors
Has no effect on previously formed thrombusHas no effect on previously formed thrombus
Antagonist is Vit KAntagonist is Vit K
OPTIMIZING WARFARIN THERAPYOPTIMIZING WARFARIN THERAPY
Use of large loading dose may lead to hemorrhage and Use of large loading dose may lead to hemorrhage and other complicationsother complications
Initial dose 2-5 mg once dailyInitial dose 2-5 mg once daily Maintenance dose 2-10 mg once dailyMaintenance dose 2-10 mg once daily If Immediate anticoagulation is requiredIf Immediate anticoagulation is required Heparin IS Heparin IS
started along with loading dose of warfarin 10 mg started along with loading dose of warfarin 10 mg Heparin is usually discontinued after 4-5 days Heparin is usually discontinued after 4-5 days Before Before discontinuing INR should be in therapeutic range for 2 discontinuing INR should be in therapeutic range for 2 consecutive daysconsecutive days
Daily monitoring of INR until INR is in therapeutic Daily monitoring of INR until INR is in therapeutic range then 3 times weekly for 1-2 weeks then less often range then 3 times weekly for 1-2 weeks then less often (every 4 to 6 weeks)(every 4 to 6 weeks)
OPTIMAL THERAPEUTIC RANGEOPTIMAL THERAPEUTIC RANGE
IndicationIndication INRINR
Prophylaxis of venous Prophylaxis of venous thromboembolismthromboembolism
20-3020-30
Treatment of venous Treatment of venous thromboembolismthromboembolism
20-3020-30
Atrial fibrillationAtrial fibrillation 20-3020-30
Mitral valve stenosisMitral valve stenosis 20-3020-30
Heart valve replacementHeart valve replacement
Bioprosthetic valveBioprosthetic valve
Mechanical valveMechanical valve
20-3020-30
25-3525-35
Myocardial infarctionMyocardial infarction 20-3020-30
25-35 25-35 (high risk patients)(high risk patients)
FACTORS INFLUENCING DOSE RESPONSEFACTORS INFLUENCING DOSE RESPONSE
Poor patient compliancePoor patient compliance Concomitant medicationsConcomitant medications Levels of dietary vitamin KLevels of dietary vitamin K Alcohol Inaccurate lab testingAlcohol Inaccurate lab testing Inaccurate lab testingInaccurate lab testing Hepatic dysfunctionHepatic dysfunction FeverFever
Contraindication for WarfarinContraindication for Warfarin
Hypersensitivity to warfarinHypersensitivity to warfarin Hemorrhagic tendencyHemorrhagic tendency Condition with risk of hemorrhageCondition with risk of hemorrhage Inadequate laboratory techniquesInadequate laboratory techniques Protein C amp S deficiencyProtein C amp S deficiency Vitamin K deficiencyVitamin K deficiency
SIDE EFFECTSSIDE EFFECTS
Hemorrhage Hemorrhage Skin necrosisSkin necrosis Purple toe syndromePurple toe syndrome Microembolization Microembolization TeratogenecityTeratogenecity Agranulocytosis leukopenia Agranulocytosis leukopenia Diarrhoeanausea anorexiaDiarrhoeanausea anorexia
MONITORING OF WARFARIN THERAPYMONITORING OF WARFARIN THERAPY
Prothrombin timeProthrombin time PT ratioPT ratio INR (International Normalized Ratio)INR (International Normalized Ratio)
PROTHROMBIN TIME (PT)PROTHROMBIN TIME (PT)
Time required for blood to coagulate Time required for blood to coagulate is called PT ( normal value ~10sec)is called PT ( normal value ~10sec)
Performed by adding a mixture of Performed by adding a mixture of calcium and thromboplastin to calcium and thromboplastin to citrated plasmacitrated plasma
As a control a normal blood sample is As a control a normal blood sample is tested continuouslytested continuously
PT ratio (PTR) = PT ratio (PTR) = Patientrsquos PTPatientrsquos PT Control PTControl PT
PROBLEMS WITH PTPTRPROBLEMS WITH PTPTR
Thromboplastins are extracts from Thromboplastins are extracts from brain lung or placenta of animalsbrain lung or placenta of animals
Thromboplastins from various Thromboplastins from various manufacturers differ in their manufacturers differ in their sensitivity to prolong PTsensitivity to prolong PT
May result in false control of May result in false control of anticoagulant therapyanticoagulant therapy
INTERNATIONAL NORMALISED RATIO (INR)INTERNATIONAL NORMALISED RATIO (INR)
International Normalized Ratio (INR) International Normalized Ratio (INR) a PT test with a a PT test with a formula based ratio to normalize the often variable source formula based ratio to normalize the often variable source of tissue factor (human rabbit recombinant)of tissue factor (human rabbit recombinant)
INR = [PTINR = [PTptpt] ] ISIISI
[PT[PTRefRef]]
PTPTpt pt ndash prothrombin time of patientndash prothrombin time of patient
PTPTRef Ref ndash prothrombin time of normal pooled samplendash prothrombin time of normal pooled sample
ISI ndash International Sensitivity IndexISI ndash International Sensitivity Index
Warfarin is given orally and titrated to achieve an INR of Warfarin is given orally and titrated to achieve an INR of typically 20 ndash 30typically 20 ndash 30
Heparin versus WarfarinHeparin versus Warfarin
Drug ActionMechan-ism
Moni-toring
Effective
HeparinDirect
Inhibition ofThrombin
ATIIIcofactor
APTTACT
Immediate
WarfarinDecreasesProductionof factors
Vitamin K PTDelay
3-5 days
INR
Recanalization or Antegrade Recanalization or Antegrade Reperfusion StrategiesReperfusion Strategies
Recanalization strategies focus on removing Recanalization strategies focus on removing andor dissolving the occlusive thrombus to re-andor dissolving the occlusive thrombus to re-establish antegrade flow Strategies may be establish antegrade flow Strategies may be classified into 7 different categories on the classified into 7 different categories on the basis of their primary mechanism of action basis of their primary mechanism of action 1) 1) IV andor intraarterial thrombolysis (IAT) IV andor intraarterial thrombolysis (IAT) 2) endovascular thrombectomy2) endovascular thrombectomy3) endovascular thromboaspiration 3) endovascular thromboaspiration 4) endovascular mechanical thrombus disruption or 4) endovascular mechanical thrombus disruption or
thromborrhexisthromborrhexis5) 5) transcranial or endovascular augmented transcranial or endovascular augmented
fibrinolysis fibrinolysis 6) endovascular thrombus entrapment and 6) endovascular thrombus entrapment and 7) temporary endovascular bypass7) temporary endovascular bypass
IAT in Acute Ischemic StrokeIAT in Acute Ischemic Stroke
IAT advantages over IV thrombolysisIAT advantages over IV thrombolysis Coaxial microcatheter techniques the occluded intracranial Coaxial microcatheter techniques the occluded intracranial
vessel is directly accessible and the fibrinolytic agent can be vessel is directly accessible and the fibrinolytic agent can be infused directly into the thrombusinfused directly into the thrombus
This permits a smaller dose of fibrinolytic agent to reach a This permits a smaller dose of fibrinolytic agent to reach a higher local concentration than that reached by systemic higher local concentration than that reached by systemic infusioninfusion
Allows more complete recanalization with lower total doses of Allows more complete recanalization with lower total doses of thrombolytic thrombolytic
With the smaller dose complications from systemic fibrinolytic With the smaller dose complications from systemic fibrinolytic effects including intracranial hemorrhage (ICH) can effects including intracranial hemorrhage (ICH) can theoretically be reduced theoretically be reduced
Treatment window for endovascular techniques can be Treatment window for endovascular techniques can be extended beyond the typical IV window of 3 hours extended beyond the typical IV window of 3 hours
IA techniques have led to higher recanalization rates than IV IA techniques have led to higher recanalization rates than IV thrombolysisthrombolysis
Major disadvantagesMajor disadvantages Relative complexity of the procedure the level Relative complexity of the procedure the level
of required technical expertise and its of required technical expertise and its relatively low availability relatively low availability
Delays in initiating treatmentDelays in initiating treatment InvasiveInvasive
ThrombolyticsThrombolytics
Plasminogen activators
Fibrinolytics
1 Plasminogen Activators 1 Plasminogen Activators drugs act by converting the inactive proenzyme drugs act by converting the inactive proenzyme plasminogen into the active enzyme plasmin Plasmin plasminogen into the active enzyme plasmin Plasmin digests fibrinogen fibrin monomers and cross-linked digests fibrinogen fibrin monomers and cross-linked fibrin (as found in a thrombus) into fibrin degradation fibrin (as found in a thrombus) into fibrin degradation productsproducts
First-Generation Agents First-Generation Agents StreptokinaseStreptokinase a protein derived from group C a protein derived from group C
szlig-hemolytic streptococci has a half-life of 16ndashszlig-hemolytic streptococci has a half-life of 16ndash90 minutes and low fibrin specificity This drug 90 minutes and low fibrin specificity This drug proved to have a very narrow therapeutic proved to have a very narrow therapeutic window and significant rates of ICH and window and significant rates of ICH and systemic hemorrhage18systemic hemorrhage18
UrokinaseUrokinase is a serine protease with a plasma is a serine protease with a plasma half life of 14 minutes and low fibrin specificity half life of 14 minutes and low fibrin specificity
The urokinase dose used in cerebral IAT has The urokinase dose used in cerebral IAT has ranged from 002 to 2 X106unitsranged from 002 to 2 X106units
Second-Generation Agents Second-Generation Agents Alteplase (rtPA) Alteplase (rtPA)
is a serine is a serine protease with a plasma half-life of 35 protease with a plasma half-life of 35 minutes and a high degree of fibrin affinity and minutes and a high degree of fibrin affinity and specificity specificity
Dose used in cerebral IAT has ranged between 20 Dose used in cerebral IAT has ranged between 20 and 60 mgand 60 mg
Disadvantages of alteplase include its relatively short Disadvantages of alteplase include its relatively short halflife and limited penetration into the clot matrix halflife and limited penetration into the clot matrix because of strong binding with surface fibrin which because of strong binding with surface fibrin which could delay recanalization and increase the risk of could delay recanalization and increase the risk of recurrent occlusion recurrent occlusion
Prourokinase (r-prourokinase) Prourokinase (r-prourokinase) is the proenzyme precursor of urokinase is the proenzyme precursor of urokinase T12 of 7 minutes and high fibrin specificity T12 of 7 minutes and high fibrin specificity
Third-Generation AgentsThird-Generation Agents
ReteplaseReteplase is a structurally modified is a structurally modified form of alteplase form of alteplase
with a longer half-life (15ndash18 minutes) In with a longer half-life (15ndash18 minutes) In addition it does not bind as highly to fibrin addition it does not bind as highly to fibrin unbound reteplase can thus theoretically better unbound reteplase can thus theoretically better penetrate the clot and potentially penetrate the clot and potentially improve in improve in vivo fibrinolytic activity vivo fibrinolytic activity
TenecteplaseTenecteplase is another modified form of rtPA with a longer is another modified form of rtPA with a longer
half-life (17 minutes)half-life (17 minutes) greater fibrin specificity and greater greater fibrin specificity and greater
resistance to plasminogen activator inhibitor-1 resistance to plasminogen activator inhibitor-1 IV tenecteplase in acute ischemic stroke IV tenecteplase in acute ischemic stroke
suggest that the drug is safe and promisingsuggest that the drug is safe and promising
Newer plasminogen activatorNewer plasminogen activator
DesmoteplaseDesmoteplase is a genetically engineered is a genetically engineered version of the clot-dissolving factor version of the clot-dissolving factor
found in the saliva found in the saliva of the vampire bat Desmodus rotundusof the vampire bat Desmodus rotundus moremore potent and more selective for fibrin-bound potent and more selective for fibrin-bound
plasminogen than any other known plasminogen plasminogen than any other known plasminogen activatoractivator
Unlike tissue plasminogen activator (tPA) desmoteplase Unlike tissue plasminogen activator (tPA) desmoteplase is not activated by fibrinogen or -amyloid proteins is not activated by fibrinogen or -amyloid proteins factors that may exacerbate the risk for ICH factors that may exacerbate the risk for ICH
The effect of IV administration of desmoteplase 3ndash9 The effect of IV administration of desmoteplase 3ndash9 hours after symptom onset in patients with stroke who hours after symptom onset in patients with stroke who present with mismatch on MR imaging or CT perfusion present with mismatch on MR imaging or CT perfusion
3 DefibrinogenatingFibrinogenolytic 3 DefibrinogenatingFibrinogenolytic Agents Agents
AncrodAncrod(Viprinex)(Viprinex) is is the purified fraction of the Malayan pit viper venomthe purified fraction of the Malayan pit viper venom It acts by directly cleaving and inactivating fibrinogen It acts by directly cleaving and inactivating fibrinogen
and thus indirectly promoting anticoagulation and thus indirectly promoting anticoagulation The reduction in the blood levels of fibrinogen also The reduction in the blood levels of fibrinogen also
leads to a reduced blood viscosity which may improve leads to a reduced blood viscosity which may improve blood flow to the affected areas of the brain blood flow to the affected areas of the brain
In the Stroke Treatment with Ancrod Trial 500 In the Stroke Treatment with Ancrod Trial 500 patients with stroke presenting within 3 hours of patients with stroke presenting within 3 hours of symptom onset were randomized to receive ancrod (symptom onset were randomized to receive ancrod (n n 248) or a placebo (n 252) Good outcome (Barthel 248) or a placebo (n 252) Good outcome (Barthel Index 95ndash100 at 3 months) was achieved in 4221 Index 95ndash100 at 3 months) was achieved in 4221 and 344 of the patients respectively and 344 of the patients respectively
2 Direct Fibrinolytics2 Direct Fibrinolytics
Microplasmin (Microplasmin (ThromboGenics Heverlee Belgium)ThromboGenics Heverlee Belgium) is a truncated form of plasmin that is more resistant to the effects is a truncated form of plasmin that is more resistant to the effects
of antiplasmin of antiplasmin microplasmin can be used upto 4ndash12 hours after stroke onset microplasmin can be used upto 4ndash12 hours after stroke onset There was no evidence of increased bleeding risk with There was no evidence of increased bleeding risk with
microplasminmicroplasmin
Alfimeprase (Nuvelo San Carlos Calif)Alfimeprase (Nuvelo San Carlos Calif) is a recombinant truncated form of fibrolase a fibrinolytic zinc metalloproteinase is a recombinant truncated form of fibrolase a fibrinolytic zinc metalloproteinase
isolated from the venom of the southern copperhead snake isolated from the venom of the southern copperhead snake It degrades fibrin directly and achieves thrombolysis independent It degrades fibrin directly and achieves thrombolysis independent
of plasmin formationof plasmin formation its thrombolytic activity appears to be localized to the site of its thrombolytic activity appears to be localized to the site of
delivery These properties should theoretically result in faster delivery These properties should theoretically result in faster recanalization and lower hemorrhagic conversion riskrecanalization and lower hemorrhagic conversion risk
Anti-fibrinolyticsAnti-fibrinolytics
to limit fibrinolytic activityto limit fibrinolytic activity -aminocaproic acid (EACA) -aminocaproic acid (EACA) competitively inhibitscompetitively inhibits plasminogen and plasminogen activators from plasminogen and plasminogen activators from
binding to fibrinbinding to fibrin
alpha2-antiplasminalpha2-antiplasmin a serine protease inhibitor that a serine protease inhibitor that neutralizes any free circulating plasminneutralizes any free circulating plasmin
Plasminogen activator inhibitor-1Plasminogen activator inhibitor-1 a serine protease a serine protease inhibitor that inhibits tissue-type plasminogen inhibitor that inhibits tissue-type plasminogen activatoractivator
Glycoprotein (GP) IIbIIIa antagonistsGlycoprotein (GP) IIbIIIa antagonists
such as ReoPro (abciximab) Integrilin such as ReoPro (abciximab) Integrilin (eptifibatide) or Aggrastat (tirofiban) in (eptifibatide) or Aggrastat (tirofiban) in ischemic stroke remains investigational ischemic stroke remains investigational Deshmukh et al38 reported 21 patients with Deshmukh et al38 reported 21 patients with large-vessel occlusion refractory to IAT with large-vessel occlusion refractory to IAT with rtPA who were treated with IV andor IA rtPA who were treated with IV andor IA abciximab eptifibatide or tirofiban abciximab eptifibatide or tirofiban
IA Mechanical Approaches in Acute Ischemic Stroke IA Mechanical Approaches in Acute Ischemic Stroke Mechanical strategies have several advantagesMechanical strategies have several advantages First they lessen and may even preclude the use of chemical First they lessen and may even preclude the use of chemical
thrombolytics in this manner very likely reducing the risk of ICHthrombolytics in this manner very likely reducing the risk of ICH Second by avoiding the use of chemical thrombolytics it is Second by avoiding the use of chemical thrombolytics it is
possible to extend the treatment window beyond the limit of 6ndash8 possible to extend the treatment window beyond the limit of 6ndash8 hours hours
Third mechanically fragmenting a clot increases the surface area Third mechanically fragmenting a clot increases the surface area accessible to fibrinolytic agents and allows inflow of fresh accessible to fibrinolytic agents and allows inflow of fresh plasminogen which in turn may increase the speed of plasminogen which in turn may increase the speed of thrombolysis thrombolysis
Finally clot-retrieval devices may provide faster recanalization Finally clot-retrieval devices may provide faster recanalization
The disadvantages of the mechanical The disadvantages of the mechanical approaches approaches technical difficulty of navigating mechanical technical difficulty of navigating mechanical
devices into the intracranial circulation excessive devices into the intracranial circulation excessive trauma to the vasculature (potentially leading to trauma to the vasculature (potentially leading to vasospasm vessel dissection perforation or vasospasm vessel dissection perforation or rupture) rupture)
fragmented thrombus causing distal embolization fragmented thrombus causing distal embolization into previously unaffected territories into previously unaffected territories
Nevertheless the advantages of mechanical stroke Nevertheless the advantages of mechanical stroke therapy appear to significantly outweigh its therapy appear to significantly outweigh its disadvantages and risksdisadvantages and risks
Contraindications to Thrombolytic Contraindications to Thrombolytic agents agents
Recent thoracic abdominal or Recent thoracic abdominal or intracranial surgeryintracranial surgery
Recent haemorrhagic CVA Head injury Recent haemorrhagic CVA Head injury or neoplasmor neoplasm
Bleeding ulcerBleeding ulcer Anticipated invasive procedures (arterial Anticipated invasive procedures (arterial
punctures biopsies)punctures biopsies) Concurrent hemostatic dysfunctionConcurrent hemostatic dysfunction
Monitoring of thrombolytic Monitoring of thrombolytic therapytherapy
Thrombin time Measures the availability of functional
fibrinogen Normal thrombin time is 10-14 sec Prolonged when fibrinogen level is below
75-100 mgdl
Half Life of ThrombolyticsHalf Life of ThrombolyticsAgent Administration Half Life
Streptokinase IA 60-80min
Urokinase IAIV 9-12min
rTPA IAIV 6min
Abciximab(Reopro) IAIV 12hour
Aspirin POIV 15-20min
Heparin IVSC 60min
Coumadin PO 15-25 days
Anti Platelet DrugsAnti Platelet DrugsDrug Drug Mechanism Mechanism UsesUsesAspirinAspirin Permanently inhibits Permanently inhibits
COX-1 and COX-2COX-1 and COX-2CADCAD
Stroke-TIAsStroke-TIAs
NSAIDsNSAIDs Reversibly inhibits Reversibly inhibits COX-1COX-1
LimitedLimited
DipyridamoleDipyridamole Inhibits PDE increases Inhibits PDE increases cAMPcAMP
TIAsTIAs
ThenopyridinesThenopyridines
(Ticlopidine(Ticlopidine
ClopidrgrelClopidrgrel))
Inhibits ADP Inhibits ADP
PlatAg PlatAg
TIAsStrokeTIAsStroke
CAD PVDCAD PVD
Abciximab (ReoPro)Abciximab (ReoPro)
Eptifibatide (Integrilin)Eptifibatide (Integrilin)
TirofibanTirofiban
GP IIBIIIA InhibitorsGP IIBIIIA Inhibitors
Stroke- TIAs Stroke- TIAs
MonitoringMonitoring
Bleeding timeBleeding time
Optical aggregometryOptical aggregometry
Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay
Bleeding timeBleeding time
Requires a skin incision (usually made on the ear lobe or Requires a skin incision (usually made on the ear lobe or forearm offorearm of
a depth that results in disruption of capillary loops and a depth that results in disruption of capillary loops and small vessels)small vessels)
AdvantagesAdvantages Universally availableUniversally available Relatively simple techniquesRelatively simple techniques Can be performed bedsideCan be performed bedside
DisadvantagesDisadvantages Insensitive inaccurate non-specific techniqueInsensitive inaccurate non-specific technique
Poorly reproducible (as depends on multiple variables)Poorly reproducible (as depends on multiple variables)
Optical aggregometryOptical aggregometry
Gold standard assay for platelet functionGold standard assay for platelet function Agonist induced aggregation is measuredAgonist induced aggregation is measured Different agonist are available for different Different agonist are available for different
agentsagents However require unique expertise and are not However require unique expertise and are not
universally availableuniversally available Aspirin measured with ADP or AA(gt70 Aspirin measured with ADP or AA(gt70
aggregation so resistance)aggregation so resistance) Clopidogrel( ADP gt 90 aggregation means Clopidogrel( ADP gt 90 aggregation means
resistance) resistance)
Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay
Can be performed bed sideCan be performed bed side Different assay devices with different Different assay devices with different
agonist are used for each of different agonist are used for each of different antiplatelet agents antiplatelet agents
For Aspirin AA is used (result is reported as aspirin For Aspirin AA is used (result is reported as aspirin reaction units [ARU] ARUgt 550 indicates non-reaction units [ARU] ARUgt 550 indicates non-responsiveness)responsiveness)
Verify IIbIIIa assay device uses TRAP as agonist for Verify IIbIIIa assay device uses TRAP as agonist for Abciximab and TirofibanAbciximab and Tirofiban
Practical Applications Practical Applications related to specific related to specific
Neurovascular Neurovascular interventionsinterventions
Acute ischemic StrokeAcute ischemic Stroke When an artery occludes neurons are affected When an artery occludes neurons are affected
differently depending upon the amount of residual blood differently depending upon the amount of residual blood flowflow
Normal cerebral blood flow is greater than 50 mL100 Normal cerebral blood flow is greater than 50 mL100 mgminmgmin
Once blood flow decreases to less than 20 mL100 Once blood flow decreases to less than 20 mL100 mgmin infarction occursmgmin infarction occurs
If blood flow decreases to less than 10 mL100 mgmin If blood flow decreases to less than 10 mL100 mgmin irreversible neuronal death occurs rapidly irreversible neuronal death occurs rapidly
Blood flow between 11 and 20 mL100 mgmin is thought Blood flow between 11 and 20 mL100 mgmin is thought to represent the ischemic penumbra an area where the to represent the ischemic penumbra an area where the cells are functionally silent because of ischemia but are cells are functionally silent because of ischemia but are still able to recover if blood flow is restored still able to recover if blood flow is restored
Many acute stroke therapies are targeted toward Many acute stroke therapies are targeted toward restoring flow or function to the ischemic penumbrarestoring flow or function to the ischemic penumbra
Therapeutic window in Therapeutic window in management of acute Ischemic management of acute Ischemic
StrokeStrokeThe early diagnosis of ischemic stroke is critical to the The early diagnosis of ischemic stroke is critical to the
with only a narrow therapeutic window in the first few with only a narrow therapeutic window in the first few hours following stroke ictushours following stroke ictus
Diagnosis in the first 3 hours postictus provides the Diagnosis in the first 3 hours postictus provides the opportunity for intravenous or intraarterial thrombolysis opportunity for intravenous or intraarterial thrombolysis and intra-arterial clot mechanical treatment which and intra-arterial clot mechanical treatment which improve the outcome improve the outcome
Diagnosis in the time period between 3 and 6 hours Diagnosis in the time period between 3 and 6 hours provides an opportunity for intra-arterial thrombolysis provides an opportunity for intra-arterial thrombolysis and mechanical treatment and mechanical treatment
Involvement of the posterior circulation especially the Involvement of the posterior circulation especially the basilar artery is treated by some regardless of time of basilar artery is treated by some regardless of time of onset or up until 12 to 24 hours in some practices This is onset or up until 12 to 24 hours in some practices This is related to the potentially high mortality and morbidity related to the potentially high mortality and morbidity associated with basilar artery thrombosisassociated with basilar artery thrombosis
Infarct evaluation on angiographyInfarct evaluation on angiography(CT angiography and catheter (CT angiography and catheter
angiography)angiography)CTA is an excellent first-line examination for CTA is an excellent first-line examination for
evaluation of the head and neck arteries evaluation of the head and neck arteries In comparison with catheter angiography In comparison with catheter angiography
what it gives up in resolution and dynamic what it gives up in resolution and dynamic properties it makes up for with rapid properties it makes up for with rapid acquisition of a 3-D dataset and the potential acquisition of a 3-D dataset and the potential for assessment of whole-brain perfusion and for assessment of whole-brain perfusion and better parenchymal evaluationbetter parenchymal evaluation
Moreover CTA illustrates not only arterial Moreover CTA illustrates not only arterial stenosis or occlusion but also the vessel wall stenosis or occlusion but also the vessel wall This factor is most important for evaluation of This factor is most important for evaluation of intramural dissection and thrombosed intramural dissection and thrombosed aneurysms which may both complicate aneurysms which may both complicate evaluation of stroke patientsevaluation of stroke patients
Early angiographic signs of strokes Early angiographic signs of strokes both CTA both CTA and DSA and DSA
Vessel occlusion or cutoff related to Vessel occlusion or cutoff related to thromboembolithromboemboli
aneurysms aneurysms arterial dissection arterial dissection Meniscus or flattened shape to clot Meniscus or flattened shape to clot
(recent) versus reverse meniscus (older)(recent) versus reverse meniscus (older) tram track (nonocclusive or recanalized tram track (nonocclusive or recanalized
clot) clot) delayed (antegrade) flow (manifest as delayed (antegrade) flow (manifest as
decreased whole-brain perfusion on CTA)decreased whole-brain perfusion on CTA) retrograde collateral flowretrograde collateral flow
Non-occlusive left MCA thrombus on 3-D imaging performed from CTA source data and was confirmed at catheter angiography
Therapy to be started within a 6-hr Therapy to be started within a 6-hr time to treatment (TTT) window time to treatment (TTT) window (while in case of IV thrombolysis (while in case of IV thrombolysis therapy to be started with in 3hrs)therapy to be started with in 3hrs)
Exclusion criteria Exclusion criteria Rapidly improving neurologic deficit or Rapidly improving neurologic deficit or Sustained blood pressure of gt180100 Sustained blood pressure of gt180100 Hemorrhage is detected on CTHemorrhage is detected on CT Infarct involving gt more than 13 rd Infarct involving gt more than 13 rd
territory of MCAterritory of MCA MRADWI-Perfusion mismatchlt 20MRADWI-Perfusion mismatchlt 20 Definite hypodensity on CTDefinite hypodensity on CT
Intra-arterial Thrombolysis
Fibrinolytics + AntiplateletsFibrinolytics + Antiplatelets
PlasminogenPlasminogen activators through fibrinolysis exposes activators through fibrinolysis exposes free thrombin and paradoxically stimulatesfree thrombin and paradoxically stimulates platelet platelet aggregation which leads to formation of aaggregation which leads to formation of a platelet platelet thrombus (white clot) thrombus (white clot)
This new thrombus is relatively resistant to This new thrombus is relatively resistant to fibrinolyticsfibrinolytics
So new regimen in case of acute stroke isSo new regimen in case of acute stroke is fibrinolytics + antiplatelet drugsfibrinolytics + antiplatelet drugs
rtPA + IIbIIIa inhibitors( tirofiban rtPA + IIbIIIa inhibitors( tirofiban abciximab) orabciximab) or
Urokinase + IIbIIIa Urokinase + IIbIIIa inhibitors( tirofiban abciximab)inhibitors( tirofiban abciximab)
Intra-arterial Thrombolysis Tirofiban (04 microgkgmin bolus for 3 min followed by Tirofiban (04 microgkgmin bolus for 3 min followed by
0125 ugkgmin)0125 ugkgmin)
++
Heparin (2000ndash3000 IU bolus followed by Heparin (2000ndash3000 IU bolus followed by 1000 IUhour infusion 1000 IUhour infusion
with ACT maintained bw 200-300) throughout the with ACT maintained bw 200-300) throughout the interventional procedure and for 24ndash48 hours thereafter when interventional procedure and for 24ndash48 hours thereafter when there is neither intraprocedural bleeding nor suspicion of there is neither intraprocedural bleeding nor suspicion of increased risk of bleeding increased risk of bleeding
Maximum dose of Urokinase Maximum dose of Urokinase Anterior circulation stroke - 500000 IU (mean 400000 Anterior circulation stroke - 500000 IU (mean 400000
IU range 300000ndash500000 IU)IU range 300000ndash500000 IU) Posterior circulation stroke -1000000 IU (mean 837000 Posterior circulation stroke -1000000 IU (mean 837000
IU range 300000ndash1000000 IU)IU range 300000ndash1000000 IU)American Journal of NeuroradiologyAmerican Journal of Neuroradiology 262595-2601 2005262595-2601 2005
Intravenous ThrombolysisIntravenous Thrombolysis
The first method to restore cerebral The first method to restore cerebral perfusion is clot lysis with the goal perfusion is clot lysis with the goal of re-establishing blood flow to the of re-establishing blood flow to the affected tissue affected tissue
IV thrombolysis rt-PA is the only IV thrombolysis rt-PA is the only FDA- approved treatment for AIS FDA- approved treatment for AIS
Fibrinolysis is enhanced powerfully Fibrinolysis is enhanced powerfully by rt-PAby rt-PA
Intravenous rTPA Intravenous rTPA administration administration protocolprotocol
Total dose of rt-PA 09 mgkg (maximum dose Total dose of rt-PA 09 mgkg (maximum dose 90 mg)90 mg)
Give 10 as initial IV bolusGive 10 as initial IV bolus Infuse remainder over 1 hourInfuse remainder over 1 hour Admit patient to an ICU or stroke unit for Admit patient to an ICU or stroke unit for
monitoringmonitoring Neurologic assessments every 15 minutes Neurologic assessments every 15 minutes
during infusion then every 30 minutes for next during infusion then every 30 minutes for next 6 hours then every hour until 24hours after 6 hours then every hour until 24hours after treatmenttreatment
Favorable Outcome vs Treatment Time Favorable Outcome vs Treatment Time with IV rTPAwith IV rTPA
Protocol limit = 3 hrs
Benefit ~ 45 hrs
Thromboembolism During coilingThromboembolism During coiling Most feared and frequent complication Most feared and frequent complication Reported incidence - Approx 7 Reported incidence - Approx 7 SourcesSources of Thromboembolism are of Thromboembolism are
- Clots at the aneurysmal neck during or immediately- Clots at the aneurysmal neck during or immediately after after embolization embolization
- Thrombus forming on catheters during- Thrombus forming on catheters during proceduresprocedures
- Stenosis of an adjacent artery dt coil mass- Stenosis of an adjacent artery dt coil mass or herniationor herniation
- Migration of intraaneurysmal- Migration of intraaneurysmal thrombus during coil thrombus during coil placement placement
- Slow flow dt vasospasm - Slow flow dt vasospasm
- Rare and unlikely causes are hypercoagulable- Rare and unlikely causes are hypercoagulable state such state such as antiphospholipid antibody syndrome or due to HITas antiphospholipid antibody syndrome or due to HIT
Occur more often with wide-necked aneurysms (dt Occur more often with wide-necked aneurysms (dt increased exposed surface area of thrombogenic coil increased exposed surface area of thrombogenic coil material)material)
Current regimen of endovascular Current regimen of endovascular managementmanagement
The The glycoprotein IIbIIIa antagonist tirofiban glycoprotein IIbIIIa antagonist tirofiban (04 (04 microgkgmin bolus for 30 minutes followed by infusion of microgkgmin bolus for 30 minutes followed by infusion of 0125 ugkgmin until the thrombus dissolved) 0125 ugkgmin until the thrombus dissolved)
Intraarterial thrombolysis with Intraarterial thrombolysis with urokinase or r- TPA urokinase or r- TPA increase of intravenous (IV) heparin (measured by increase of intravenous (IV) heparin (measured by
ACT) ACT) Intravenous aspirin Intravenous aspirin
Coil-related platelet aggregation (white clot) is Coil-related platelet aggregation (white clot) is unlikely to respond to fibrinolytics but has a high risk unlikely to respond to fibrinolytics but has a high risk of hemorrhage (In ISAT) all 5 patients who had of hemorrhage (In ISAT) all 5 patients who had received thrombolytic therapy with tPA to treat a received thrombolytic therapy with tPA to treat a thromboembolic complication after endovascular thromboembolic complication after endovascular treatment rebleed and all of these patients died)treatment rebleed and all of these patients died)
IntracranialIntracranial Stenting Stenting Metallic foreign body such as stent will accumulate Metallic foreign body such as stent will accumulate
thrombus in the absence of platelet inhibitionthrombus in the absence of platelet inhibition Antiplatelet drugs are important to prevent peri or Antiplatelet drugs are important to prevent peri or
post-interventional thromboembolic eventspost-interventional thromboembolic events Optimal treatment regimens has not been determined Optimal treatment regimens has not been determined
but usually but usually Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-
procedureprocedureOrOr
Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on
morning of proceduremorning of procedure
If need to use stent is not pre-planned thanIf need to use stent is not pre-planned than
Abciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkgAbciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkg IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)
Glycoprotein IIbIIIa inhibitor are not used routinely during elective Glycoprotein IIbIIIa inhibitor are not used routinely during elective stenting procedure dt increased risk of ICH stenting procedure dt increased risk of ICH
Carotid StentingCarotid Stenting
Pre-procedurePre-procedure
Double Antiplatelet therapy is routinely given Double Antiplatelet therapy is routinely given beginning at least 3beginning at least 3
days before the proceduredays before the procedure
Aspirin 325mgd+Clopidogrel 75mgdAspirin 325mgd+Clopidogrel 75mgd During procedureDuring procedure
Heparin is given with target clotting time of 250-Heparin is given with target clotting time of 250-300sec300sec
Post-procedure Post-procedure
Aspirin 325mg is continued indefinitely and Aspirin 325mg is continued indefinitely and
Clopidogrel 75mgd for at least 6 weeks Clopidogrel 75mgd for at least 6 weeks
Inclusion criteria for Local ThrombolysisInclusion criteria for Local Thrombolysis a)a) Patients in severe clinical grade on admission Patients in severe clinical grade on admission
with evidence of dural venous sinus with evidence of dural venous sinus thrombosis and restrictive venous outflow on thrombosis and restrictive venous outflow on cerebral angiogramcerebral angiogram
b)b) Patients in clinical grade 3 worsening on Patients in clinical grade 3 worsening on heparin therapy Restriction to venous heparin therapy Restriction to venous outflow was defined as an increase in brain outflow was defined as an increase in brain circulation time gt 12 s delay in the drainage circulation time gt 12 s delay in the drainage of cortical veins with cortical veins hanging of cortical veins with cortical veins hanging in spacein space
Treatment Options for Venous Thrombosis
CT Grading for Venous ThrombosisCT Grading for Venous Thrombosis Grade I no parenchymal change Grade I no parenchymal change
(hyperdense (hyperdense sinuses cortical veins empty sinuses cortical veins empty delta sign)delta sign)
Grade II non hemorrhagic venous infarct Grade II non hemorrhagic venous infarct without mass effect without mass effect
Grade III non-hemorrhagic infarct with Grade III non-hemorrhagic infarct with mass effectmass effect
Grade IV hemorrhagic venous infarct (max Grade IV hemorrhagic venous infarct (max diameter lt 3 cm) with no mass effectdiameter lt 3 cm) with no mass effect
Grade V hemorrhagic venous infarct (max Grade V hemorrhagic venous infarct (max diameter gt 3 cm) with mass effect diameter gt 3 cm) with mass effect
Local ThrombolysisLocal Thrombolysis
Femoral Jugular access was secured and a guiding Femoral Jugular access was secured and a guiding catheter was placed in the jugular bulb catheter was placed in the jugular bulb Mechanical Mechanical clot maceration clot maceration was done with the guidewire was done with the guidewire following which a microcatheter (was navigated and following which a microcatheter (was navigated and placed in the thrombosed segment of sinus confirmed placed in the thrombosed segment of sinus confirmed on a selective venogram on a selective venogram
Urokinase infusion Bolus dose of 2-6 lacs followed Urokinase infusion Bolus dose of 2-6 lacs followed by 60000 to 100000 units per hour along with by 60000 to 100000 units per hour along with periodic check venogram Along with maintenance periodic check venogram Along with maintenance systemic infusion of Heparinsystemic infusion of Heparin Other agents such as Other agents such as streptokinase altepase or rTPAstreptokinase altepase or rTPA can be also used can be also used
After thrombolysis patient should subjected to oral After thrombolysis patient should subjected to oral anticoagulation for six monthsanticoagulation for six months
Low-molecular-weight Low-molecular-weight heparinheparin
PharmacologyPharmacologyLMWH as its name suggests is a glycosaminoglycan that is approximatelyLMWH as its name suggests is a glycosaminoglycan that is approximately
one third the molecular weight of UFH It is derived from UFH through one third the molecular weight of UFH It is derived from UFH through variousvarious
depolymerization processes LMWH binds to antithrombin which in turn depolymerization processes LMWH binds to antithrombin which in turn
Neutralizes actors Xa and IIa Because LMWH lacks many of the longer Neutralizes actors Xa and IIa Because LMWH lacks many of the longer chains chains
required for binding to thrombin it has less ability to neutralize thrombin required for binding to thrombin it has less ability to neutralize thrombin
relativeto its ability to neutralize factor Xa LMWH also has less relativeto its ability to neutralize factor Xa LMWH also has less nonspecific nonspecific
binding to other proteins There is greater bioavailability with more binding to other proteins There is greater bioavailability with more predictable predictable
pharmacokinetics that eliminates the need for monitoring The smaller pharmacokinetics that eliminates the need for monitoring The smaller size also size also
allows for enhanced subcutaneous absorption when compared with UFHallows for enhanced subcutaneous absorption when compared with UFH
Three LMWH preparations are Three LMWH preparations are currently approved for use in the currently approved for use in the United States (1) enoxaparin (2) United States (1) enoxaparin (2) dalteparin and (3) tinzaparin dalteparin and (3) tinzaparin
They are all administered They are all administered subcutaneously at intervals of either subcutaneously at intervals of either once or twice daily for both once or twice daily for both prophylaxis and treatment dosesprophylaxis and treatment doses
Few Experiences of Few Experiences of ThrombolysisThrombolysis
Vickey 25 Yrs male patient presented Vickey 25 Yrs male patient presented with 12with 12thth day HO severe headache with day HO severe headache with right sided hemiplegiaright sided hemiplegia
MRI shows thrombosis of the superior MRI shows thrombosis of the superior sagittal left transverse left sigmoid sagittal left transverse left sigmoid sinuses and cortical veins in the fronto-sinuses and cortical veins in the fronto-parietal regions with eo haemorrhagic parietal regions with eo haemorrhagic infarct in the left cerebral hemisphere infarct in the left cerebral hemisphere with mass effect( Grade ndashV)with mass effect( Grade ndashV)
Sashi Srivastava 64 yrs FSashi Srivastava 64 yrs F In a follow up case of MRD with infra-renal In a follow up case of MRD with infra-renal
aortic abdominal and bilateral renal artery aortic abdominal and bilateral renal artery thrombosis renal angiogram shows filling thrombosis renal angiogram shows filling defects in the right Renal artery defects in the right Renal artery
Initially Renal angioplasty was done Initially Renal angioplasty was done Following angioplasty few thrombi are seem Following angioplasty few thrombi are seem to extends into the segmental branches and to extends into the segmental branches and causing blockage So Thrombolysis was causing blockage So Thrombolysis was plane to dissolve the run-out thrombi with plane to dissolve the run-out thrombi with urokinase urokinase
Rakesh 34yrsMRakesh 34yrsM Left SFA pseudoaneurysm with Left SFA pseudoaneurysm with
Covered stent placementCovered stent placement Pre operative antiplatelets with post Pre operative antiplatelets with post
procedure heparin Tirofiban procedure heparin Tirofiban followed by aspirin and clopidogrel followed by aspirin and clopidogrel were usedwere used
IAT may be a treatment option for selected patients IAT may be a treatment option for selected patients Possible selection criteria include Possible selection criteria include
presentation between 3 and 6 hours from symptom onsetpresentation between 3 and 6 hours from symptom onset major cerebral artery occlusion major cerebral artery occlusion severe neurologic deficits severe neurologic deficits high risk of systemic hemorrhage with IV rt-PA (eg recent high risk of systemic hemorrhage with IV rt-PA (eg recent
surgery) surgery) The MERCI (Mechanical Embolus Removal in Cerebral The MERCI (Mechanical Embolus Removal in Cerebral
Ischemia) retrievalIschemia) retrieval system system
Has been FDA-approved for recanalizing acutely occluded Has been FDA-approved for recanalizing acutely occluded cerebral arteries cerebral arteries
In the Multi-MERCI study patients who did not improve In the Multi-MERCI study patients who did not improve immediately after IV rt-PA underwent mechanical immediately after IV rt-PA underwent mechanical embolectomy within 8 hours of symptom onset embolectomy within 8 hours of symptom onset
Partial or complete recanalization occurred in 74 of Partial or complete recanalization occurred in 74 of patientspatients
with a symptomatic intracerebral hemorrhage (sICH) rate of with a symptomatic intracerebral hemorrhage (sICH) rate of 67 67
Mechanical embolectomy with the MERCI retriever may be a Mechanical embolectomy with the MERCI retriever may be a feasible and safe option for patients after IV rt-PAfeasible and safe option for patients after IV rt-PA
Penumbra stroke systemPenumbra stroke system This device combines two methods of clot This device combines two methods of clot
extraction aspiration and mechanical extraction aspiration and mechanical extraction extraction
First the clot is aspirated then a thrombus First the clot is aspirated then a thrombus removal ring can be used if necessary to removal ring can be used if necessary to remove remaining clot remove remaining clot
successful recanalizing 82successful recanalizing 82 Bridging therapyBridging therapy
06 mgkg IV rt-PA followed by IAT with IA rt-06 mgkg IV rt-PA followed by IAT with IA rt-PA (up to 20 mg)PA (up to 20 mg)
achieved a higher recanalization rateachieved a higher recanalization rate
Criteria for thrombolysis with rTPACriteria for thrombolysis with rTPA
Inclusion criteriaInclusion criteria Clinical signs and symptoms consistent with ischemic Clinical signs and symptoms consistent with ischemic
strokestroke Patient last seen normal within 3 hoursPatient last seen normal within 3 hours Measurable neurologic deficitMeasurable neurologic deficit
Exclusion criteriaExclusion criteria Any hemorrhage on neuroimaging (CT or MRI)Any hemorrhage on neuroimaging (CT or MRI) Symptoms suggestive of subarachnoid hemorrhageSymptoms suggestive of subarachnoid hemorrhage Seizure at stroke onset that is thought to contribute to Seizure at stroke onset that is thought to contribute to
neurologic deficitneurologic deficit Hypodensity greater than one third cerebral hemisphere Hypodensity greater than one third cerebral hemisphere
on CTon CT SBP greater than 185 mm Hg or DBP greater than 110 SBP greater than 185 mm Hg or DBP greater than 110
mm Hgmm Hg International normalized ratio (INR) greater than 17International normalized ratio (INR) greater than 17
Ischemic Stroke Ischemic Stroke Treatment ndash 2006Treatment ndash 2006
IV tissue plasminogen activator (tPA)IV tissue plasminogen activator (tPA) ndash ndash Only FDA-approved acute stroke drugOnly FDA-approved acute stroke drug ndash ndash 3 hour treatment window3 hour treatment window
MERCI - Concentric clot retrieval MERCI - Concentric clot retrieval devicedevice ndash ndash Rescue therapy - approved 2004Rescue therapy - approved 2004 ndash ndash Device approval (not outcomes-based)Device approval (not outcomes-based)
Off label approachesOff label approaches ndash ndash IV tPA after 3 hoursIV tPA after 3 hours ndash ndash IV-IA tPA sequential strategiesIV-IA tPA sequential strategies ndash ndash IA tPA clot angioplasty fragmentationIA tPA clot angioplasty fragmentation ndash ndash Ultrasound-assisted tPA lysisUltrasound-assisted tPA lysis
rt-PA Trials NINDSrt-PA Trials NINDS
Acute stroke - 624 patientsAcute stroke - 624 patients Treat within 3 hrsTreat within 3 hrs Intravenous 09 mgkg rt-PA vs placeboIntravenous 09 mgkg rt-PA vs placebo Hemorrhage 64 tPA 06 placeboHemorrhage 64 tPA 06 placebo Neurologic recovery better with tPA 30 Neurologic recovery better with tPA 30
more like to have minimal or no disabilitymore like to have minimal or no disability
First proven approved treatment for First proven approved treatment for strokestroke
Limitations of tPALimitations of tPA Only 4 of acute strokes receive tPAOnly 4 of acute strokes receive tPA (Kleindorfer et al Stroke 2004 35 e27-e29)(Kleindorfer et al Stroke 2004 35 e27-e29)
Only 22 of patients present within 3 hoursOnly 22 of patients present within 3 hours1048707 1048707 51 of these ineligible due to51 of these ineligible due to
bull bull Mild severityMild severity bull bull Medical or surgical historyMedical or surgical history bull bull Blood testsBlood tests
Sustained recanalization only 13Sustained recanalization only 13 (Alexandrov et al NEJM 2004 351 2170-8)(Alexandrov et al NEJM 2004 351 2170-8)
Concern for hemorrhageConcern for hemorrhage tPA potentiates apoptotic injury tPA potentiates apoptotic injury (Liu et al Nature Med 2004 101379-83)(Liu et al Nature Med 2004 101379-83)
PROACT II IA Lysis TrialPROACT II IA Lysis Trial Baseline 24 hours 8 days
Baseline 60 minutes 120 minutes
9mg IAProurokinase
Desmoteplase Trials DEDAS Desmoteplase Trials DEDAS DIASDIAS
Trial OverviewTrial Overview Double blind randomized placebo Double blind randomized placebo
controlled trialscontrolled trials IV delivery 3-9 hour time windowIV delivery 3-9 hour time window Plasminogen activator ndash from Plasminogen activator ndash from vampire bat vampire bat
salivasaliva Selection based on PWI-DWI MismatchSelection based on PWI-DWI Mismatch
MRI InclusionMRI Inclusion PWI defect at least 2 cm AND ~20 larger PWI defect at least 2 cm AND ~20 larger
than DWIthan DWI PWI should be obvious even visible on PWI should be obvious even visible on
raw imagesraw imagesMRI ExclusionMRI Exclusion
DWI gt 13 MCADWI gt 13 MCA MRA ICA occlusionMRA ICA occlusion
Desmoteplase ndash DIAS Desmoteplase ndash DIAS ResultsResults
Mechanical Thrombolysis Mechanical Thrombolysis devicesdevices
mechanical thrombolysis potentially extends the treatment mechanical thrombolysis potentially extends the treatment window because they act promptly at the site of the thrombuswindow because they act promptly at the site of the thrombus
The devices can retrieve large clots that pharmaceutical agents The devices can retrieve large clots that pharmaceutical agents may not successfully lysemay not successfully lyse
Patients treated with IV tPA may be considered for treatment of Patients treated with IV tPA may be considered for treatment of residual clot with some of these devicesresidual clot with some of these devices
suction-creating saline jets suction-creating saline jets laser energy ultrasound laser energy ultrasound a corkscrew apparatus to treat strokesa corkscrew apparatus to treat strokes The AngioJet systemThe AngioJet system uses saline jets that are directed back into the catheter to uses saline jets that are directed back into the catheter to
create a low-pressure zone around the catheter tip inducing create a low-pressure zone around the catheter tip inducing suction suction
The clot is pulled into the exhaust lumen and removed from the The clot is pulled into the exhaust lumen and removed from the vessel Although US Food and Drug Administration (FDA) has vessel Although US Food and Drug Administration (FDA) has approved this device for use in arteriovenous dialysis grafts and approved this device for use in arteriovenous dialysis grafts and fistulae and for the treatment of coronary arteries saphenous fistulae and for the treatment of coronary arteries saphenous vein grafts and peripheral vessels clinical trials for the vein grafts and peripheral vessels clinical trials for the treatment of acute stroke are no longer in progress treatment of acute stroke are no longer in progress
Most devices are used in cerebral vessels that 2-5 mm
The Latis laser device The Latis laser device used laser energy to ablate clots used laser energy to ablate clots Arteries 2-5 mm in diameter could be Arteries 2-5 mm in diameter could be
treated including the ICA M1 or M2 treated including the ICA M1 or M2 branch of the MCA A1 branch of the branch of the MCA A1 branch of the anterior cerebral artery (ACA) basilar anterior cerebral artery (ACA) basilar artery posterior cerebral artery (PCA) artery posterior cerebral artery (PCA) and vertebral and vertebral
Patients could receive treatment as late Patients could receive treatment as late as 8 hours after symptom onset in the as 8 hours after symptom onset in the anterior circulation and within 24 hours in anterior circulation and within 24 hours in the posterior circulation the posterior circulation
Endovascular Photo Acoustic Endovascular Photo Acoustic Recanalization (EPAR) Recanalization (EPAR)
A laser power source generated energy for the A laser power source generated energy for the systemsystem
The energy was delivered by means of The energy was delivered by means of fiberoptics to the tip of the catheter at the fiberoptics to the tip of the catheter at the treatment sitetreatment site
Absorption of laser light by darkly pigmented Absorption of laser light by darkly pigmented materials (ie the clot) occurred inside the 1-mm materials (ie the clot) occurred inside the 1-mm catheter tipcatheter tip
the system was designed to minimize scattering the system was designed to minimize scattering of laser light of laser light
Absorption converted photo energy to acoustic Absorption converted photo energy to acoustic energy which then emulsified the clot inside the energy which then emulsified the clot inside the catheter tip catheter tip
EKOS ultrasound( the EKOS ultrasound( the Ultrasound Thrombolytic Ultrasound Thrombolytic
Infusion Catheter) Infusion Catheter) combines the use of a distal ultrasound transducer with combines the use of a distal ultrasound transducer with
infusion of a thrombolytic agent through the infusion of a thrombolytic agent through the microcathetermicrocatheter
Ultrasound changes the structure of the clot to Ultrasound changes the structure of the clot to temporarily increase its permeability while providing an temporarily increase its permeability while providing an acoustic pressure gradient to move the drug into the clot acoustic pressure gradient to move the drug into the clot to speed its dissolution to speed its dissolution
The EKOS catheter is placed in the proximal portion of the The EKOS catheter is placed in the proximal portion of the clot clot
After a 2-mg bolus of tPA was injected through the After a 2-mg bolus of tPA was injected through the catheter catheter
the patient received a continuous infusion of IA tPA 03 the patient received a continuous infusion of IA tPA 03 mgmin to a maximum of 20 mg and simultaneous mgmin to a maximum of 20 mg and simultaneous ultrasound transmission for as long as 60 minutes ultrasound transmission for as long as 60 minutes
One patient was treated with a total of 4 units of One patient was treated with a total of 4 units of recombinant reteplase (Retavase) hand-injected over 60 recombinant reteplase (Retavase) hand-injected over 60 minutes minutes
Penumbra system Penumbra system The Penumbra system (Penumbra Inc) provides a dual The Penumbra system (Penumbra Inc) provides a dual
approach to clot extraction using aspiration followed by approach to clot extraction using aspiration followed by clot retrieval with a ring device if needed clot retrieval with a ring device if needed
Mechanical Embolus Removal in Cerebral Ischemia Mechanical Embolus Removal in Cerebral Ischemia (MERCI)(MERCI)
a corkscrew-like apparatus to remove blood clots from a corkscrew-like apparatus to remove blood clots from the brain in patients experiencing an ischemic stroke the brain in patients experiencing an ischemic stroke
The corkscrew itself resides in the catheter tip which The corkscrew itself resides in the catheter tip which shields it from the wall of the vessel until it is ready to be shields it from the wall of the vessel until it is ready to be burrowed into the clot Once lodged in the clot the device burrowed into the clot Once lodged in the clot the device and clot are withdrawn from the vessel and clot are withdrawn from the vessel
Snarelike devicesSnarelike devices Snares such as the Neuronet snare (Guidant Snares such as the Neuronet snare (Guidant
Endovascular Santa Clara CA) have been developed Endovascular Santa Clara CA) have been developed specifically for use in the treatment of strokes specifically for use in the treatment of strokes
These devices are simple in design and do not require the These devices are simple in design and do not require the clot to be amenable to emulsification clot to be amenable to emulsification
X-Sizer deviceX-Sizer device a device with small moving blades at the a device with small moving blades at the
catheter tip catheter tip This device the X-Sizer device (EndiCor Medical This device the X-Sizer device (EndiCor Medical
San Clemente CA) can be used to excise the San Clemente CA) can be used to excise the thrombus and aspirate it thrombus and aspirate it
The device was being evaluated in randomized The device was being evaluated in randomized studies of coronary vessels and in a registry of studies of coronary vessels and in a registry of patients with acute myocardial infarctionpatients with acute myocardial infarction
Although the manufacturer had modified the Although the manufacturer had modified the device for use in cerebral vessels a safety and device for use in cerebral vessels a safety and feasibility study was indefinitely suspended after feasibility study was indefinitely suspended after only 1 patient was treated with the device in only 1 patient was treated with the device in Europe Europe
Suction thrombectomySuction thrombectomy This method of mechanical thrombolysis is one of the This method of mechanical thrombolysis is one of the
simplestsimplest In this readily available technique suction is applied with In this readily available technique suction is applied with
a syringe to remove thrombus in the ICA a syringe to remove thrombus in the ICA It requires no other devicesIt requires no other devices A catheter with a large inner diameter (Brite Tip Cordis A catheter with a large inner diameter (Brite Tip Cordis
Corporation Miami FL) was placed in the symptomatic Corporation Miami FL) was placed in the symptomatic vessel and navigated over a guidewire into the thrombusvessel and navigated over a guidewire into the thrombus
A 60-mL syringe was used to aspirate the thrombus A 60-mL syringe was used to aspirate the thrombus Each patient required angioplasty and stenting of carotid Each patient required angioplasty and stenting of carotid
bifurcation stenosis and received daily aspirin and bifurcation stenosis and received daily aspirin and ticlopidine after the procedure No complications ticlopidine after the procedure No complications occurred occurred
Summary Acute Stroke Summary Acute Stroke ImagingImaging
PhysiologyPhysiology importance collaterals importance collaterals
ndash ndashGrowing role for perfusion Growing role for perfusion assessmentassessment
tPAtPA guidelines amp limitations guidelines amp limitations Signs on CT amp MRSigns on CT amp MR follow physiology follow physiology Stroke trialsStroke trials PWI-DWI mismatch PWI-DWI mismatch
ndash ndashTreat based on physiology not timeTreat based on physiology not time ProtocolsProtocols should be fast and should be fast and
comprehensivecomprehensive
ThrombolyticsThrombolytics
Plasminogen activators
Fibrinolytics
Anti Platelet DrugsAnti Platelet DrugsDrug Mechanism UsesDrug Mechanism UsesAspirinAspirin Permanently inhibits Permanently inhibits
COX-1 and COX-2COX-1 and COX-2CADCAD
Stroke-TIAsStroke-TIAs
NSAIDsNSAIDs Reversibly inhibits Reversibly inhibits COX-1COX-1
LimitedLimited
DipyridamoleDipyridamole Inhibits PDE Inhibits PDE increases cAMPincreases cAMP
TIAsTIAs
ThenopyridinesThenopyridines
(Ticlopidine(Ticlopidine
Clopidegrel)Clopidegrel)
Inhibits ADP Inhibits ADP
PlatAg PlatAg
TIAsStrokeTIAsStroke
CAD PVDCAD PVD
Abciximab (ReoPro)Abciximab (ReoPro)
Eptifibatide Eptifibatide (Integrilin)(Integrilin)
TirofibaTirofibann
GP IIBIIIA InhibitorsGP IIBIIIA Inhibitors
Stroke- TIAs Stroke- TIAs
Maintainance of patency Maintainance of patency of vascular of vascular grafts catheters shunts bypassesgrafts catheters shunts bypasses
Arterial thromboembolic diseaseArterial thromboembolic diseasebull Transient ischemic attacksTransient ischemic attacksbull Stroke in evolutionStroke in evolution
Ischemic events occurs in Ischemic events occurs in 1313 of of conventional neuroangiographic conventional neuroangiographic procedures without Endovascular surgeryprocedures without Endovascular surgery
Indications for Antithrombotic Therapy in Indications for Antithrombotic Therapy in Diagnostics and Interventional ProceduresDiagnostics and Interventional Procedures
WHY TO MONITOR ANTICOAGULANT THERAPYWHY TO MONITOR ANTICOAGULANT THERAPY
Narrow therapeutic rangeNarrow therapeutic range
Can increase risk of bleedingCan increase risk of bleeding
Coagulation TestingCoagulation Testing
Monitoring therapyMonitoring therapy
Intrinsic Pathway
Extrinsic Pathway
Common Pathway
CLOT
Heparin Coumadin
Monitor with
ACT aPTT
Monitor with PTINR
Thrombolytics
Monitor with TT Fibrinogen
Monitoring of Monitoring of Anti platelet drugsAnti platelet drugs
Bleeding timeBleeding time
Optical aggregometryOptical aggregometry
Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay
HeparinHeparin
Heterogeneous 3000-30000 dalton in Heterogeneous 3000-30000 dalton in molecular weight molecular weight
Average=15000 d (~45monosaccharide Average=15000 d (~45monosaccharide chains)chains)
About About 13 of dose binds to AT III and forms 13 of dose binds to AT III and forms the AT IIIHeparinClotting Factor Complexthe AT IIIHeparinClotting Factor Complex
Complex binds to clotting factors of the Complex binds to clotting factors of the intrinsic and common pathway (Xa IIa IXa intrinsic and common pathway (Xa IIa IXa XIa XIIa XIIIa) and inactivates themXIa XIIa XIIIa) and inactivates them
Anticoagulant of choice in pregnancy (not Anticoagulant of choice in pregnancy (not crosses placenta)crosses placenta)
Heparin and Low molecular weight heparinsHeparin and Low molecular weight heparins
Structure and sequence
O
OH
OH
O
COO
O
O
CH2OH
NHSO3
OH
_
_
O
O
CH2OSO3
NHSO3
OH
_
_
O
OH
OH
O
COOO
O
CH2OSO3
NHSO3
OH
_
_
O
OSO3
OHO
COOO
O
CH2OSO3
NHCOCH3
OH
_
_ _
_
_
O
OH
OH
O
COO
1
23
4
5
6
-D-glucosamine -L-iduronic acid -D-glucuronic acid
O
O
CH2OH
NH2
OH 12
3
4
5
6
O
OH
OHO
COO_
1
23
4
5
6
polymeric structure of heparin
Anticoagulant Properties of Anticoagulant Properties of HeparinHeparin
11 Inhibits the thrombin-mediated conversion of Inhibits the thrombin-mediated conversion of fibrinogen to fibrinfibrinogen to fibrin
22 Inhibits the aggregation of platelets by thrombin Inhibits the aggregation of platelets by thrombin (prolongs bleeding time)(prolongs bleeding time)
33 Inhibits activation of fibrin stabilizing enzymeInhibits activation of fibrin stabilizing enzyme
44 Inhibits activated factors XII XI IX X and IIInhibits activated factors XII XI IX X and II All available forms of heparin must be All available forms of heparin must be
administered administered parenterally since they are parenterally since they are highly charged and rapidlyhighly charged and rapidly hydrolyzed in the hydrolyzed in the GI tractGI tract
Heparin antagonist Protamine sulfate (Heparin antagonist Protamine sulfate (10mg for 10mg for 1000 unit of heparin)1000 unit of heparin)
Monitoring of heparin Monitoring of heparin
Subcutenous Subcutenous no monitoring requiredno monitoring required Intravenous Intravenous
Partial thromboplastin time (PTT normal value Partial thromboplastin time (PTT normal value ~30sec) ~30sec)
Activated clotting time ( ACT normal value ~90-Activated clotting time ( ACT normal value ~90-120sec)120sec)
Daily or more frequent if PTT ACT variesDaily or more frequent if PTT ACT varies
Mechanism Mechanism ndash measures intrinsic pathwayndash measures intrinsic pathway Therapeutic goal Therapeutic goal 2-25 times normal control value 2-25 times normal control value
ACT or aPTTACT or aPTT
Determine when to pull the femoral sheath Determine when to pull the femoral sheath Premature sheath pull can lead to bleedingPremature sheath pull can lead to bleeding Delayed removal can increase time in ICUDelayed removal can increase time in ICU Target set Target set at each siteat each site
ACT targets range from 150 ndash 220 ACT targets range from 150 ndash 220 secondsseconds
aPTT targets range from 40 ndash 70 seconds aPTT targets range from 40 ndash 70 seconds
During neuroangiography-During neuroangiography- Recommended therapeutic range of heparin in Recommended therapeutic range of heparin in
plasma is 02-08 uml ( corresponding to aPTT plasma is 02-08 uml ( corresponding to aPTT ACT values 15-25 times the baseline values)ACT values 15-25 times the baseline values)
Dose In diagnostic angiography bolus dose of Dose In diagnostic angiography bolus dose of 2500 iu is used followed by 1000 iu hour2500 iu is used followed by 1000 iu hour
Bolus dose is Bolus dose is 60 ukg to maintain the therapeutic 60 ukg to maintain the therapeutic range range If procedure continues for more than 75 If procedure continues for more than 75 minutes additional dose is required ( half of the minutes additional dose is required ( half of the initial dose for another 75 minutes) initial dose for another 75 minutes)
(AJNR 199415 51-54)
Mechanisms of HIT( Mechanisms of HIT( Heparin Heparin induced Thrombocytopeniainduced Thrombocytopenia))
Type 1Type 1 Fall in platelet count occurs within the first two Fall in platelet count occurs within the first two
days after heparin initiation often returns to days after heparin initiation often returns to normal with continued heparin administration normal with continued heparin administration and is of no clinical consequence and is of no clinical consequence
The mechanism of the thrombocytopenia is non-The mechanism of the thrombocytopenia is non-immune and appears to be due to a direct effect of immune and appears to be due to a direct effect of heparin on platelet activationheparin on platelet activation
Type 2Type 2 Approximately 03 to 3 percent of patients Approximately 03 to 3 percent of patients
receiving heparin develop an immune receiving heparin develop an immune thrombocytopenia mediated by antibodies to a thrombocytopenia mediated by antibodies to a heparin-platelet factor 4 complex heparin-platelet factor 4 complex
(AJNR 28155-158 2007)
Treatment of heparin-induced Treatment of heparin-induced thrombocytopeniathrombocytopenia
When HIT is diagnosed it is important to When HIT is diagnosed it is important to stop heparin mainly in type 2 and to avoid stop heparin mainly in type 2 and to avoid the use of LMWH the use of LMWH
Because of the increased risk of thrombosis Because of the increased risk of thrombosis however continuation of an anticoagulant however continuation of an anticoagulant must be considered must be considered
The drugs currently approved for the The drugs currently approved for the treatment of HIT in the United States are treatment of HIT in the United States are direct thrombin inhibitors argatroban and direct thrombin inhibitors argatroban and lepirudinlepirudin
WARFARIN MECHANISM OF ACTIONWARFARIN MECHANISM OF ACTION
Inactive factors II VII IX and X
Proteins S and C
Active factors II VII IX and X
Proteins S and C
Vitamin K epoxide
Vitamin K reduced
WA
RF
AR
IN
Prevents the reduction of vitamin K which is essential for Prevents the reduction of vitamin K which is essential for activation of certain factorsactivation of certain factors
Has no effect on previously formed thrombusHas no effect on previously formed thrombus
Antagonist is Vit KAntagonist is Vit K
OPTIMIZING WARFARIN THERAPYOPTIMIZING WARFARIN THERAPY
Use of large loading dose may lead to hemorrhage and Use of large loading dose may lead to hemorrhage and other complicationsother complications
Initial dose 2-5 mg once dailyInitial dose 2-5 mg once daily Maintenance dose 2-10 mg once dailyMaintenance dose 2-10 mg once daily If Immediate anticoagulation is requiredIf Immediate anticoagulation is required Heparin IS Heparin IS
started along with loading dose of warfarin 10 mg started along with loading dose of warfarin 10 mg Heparin is usually discontinued after 4-5 days Heparin is usually discontinued after 4-5 days Before Before discontinuing INR should be in therapeutic range for 2 discontinuing INR should be in therapeutic range for 2 consecutive daysconsecutive days
Daily monitoring of INR until INR is in therapeutic Daily monitoring of INR until INR is in therapeutic range then 3 times weekly for 1-2 weeks then less often range then 3 times weekly for 1-2 weeks then less often (every 4 to 6 weeks)(every 4 to 6 weeks)
OPTIMAL THERAPEUTIC RANGEOPTIMAL THERAPEUTIC RANGE
IndicationIndication INRINR
Prophylaxis of venous Prophylaxis of venous thromboembolismthromboembolism
20-3020-30
Treatment of venous Treatment of venous thromboembolismthromboembolism
20-3020-30
Atrial fibrillationAtrial fibrillation 20-3020-30
Mitral valve stenosisMitral valve stenosis 20-3020-30
Heart valve replacementHeart valve replacement
Bioprosthetic valveBioprosthetic valve
Mechanical valveMechanical valve
20-3020-30
25-3525-35
Myocardial infarctionMyocardial infarction 20-3020-30
25-35 25-35 (high risk patients)(high risk patients)
FACTORS INFLUENCING DOSE RESPONSEFACTORS INFLUENCING DOSE RESPONSE
Poor patient compliancePoor patient compliance Concomitant medicationsConcomitant medications Levels of dietary vitamin KLevels of dietary vitamin K Alcohol Inaccurate lab testingAlcohol Inaccurate lab testing Inaccurate lab testingInaccurate lab testing Hepatic dysfunctionHepatic dysfunction FeverFever
Contraindication for WarfarinContraindication for Warfarin
Hypersensitivity to warfarinHypersensitivity to warfarin Hemorrhagic tendencyHemorrhagic tendency Condition with risk of hemorrhageCondition with risk of hemorrhage Inadequate laboratory techniquesInadequate laboratory techniques Protein C amp S deficiencyProtein C amp S deficiency Vitamin K deficiencyVitamin K deficiency
SIDE EFFECTSSIDE EFFECTS
Hemorrhage Hemorrhage Skin necrosisSkin necrosis Purple toe syndromePurple toe syndrome Microembolization Microembolization TeratogenecityTeratogenecity Agranulocytosis leukopenia Agranulocytosis leukopenia Diarrhoeanausea anorexiaDiarrhoeanausea anorexia
MONITORING OF WARFARIN THERAPYMONITORING OF WARFARIN THERAPY
Prothrombin timeProthrombin time PT ratioPT ratio INR (International Normalized Ratio)INR (International Normalized Ratio)
PROTHROMBIN TIME (PT)PROTHROMBIN TIME (PT)
Time required for blood to coagulate Time required for blood to coagulate is called PT ( normal value ~10sec)is called PT ( normal value ~10sec)
Performed by adding a mixture of Performed by adding a mixture of calcium and thromboplastin to calcium and thromboplastin to citrated plasmacitrated plasma
As a control a normal blood sample is As a control a normal blood sample is tested continuouslytested continuously
PT ratio (PTR) = PT ratio (PTR) = Patientrsquos PTPatientrsquos PT Control PTControl PT
PROBLEMS WITH PTPTRPROBLEMS WITH PTPTR
Thromboplastins are extracts from Thromboplastins are extracts from brain lung or placenta of animalsbrain lung or placenta of animals
Thromboplastins from various Thromboplastins from various manufacturers differ in their manufacturers differ in their sensitivity to prolong PTsensitivity to prolong PT
May result in false control of May result in false control of anticoagulant therapyanticoagulant therapy
INTERNATIONAL NORMALISED RATIO (INR)INTERNATIONAL NORMALISED RATIO (INR)
International Normalized Ratio (INR) International Normalized Ratio (INR) a PT test with a a PT test with a formula based ratio to normalize the often variable source formula based ratio to normalize the often variable source of tissue factor (human rabbit recombinant)of tissue factor (human rabbit recombinant)
INR = [PTINR = [PTptpt] ] ISIISI
[PT[PTRefRef]]
PTPTpt pt ndash prothrombin time of patientndash prothrombin time of patient
PTPTRef Ref ndash prothrombin time of normal pooled samplendash prothrombin time of normal pooled sample
ISI ndash International Sensitivity IndexISI ndash International Sensitivity Index
Warfarin is given orally and titrated to achieve an INR of Warfarin is given orally and titrated to achieve an INR of typically 20 ndash 30typically 20 ndash 30
Heparin versus WarfarinHeparin versus Warfarin
Drug ActionMechan-ism
Moni-toring
Effective
HeparinDirect
Inhibition ofThrombin
ATIIIcofactor
APTTACT
Immediate
WarfarinDecreasesProductionof factors
Vitamin K PTDelay
3-5 days
INR
Recanalization or Antegrade Recanalization or Antegrade Reperfusion StrategiesReperfusion Strategies
Recanalization strategies focus on removing Recanalization strategies focus on removing andor dissolving the occlusive thrombus to re-andor dissolving the occlusive thrombus to re-establish antegrade flow Strategies may be establish antegrade flow Strategies may be classified into 7 different categories on the classified into 7 different categories on the basis of their primary mechanism of action basis of their primary mechanism of action 1) 1) IV andor intraarterial thrombolysis (IAT) IV andor intraarterial thrombolysis (IAT) 2) endovascular thrombectomy2) endovascular thrombectomy3) endovascular thromboaspiration 3) endovascular thromboaspiration 4) endovascular mechanical thrombus disruption or 4) endovascular mechanical thrombus disruption or
thromborrhexisthromborrhexis5) 5) transcranial or endovascular augmented transcranial or endovascular augmented
fibrinolysis fibrinolysis 6) endovascular thrombus entrapment and 6) endovascular thrombus entrapment and 7) temporary endovascular bypass7) temporary endovascular bypass
IAT in Acute Ischemic StrokeIAT in Acute Ischemic Stroke
IAT advantages over IV thrombolysisIAT advantages over IV thrombolysis Coaxial microcatheter techniques the occluded intracranial Coaxial microcatheter techniques the occluded intracranial
vessel is directly accessible and the fibrinolytic agent can be vessel is directly accessible and the fibrinolytic agent can be infused directly into the thrombusinfused directly into the thrombus
This permits a smaller dose of fibrinolytic agent to reach a This permits a smaller dose of fibrinolytic agent to reach a higher local concentration than that reached by systemic higher local concentration than that reached by systemic infusioninfusion
Allows more complete recanalization with lower total doses of Allows more complete recanalization with lower total doses of thrombolytic thrombolytic
With the smaller dose complications from systemic fibrinolytic With the smaller dose complications from systemic fibrinolytic effects including intracranial hemorrhage (ICH) can effects including intracranial hemorrhage (ICH) can theoretically be reduced theoretically be reduced
Treatment window for endovascular techniques can be Treatment window for endovascular techniques can be extended beyond the typical IV window of 3 hours extended beyond the typical IV window of 3 hours
IA techniques have led to higher recanalization rates than IV IA techniques have led to higher recanalization rates than IV thrombolysisthrombolysis
Major disadvantagesMajor disadvantages Relative complexity of the procedure the level Relative complexity of the procedure the level
of required technical expertise and its of required technical expertise and its relatively low availability relatively low availability
Delays in initiating treatmentDelays in initiating treatment InvasiveInvasive
ThrombolyticsThrombolytics
Plasminogen activators
Fibrinolytics
1 Plasminogen Activators 1 Plasminogen Activators drugs act by converting the inactive proenzyme drugs act by converting the inactive proenzyme plasminogen into the active enzyme plasmin Plasmin plasminogen into the active enzyme plasmin Plasmin digests fibrinogen fibrin monomers and cross-linked digests fibrinogen fibrin monomers and cross-linked fibrin (as found in a thrombus) into fibrin degradation fibrin (as found in a thrombus) into fibrin degradation productsproducts
First-Generation Agents First-Generation Agents StreptokinaseStreptokinase a protein derived from group C a protein derived from group C
szlig-hemolytic streptococci has a half-life of 16ndashszlig-hemolytic streptococci has a half-life of 16ndash90 minutes and low fibrin specificity This drug 90 minutes and low fibrin specificity This drug proved to have a very narrow therapeutic proved to have a very narrow therapeutic window and significant rates of ICH and window and significant rates of ICH and systemic hemorrhage18systemic hemorrhage18
UrokinaseUrokinase is a serine protease with a plasma is a serine protease with a plasma half life of 14 minutes and low fibrin specificity half life of 14 minutes and low fibrin specificity
The urokinase dose used in cerebral IAT has The urokinase dose used in cerebral IAT has ranged from 002 to 2 X106unitsranged from 002 to 2 X106units
Second-Generation Agents Second-Generation Agents Alteplase (rtPA) Alteplase (rtPA)
is a serine is a serine protease with a plasma half-life of 35 protease with a plasma half-life of 35 minutes and a high degree of fibrin affinity and minutes and a high degree of fibrin affinity and specificity specificity
Dose used in cerebral IAT has ranged between 20 Dose used in cerebral IAT has ranged between 20 and 60 mgand 60 mg
Disadvantages of alteplase include its relatively short Disadvantages of alteplase include its relatively short halflife and limited penetration into the clot matrix halflife and limited penetration into the clot matrix because of strong binding with surface fibrin which because of strong binding with surface fibrin which could delay recanalization and increase the risk of could delay recanalization and increase the risk of recurrent occlusion recurrent occlusion
Prourokinase (r-prourokinase) Prourokinase (r-prourokinase) is the proenzyme precursor of urokinase is the proenzyme precursor of urokinase T12 of 7 minutes and high fibrin specificity T12 of 7 minutes and high fibrin specificity
Third-Generation AgentsThird-Generation Agents
ReteplaseReteplase is a structurally modified is a structurally modified form of alteplase form of alteplase
with a longer half-life (15ndash18 minutes) In with a longer half-life (15ndash18 minutes) In addition it does not bind as highly to fibrin addition it does not bind as highly to fibrin unbound reteplase can thus theoretically better unbound reteplase can thus theoretically better penetrate the clot and potentially penetrate the clot and potentially improve in improve in vivo fibrinolytic activity vivo fibrinolytic activity
TenecteplaseTenecteplase is another modified form of rtPA with a longer is another modified form of rtPA with a longer
half-life (17 minutes)half-life (17 minutes) greater fibrin specificity and greater greater fibrin specificity and greater
resistance to plasminogen activator inhibitor-1 resistance to plasminogen activator inhibitor-1 IV tenecteplase in acute ischemic stroke IV tenecteplase in acute ischemic stroke
suggest that the drug is safe and promisingsuggest that the drug is safe and promising
Newer plasminogen activatorNewer plasminogen activator
DesmoteplaseDesmoteplase is a genetically engineered is a genetically engineered version of the clot-dissolving factor version of the clot-dissolving factor
found in the saliva found in the saliva of the vampire bat Desmodus rotundusof the vampire bat Desmodus rotundus moremore potent and more selective for fibrin-bound potent and more selective for fibrin-bound
plasminogen than any other known plasminogen plasminogen than any other known plasminogen activatoractivator
Unlike tissue plasminogen activator (tPA) desmoteplase Unlike tissue plasminogen activator (tPA) desmoteplase is not activated by fibrinogen or -amyloid proteins is not activated by fibrinogen or -amyloid proteins factors that may exacerbate the risk for ICH factors that may exacerbate the risk for ICH
The effect of IV administration of desmoteplase 3ndash9 The effect of IV administration of desmoteplase 3ndash9 hours after symptom onset in patients with stroke who hours after symptom onset in patients with stroke who present with mismatch on MR imaging or CT perfusion present with mismatch on MR imaging or CT perfusion
3 DefibrinogenatingFibrinogenolytic 3 DefibrinogenatingFibrinogenolytic Agents Agents
AncrodAncrod(Viprinex)(Viprinex) is is the purified fraction of the Malayan pit viper venomthe purified fraction of the Malayan pit viper venom It acts by directly cleaving and inactivating fibrinogen It acts by directly cleaving and inactivating fibrinogen
and thus indirectly promoting anticoagulation and thus indirectly promoting anticoagulation The reduction in the blood levels of fibrinogen also The reduction in the blood levels of fibrinogen also
leads to a reduced blood viscosity which may improve leads to a reduced blood viscosity which may improve blood flow to the affected areas of the brain blood flow to the affected areas of the brain
In the Stroke Treatment with Ancrod Trial 500 In the Stroke Treatment with Ancrod Trial 500 patients with stroke presenting within 3 hours of patients with stroke presenting within 3 hours of symptom onset were randomized to receive ancrod (symptom onset were randomized to receive ancrod (n n 248) or a placebo (n 252) Good outcome (Barthel 248) or a placebo (n 252) Good outcome (Barthel Index 95ndash100 at 3 months) was achieved in 4221 Index 95ndash100 at 3 months) was achieved in 4221 and 344 of the patients respectively and 344 of the patients respectively
2 Direct Fibrinolytics2 Direct Fibrinolytics
Microplasmin (Microplasmin (ThromboGenics Heverlee Belgium)ThromboGenics Heverlee Belgium) is a truncated form of plasmin that is more resistant to the effects is a truncated form of plasmin that is more resistant to the effects
of antiplasmin of antiplasmin microplasmin can be used upto 4ndash12 hours after stroke onset microplasmin can be used upto 4ndash12 hours after stroke onset There was no evidence of increased bleeding risk with There was no evidence of increased bleeding risk with
microplasminmicroplasmin
Alfimeprase (Nuvelo San Carlos Calif)Alfimeprase (Nuvelo San Carlos Calif) is a recombinant truncated form of fibrolase a fibrinolytic zinc metalloproteinase is a recombinant truncated form of fibrolase a fibrinolytic zinc metalloproteinase
isolated from the venom of the southern copperhead snake isolated from the venom of the southern copperhead snake It degrades fibrin directly and achieves thrombolysis independent It degrades fibrin directly and achieves thrombolysis independent
of plasmin formationof plasmin formation its thrombolytic activity appears to be localized to the site of its thrombolytic activity appears to be localized to the site of
delivery These properties should theoretically result in faster delivery These properties should theoretically result in faster recanalization and lower hemorrhagic conversion riskrecanalization and lower hemorrhagic conversion risk
Anti-fibrinolyticsAnti-fibrinolytics
to limit fibrinolytic activityto limit fibrinolytic activity -aminocaproic acid (EACA) -aminocaproic acid (EACA) competitively inhibitscompetitively inhibits plasminogen and plasminogen activators from plasminogen and plasminogen activators from
binding to fibrinbinding to fibrin
alpha2-antiplasminalpha2-antiplasmin a serine protease inhibitor that a serine protease inhibitor that neutralizes any free circulating plasminneutralizes any free circulating plasmin
Plasminogen activator inhibitor-1Plasminogen activator inhibitor-1 a serine protease a serine protease inhibitor that inhibits tissue-type plasminogen inhibitor that inhibits tissue-type plasminogen activatoractivator
Glycoprotein (GP) IIbIIIa antagonistsGlycoprotein (GP) IIbIIIa antagonists
such as ReoPro (abciximab) Integrilin such as ReoPro (abciximab) Integrilin (eptifibatide) or Aggrastat (tirofiban) in (eptifibatide) or Aggrastat (tirofiban) in ischemic stroke remains investigational ischemic stroke remains investigational Deshmukh et al38 reported 21 patients with Deshmukh et al38 reported 21 patients with large-vessel occlusion refractory to IAT with large-vessel occlusion refractory to IAT with rtPA who were treated with IV andor IA rtPA who were treated with IV andor IA abciximab eptifibatide or tirofiban abciximab eptifibatide or tirofiban
IA Mechanical Approaches in Acute Ischemic Stroke IA Mechanical Approaches in Acute Ischemic Stroke Mechanical strategies have several advantagesMechanical strategies have several advantages First they lessen and may even preclude the use of chemical First they lessen and may even preclude the use of chemical
thrombolytics in this manner very likely reducing the risk of ICHthrombolytics in this manner very likely reducing the risk of ICH Second by avoiding the use of chemical thrombolytics it is Second by avoiding the use of chemical thrombolytics it is
possible to extend the treatment window beyond the limit of 6ndash8 possible to extend the treatment window beyond the limit of 6ndash8 hours hours
Third mechanically fragmenting a clot increases the surface area Third mechanically fragmenting a clot increases the surface area accessible to fibrinolytic agents and allows inflow of fresh accessible to fibrinolytic agents and allows inflow of fresh plasminogen which in turn may increase the speed of plasminogen which in turn may increase the speed of thrombolysis thrombolysis
Finally clot-retrieval devices may provide faster recanalization Finally clot-retrieval devices may provide faster recanalization
The disadvantages of the mechanical The disadvantages of the mechanical approaches approaches technical difficulty of navigating mechanical technical difficulty of navigating mechanical
devices into the intracranial circulation excessive devices into the intracranial circulation excessive trauma to the vasculature (potentially leading to trauma to the vasculature (potentially leading to vasospasm vessel dissection perforation or vasospasm vessel dissection perforation or rupture) rupture)
fragmented thrombus causing distal embolization fragmented thrombus causing distal embolization into previously unaffected territories into previously unaffected territories
Nevertheless the advantages of mechanical stroke Nevertheless the advantages of mechanical stroke therapy appear to significantly outweigh its therapy appear to significantly outweigh its disadvantages and risksdisadvantages and risks
Contraindications to Thrombolytic Contraindications to Thrombolytic agents agents
Recent thoracic abdominal or Recent thoracic abdominal or intracranial surgeryintracranial surgery
Recent haemorrhagic CVA Head injury Recent haemorrhagic CVA Head injury or neoplasmor neoplasm
Bleeding ulcerBleeding ulcer Anticipated invasive procedures (arterial Anticipated invasive procedures (arterial
punctures biopsies)punctures biopsies) Concurrent hemostatic dysfunctionConcurrent hemostatic dysfunction
Monitoring of thrombolytic Monitoring of thrombolytic therapytherapy
Thrombin time Measures the availability of functional
fibrinogen Normal thrombin time is 10-14 sec Prolonged when fibrinogen level is below
75-100 mgdl
Half Life of ThrombolyticsHalf Life of ThrombolyticsAgent Administration Half Life
Streptokinase IA 60-80min
Urokinase IAIV 9-12min
rTPA IAIV 6min
Abciximab(Reopro) IAIV 12hour
Aspirin POIV 15-20min
Heparin IVSC 60min
Coumadin PO 15-25 days
Anti Platelet DrugsAnti Platelet DrugsDrug Drug Mechanism Mechanism UsesUsesAspirinAspirin Permanently inhibits Permanently inhibits
COX-1 and COX-2COX-1 and COX-2CADCAD
Stroke-TIAsStroke-TIAs
NSAIDsNSAIDs Reversibly inhibits Reversibly inhibits COX-1COX-1
LimitedLimited
DipyridamoleDipyridamole Inhibits PDE increases Inhibits PDE increases cAMPcAMP
TIAsTIAs
ThenopyridinesThenopyridines
(Ticlopidine(Ticlopidine
ClopidrgrelClopidrgrel))
Inhibits ADP Inhibits ADP
PlatAg PlatAg
TIAsStrokeTIAsStroke
CAD PVDCAD PVD
Abciximab (ReoPro)Abciximab (ReoPro)
Eptifibatide (Integrilin)Eptifibatide (Integrilin)
TirofibanTirofiban
GP IIBIIIA InhibitorsGP IIBIIIA Inhibitors
Stroke- TIAs Stroke- TIAs
MonitoringMonitoring
Bleeding timeBleeding time
Optical aggregometryOptical aggregometry
Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay
Bleeding timeBleeding time
Requires a skin incision (usually made on the ear lobe or Requires a skin incision (usually made on the ear lobe or forearm offorearm of
a depth that results in disruption of capillary loops and a depth that results in disruption of capillary loops and small vessels)small vessels)
AdvantagesAdvantages Universally availableUniversally available Relatively simple techniquesRelatively simple techniques Can be performed bedsideCan be performed bedside
DisadvantagesDisadvantages Insensitive inaccurate non-specific techniqueInsensitive inaccurate non-specific technique
Poorly reproducible (as depends on multiple variables)Poorly reproducible (as depends on multiple variables)
Optical aggregometryOptical aggregometry
Gold standard assay for platelet functionGold standard assay for platelet function Agonist induced aggregation is measuredAgonist induced aggregation is measured Different agonist are available for different Different agonist are available for different
agentsagents However require unique expertise and are not However require unique expertise and are not
universally availableuniversally available Aspirin measured with ADP or AA(gt70 Aspirin measured with ADP or AA(gt70
aggregation so resistance)aggregation so resistance) Clopidogrel( ADP gt 90 aggregation means Clopidogrel( ADP gt 90 aggregation means
resistance) resistance)
Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay
Can be performed bed sideCan be performed bed side Different assay devices with different Different assay devices with different
agonist are used for each of different agonist are used for each of different antiplatelet agents antiplatelet agents
For Aspirin AA is used (result is reported as aspirin For Aspirin AA is used (result is reported as aspirin reaction units [ARU] ARUgt 550 indicates non-reaction units [ARU] ARUgt 550 indicates non-responsiveness)responsiveness)
Verify IIbIIIa assay device uses TRAP as agonist for Verify IIbIIIa assay device uses TRAP as agonist for Abciximab and TirofibanAbciximab and Tirofiban
Practical Applications Practical Applications related to specific related to specific
Neurovascular Neurovascular interventionsinterventions
Acute ischemic StrokeAcute ischemic Stroke When an artery occludes neurons are affected When an artery occludes neurons are affected
differently depending upon the amount of residual blood differently depending upon the amount of residual blood flowflow
Normal cerebral blood flow is greater than 50 mL100 Normal cerebral blood flow is greater than 50 mL100 mgminmgmin
Once blood flow decreases to less than 20 mL100 Once blood flow decreases to less than 20 mL100 mgmin infarction occursmgmin infarction occurs
If blood flow decreases to less than 10 mL100 mgmin If blood flow decreases to less than 10 mL100 mgmin irreversible neuronal death occurs rapidly irreversible neuronal death occurs rapidly
Blood flow between 11 and 20 mL100 mgmin is thought Blood flow between 11 and 20 mL100 mgmin is thought to represent the ischemic penumbra an area where the to represent the ischemic penumbra an area where the cells are functionally silent because of ischemia but are cells are functionally silent because of ischemia but are still able to recover if blood flow is restored still able to recover if blood flow is restored
Many acute stroke therapies are targeted toward Many acute stroke therapies are targeted toward restoring flow or function to the ischemic penumbrarestoring flow or function to the ischemic penumbra
Therapeutic window in Therapeutic window in management of acute Ischemic management of acute Ischemic
StrokeStrokeThe early diagnosis of ischemic stroke is critical to the The early diagnosis of ischemic stroke is critical to the
with only a narrow therapeutic window in the first few with only a narrow therapeutic window in the first few hours following stroke ictushours following stroke ictus
Diagnosis in the first 3 hours postictus provides the Diagnosis in the first 3 hours postictus provides the opportunity for intravenous or intraarterial thrombolysis opportunity for intravenous or intraarterial thrombolysis and intra-arterial clot mechanical treatment which and intra-arterial clot mechanical treatment which improve the outcome improve the outcome
Diagnosis in the time period between 3 and 6 hours Diagnosis in the time period between 3 and 6 hours provides an opportunity for intra-arterial thrombolysis provides an opportunity for intra-arterial thrombolysis and mechanical treatment and mechanical treatment
Involvement of the posterior circulation especially the Involvement of the posterior circulation especially the basilar artery is treated by some regardless of time of basilar artery is treated by some regardless of time of onset or up until 12 to 24 hours in some practices This is onset or up until 12 to 24 hours in some practices This is related to the potentially high mortality and morbidity related to the potentially high mortality and morbidity associated with basilar artery thrombosisassociated with basilar artery thrombosis
Infarct evaluation on angiographyInfarct evaluation on angiography(CT angiography and catheter (CT angiography and catheter
angiography)angiography)CTA is an excellent first-line examination for CTA is an excellent first-line examination for
evaluation of the head and neck arteries evaluation of the head and neck arteries In comparison with catheter angiography In comparison with catheter angiography
what it gives up in resolution and dynamic what it gives up in resolution and dynamic properties it makes up for with rapid properties it makes up for with rapid acquisition of a 3-D dataset and the potential acquisition of a 3-D dataset and the potential for assessment of whole-brain perfusion and for assessment of whole-brain perfusion and better parenchymal evaluationbetter parenchymal evaluation
Moreover CTA illustrates not only arterial Moreover CTA illustrates not only arterial stenosis or occlusion but also the vessel wall stenosis or occlusion but also the vessel wall This factor is most important for evaluation of This factor is most important for evaluation of intramural dissection and thrombosed intramural dissection and thrombosed aneurysms which may both complicate aneurysms which may both complicate evaluation of stroke patientsevaluation of stroke patients
Early angiographic signs of strokes Early angiographic signs of strokes both CTA both CTA and DSA and DSA
Vessel occlusion or cutoff related to Vessel occlusion or cutoff related to thromboembolithromboemboli
aneurysms aneurysms arterial dissection arterial dissection Meniscus or flattened shape to clot Meniscus or flattened shape to clot
(recent) versus reverse meniscus (older)(recent) versus reverse meniscus (older) tram track (nonocclusive or recanalized tram track (nonocclusive or recanalized
clot) clot) delayed (antegrade) flow (manifest as delayed (antegrade) flow (manifest as
decreased whole-brain perfusion on CTA)decreased whole-brain perfusion on CTA) retrograde collateral flowretrograde collateral flow
Non-occlusive left MCA thrombus on 3-D imaging performed from CTA source data and was confirmed at catheter angiography
Therapy to be started within a 6-hr Therapy to be started within a 6-hr time to treatment (TTT) window time to treatment (TTT) window (while in case of IV thrombolysis (while in case of IV thrombolysis therapy to be started with in 3hrs)therapy to be started with in 3hrs)
Exclusion criteria Exclusion criteria Rapidly improving neurologic deficit or Rapidly improving neurologic deficit or Sustained blood pressure of gt180100 Sustained blood pressure of gt180100 Hemorrhage is detected on CTHemorrhage is detected on CT Infarct involving gt more than 13 rd Infarct involving gt more than 13 rd
territory of MCAterritory of MCA MRADWI-Perfusion mismatchlt 20MRADWI-Perfusion mismatchlt 20 Definite hypodensity on CTDefinite hypodensity on CT
Intra-arterial Thrombolysis
Fibrinolytics + AntiplateletsFibrinolytics + Antiplatelets
PlasminogenPlasminogen activators through fibrinolysis exposes activators through fibrinolysis exposes free thrombin and paradoxically stimulatesfree thrombin and paradoxically stimulates platelet platelet aggregation which leads to formation of aaggregation which leads to formation of a platelet platelet thrombus (white clot) thrombus (white clot)
This new thrombus is relatively resistant to This new thrombus is relatively resistant to fibrinolyticsfibrinolytics
So new regimen in case of acute stroke isSo new regimen in case of acute stroke is fibrinolytics + antiplatelet drugsfibrinolytics + antiplatelet drugs
rtPA + IIbIIIa inhibitors( tirofiban rtPA + IIbIIIa inhibitors( tirofiban abciximab) orabciximab) or
Urokinase + IIbIIIa Urokinase + IIbIIIa inhibitors( tirofiban abciximab)inhibitors( tirofiban abciximab)
Intra-arterial Thrombolysis Tirofiban (04 microgkgmin bolus for 3 min followed by Tirofiban (04 microgkgmin bolus for 3 min followed by
0125 ugkgmin)0125 ugkgmin)
++
Heparin (2000ndash3000 IU bolus followed by Heparin (2000ndash3000 IU bolus followed by 1000 IUhour infusion 1000 IUhour infusion
with ACT maintained bw 200-300) throughout the with ACT maintained bw 200-300) throughout the interventional procedure and for 24ndash48 hours thereafter when interventional procedure and for 24ndash48 hours thereafter when there is neither intraprocedural bleeding nor suspicion of there is neither intraprocedural bleeding nor suspicion of increased risk of bleeding increased risk of bleeding
Maximum dose of Urokinase Maximum dose of Urokinase Anterior circulation stroke - 500000 IU (mean 400000 Anterior circulation stroke - 500000 IU (mean 400000
IU range 300000ndash500000 IU)IU range 300000ndash500000 IU) Posterior circulation stroke -1000000 IU (mean 837000 Posterior circulation stroke -1000000 IU (mean 837000
IU range 300000ndash1000000 IU)IU range 300000ndash1000000 IU)American Journal of NeuroradiologyAmerican Journal of Neuroradiology 262595-2601 2005262595-2601 2005
Intravenous ThrombolysisIntravenous Thrombolysis
The first method to restore cerebral The first method to restore cerebral perfusion is clot lysis with the goal perfusion is clot lysis with the goal of re-establishing blood flow to the of re-establishing blood flow to the affected tissue affected tissue
IV thrombolysis rt-PA is the only IV thrombolysis rt-PA is the only FDA- approved treatment for AIS FDA- approved treatment for AIS
Fibrinolysis is enhanced powerfully Fibrinolysis is enhanced powerfully by rt-PAby rt-PA
Intravenous rTPA Intravenous rTPA administration administration protocolprotocol
Total dose of rt-PA 09 mgkg (maximum dose Total dose of rt-PA 09 mgkg (maximum dose 90 mg)90 mg)
Give 10 as initial IV bolusGive 10 as initial IV bolus Infuse remainder over 1 hourInfuse remainder over 1 hour Admit patient to an ICU or stroke unit for Admit patient to an ICU or stroke unit for
monitoringmonitoring Neurologic assessments every 15 minutes Neurologic assessments every 15 minutes
during infusion then every 30 minutes for next during infusion then every 30 minutes for next 6 hours then every hour until 24hours after 6 hours then every hour until 24hours after treatmenttreatment
Favorable Outcome vs Treatment Time Favorable Outcome vs Treatment Time with IV rTPAwith IV rTPA
Protocol limit = 3 hrs
Benefit ~ 45 hrs
Thromboembolism During coilingThromboembolism During coiling Most feared and frequent complication Most feared and frequent complication Reported incidence - Approx 7 Reported incidence - Approx 7 SourcesSources of Thromboembolism are of Thromboembolism are
- Clots at the aneurysmal neck during or immediately- Clots at the aneurysmal neck during or immediately after after embolization embolization
- Thrombus forming on catheters during- Thrombus forming on catheters during proceduresprocedures
- Stenosis of an adjacent artery dt coil mass- Stenosis of an adjacent artery dt coil mass or herniationor herniation
- Migration of intraaneurysmal- Migration of intraaneurysmal thrombus during coil thrombus during coil placement placement
- Slow flow dt vasospasm - Slow flow dt vasospasm
- Rare and unlikely causes are hypercoagulable- Rare and unlikely causes are hypercoagulable state such state such as antiphospholipid antibody syndrome or due to HITas antiphospholipid antibody syndrome or due to HIT
Occur more often with wide-necked aneurysms (dt Occur more often with wide-necked aneurysms (dt increased exposed surface area of thrombogenic coil increased exposed surface area of thrombogenic coil material)material)
Current regimen of endovascular Current regimen of endovascular managementmanagement
The The glycoprotein IIbIIIa antagonist tirofiban glycoprotein IIbIIIa antagonist tirofiban (04 (04 microgkgmin bolus for 30 minutes followed by infusion of microgkgmin bolus for 30 minutes followed by infusion of 0125 ugkgmin until the thrombus dissolved) 0125 ugkgmin until the thrombus dissolved)
Intraarterial thrombolysis with Intraarterial thrombolysis with urokinase or r- TPA urokinase or r- TPA increase of intravenous (IV) heparin (measured by increase of intravenous (IV) heparin (measured by
ACT) ACT) Intravenous aspirin Intravenous aspirin
Coil-related platelet aggregation (white clot) is Coil-related platelet aggregation (white clot) is unlikely to respond to fibrinolytics but has a high risk unlikely to respond to fibrinolytics but has a high risk of hemorrhage (In ISAT) all 5 patients who had of hemorrhage (In ISAT) all 5 patients who had received thrombolytic therapy with tPA to treat a received thrombolytic therapy with tPA to treat a thromboembolic complication after endovascular thromboembolic complication after endovascular treatment rebleed and all of these patients died)treatment rebleed and all of these patients died)
IntracranialIntracranial Stenting Stenting Metallic foreign body such as stent will accumulate Metallic foreign body such as stent will accumulate
thrombus in the absence of platelet inhibitionthrombus in the absence of platelet inhibition Antiplatelet drugs are important to prevent peri or Antiplatelet drugs are important to prevent peri or
post-interventional thromboembolic eventspost-interventional thromboembolic events Optimal treatment regimens has not been determined Optimal treatment regimens has not been determined
but usually but usually Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-
procedureprocedureOrOr
Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on
morning of proceduremorning of procedure
If need to use stent is not pre-planned thanIf need to use stent is not pre-planned than
Abciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkgAbciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkg IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)
Glycoprotein IIbIIIa inhibitor are not used routinely during elective Glycoprotein IIbIIIa inhibitor are not used routinely during elective stenting procedure dt increased risk of ICH stenting procedure dt increased risk of ICH
Carotid StentingCarotid Stenting
Pre-procedurePre-procedure
Double Antiplatelet therapy is routinely given Double Antiplatelet therapy is routinely given beginning at least 3beginning at least 3
days before the proceduredays before the procedure
Aspirin 325mgd+Clopidogrel 75mgdAspirin 325mgd+Clopidogrel 75mgd During procedureDuring procedure
Heparin is given with target clotting time of 250-Heparin is given with target clotting time of 250-300sec300sec
Post-procedure Post-procedure
Aspirin 325mg is continued indefinitely and Aspirin 325mg is continued indefinitely and
Clopidogrel 75mgd for at least 6 weeks Clopidogrel 75mgd for at least 6 weeks
Inclusion criteria for Local ThrombolysisInclusion criteria for Local Thrombolysis a)a) Patients in severe clinical grade on admission Patients in severe clinical grade on admission
with evidence of dural venous sinus with evidence of dural venous sinus thrombosis and restrictive venous outflow on thrombosis and restrictive venous outflow on cerebral angiogramcerebral angiogram
b)b) Patients in clinical grade 3 worsening on Patients in clinical grade 3 worsening on heparin therapy Restriction to venous heparin therapy Restriction to venous outflow was defined as an increase in brain outflow was defined as an increase in brain circulation time gt 12 s delay in the drainage circulation time gt 12 s delay in the drainage of cortical veins with cortical veins hanging of cortical veins with cortical veins hanging in spacein space
Treatment Options for Venous Thrombosis
CT Grading for Venous ThrombosisCT Grading for Venous Thrombosis Grade I no parenchymal change Grade I no parenchymal change
(hyperdense (hyperdense sinuses cortical veins empty sinuses cortical veins empty delta sign)delta sign)
Grade II non hemorrhagic venous infarct Grade II non hemorrhagic venous infarct without mass effect without mass effect
Grade III non-hemorrhagic infarct with Grade III non-hemorrhagic infarct with mass effectmass effect
Grade IV hemorrhagic venous infarct (max Grade IV hemorrhagic venous infarct (max diameter lt 3 cm) with no mass effectdiameter lt 3 cm) with no mass effect
Grade V hemorrhagic venous infarct (max Grade V hemorrhagic venous infarct (max diameter gt 3 cm) with mass effect diameter gt 3 cm) with mass effect
Local ThrombolysisLocal Thrombolysis
Femoral Jugular access was secured and a guiding Femoral Jugular access was secured and a guiding catheter was placed in the jugular bulb catheter was placed in the jugular bulb Mechanical Mechanical clot maceration clot maceration was done with the guidewire was done with the guidewire following which a microcatheter (was navigated and following which a microcatheter (was navigated and placed in the thrombosed segment of sinus confirmed placed in the thrombosed segment of sinus confirmed on a selective venogram on a selective venogram
Urokinase infusion Bolus dose of 2-6 lacs followed Urokinase infusion Bolus dose of 2-6 lacs followed by 60000 to 100000 units per hour along with by 60000 to 100000 units per hour along with periodic check venogram Along with maintenance periodic check venogram Along with maintenance systemic infusion of Heparinsystemic infusion of Heparin Other agents such as Other agents such as streptokinase altepase or rTPAstreptokinase altepase or rTPA can be also used can be also used
After thrombolysis patient should subjected to oral After thrombolysis patient should subjected to oral anticoagulation for six monthsanticoagulation for six months
Low-molecular-weight Low-molecular-weight heparinheparin
PharmacologyPharmacologyLMWH as its name suggests is a glycosaminoglycan that is approximatelyLMWH as its name suggests is a glycosaminoglycan that is approximately
one third the molecular weight of UFH It is derived from UFH through one third the molecular weight of UFH It is derived from UFH through variousvarious
depolymerization processes LMWH binds to antithrombin which in turn depolymerization processes LMWH binds to antithrombin which in turn
Neutralizes actors Xa and IIa Because LMWH lacks many of the longer Neutralizes actors Xa and IIa Because LMWH lacks many of the longer chains chains
required for binding to thrombin it has less ability to neutralize thrombin required for binding to thrombin it has less ability to neutralize thrombin
relativeto its ability to neutralize factor Xa LMWH also has less relativeto its ability to neutralize factor Xa LMWH also has less nonspecific nonspecific
binding to other proteins There is greater bioavailability with more binding to other proteins There is greater bioavailability with more predictable predictable
pharmacokinetics that eliminates the need for monitoring The smaller pharmacokinetics that eliminates the need for monitoring The smaller size also size also
allows for enhanced subcutaneous absorption when compared with UFHallows for enhanced subcutaneous absorption when compared with UFH
Three LMWH preparations are Three LMWH preparations are currently approved for use in the currently approved for use in the United States (1) enoxaparin (2) United States (1) enoxaparin (2) dalteparin and (3) tinzaparin dalteparin and (3) tinzaparin
They are all administered They are all administered subcutaneously at intervals of either subcutaneously at intervals of either once or twice daily for both once or twice daily for both prophylaxis and treatment dosesprophylaxis and treatment doses
Few Experiences of Few Experiences of ThrombolysisThrombolysis
Vickey 25 Yrs male patient presented Vickey 25 Yrs male patient presented with 12with 12thth day HO severe headache with day HO severe headache with right sided hemiplegiaright sided hemiplegia
MRI shows thrombosis of the superior MRI shows thrombosis of the superior sagittal left transverse left sigmoid sagittal left transverse left sigmoid sinuses and cortical veins in the fronto-sinuses and cortical veins in the fronto-parietal regions with eo haemorrhagic parietal regions with eo haemorrhagic infarct in the left cerebral hemisphere infarct in the left cerebral hemisphere with mass effect( Grade ndashV)with mass effect( Grade ndashV)
Sashi Srivastava 64 yrs FSashi Srivastava 64 yrs F In a follow up case of MRD with infra-renal In a follow up case of MRD with infra-renal
aortic abdominal and bilateral renal artery aortic abdominal and bilateral renal artery thrombosis renal angiogram shows filling thrombosis renal angiogram shows filling defects in the right Renal artery defects in the right Renal artery
Initially Renal angioplasty was done Initially Renal angioplasty was done Following angioplasty few thrombi are seem Following angioplasty few thrombi are seem to extends into the segmental branches and to extends into the segmental branches and causing blockage So Thrombolysis was causing blockage So Thrombolysis was plane to dissolve the run-out thrombi with plane to dissolve the run-out thrombi with urokinase urokinase
Rakesh 34yrsMRakesh 34yrsM Left SFA pseudoaneurysm with Left SFA pseudoaneurysm with
Covered stent placementCovered stent placement Pre operative antiplatelets with post Pre operative antiplatelets with post
procedure heparin Tirofiban procedure heparin Tirofiban followed by aspirin and clopidogrel followed by aspirin and clopidogrel were usedwere used
IAT may be a treatment option for selected patients IAT may be a treatment option for selected patients Possible selection criteria include Possible selection criteria include
presentation between 3 and 6 hours from symptom onsetpresentation between 3 and 6 hours from symptom onset major cerebral artery occlusion major cerebral artery occlusion severe neurologic deficits severe neurologic deficits high risk of systemic hemorrhage with IV rt-PA (eg recent high risk of systemic hemorrhage with IV rt-PA (eg recent
surgery) surgery) The MERCI (Mechanical Embolus Removal in Cerebral The MERCI (Mechanical Embolus Removal in Cerebral
Ischemia) retrievalIschemia) retrieval system system
Has been FDA-approved for recanalizing acutely occluded Has been FDA-approved for recanalizing acutely occluded cerebral arteries cerebral arteries
In the Multi-MERCI study patients who did not improve In the Multi-MERCI study patients who did not improve immediately after IV rt-PA underwent mechanical immediately after IV rt-PA underwent mechanical embolectomy within 8 hours of symptom onset embolectomy within 8 hours of symptom onset
Partial or complete recanalization occurred in 74 of Partial or complete recanalization occurred in 74 of patientspatients
with a symptomatic intracerebral hemorrhage (sICH) rate of with a symptomatic intracerebral hemorrhage (sICH) rate of 67 67
Mechanical embolectomy with the MERCI retriever may be a Mechanical embolectomy with the MERCI retriever may be a feasible and safe option for patients after IV rt-PAfeasible and safe option for patients after IV rt-PA
Penumbra stroke systemPenumbra stroke system This device combines two methods of clot This device combines two methods of clot
extraction aspiration and mechanical extraction aspiration and mechanical extraction extraction
First the clot is aspirated then a thrombus First the clot is aspirated then a thrombus removal ring can be used if necessary to removal ring can be used if necessary to remove remaining clot remove remaining clot
successful recanalizing 82successful recanalizing 82 Bridging therapyBridging therapy
06 mgkg IV rt-PA followed by IAT with IA rt-06 mgkg IV rt-PA followed by IAT with IA rt-PA (up to 20 mg)PA (up to 20 mg)
achieved a higher recanalization rateachieved a higher recanalization rate
Criteria for thrombolysis with rTPACriteria for thrombolysis with rTPA
Inclusion criteriaInclusion criteria Clinical signs and symptoms consistent with ischemic Clinical signs and symptoms consistent with ischemic
strokestroke Patient last seen normal within 3 hoursPatient last seen normal within 3 hours Measurable neurologic deficitMeasurable neurologic deficit
Exclusion criteriaExclusion criteria Any hemorrhage on neuroimaging (CT or MRI)Any hemorrhage on neuroimaging (CT or MRI) Symptoms suggestive of subarachnoid hemorrhageSymptoms suggestive of subarachnoid hemorrhage Seizure at stroke onset that is thought to contribute to Seizure at stroke onset that is thought to contribute to
neurologic deficitneurologic deficit Hypodensity greater than one third cerebral hemisphere Hypodensity greater than one third cerebral hemisphere
on CTon CT SBP greater than 185 mm Hg or DBP greater than 110 SBP greater than 185 mm Hg or DBP greater than 110
mm Hgmm Hg International normalized ratio (INR) greater than 17International normalized ratio (INR) greater than 17
Ischemic Stroke Ischemic Stroke Treatment ndash 2006Treatment ndash 2006
IV tissue plasminogen activator (tPA)IV tissue plasminogen activator (tPA) ndash ndash Only FDA-approved acute stroke drugOnly FDA-approved acute stroke drug ndash ndash 3 hour treatment window3 hour treatment window
MERCI - Concentric clot retrieval MERCI - Concentric clot retrieval devicedevice ndash ndash Rescue therapy - approved 2004Rescue therapy - approved 2004 ndash ndash Device approval (not outcomes-based)Device approval (not outcomes-based)
Off label approachesOff label approaches ndash ndash IV tPA after 3 hoursIV tPA after 3 hours ndash ndash IV-IA tPA sequential strategiesIV-IA tPA sequential strategies ndash ndash IA tPA clot angioplasty fragmentationIA tPA clot angioplasty fragmentation ndash ndash Ultrasound-assisted tPA lysisUltrasound-assisted tPA lysis
rt-PA Trials NINDSrt-PA Trials NINDS
Acute stroke - 624 patientsAcute stroke - 624 patients Treat within 3 hrsTreat within 3 hrs Intravenous 09 mgkg rt-PA vs placeboIntravenous 09 mgkg rt-PA vs placebo Hemorrhage 64 tPA 06 placeboHemorrhage 64 tPA 06 placebo Neurologic recovery better with tPA 30 Neurologic recovery better with tPA 30
more like to have minimal or no disabilitymore like to have minimal or no disability
First proven approved treatment for First proven approved treatment for strokestroke
Limitations of tPALimitations of tPA Only 4 of acute strokes receive tPAOnly 4 of acute strokes receive tPA (Kleindorfer et al Stroke 2004 35 e27-e29)(Kleindorfer et al Stroke 2004 35 e27-e29)
Only 22 of patients present within 3 hoursOnly 22 of patients present within 3 hours1048707 1048707 51 of these ineligible due to51 of these ineligible due to
bull bull Mild severityMild severity bull bull Medical or surgical historyMedical or surgical history bull bull Blood testsBlood tests
Sustained recanalization only 13Sustained recanalization only 13 (Alexandrov et al NEJM 2004 351 2170-8)(Alexandrov et al NEJM 2004 351 2170-8)
Concern for hemorrhageConcern for hemorrhage tPA potentiates apoptotic injury tPA potentiates apoptotic injury (Liu et al Nature Med 2004 101379-83)(Liu et al Nature Med 2004 101379-83)
PROACT II IA Lysis TrialPROACT II IA Lysis Trial Baseline 24 hours 8 days
Baseline 60 minutes 120 minutes
9mg IAProurokinase
Desmoteplase Trials DEDAS Desmoteplase Trials DEDAS DIASDIAS
Trial OverviewTrial Overview Double blind randomized placebo Double blind randomized placebo
controlled trialscontrolled trials IV delivery 3-9 hour time windowIV delivery 3-9 hour time window Plasminogen activator ndash from Plasminogen activator ndash from vampire bat vampire bat
salivasaliva Selection based on PWI-DWI MismatchSelection based on PWI-DWI Mismatch
MRI InclusionMRI Inclusion PWI defect at least 2 cm AND ~20 larger PWI defect at least 2 cm AND ~20 larger
than DWIthan DWI PWI should be obvious even visible on PWI should be obvious even visible on
raw imagesraw imagesMRI ExclusionMRI Exclusion
DWI gt 13 MCADWI gt 13 MCA MRA ICA occlusionMRA ICA occlusion
Desmoteplase ndash DIAS Desmoteplase ndash DIAS ResultsResults
Mechanical Thrombolysis Mechanical Thrombolysis devicesdevices
mechanical thrombolysis potentially extends the treatment mechanical thrombolysis potentially extends the treatment window because they act promptly at the site of the thrombuswindow because they act promptly at the site of the thrombus
The devices can retrieve large clots that pharmaceutical agents The devices can retrieve large clots that pharmaceutical agents may not successfully lysemay not successfully lyse
Patients treated with IV tPA may be considered for treatment of Patients treated with IV tPA may be considered for treatment of residual clot with some of these devicesresidual clot with some of these devices
suction-creating saline jets suction-creating saline jets laser energy ultrasound laser energy ultrasound a corkscrew apparatus to treat strokesa corkscrew apparatus to treat strokes The AngioJet systemThe AngioJet system uses saline jets that are directed back into the catheter to uses saline jets that are directed back into the catheter to
create a low-pressure zone around the catheter tip inducing create a low-pressure zone around the catheter tip inducing suction suction
The clot is pulled into the exhaust lumen and removed from the The clot is pulled into the exhaust lumen and removed from the vessel Although US Food and Drug Administration (FDA) has vessel Although US Food and Drug Administration (FDA) has approved this device for use in arteriovenous dialysis grafts and approved this device for use in arteriovenous dialysis grafts and fistulae and for the treatment of coronary arteries saphenous fistulae and for the treatment of coronary arteries saphenous vein grafts and peripheral vessels clinical trials for the vein grafts and peripheral vessels clinical trials for the treatment of acute stroke are no longer in progress treatment of acute stroke are no longer in progress
Most devices are used in cerebral vessels that 2-5 mm
The Latis laser device The Latis laser device used laser energy to ablate clots used laser energy to ablate clots Arteries 2-5 mm in diameter could be Arteries 2-5 mm in diameter could be
treated including the ICA M1 or M2 treated including the ICA M1 or M2 branch of the MCA A1 branch of the branch of the MCA A1 branch of the anterior cerebral artery (ACA) basilar anterior cerebral artery (ACA) basilar artery posterior cerebral artery (PCA) artery posterior cerebral artery (PCA) and vertebral and vertebral
Patients could receive treatment as late Patients could receive treatment as late as 8 hours after symptom onset in the as 8 hours after symptom onset in the anterior circulation and within 24 hours in anterior circulation and within 24 hours in the posterior circulation the posterior circulation
Endovascular Photo Acoustic Endovascular Photo Acoustic Recanalization (EPAR) Recanalization (EPAR)
A laser power source generated energy for the A laser power source generated energy for the systemsystem
The energy was delivered by means of The energy was delivered by means of fiberoptics to the tip of the catheter at the fiberoptics to the tip of the catheter at the treatment sitetreatment site
Absorption of laser light by darkly pigmented Absorption of laser light by darkly pigmented materials (ie the clot) occurred inside the 1-mm materials (ie the clot) occurred inside the 1-mm catheter tipcatheter tip
the system was designed to minimize scattering the system was designed to minimize scattering of laser light of laser light
Absorption converted photo energy to acoustic Absorption converted photo energy to acoustic energy which then emulsified the clot inside the energy which then emulsified the clot inside the catheter tip catheter tip
EKOS ultrasound( the EKOS ultrasound( the Ultrasound Thrombolytic Ultrasound Thrombolytic
Infusion Catheter) Infusion Catheter) combines the use of a distal ultrasound transducer with combines the use of a distal ultrasound transducer with
infusion of a thrombolytic agent through the infusion of a thrombolytic agent through the microcathetermicrocatheter
Ultrasound changes the structure of the clot to Ultrasound changes the structure of the clot to temporarily increase its permeability while providing an temporarily increase its permeability while providing an acoustic pressure gradient to move the drug into the clot acoustic pressure gradient to move the drug into the clot to speed its dissolution to speed its dissolution
The EKOS catheter is placed in the proximal portion of the The EKOS catheter is placed in the proximal portion of the clot clot
After a 2-mg bolus of tPA was injected through the After a 2-mg bolus of tPA was injected through the catheter catheter
the patient received a continuous infusion of IA tPA 03 the patient received a continuous infusion of IA tPA 03 mgmin to a maximum of 20 mg and simultaneous mgmin to a maximum of 20 mg and simultaneous ultrasound transmission for as long as 60 minutes ultrasound transmission for as long as 60 minutes
One patient was treated with a total of 4 units of One patient was treated with a total of 4 units of recombinant reteplase (Retavase) hand-injected over 60 recombinant reteplase (Retavase) hand-injected over 60 minutes minutes
Penumbra system Penumbra system The Penumbra system (Penumbra Inc) provides a dual The Penumbra system (Penumbra Inc) provides a dual
approach to clot extraction using aspiration followed by approach to clot extraction using aspiration followed by clot retrieval with a ring device if needed clot retrieval with a ring device if needed
Mechanical Embolus Removal in Cerebral Ischemia Mechanical Embolus Removal in Cerebral Ischemia (MERCI)(MERCI)
a corkscrew-like apparatus to remove blood clots from a corkscrew-like apparatus to remove blood clots from the brain in patients experiencing an ischemic stroke the brain in patients experiencing an ischemic stroke
The corkscrew itself resides in the catheter tip which The corkscrew itself resides in the catheter tip which shields it from the wall of the vessel until it is ready to be shields it from the wall of the vessel until it is ready to be burrowed into the clot Once lodged in the clot the device burrowed into the clot Once lodged in the clot the device and clot are withdrawn from the vessel and clot are withdrawn from the vessel
Snarelike devicesSnarelike devices Snares such as the Neuronet snare (Guidant Snares such as the Neuronet snare (Guidant
Endovascular Santa Clara CA) have been developed Endovascular Santa Clara CA) have been developed specifically for use in the treatment of strokes specifically for use in the treatment of strokes
These devices are simple in design and do not require the These devices are simple in design and do not require the clot to be amenable to emulsification clot to be amenable to emulsification
X-Sizer deviceX-Sizer device a device with small moving blades at the a device with small moving blades at the
catheter tip catheter tip This device the X-Sizer device (EndiCor Medical This device the X-Sizer device (EndiCor Medical
San Clemente CA) can be used to excise the San Clemente CA) can be used to excise the thrombus and aspirate it thrombus and aspirate it
The device was being evaluated in randomized The device was being evaluated in randomized studies of coronary vessels and in a registry of studies of coronary vessels and in a registry of patients with acute myocardial infarctionpatients with acute myocardial infarction
Although the manufacturer had modified the Although the manufacturer had modified the device for use in cerebral vessels a safety and device for use in cerebral vessels a safety and feasibility study was indefinitely suspended after feasibility study was indefinitely suspended after only 1 patient was treated with the device in only 1 patient was treated with the device in Europe Europe
Suction thrombectomySuction thrombectomy This method of mechanical thrombolysis is one of the This method of mechanical thrombolysis is one of the
simplestsimplest In this readily available technique suction is applied with In this readily available technique suction is applied with
a syringe to remove thrombus in the ICA a syringe to remove thrombus in the ICA It requires no other devicesIt requires no other devices A catheter with a large inner diameter (Brite Tip Cordis A catheter with a large inner diameter (Brite Tip Cordis
Corporation Miami FL) was placed in the symptomatic Corporation Miami FL) was placed in the symptomatic vessel and navigated over a guidewire into the thrombusvessel and navigated over a guidewire into the thrombus
A 60-mL syringe was used to aspirate the thrombus A 60-mL syringe was used to aspirate the thrombus Each patient required angioplasty and stenting of carotid Each patient required angioplasty and stenting of carotid
bifurcation stenosis and received daily aspirin and bifurcation stenosis and received daily aspirin and ticlopidine after the procedure No complications ticlopidine after the procedure No complications occurred occurred
Summary Acute Stroke Summary Acute Stroke ImagingImaging
PhysiologyPhysiology importance collaterals importance collaterals
ndash ndashGrowing role for perfusion Growing role for perfusion assessmentassessment
tPAtPA guidelines amp limitations guidelines amp limitations Signs on CT amp MRSigns on CT amp MR follow physiology follow physiology Stroke trialsStroke trials PWI-DWI mismatch PWI-DWI mismatch
ndash ndashTreat based on physiology not timeTreat based on physiology not time ProtocolsProtocols should be fast and should be fast and
comprehensivecomprehensive
Anti Platelet DrugsAnti Platelet DrugsDrug Mechanism UsesDrug Mechanism UsesAspirinAspirin Permanently inhibits Permanently inhibits
COX-1 and COX-2COX-1 and COX-2CADCAD
Stroke-TIAsStroke-TIAs
NSAIDsNSAIDs Reversibly inhibits Reversibly inhibits COX-1COX-1
LimitedLimited
DipyridamoleDipyridamole Inhibits PDE Inhibits PDE increases cAMPincreases cAMP
TIAsTIAs
ThenopyridinesThenopyridines
(Ticlopidine(Ticlopidine
Clopidegrel)Clopidegrel)
Inhibits ADP Inhibits ADP
PlatAg PlatAg
TIAsStrokeTIAsStroke
CAD PVDCAD PVD
Abciximab (ReoPro)Abciximab (ReoPro)
Eptifibatide Eptifibatide (Integrilin)(Integrilin)
TirofibaTirofibann
GP IIBIIIA InhibitorsGP IIBIIIA Inhibitors
Stroke- TIAs Stroke- TIAs
Maintainance of patency Maintainance of patency of vascular of vascular grafts catheters shunts bypassesgrafts catheters shunts bypasses
Arterial thromboembolic diseaseArterial thromboembolic diseasebull Transient ischemic attacksTransient ischemic attacksbull Stroke in evolutionStroke in evolution
Ischemic events occurs in Ischemic events occurs in 1313 of of conventional neuroangiographic conventional neuroangiographic procedures without Endovascular surgeryprocedures without Endovascular surgery
Indications for Antithrombotic Therapy in Indications for Antithrombotic Therapy in Diagnostics and Interventional ProceduresDiagnostics and Interventional Procedures
WHY TO MONITOR ANTICOAGULANT THERAPYWHY TO MONITOR ANTICOAGULANT THERAPY
Narrow therapeutic rangeNarrow therapeutic range
Can increase risk of bleedingCan increase risk of bleeding
Coagulation TestingCoagulation Testing
Monitoring therapyMonitoring therapy
Intrinsic Pathway
Extrinsic Pathway
Common Pathway
CLOT
Heparin Coumadin
Monitor with
ACT aPTT
Monitor with PTINR
Thrombolytics
Monitor with TT Fibrinogen
Monitoring of Monitoring of Anti platelet drugsAnti platelet drugs
Bleeding timeBleeding time
Optical aggregometryOptical aggregometry
Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay
HeparinHeparin
Heterogeneous 3000-30000 dalton in Heterogeneous 3000-30000 dalton in molecular weight molecular weight
Average=15000 d (~45monosaccharide Average=15000 d (~45monosaccharide chains)chains)
About About 13 of dose binds to AT III and forms 13 of dose binds to AT III and forms the AT IIIHeparinClotting Factor Complexthe AT IIIHeparinClotting Factor Complex
Complex binds to clotting factors of the Complex binds to clotting factors of the intrinsic and common pathway (Xa IIa IXa intrinsic and common pathway (Xa IIa IXa XIa XIIa XIIIa) and inactivates themXIa XIIa XIIIa) and inactivates them
Anticoagulant of choice in pregnancy (not Anticoagulant of choice in pregnancy (not crosses placenta)crosses placenta)
Heparin and Low molecular weight heparinsHeparin and Low molecular weight heparins
Structure and sequence
O
OH
OH
O
COO
O
O
CH2OH
NHSO3
OH
_
_
O
O
CH2OSO3
NHSO3
OH
_
_
O
OH
OH
O
COOO
O
CH2OSO3
NHSO3
OH
_
_
O
OSO3
OHO
COOO
O
CH2OSO3
NHCOCH3
OH
_
_ _
_
_
O
OH
OH
O
COO
1
23
4
5
6
-D-glucosamine -L-iduronic acid -D-glucuronic acid
O
O
CH2OH
NH2
OH 12
3
4
5
6
O
OH
OHO
COO_
1
23
4
5
6
polymeric structure of heparin
Anticoagulant Properties of Anticoagulant Properties of HeparinHeparin
11 Inhibits the thrombin-mediated conversion of Inhibits the thrombin-mediated conversion of fibrinogen to fibrinfibrinogen to fibrin
22 Inhibits the aggregation of platelets by thrombin Inhibits the aggregation of platelets by thrombin (prolongs bleeding time)(prolongs bleeding time)
33 Inhibits activation of fibrin stabilizing enzymeInhibits activation of fibrin stabilizing enzyme
44 Inhibits activated factors XII XI IX X and IIInhibits activated factors XII XI IX X and II All available forms of heparin must be All available forms of heparin must be
administered administered parenterally since they are parenterally since they are highly charged and rapidlyhighly charged and rapidly hydrolyzed in the hydrolyzed in the GI tractGI tract
Heparin antagonist Protamine sulfate (Heparin antagonist Protamine sulfate (10mg for 10mg for 1000 unit of heparin)1000 unit of heparin)
Monitoring of heparin Monitoring of heparin
Subcutenous Subcutenous no monitoring requiredno monitoring required Intravenous Intravenous
Partial thromboplastin time (PTT normal value Partial thromboplastin time (PTT normal value ~30sec) ~30sec)
Activated clotting time ( ACT normal value ~90-Activated clotting time ( ACT normal value ~90-120sec)120sec)
Daily or more frequent if PTT ACT variesDaily or more frequent if PTT ACT varies
Mechanism Mechanism ndash measures intrinsic pathwayndash measures intrinsic pathway Therapeutic goal Therapeutic goal 2-25 times normal control value 2-25 times normal control value
ACT or aPTTACT or aPTT
Determine when to pull the femoral sheath Determine when to pull the femoral sheath Premature sheath pull can lead to bleedingPremature sheath pull can lead to bleeding Delayed removal can increase time in ICUDelayed removal can increase time in ICU Target set Target set at each siteat each site
ACT targets range from 150 ndash 220 ACT targets range from 150 ndash 220 secondsseconds
aPTT targets range from 40 ndash 70 seconds aPTT targets range from 40 ndash 70 seconds
During neuroangiography-During neuroangiography- Recommended therapeutic range of heparin in Recommended therapeutic range of heparin in
plasma is 02-08 uml ( corresponding to aPTT plasma is 02-08 uml ( corresponding to aPTT ACT values 15-25 times the baseline values)ACT values 15-25 times the baseline values)
Dose In diagnostic angiography bolus dose of Dose In diagnostic angiography bolus dose of 2500 iu is used followed by 1000 iu hour2500 iu is used followed by 1000 iu hour
Bolus dose is Bolus dose is 60 ukg to maintain the therapeutic 60 ukg to maintain the therapeutic range range If procedure continues for more than 75 If procedure continues for more than 75 minutes additional dose is required ( half of the minutes additional dose is required ( half of the initial dose for another 75 minutes) initial dose for another 75 minutes)
(AJNR 199415 51-54)
Mechanisms of HIT( Mechanisms of HIT( Heparin Heparin induced Thrombocytopeniainduced Thrombocytopenia))
Type 1Type 1 Fall in platelet count occurs within the first two Fall in platelet count occurs within the first two
days after heparin initiation often returns to days after heparin initiation often returns to normal with continued heparin administration normal with continued heparin administration and is of no clinical consequence and is of no clinical consequence
The mechanism of the thrombocytopenia is non-The mechanism of the thrombocytopenia is non-immune and appears to be due to a direct effect of immune and appears to be due to a direct effect of heparin on platelet activationheparin on platelet activation
Type 2Type 2 Approximately 03 to 3 percent of patients Approximately 03 to 3 percent of patients
receiving heparin develop an immune receiving heparin develop an immune thrombocytopenia mediated by antibodies to a thrombocytopenia mediated by antibodies to a heparin-platelet factor 4 complex heparin-platelet factor 4 complex
(AJNR 28155-158 2007)
Treatment of heparin-induced Treatment of heparin-induced thrombocytopeniathrombocytopenia
When HIT is diagnosed it is important to When HIT is diagnosed it is important to stop heparin mainly in type 2 and to avoid stop heparin mainly in type 2 and to avoid the use of LMWH the use of LMWH
Because of the increased risk of thrombosis Because of the increased risk of thrombosis however continuation of an anticoagulant however continuation of an anticoagulant must be considered must be considered
The drugs currently approved for the The drugs currently approved for the treatment of HIT in the United States are treatment of HIT in the United States are direct thrombin inhibitors argatroban and direct thrombin inhibitors argatroban and lepirudinlepirudin
WARFARIN MECHANISM OF ACTIONWARFARIN MECHANISM OF ACTION
Inactive factors II VII IX and X
Proteins S and C
Active factors II VII IX and X
Proteins S and C
Vitamin K epoxide
Vitamin K reduced
WA
RF
AR
IN
Prevents the reduction of vitamin K which is essential for Prevents the reduction of vitamin K which is essential for activation of certain factorsactivation of certain factors
Has no effect on previously formed thrombusHas no effect on previously formed thrombus
Antagonist is Vit KAntagonist is Vit K
OPTIMIZING WARFARIN THERAPYOPTIMIZING WARFARIN THERAPY
Use of large loading dose may lead to hemorrhage and Use of large loading dose may lead to hemorrhage and other complicationsother complications
Initial dose 2-5 mg once dailyInitial dose 2-5 mg once daily Maintenance dose 2-10 mg once dailyMaintenance dose 2-10 mg once daily If Immediate anticoagulation is requiredIf Immediate anticoagulation is required Heparin IS Heparin IS
started along with loading dose of warfarin 10 mg started along with loading dose of warfarin 10 mg Heparin is usually discontinued after 4-5 days Heparin is usually discontinued after 4-5 days Before Before discontinuing INR should be in therapeutic range for 2 discontinuing INR should be in therapeutic range for 2 consecutive daysconsecutive days
Daily monitoring of INR until INR is in therapeutic Daily monitoring of INR until INR is in therapeutic range then 3 times weekly for 1-2 weeks then less often range then 3 times weekly for 1-2 weeks then less often (every 4 to 6 weeks)(every 4 to 6 weeks)
OPTIMAL THERAPEUTIC RANGEOPTIMAL THERAPEUTIC RANGE
IndicationIndication INRINR
Prophylaxis of venous Prophylaxis of venous thromboembolismthromboembolism
20-3020-30
Treatment of venous Treatment of venous thromboembolismthromboembolism
20-3020-30
Atrial fibrillationAtrial fibrillation 20-3020-30
Mitral valve stenosisMitral valve stenosis 20-3020-30
Heart valve replacementHeart valve replacement
Bioprosthetic valveBioprosthetic valve
Mechanical valveMechanical valve
20-3020-30
25-3525-35
Myocardial infarctionMyocardial infarction 20-3020-30
25-35 25-35 (high risk patients)(high risk patients)
FACTORS INFLUENCING DOSE RESPONSEFACTORS INFLUENCING DOSE RESPONSE
Poor patient compliancePoor patient compliance Concomitant medicationsConcomitant medications Levels of dietary vitamin KLevels of dietary vitamin K Alcohol Inaccurate lab testingAlcohol Inaccurate lab testing Inaccurate lab testingInaccurate lab testing Hepatic dysfunctionHepatic dysfunction FeverFever
Contraindication for WarfarinContraindication for Warfarin
Hypersensitivity to warfarinHypersensitivity to warfarin Hemorrhagic tendencyHemorrhagic tendency Condition with risk of hemorrhageCondition with risk of hemorrhage Inadequate laboratory techniquesInadequate laboratory techniques Protein C amp S deficiencyProtein C amp S deficiency Vitamin K deficiencyVitamin K deficiency
SIDE EFFECTSSIDE EFFECTS
Hemorrhage Hemorrhage Skin necrosisSkin necrosis Purple toe syndromePurple toe syndrome Microembolization Microembolization TeratogenecityTeratogenecity Agranulocytosis leukopenia Agranulocytosis leukopenia Diarrhoeanausea anorexiaDiarrhoeanausea anorexia
MONITORING OF WARFARIN THERAPYMONITORING OF WARFARIN THERAPY
Prothrombin timeProthrombin time PT ratioPT ratio INR (International Normalized Ratio)INR (International Normalized Ratio)
PROTHROMBIN TIME (PT)PROTHROMBIN TIME (PT)
Time required for blood to coagulate Time required for blood to coagulate is called PT ( normal value ~10sec)is called PT ( normal value ~10sec)
Performed by adding a mixture of Performed by adding a mixture of calcium and thromboplastin to calcium and thromboplastin to citrated plasmacitrated plasma
As a control a normal blood sample is As a control a normal blood sample is tested continuouslytested continuously
PT ratio (PTR) = PT ratio (PTR) = Patientrsquos PTPatientrsquos PT Control PTControl PT
PROBLEMS WITH PTPTRPROBLEMS WITH PTPTR
Thromboplastins are extracts from Thromboplastins are extracts from brain lung or placenta of animalsbrain lung or placenta of animals
Thromboplastins from various Thromboplastins from various manufacturers differ in their manufacturers differ in their sensitivity to prolong PTsensitivity to prolong PT
May result in false control of May result in false control of anticoagulant therapyanticoagulant therapy
INTERNATIONAL NORMALISED RATIO (INR)INTERNATIONAL NORMALISED RATIO (INR)
International Normalized Ratio (INR) International Normalized Ratio (INR) a PT test with a a PT test with a formula based ratio to normalize the often variable source formula based ratio to normalize the often variable source of tissue factor (human rabbit recombinant)of tissue factor (human rabbit recombinant)
INR = [PTINR = [PTptpt] ] ISIISI
[PT[PTRefRef]]
PTPTpt pt ndash prothrombin time of patientndash prothrombin time of patient
PTPTRef Ref ndash prothrombin time of normal pooled samplendash prothrombin time of normal pooled sample
ISI ndash International Sensitivity IndexISI ndash International Sensitivity Index
Warfarin is given orally and titrated to achieve an INR of Warfarin is given orally and titrated to achieve an INR of typically 20 ndash 30typically 20 ndash 30
Heparin versus WarfarinHeparin versus Warfarin
Drug ActionMechan-ism
Moni-toring
Effective
HeparinDirect
Inhibition ofThrombin
ATIIIcofactor
APTTACT
Immediate
WarfarinDecreasesProductionof factors
Vitamin K PTDelay
3-5 days
INR
Recanalization or Antegrade Recanalization or Antegrade Reperfusion StrategiesReperfusion Strategies
Recanalization strategies focus on removing Recanalization strategies focus on removing andor dissolving the occlusive thrombus to re-andor dissolving the occlusive thrombus to re-establish antegrade flow Strategies may be establish antegrade flow Strategies may be classified into 7 different categories on the classified into 7 different categories on the basis of their primary mechanism of action basis of their primary mechanism of action 1) 1) IV andor intraarterial thrombolysis (IAT) IV andor intraarterial thrombolysis (IAT) 2) endovascular thrombectomy2) endovascular thrombectomy3) endovascular thromboaspiration 3) endovascular thromboaspiration 4) endovascular mechanical thrombus disruption or 4) endovascular mechanical thrombus disruption or
thromborrhexisthromborrhexis5) 5) transcranial or endovascular augmented transcranial or endovascular augmented
fibrinolysis fibrinolysis 6) endovascular thrombus entrapment and 6) endovascular thrombus entrapment and 7) temporary endovascular bypass7) temporary endovascular bypass
IAT in Acute Ischemic StrokeIAT in Acute Ischemic Stroke
IAT advantages over IV thrombolysisIAT advantages over IV thrombolysis Coaxial microcatheter techniques the occluded intracranial Coaxial microcatheter techniques the occluded intracranial
vessel is directly accessible and the fibrinolytic agent can be vessel is directly accessible and the fibrinolytic agent can be infused directly into the thrombusinfused directly into the thrombus
This permits a smaller dose of fibrinolytic agent to reach a This permits a smaller dose of fibrinolytic agent to reach a higher local concentration than that reached by systemic higher local concentration than that reached by systemic infusioninfusion
Allows more complete recanalization with lower total doses of Allows more complete recanalization with lower total doses of thrombolytic thrombolytic
With the smaller dose complications from systemic fibrinolytic With the smaller dose complications from systemic fibrinolytic effects including intracranial hemorrhage (ICH) can effects including intracranial hemorrhage (ICH) can theoretically be reduced theoretically be reduced
Treatment window for endovascular techniques can be Treatment window for endovascular techniques can be extended beyond the typical IV window of 3 hours extended beyond the typical IV window of 3 hours
IA techniques have led to higher recanalization rates than IV IA techniques have led to higher recanalization rates than IV thrombolysisthrombolysis
Major disadvantagesMajor disadvantages Relative complexity of the procedure the level Relative complexity of the procedure the level
of required technical expertise and its of required technical expertise and its relatively low availability relatively low availability
Delays in initiating treatmentDelays in initiating treatment InvasiveInvasive
ThrombolyticsThrombolytics
Plasminogen activators
Fibrinolytics
1 Plasminogen Activators 1 Plasminogen Activators drugs act by converting the inactive proenzyme drugs act by converting the inactive proenzyme plasminogen into the active enzyme plasmin Plasmin plasminogen into the active enzyme plasmin Plasmin digests fibrinogen fibrin monomers and cross-linked digests fibrinogen fibrin monomers and cross-linked fibrin (as found in a thrombus) into fibrin degradation fibrin (as found in a thrombus) into fibrin degradation productsproducts
First-Generation Agents First-Generation Agents StreptokinaseStreptokinase a protein derived from group C a protein derived from group C
szlig-hemolytic streptococci has a half-life of 16ndashszlig-hemolytic streptococci has a half-life of 16ndash90 minutes and low fibrin specificity This drug 90 minutes and low fibrin specificity This drug proved to have a very narrow therapeutic proved to have a very narrow therapeutic window and significant rates of ICH and window and significant rates of ICH and systemic hemorrhage18systemic hemorrhage18
UrokinaseUrokinase is a serine protease with a plasma is a serine protease with a plasma half life of 14 minutes and low fibrin specificity half life of 14 minutes and low fibrin specificity
The urokinase dose used in cerebral IAT has The urokinase dose used in cerebral IAT has ranged from 002 to 2 X106unitsranged from 002 to 2 X106units
Second-Generation Agents Second-Generation Agents Alteplase (rtPA) Alteplase (rtPA)
is a serine is a serine protease with a plasma half-life of 35 protease with a plasma half-life of 35 minutes and a high degree of fibrin affinity and minutes and a high degree of fibrin affinity and specificity specificity
Dose used in cerebral IAT has ranged between 20 Dose used in cerebral IAT has ranged between 20 and 60 mgand 60 mg
Disadvantages of alteplase include its relatively short Disadvantages of alteplase include its relatively short halflife and limited penetration into the clot matrix halflife and limited penetration into the clot matrix because of strong binding with surface fibrin which because of strong binding with surface fibrin which could delay recanalization and increase the risk of could delay recanalization and increase the risk of recurrent occlusion recurrent occlusion
Prourokinase (r-prourokinase) Prourokinase (r-prourokinase) is the proenzyme precursor of urokinase is the proenzyme precursor of urokinase T12 of 7 minutes and high fibrin specificity T12 of 7 minutes and high fibrin specificity
Third-Generation AgentsThird-Generation Agents
ReteplaseReteplase is a structurally modified is a structurally modified form of alteplase form of alteplase
with a longer half-life (15ndash18 minutes) In with a longer half-life (15ndash18 minutes) In addition it does not bind as highly to fibrin addition it does not bind as highly to fibrin unbound reteplase can thus theoretically better unbound reteplase can thus theoretically better penetrate the clot and potentially penetrate the clot and potentially improve in improve in vivo fibrinolytic activity vivo fibrinolytic activity
TenecteplaseTenecteplase is another modified form of rtPA with a longer is another modified form of rtPA with a longer
half-life (17 minutes)half-life (17 minutes) greater fibrin specificity and greater greater fibrin specificity and greater
resistance to plasminogen activator inhibitor-1 resistance to plasminogen activator inhibitor-1 IV tenecteplase in acute ischemic stroke IV tenecteplase in acute ischemic stroke
suggest that the drug is safe and promisingsuggest that the drug is safe and promising
Newer plasminogen activatorNewer plasminogen activator
DesmoteplaseDesmoteplase is a genetically engineered is a genetically engineered version of the clot-dissolving factor version of the clot-dissolving factor
found in the saliva found in the saliva of the vampire bat Desmodus rotundusof the vampire bat Desmodus rotundus moremore potent and more selective for fibrin-bound potent and more selective for fibrin-bound
plasminogen than any other known plasminogen plasminogen than any other known plasminogen activatoractivator
Unlike tissue plasminogen activator (tPA) desmoteplase Unlike tissue plasminogen activator (tPA) desmoteplase is not activated by fibrinogen or -amyloid proteins is not activated by fibrinogen or -amyloid proteins factors that may exacerbate the risk for ICH factors that may exacerbate the risk for ICH
The effect of IV administration of desmoteplase 3ndash9 The effect of IV administration of desmoteplase 3ndash9 hours after symptom onset in patients with stroke who hours after symptom onset in patients with stroke who present with mismatch on MR imaging or CT perfusion present with mismatch on MR imaging or CT perfusion
3 DefibrinogenatingFibrinogenolytic 3 DefibrinogenatingFibrinogenolytic Agents Agents
AncrodAncrod(Viprinex)(Viprinex) is is the purified fraction of the Malayan pit viper venomthe purified fraction of the Malayan pit viper venom It acts by directly cleaving and inactivating fibrinogen It acts by directly cleaving and inactivating fibrinogen
and thus indirectly promoting anticoagulation and thus indirectly promoting anticoagulation The reduction in the blood levels of fibrinogen also The reduction in the blood levels of fibrinogen also
leads to a reduced blood viscosity which may improve leads to a reduced blood viscosity which may improve blood flow to the affected areas of the brain blood flow to the affected areas of the brain
In the Stroke Treatment with Ancrod Trial 500 In the Stroke Treatment with Ancrod Trial 500 patients with stroke presenting within 3 hours of patients with stroke presenting within 3 hours of symptom onset were randomized to receive ancrod (symptom onset were randomized to receive ancrod (n n 248) or a placebo (n 252) Good outcome (Barthel 248) or a placebo (n 252) Good outcome (Barthel Index 95ndash100 at 3 months) was achieved in 4221 Index 95ndash100 at 3 months) was achieved in 4221 and 344 of the patients respectively and 344 of the patients respectively
2 Direct Fibrinolytics2 Direct Fibrinolytics
Microplasmin (Microplasmin (ThromboGenics Heverlee Belgium)ThromboGenics Heverlee Belgium) is a truncated form of plasmin that is more resistant to the effects is a truncated form of plasmin that is more resistant to the effects
of antiplasmin of antiplasmin microplasmin can be used upto 4ndash12 hours after stroke onset microplasmin can be used upto 4ndash12 hours after stroke onset There was no evidence of increased bleeding risk with There was no evidence of increased bleeding risk with
microplasminmicroplasmin
Alfimeprase (Nuvelo San Carlos Calif)Alfimeprase (Nuvelo San Carlos Calif) is a recombinant truncated form of fibrolase a fibrinolytic zinc metalloproteinase is a recombinant truncated form of fibrolase a fibrinolytic zinc metalloproteinase
isolated from the venom of the southern copperhead snake isolated from the venom of the southern copperhead snake It degrades fibrin directly and achieves thrombolysis independent It degrades fibrin directly and achieves thrombolysis independent
of plasmin formationof plasmin formation its thrombolytic activity appears to be localized to the site of its thrombolytic activity appears to be localized to the site of
delivery These properties should theoretically result in faster delivery These properties should theoretically result in faster recanalization and lower hemorrhagic conversion riskrecanalization and lower hemorrhagic conversion risk
Anti-fibrinolyticsAnti-fibrinolytics
to limit fibrinolytic activityto limit fibrinolytic activity -aminocaproic acid (EACA) -aminocaproic acid (EACA) competitively inhibitscompetitively inhibits plasminogen and plasminogen activators from plasminogen and plasminogen activators from
binding to fibrinbinding to fibrin
alpha2-antiplasminalpha2-antiplasmin a serine protease inhibitor that a serine protease inhibitor that neutralizes any free circulating plasminneutralizes any free circulating plasmin
Plasminogen activator inhibitor-1Plasminogen activator inhibitor-1 a serine protease a serine protease inhibitor that inhibits tissue-type plasminogen inhibitor that inhibits tissue-type plasminogen activatoractivator
Glycoprotein (GP) IIbIIIa antagonistsGlycoprotein (GP) IIbIIIa antagonists
such as ReoPro (abciximab) Integrilin such as ReoPro (abciximab) Integrilin (eptifibatide) or Aggrastat (tirofiban) in (eptifibatide) or Aggrastat (tirofiban) in ischemic stroke remains investigational ischemic stroke remains investigational Deshmukh et al38 reported 21 patients with Deshmukh et al38 reported 21 patients with large-vessel occlusion refractory to IAT with large-vessel occlusion refractory to IAT with rtPA who were treated with IV andor IA rtPA who were treated with IV andor IA abciximab eptifibatide or tirofiban abciximab eptifibatide or tirofiban
IA Mechanical Approaches in Acute Ischemic Stroke IA Mechanical Approaches in Acute Ischemic Stroke Mechanical strategies have several advantagesMechanical strategies have several advantages First they lessen and may even preclude the use of chemical First they lessen and may even preclude the use of chemical
thrombolytics in this manner very likely reducing the risk of ICHthrombolytics in this manner very likely reducing the risk of ICH Second by avoiding the use of chemical thrombolytics it is Second by avoiding the use of chemical thrombolytics it is
possible to extend the treatment window beyond the limit of 6ndash8 possible to extend the treatment window beyond the limit of 6ndash8 hours hours
Third mechanically fragmenting a clot increases the surface area Third mechanically fragmenting a clot increases the surface area accessible to fibrinolytic agents and allows inflow of fresh accessible to fibrinolytic agents and allows inflow of fresh plasminogen which in turn may increase the speed of plasminogen which in turn may increase the speed of thrombolysis thrombolysis
Finally clot-retrieval devices may provide faster recanalization Finally clot-retrieval devices may provide faster recanalization
The disadvantages of the mechanical The disadvantages of the mechanical approaches approaches technical difficulty of navigating mechanical technical difficulty of navigating mechanical
devices into the intracranial circulation excessive devices into the intracranial circulation excessive trauma to the vasculature (potentially leading to trauma to the vasculature (potentially leading to vasospasm vessel dissection perforation or vasospasm vessel dissection perforation or rupture) rupture)
fragmented thrombus causing distal embolization fragmented thrombus causing distal embolization into previously unaffected territories into previously unaffected territories
Nevertheless the advantages of mechanical stroke Nevertheless the advantages of mechanical stroke therapy appear to significantly outweigh its therapy appear to significantly outweigh its disadvantages and risksdisadvantages and risks
Contraindications to Thrombolytic Contraindications to Thrombolytic agents agents
Recent thoracic abdominal or Recent thoracic abdominal or intracranial surgeryintracranial surgery
Recent haemorrhagic CVA Head injury Recent haemorrhagic CVA Head injury or neoplasmor neoplasm
Bleeding ulcerBleeding ulcer Anticipated invasive procedures (arterial Anticipated invasive procedures (arterial
punctures biopsies)punctures biopsies) Concurrent hemostatic dysfunctionConcurrent hemostatic dysfunction
Monitoring of thrombolytic Monitoring of thrombolytic therapytherapy
Thrombin time Measures the availability of functional
fibrinogen Normal thrombin time is 10-14 sec Prolonged when fibrinogen level is below
75-100 mgdl
Half Life of ThrombolyticsHalf Life of ThrombolyticsAgent Administration Half Life
Streptokinase IA 60-80min
Urokinase IAIV 9-12min
rTPA IAIV 6min
Abciximab(Reopro) IAIV 12hour
Aspirin POIV 15-20min
Heparin IVSC 60min
Coumadin PO 15-25 days
Anti Platelet DrugsAnti Platelet DrugsDrug Drug Mechanism Mechanism UsesUsesAspirinAspirin Permanently inhibits Permanently inhibits
COX-1 and COX-2COX-1 and COX-2CADCAD
Stroke-TIAsStroke-TIAs
NSAIDsNSAIDs Reversibly inhibits Reversibly inhibits COX-1COX-1
LimitedLimited
DipyridamoleDipyridamole Inhibits PDE increases Inhibits PDE increases cAMPcAMP
TIAsTIAs
ThenopyridinesThenopyridines
(Ticlopidine(Ticlopidine
ClopidrgrelClopidrgrel))
Inhibits ADP Inhibits ADP
PlatAg PlatAg
TIAsStrokeTIAsStroke
CAD PVDCAD PVD
Abciximab (ReoPro)Abciximab (ReoPro)
Eptifibatide (Integrilin)Eptifibatide (Integrilin)
TirofibanTirofiban
GP IIBIIIA InhibitorsGP IIBIIIA Inhibitors
Stroke- TIAs Stroke- TIAs
MonitoringMonitoring
Bleeding timeBleeding time
Optical aggregometryOptical aggregometry
Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay
Bleeding timeBleeding time
Requires a skin incision (usually made on the ear lobe or Requires a skin incision (usually made on the ear lobe or forearm offorearm of
a depth that results in disruption of capillary loops and a depth that results in disruption of capillary loops and small vessels)small vessels)
AdvantagesAdvantages Universally availableUniversally available Relatively simple techniquesRelatively simple techniques Can be performed bedsideCan be performed bedside
DisadvantagesDisadvantages Insensitive inaccurate non-specific techniqueInsensitive inaccurate non-specific technique
Poorly reproducible (as depends on multiple variables)Poorly reproducible (as depends on multiple variables)
Optical aggregometryOptical aggregometry
Gold standard assay for platelet functionGold standard assay for platelet function Agonist induced aggregation is measuredAgonist induced aggregation is measured Different agonist are available for different Different agonist are available for different
agentsagents However require unique expertise and are not However require unique expertise and are not
universally availableuniversally available Aspirin measured with ADP or AA(gt70 Aspirin measured with ADP or AA(gt70
aggregation so resistance)aggregation so resistance) Clopidogrel( ADP gt 90 aggregation means Clopidogrel( ADP gt 90 aggregation means
resistance) resistance)
Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay
Can be performed bed sideCan be performed bed side Different assay devices with different Different assay devices with different
agonist are used for each of different agonist are used for each of different antiplatelet agents antiplatelet agents
For Aspirin AA is used (result is reported as aspirin For Aspirin AA is used (result is reported as aspirin reaction units [ARU] ARUgt 550 indicates non-reaction units [ARU] ARUgt 550 indicates non-responsiveness)responsiveness)
Verify IIbIIIa assay device uses TRAP as agonist for Verify IIbIIIa assay device uses TRAP as agonist for Abciximab and TirofibanAbciximab and Tirofiban
Practical Applications Practical Applications related to specific related to specific
Neurovascular Neurovascular interventionsinterventions
Acute ischemic StrokeAcute ischemic Stroke When an artery occludes neurons are affected When an artery occludes neurons are affected
differently depending upon the amount of residual blood differently depending upon the amount of residual blood flowflow
Normal cerebral blood flow is greater than 50 mL100 Normal cerebral blood flow is greater than 50 mL100 mgminmgmin
Once blood flow decreases to less than 20 mL100 Once blood flow decreases to less than 20 mL100 mgmin infarction occursmgmin infarction occurs
If blood flow decreases to less than 10 mL100 mgmin If blood flow decreases to less than 10 mL100 mgmin irreversible neuronal death occurs rapidly irreversible neuronal death occurs rapidly
Blood flow between 11 and 20 mL100 mgmin is thought Blood flow between 11 and 20 mL100 mgmin is thought to represent the ischemic penumbra an area where the to represent the ischemic penumbra an area where the cells are functionally silent because of ischemia but are cells are functionally silent because of ischemia but are still able to recover if blood flow is restored still able to recover if blood flow is restored
Many acute stroke therapies are targeted toward Many acute stroke therapies are targeted toward restoring flow or function to the ischemic penumbrarestoring flow or function to the ischemic penumbra
Therapeutic window in Therapeutic window in management of acute Ischemic management of acute Ischemic
StrokeStrokeThe early diagnosis of ischemic stroke is critical to the The early diagnosis of ischemic stroke is critical to the
with only a narrow therapeutic window in the first few with only a narrow therapeutic window in the first few hours following stroke ictushours following stroke ictus
Diagnosis in the first 3 hours postictus provides the Diagnosis in the first 3 hours postictus provides the opportunity for intravenous or intraarterial thrombolysis opportunity for intravenous or intraarterial thrombolysis and intra-arterial clot mechanical treatment which and intra-arterial clot mechanical treatment which improve the outcome improve the outcome
Diagnosis in the time period between 3 and 6 hours Diagnosis in the time period between 3 and 6 hours provides an opportunity for intra-arterial thrombolysis provides an opportunity for intra-arterial thrombolysis and mechanical treatment and mechanical treatment
Involvement of the posterior circulation especially the Involvement of the posterior circulation especially the basilar artery is treated by some regardless of time of basilar artery is treated by some regardless of time of onset or up until 12 to 24 hours in some practices This is onset or up until 12 to 24 hours in some practices This is related to the potentially high mortality and morbidity related to the potentially high mortality and morbidity associated with basilar artery thrombosisassociated with basilar artery thrombosis
Infarct evaluation on angiographyInfarct evaluation on angiography(CT angiography and catheter (CT angiography and catheter
angiography)angiography)CTA is an excellent first-line examination for CTA is an excellent first-line examination for
evaluation of the head and neck arteries evaluation of the head and neck arteries In comparison with catheter angiography In comparison with catheter angiography
what it gives up in resolution and dynamic what it gives up in resolution and dynamic properties it makes up for with rapid properties it makes up for with rapid acquisition of a 3-D dataset and the potential acquisition of a 3-D dataset and the potential for assessment of whole-brain perfusion and for assessment of whole-brain perfusion and better parenchymal evaluationbetter parenchymal evaluation
Moreover CTA illustrates not only arterial Moreover CTA illustrates not only arterial stenosis or occlusion but also the vessel wall stenosis or occlusion but also the vessel wall This factor is most important for evaluation of This factor is most important for evaluation of intramural dissection and thrombosed intramural dissection and thrombosed aneurysms which may both complicate aneurysms which may both complicate evaluation of stroke patientsevaluation of stroke patients
Early angiographic signs of strokes Early angiographic signs of strokes both CTA both CTA and DSA and DSA
Vessel occlusion or cutoff related to Vessel occlusion or cutoff related to thromboembolithromboemboli
aneurysms aneurysms arterial dissection arterial dissection Meniscus or flattened shape to clot Meniscus or flattened shape to clot
(recent) versus reverse meniscus (older)(recent) versus reverse meniscus (older) tram track (nonocclusive or recanalized tram track (nonocclusive or recanalized
clot) clot) delayed (antegrade) flow (manifest as delayed (antegrade) flow (manifest as
decreased whole-brain perfusion on CTA)decreased whole-brain perfusion on CTA) retrograde collateral flowretrograde collateral flow
Non-occlusive left MCA thrombus on 3-D imaging performed from CTA source data and was confirmed at catheter angiography
Therapy to be started within a 6-hr Therapy to be started within a 6-hr time to treatment (TTT) window time to treatment (TTT) window (while in case of IV thrombolysis (while in case of IV thrombolysis therapy to be started with in 3hrs)therapy to be started with in 3hrs)
Exclusion criteria Exclusion criteria Rapidly improving neurologic deficit or Rapidly improving neurologic deficit or Sustained blood pressure of gt180100 Sustained blood pressure of gt180100 Hemorrhage is detected on CTHemorrhage is detected on CT Infarct involving gt more than 13 rd Infarct involving gt more than 13 rd
territory of MCAterritory of MCA MRADWI-Perfusion mismatchlt 20MRADWI-Perfusion mismatchlt 20 Definite hypodensity on CTDefinite hypodensity on CT
Intra-arterial Thrombolysis
Fibrinolytics + AntiplateletsFibrinolytics + Antiplatelets
PlasminogenPlasminogen activators through fibrinolysis exposes activators through fibrinolysis exposes free thrombin and paradoxically stimulatesfree thrombin and paradoxically stimulates platelet platelet aggregation which leads to formation of aaggregation which leads to formation of a platelet platelet thrombus (white clot) thrombus (white clot)
This new thrombus is relatively resistant to This new thrombus is relatively resistant to fibrinolyticsfibrinolytics
So new regimen in case of acute stroke isSo new regimen in case of acute stroke is fibrinolytics + antiplatelet drugsfibrinolytics + antiplatelet drugs
rtPA + IIbIIIa inhibitors( tirofiban rtPA + IIbIIIa inhibitors( tirofiban abciximab) orabciximab) or
Urokinase + IIbIIIa Urokinase + IIbIIIa inhibitors( tirofiban abciximab)inhibitors( tirofiban abciximab)
Intra-arterial Thrombolysis Tirofiban (04 microgkgmin bolus for 3 min followed by Tirofiban (04 microgkgmin bolus for 3 min followed by
0125 ugkgmin)0125 ugkgmin)
++
Heparin (2000ndash3000 IU bolus followed by Heparin (2000ndash3000 IU bolus followed by 1000 IUhour infusion 1000 IUhour infusion
with ACT maintained bw 200-300) throughout the with ACT maintained bw 200-300) throughout the interventional procedure and for 24ndash48 hours thereafter when interventional procedure and for 24ndash48 hours thereafter when there is neither intraprocedural bleeding nor suspicion of there is neither intraprocedural bleeding nor suspicion of increased risk of bleeding increased risk of bleeding
Maximum dose of Urokinase Maximum dose of Urokinase Anterior circulation stroke - 500000 IU (mean 400000 Anterior circulation stroke - 500000 IU (mean 400000
IU range 300000ndash500000 IU)IU range 300000ndash500000 IU) Posterior circulation stroke -1000000 IU (mean 837000 Posterior circulation stroke -1000000 IU (mean 837000
IU range 300000ndash1000000 IU)IU range 300000ndash1000000 IU)American Journal of NeuroradiologyAmerican Journal of Neuroradiology 262595-2601 2005262595-2601 2005
Intravenous ThrombolysisIntravenous Thrombolysis
The first method to restore cerebral The first method to restore cerebral perfusion is clot lysis with the goal perfusion is clot lysis with the goal of re-establishing blood flow to the of re-establishing blood flow to the affected tissue affected tissue
IV thrombolysis rt-PA is the only IV thrombolysis rt-PA is the only FDA- approved treatment for AIS FDA- approved treatment for AIS
Fibrinolysis is enhanced powerfully Fibrinolysis is enhanced powerfully by rt-PAby rt-PA
Intravenous rTPA Intravenous rTPA administration administration protocolprotocol
Total dose of rt-PA 09 mgkg (maximum dose Total dose of rt-PA 09 mgkg (maximum dose 90 mg)90 mg)
Give 10 as initial IV bolusGive 10 as initial IV bolus Infuse remainder over 1 hourInfuse remainder over 1 hour Admit patient to an ICU or stroke unit for Admit patient to an ICU or stroke unit for
monitoringmonitoring Neurologic assessments every 15 minutes Neurologic assessments every 15 minutes
during infusion then every 30 minutes for next during infusion then every 30 minutes for next 6 hours then every hour until 24hours after 6 hours then every hour until 24hours after treatmenttreatment
Favorable Outcome vs Treatment Time Favorable Outcome vs Treatment Time with IV rTPAwith IV rTPA
Protocol limit = 3 hrs
Benefit ~ 45 hrs
Thromboembolism During coilingThromboembolism During coiling Most feared and frequent complication Most feared and frequent complication Reported incidence - Approx 7 Reported incidence - Approx 7 SourcesSources of Thromboembolism are of Thromboembolism are
- Clots at the aneurysmal neck during or immediately- Clots at the aneurysmal neck during or immediately after after embolization embolization
- Thrombus forming on catheters during- Thrombus forming on catheters during proceduresprocedures
- Stenosis of an adjacent artery dt coil mass- Stenosis of an adjacent artery dt coil mass or herniationor herniation
- Migration of intraaneurysmal- Migration of intraaneurysmal thrombus during coil thrombus during coil placement placement
- Slow flow dt vasospasm - Slow flow dt vasospasm
- Rare and unlikely causes are hypercoagulable- Rare and unlikely causes are hypercoagulable state such state such as antiphospholipid antibody syndrome or due to HITas antiphospholipid antibody syndrome or due to HIT
Occur more often with wide-necked aneurysms (dt Occur more often with wide-necked aneurysms (dt increased exposed surface area of thrombogenic coil increased exposed surface area of thrombogenic coil material)material)
Current regimen of endovascular Current regimen of endovascular managementmanagement
The The glycoprotein IIbIIIa antagonist tirofiban glycoprotein IIbIIIa antagonist tirofiban (04 (04 microgkgmin bolus for 30 minutes followed by infusion of microgkgmin bolus for 30 minutes followed by infusion of 0125 ugkgmin until the thrombus dissolved) 0125 ugkgmin until the thrombus dissolved)
Intraarterial thrombolysis with Intraarterial thrombolysis with urokinase or r- TPA urokinase or r- TPA increase of intravenous (IV) heparin (measured by increase of intravenous (IV) heparin (measured by
ACT) ACT) Intravenous aspirin Intravenous aspirin
Coil-related platelet aggregation (white clot) is Coil-related platelet aggregation (white clot) is unlikely to respond to fibrinolytics but has a high risk unlikely to respond to fibrinolytics but has a high risk of hemorrhage (In ISAT) all 5 patients who had of hemorrhage (In ISAT) all 5 patients who had received thrombolytic therapy with tPA to treat a received thrombolytic therapy with tPA to treat a thromboembolic complication after endovascular thromboembolic complication after endovascular treatment rebleed and all of these patients died)treatment rebleed and all of these patients died)
IntracranialIntracranial Stenting Stenting Metallic foreign body such as stent will accumulate Metallic foreign body such as stent will accumulate
thrombus in the absence of platelet inhibitionthrombus in the absence of platelet inhibition Antiplatelet drugs are important to prevent peri or Antiplatelet drugs are important to prevent peri or
post-interventional thromboembolic eventspost-interventional thromboembolic events Optimal treatment regimens has not been determined Optimal treatment regimens has not been determined
but usually but usually Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-
procedureprocedureOrOr
Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on
morning of proceduremorning of procedure
If need to use stent is not pre-planned thanIf need to use stent is not pre-planned than
Abciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkgAbciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkg IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)
Glycoprotein IIbIIIa inhibitor are not used routinely during elective Glycoprotein IIbIIIa inhibitor are not used routinely during elective stenting procedure dt increased risk of ICH stenting procedure dt increased risk of ICH
Carotid StentingCarotid Stenting
Pre-procedurePre-procedure
Double Antiplatelet therapy is routinely given Double Antiplatelet therapy is routinely given beginning at least 3beginning at least 3
days before the proceduredays before the procedure
Aspirin 325mgd+Clopidogrel 75mgdAspirin 325mgd+Clopidogrel 75mgd During procedureDuring procedure
Heparin is given with target clotting time of 250-Heparin is given with target clotting time of 250-300sec300sec
Post-procedure Post-procedure
Aspirin 325mg is continued indefinitely and Aspirin 325mg is continued indefinitely and
Clopidogrel 75mgd for at least 6 weeks Clopidogrel 75mgd for at least 6 weeks
Inclusion criteria for Local ThrombolysisInclusion criteria for Local Thrombolysis a)a) Patients in severe clinical grade on admission Patients in severe clinical grade on admission
with evidence of dural venous sinus with evidence of dural venous sinus thrombosis and restrictive venous outflow on thrombosis and restrictive venous outflow on cerebral angiogramcerebral angiogram
b)b) Patients in clinical grade 3 worsening on Patients in clinical grade 3 worsening on heparin therapy Restriction to venous heparin therapy Restriction to venous outflow was defined as an increase in brain outflow was defined as an increase in brain circulation time gt 12 s delay in the drainage circulation time gt 12 s delay in the drainage of cortical veins with cortical veins hanging of cortical veins with cortical veins hanging in spacein space
Treatment Options for Venous Thrombosis
CT Grading for Venous ThrombosisCT Grading for Venous Thrombosis Grade I no parenchymal change Grade I no parenchymal change
(hyperdense (hyperdense sinuses cortical veins empty sinuses cortical veins empty delta sign)delta sign)
Grade II non hemorrhagic venous infarct Grade II non hemorrhagic venous infarct without mass effect without mass effect
Grade III non-hemorrhagic infarct with Grade III non-hemorrhagic infarct with mass effectmass effect
Grade IV hemorrhagic venous infarct (max Grade IV hemorrhagic venous infarct (max diameter lt 3 cm) with no mass effectdiameter lt 3 cm) with no mass effect
Grade V hemorrhagic venous infarct (max Grade V hemorrhagic venous infarct (max diameter gt 3 cm) with mass effect diameter gt 3 cm) with mass effect
Local ThrombolysisLocal Thrombolysis
Femoral Jugular access was secured and a guiding Femoral Jugular access was secured and a guiding catheter was placed in the jugular bulb catheter was placed in the jugular bulb Mechanical Mechanical clot maceration clot maceration was done with the guidewire was done with the guidewire following which a microcatheter (was navigated and following which a microcatheter (was navigated and placed in the thrombosed segment of sinus confirmed placed in the thrombosed segment of sinus confirmed on a selective venogram on a selective venogram
Urokinase infusion Bolus dose of 2-6 lacs followed Urokinase infusion Bolus dose of 2-6 lacs followed by 60000 to 100000 units per hour along with by 60000 to 100000 units per hour along with periodic check venogram Along with maintenance periodic check venogram Along with maintenance systemic infusion of Heparinsystemic infusion of Heparin Other agents such as Other agents such as streptokinase altepase or rTPAstreptokinase altepase or rTPA can be also used can be also used
After thrombolysis patient should subjected to oral After thrombolysis patient should subjected to oral anticoagulation for six monthsanticoagulation for six months
Low-molecular-weight Low-molecular-weight heparinheparin
PharmacologyPharmacologyLMWH as its name suggests is a glycosaminoglycan that is approximatelyLMWH as its name suggests is a glycosaminoglycan that is approximately
one third the molecular weight of UFH It is derived from UFH through one third the molecular weight of UFH It is derived from UFH through variousvarious
depolymerization processes LMWH binds to antithrombin which in turn depolymerization processes LMWH binds to antithrombin which in turn
Neutralizes actors Xa and IIa Because LMWH lacks many of the longer Neutralizes actors Xa and IIa Because LMWH lacks many of the longer chains chains
required for binding to thrombin it has less ability to neutralize thrombin required for binding to thrombin it has less ability to neutralize thrombin
relativeto its ability to neutralize factor Xa LMWH also has less relativeto its ability to neutralize factor Xa LMWH also has less nonspecific nonspecific
binding to other proteins There is greater bioavailability with more binding to other proteins There is greater bioavailability with more predictable predictable
pharmacokinetics that eliminates the need for monitoring The smaller pharmacokinetics that eliminates the need for monitoring The smaller size also size also
allows for enhanced subcutaneous absorption when compared with UFHallows for enhanced subcutaneous absorption when compared with UFH
Three LMWH preparations are Three LMWH preparations are currently approved for use in the currently approved for use in the United States (1) enoxaparin (2) United States (1) enoxaparin (2) dalteparin and (3) tinzaparin dalteparin and (3) tinzaparin
They are all administered They are all administered subcutaneously at intervals of either subcutaneously at intervals of either once or twice daily for both once or twice daily for both prophylaxis and treatment dosesprophylaxis and treatment doses
Few Experiences of Few Experiences of ThrombolysisThrombolysis
Vickey 25 Yrs male patient presented Vickey 25 Yrs male patient presented with 12with 12thth day HO severe headache with day HO severe headache with right sided hemiplegiaright sided hemiplegia
MRI shows thrombosis of the superior MRI shows thrombosis of the superior sagittal left transverse left sigmoid sagittal left transverse left sigmoid sinuses and cortical veins in the fronto-sinuses and cortical veins in the fronto-parietal regions with eo haemorrhagic parietal regions with eo haemorrhagic infarct in the left cerebral hemisphere infarct in the left cerebral hemisphere with mass effect( Grade ndashV)with mass effect( Grade ndashV)
Sashi Srivastava 64 yrs FSashi Srivastava 64 yrs F In a follow up case of MRD with infra-renal In a follow up case of MRD with infra-renal
aortic abdominal and bilateral renal artery aortic abdominal and bilateral renal artery thrombosis renal angiogram shows filling thrombosis renal angiogram shows filling defects in the right Renal artery defects in the right Renal artery
Initially Renal angioplasty was done Initially Renal angioplasty was done Following angioplasty few thrombi are seem Following angioplasty few thrombi are seem to extends into the segmental branches and to extends into the segmental branches and causing blockage So Thrombolysis was causing blockage So Thrombolysis was plane to dissolve the run-out thrombi with plane to dissolve the run-out thrombi with urokinase urokinase
Rakesh 34yrsMRakesh 34yrsM Left SFA pseudoaneurysm with Left SFA pseudoaneurysm with
Covered stent placementCovered stent placement Pre operative antiplatelets with post Pre operative antiplatelets with post
procedure heparin Tirofiban procedure heparin Tirofiban followed by aspirin and clopidogrel followed by aspirin and clopidogrel were usedwere used
IAT may be a treatment option for selected patients IAT may be a treatment option for selected patients Possible selection criteria include Possible selection criteria include
presentation between 3 and 6 hours from symptom onsetpresentation between 3 and 6 hours from symptom onset major cerebral artery occlusion major cerebral artery occlusion severe neurologic deficits severe neurologic deficits high risk of systemic hemorrhage with IV rt-PA (eg recent high risk of systemic hemorrhage with IV rt-PA (eg recent
surgery) surgery) The MERCI (Mechanical Embolus Removal in Cerebral The MERCI (Mechanical Embolus Removal in Cerebral
Ischemia) retrievalIschemia) retrieval system system
Has been FDA-approved for recanalizing acutely occluded Has been FDA-approved for recanalizing acutely occluded cerebral arteries cerebral arteries
In the Multi-MERCI study patients who did not improve In the Multi-MERCI study patients who did not improve immediately after IV rt-PA underwent mechanical immediately after IV rt-PA underwent mechanical embolectomy within 8 hours of symptom onset embolectomy within 8 hours of symptom onset
Partial or complete recanalization occurred in 74 of Partial or complete recanalization occurred in 74 of patientspatients
with a symptomatic intracerebral hemorrhage (sICH) rate of with a symptomatic intracerebral hemorrhage (sICH) rate of 67 67
Mechanical embolectomy with the MERCI retriever may be a Mechanical embolectomy with the MERCI retriever may be a feasible and safe option for patients after IV rt-PAfeasible and safe option for patients after IV rt-PA
Penumbra stroke systemPenumbra stroke system This device combines two methods of clot This device combines two methods of clot
extraction aspiration and mechanical extraction aspiration and mechanical extraction extraction
First the clot is aspirated then a thrombus First the clot is aspirated then a thrombus removal ring can be used if necessary to removal ring can be used if necessary to remove remaining clot remove remaining clot
successful recanalizing 82successful recanalizing 82 Bridging therapyBridging therapy
06 mgkg IV rt-PA followed by IAT with IA rt-06 mgkg IV rt-PA followed by IAT with IA rt-PA (up to 20 mg)PA (up to 20 mg)
achieved a higher recanalization rateachieved a higher recanalization rate
Criteria for thrombolysis with rTPACriteria for thrombolysis with rTPA
Inclusion criteriaInclusion criteria Clinical signs and symptoms consistent with ischemic Clinical signs and symptoms consistent with ischemic
strokestroke Patient last seen normal within 3 hoursPatient last seen normal within 3 hours Measurable neurologic deficitMeasurable neurologic deficit
Exclusion criteriaExclusion criteria Any hemorrhage on neuroimaging (CT or MRI)Any hemorrhage on neuroimaging (CT or MRI) Symptoms suggestive of subarachnoid hemorrhageSymptoms suggestive of subarachnoid hemorrhage Seizure at stroke onset that is thought to contribute to Seizure at stroke onset that is thought to contribute to
neurologic deficitneurologic deficit Hypodensity greater than one third cerebral hemisphere Hypodensity greater than one third cerebral hemisphere
on CTon CT SBP greater than 185 mm Hg or DBP greater than 110 SBP greater than 185 mm Hg or DBP greater than 110
mm Hgmm Hg International normalized ratio (INR) greater than 17International normalized ratio (INR) greater than 17
Ischemic Stroke Ischemic Stroke Treatment ndash 2006Treatment ndash 2006
IV tissue plasminogen activator (tPA)IV tissue plasminogen activator (tPA) ndash ndash Only FDA-approved acute stroke drugOnly FDA-approved acute stroke drug ndash ndash 3 hour treatment window3 hour treatment window
MERCI - Concentric clot retrieval MERCI - Concentric clot retrieval devicedevice ndash ndash Rescue therapy - approved 2004Rescue therapy - approved 2004 ndash ndash Device approval (not outcomes-based)Device approval (not outcomes-based)
Off label approachesOff label approaches ndash ndash IV tPA after 3 hoursIV tPA after 3 hours ndash ndash IV-IA tPA sequential strategiesIV-IA tPA sequential strategies ndash ndash IA tPA clot angioplasty fragmentationIA tPA clot angioplasty fragmentation ndash ndash Ultrasound-assisted tPA lysisUltrasound-assisted tPA lysis
rt-PA Trials NINDSrt-PA Trials NINDS
Acute stroke - 624 patientsAcute stroke - 624 patients Treat within 3 hrsTreat within 3 hrs Intravenous 09 mgkg rt-PA vs placeboIntravenous 09 mgkg rt-PA vs placebo Hemorrhage 64 tPA 06 placeboHemorrhage 64 tPA 06 placebo Neurologic recovery better with tPA 30 Neurologic recovery better with tPA 30
more like to have minimal or no disabilitymore like to have minimal or no disability
First proven approved treatment for First proven approved treatment for strokestroke
Limitations of tPALimitations of tPA Only 4 of acute strokes receive tPAOnly 4 of acute strokes receive tPA (Kleindorfer et al Stroke 2004 35 e27-e29)(Kleindorfer et al Stroke 2004 35 e27-e29)
Only 22 of patients present within 3 hoursOnly 22 of patients present within 3 hours1048707 1048707 51 of these ineligible due to51 of these ineligible due to
bull bull Mild severityMild severity bull bull Medical or surgical historyMedical or surgical history bull bull Blood testsBlood tests
Sustained recanalization only 13Sustained recanalization only 13 (Alexandrov et al NEJM 2004 351 2170-8)(Alexandrov et al NEJM 2004 351 2170-8)
Concern for hemorrhageConcern for hemorrhage tPA potentiates apoptotic injury tPA potentiates apoptotic injury (Liu et al Nature Med 2004 101379-83)(Liu et al Nature Med 2004 101379-83)
PROACT II IA Lysis TrialPROACT II IA Lysis Trial Baseline 24 hours 8 days
Baseline 60 minutes 120 minutes
9mg IAProurokinase
Desmoteplase Trials DEDAS Desmoteplase Trials DEDAS DIASDIAS
Trial OverviewTrial Overview Double blind randomized placebo Double blind randomized placebo
controlled trialscontrolled trials IV delivery 3-9 hour time windowIV delivery 3-9 hour time window Plasminogen activator ndash from Plasminogen activator ndash from vampire bat vampire bat
salivasaliva Selection based on PWI-DWI MismatchSelection based on PWI-DWI Mismatch
MRI InclusionMRI Inclusion PWI defect at least 2 cm AND ~20 larger PWI defect at least 2 cm AND ~20 larger
than DWIthan DWI PWI should be obvious even visible on PWI should be obvious even visible on
raw imagesraw imagesMRI ExclusionMRI Exclusion
DWI gt 13 MCADWI gt 13 MCA MRA ICA occlusionMRA ICA occlusion
Desmoteplase ndash DIAS Desmoteplase ndash DIAS ResultsResults
Mechanical Thrombolysis Mechanical Thrombolysis devicesdevices
mechanical thrombolysis potentially extends the treatment mechanical thrombolysis potentially extends the treatment window because they act promptly at the site of the thrombuswindow because they act promptly at the site of the thrombus
The devices can retrieve large clots that pharmaceutical agents The devices can retrieve large clots that pharmaceutical agents may not successfully lysemay not successfully lyse
Patients treated with IV tPA may be considered for treatment of Patients treated with IV tPA may be considered for treatment of residual clot with some of these devicesresidual clot with some of these devices
suction-creating saline jets suction-creating saline jets laser energy ultrasound laser energy ultrasound a corkscrew apparatus to treat strokesa corkscrew apparatus to treat strokes The AngioJet systemThe AngioJet system uses saline jets that are directed back into the catheter to uses saline jets that are directed back into the catheter to
create a low-pressure zone around the catheter tip inducing create a low-pressure zone around the catheter tip inducing suction suction
The clot is pulled into the exhaust lumen and removed from the The clot is pulled into the exhaust lumen and removed from the vessel Although US Food and Drug Administration (FDA) has vessel Although US Food and Drug Administration (FDA) has approved this device for use in arteriovenous dialysis grafts and approved this device for use in arteriovenous dialysis grafts and fistulae and for the treatment of coronary arteries saphenous fistulae and for the treatment of coronary arteries saphenous vein grafts and peripheral vessels clinical trials for the vein grafts and peripheral vessels clinical trials for the treatment of acute stroke are no longer in progress treatment of acute stroke are no longer in progress
Most devices are used in cerebral vessels that 2-5 mm
The Latis laser device The Latis laser device used laser energy to ablate clots used laser energy to ablate clots Arteries 2-5 mm in diameter could be Arteries 2-5 mm in diameter could be
treated including the ICA M1 or M2 treated including the ICA M1 or M2 branch of the MCA A1 branch of the branch of the MCA A1 branch of the anterior cerebral artery (ACA) basilar anterior cerebral artery (ACA) basilar artery posterior cerebral artery (PCA) artery posterior cerebral artery (PCA) and vertebral and vertebral
Patients could receive treatment as late Patients could receive treatment as late as 8 hours after symptom onset in the as 8 hours after symptom onset in the anterior circulation and within 24 hours in anterior circulation and within 24 hours in the posterior circulation the posterior circulation
Endovascular Photo Acoustic Endovascular Photo Acoustic Recanalization (EPAR) Recanalization (EPAR)
A laser power source generated energy for the A laser power source generated energy for the systemsystem
The energy was delivered by means of The energy was delivered by means of fiberoptics to the tip of the catheter at the fiberoptics to the tip of the catheter at the treatment sitetreatment site
Absorption of laser light by darkly pigmented Absorption of laser light by darkly pigmented materials (ie the clot) occurred inside the 1-mm materials (ie the clot) occurred inside the 1-mm catheter tipcatheter tip
the system was designed to minimize scattering the system was designed to minimize scattering of laser light of laser light
Absorption converted photo energy to acoustic Absorption converted photo energy to acoustic energy which then emulsified the clot inside the energy which then emulsified the clot inside the catheter tip catheter tip
EKOS ultrasound( the EKOS ultrasound( the Ultrasound Thrombolytic Ultrasound Thrombolytic
Infusion Catheter) Infusion Catheter) combines the use of a distal ultrasound transducer with combines the use of a distal ultrasound transducer with
infusion of a thrombolytic agent through the infusion of a thrombolytic agent through the microcathetermicrocatheter
Ultrasound changes the structure of the clot to Ultrasound changes the structure of the clot to temporarily increase its permeability while providing an temporarily increase its permeability while providing an acoustic pressure gradient to move the drug into the clot acoustic pressure gradient to move the drug into the clot to speed its dissolution to speed its dissolution
The EKOS catheter is placed in the proximal portion of the The EKOS catheter is placed in the proximal portion of the clot clot
After a 2-mg bolus of tPA was injected through the After a 2-mg bolus of tPA was injected through the catheter catheter
the patient received a continuous infusion of IA tPA 03 the patient received a continuous infusion of IA tPA 03 mgmin to a maximum of 20 mg and simultaneous mgmin to a maximum of 20 mg and simultaneous ultrasound transmission for as long as 60 minutes ultrasound transmission for as long as 60 minutes
One patient was treated with a total of 4 units of One patient was treated with a total of 4 units of recombinant reteplase (Retavase) hand-injected over 60 recombinant reteplase (Retavase) hand-injected over 60 minutes minutes
Penumbra system Penumbra system The Penumbra system (Penumbra Inc) provides a dual The Penumbra system (Penumbra Inc) provides a dual
approach to clot extraction using aspiration followed by approach to clot extraction using aspiration followed by clot retrieval with a ring device if needed clot retrieval with a ring device if needed
Mechanical Embolus Removal in Cerebral Ischemia Mechanical Embolus Removal in Cerebral Ischemia (MERCI)(MERCI)
a corkscrew-like apparatus to remove blood clots from a corkscrew-like apparatus to remove blood clots from the brain in patients experiencing an ischemic stroke the brain in patients experiencing an ischemic stroke
The corkscrew itself resides in the catheter tip which The corkscrew itself resides in the catheter tip which shields it from the wall of the vessel until it is ready to be shields it from the wall of the vessel until it is ready to be burrowed into the clot Once lodged in the clot the device burrowed into the clot Once lodged in the clot the device and clot are withdrawn from the vessel and clot are withdrawn from the vessel
Snarelike devicesSnarelike devices Snares such as the Neuronet snare (Guidant Snares such as the Neuronet snare (Guidant
Endovascular Santa Clara CA) have been developed Endovascular Santa Clara CA) have been developed specifically for use in the treatment of strokes specifically for use in the treatment of strokes
These devices are simple in design and do not require the These devices are simple in design and do not require the clot to be amenable to emulsification clot to be amenable to emulsification
X-Sizer deviceX-Sizer device a device with small moving blades at the a device with small moving blades at the
catheter tip catheter tip This device the X-Sizer device (EndiCor Medical This device the X-Sizer device (EndiCor Medical
San Clemente CA) can be used to excise the San Clemente CA) can be used to excise the thrombus and aspirate it thrombus and aspirate it
The device was being evaluated in randomized The device was being evaluated in randomized studies of coronary vessels and in a registry of studies of coronary vessels and in a registry of patients with acute myocardial infarctionpatients with acute myocardial infarction
Although the manufacturer had modified the Although the manufacturer had modified the device for use in cerebral vessels a safety and device for use in cerebral vessels a safety and feasibility study was indefinitely suspended after feasibility study was indefinitely suspended after only 1 patient was treated with the device in only 1 patient was treated with the device in Europe Europe
Suction thrombectomySuction thrombectomy This method of mechanical thrombolysis is one of the This method of mechanical thrombolysis is one of the
simplestsimplest In this readily available technique suction is applied with In this readily available technique suction is applied with
a syringe to remove thrombus in the ICA a syringe to remove thrombus in the ICA It requires no other devicesIt requires no other devices A catheter with a large inner diameter (Brite Tip Cordis A catheter with a large inner diameter (Brite Tip Cordis
Corporation Miami FL) was placed in the symptomatic Corporation Miami FL) was placed in the symptomatic vessel and navigated over a guidewire into the thrombusvessel and navigated over a guidewire into the thrombus
A 60-mL syringe was used to aspirate the thrombus A 60-mL syringe was used to aspirate the thrombus Each patient required angioplasty and stenting of carotid Each patient required angioplasty and stenting of carotid
bifurcation stenosis and received daily aspirin and bifurcation stenosis and received daily aspirin and ticlopidine after the procedure No complications ticlopidine after the procedure No complications occurred occurred
Summary Acute Stroke Summary Acute Stroke ImagingImaging
PhysiologyPhysiology importance collaterals importance collaterals
ndash ndashGrowing role for perfusion Growing role for perfusion assessmentassessment
tPAtPA guidelines amp limitations guidelines amp limitations Signs on CT amp MRSigns on CT amp MR follow physiology follow physiology Stroke trialsStroke trials PWI-DWI mismatch PWI-DWI mismatch
ndash ndashTreat based on physiology not timeTreat based on physiology not time ProtocolsProtocols should be fast and should be fast and
comprehensivecomprehensive
Maintainance of patency Maintainance of patency of vascular of vascular grafts catheters shunts bypassesgrafts catheters shunts bypasses
Arterial thromboembolic diseaseArterial thromboembolic diseasebull Transient ischemic attacksTransient ischemic attacksbull Stroke in evolutionStroke in evolution
Ischemic events occurs in Ischemic events occurs in 1313 of of conventional neuroangiographic conventional neuroangiographic procedures without Endovascular surgeryprocedures without Endovascular surgery
Indications for Antithrombotic Therapy in Indications for Antithrombotic Therapy in Diagnostics and Interventional ProceduresDiagnostics and Interventional Procedures
WHY TO MONITOR ANTICOAGULANT THERAPYWHY TO MONITOR ANTICOAGULANT THERAPY
Narrow therapeutic rangeNarrow therapeutic range
Can increase risk of bleedingCan increase risk of bleeding
Coagulation TestingCoagulation Testing
Monitoring therapyMonitoring therapy
Intrinsic Pathway
Extrinsic Pathway
Common Pathway
CLOT
Heparin Coumadin
Monitor with
ACT aPTT
Monitor with PTINR
Thrombolytics
Monitor with TT Fibrinogen
Monitoring of Monitoring of Anti platelet drugsAnti platelet drugs
Bleeding timeBleeding time
Optical aggregometryOptical aggregometry
Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay
HeparinHeparin
Heterogeneous 3000-30000 dalton in Heterogeneous 3000-30000 dalton in molecular weight molecular weight
Average=15000 d (~45monosaccharide Average=15000 d (~45monosaccharide chains)chains)
About About 13 of dose binds to AT III and forms 13 of dose binds to AT III and forms the AT IIIHeparinClotting Factor Complexthe AT IIIHeparinClotting Factor Complex
Complex binds to clotting factors of the Complex binds to clotting factors of the intrinsic and common pathway (Xa IIa IXa intrinsic and common pathway (Xa IIa IXa XIa XIIa XIIIa) and inactivates themXIa XIIa XIIIa) and inactivates them
Anticoagulant of choice in pregnancy (not Anticoagulant of choice in pregnancy (not crosses placenta)crosses placenta)
Heparin and Low molecular weight heparinsHeparin and Low molecular weight heparins
Structure and sequence
O
OH
OH
O
COO
O
O
CH2OH
NHSO3
OH
_
_
O
O
CH2OSO3
NHSO3
OH
_
_
O
OH
OH
O
COOO
O
CH2OSO3
NHSO3
OH
_
_
O
OSO3
OHO
COOO
O
CH2OSO3
NHCOCH3
OH
_
_ _
_
_
O
OH
OH
O
COO
1
23
4
5
6
-D-glucosamine -L-iduronic acid -D-glucuronic acid
O
O
CH2OH
NH2
OH 12
3
4
5
6
O
OH
OHO
COO_
1
23
4
5
6
polymeric structure of heparin
Anticoagulant Properties of Anticoagulant Properties of HeparinHeparin
11 Inhibits the thrombin-mediated conversion of Inhibits the thrombin-mediated conversion of fibrinogen to fibrinfibrinogen to fibrin
22 Inhibits the aggregation of platelets by thrombin Inhibits the aggregation of platelets by thrombin (prolongs bleeding time)(prolongs bleeding time)
33 Inhibits activation of fibrin stabilizing enzymeInhibits activation of fibrin stabilizing enzyme
44 Inhibits activated factors XII XI IX X and IIInhibits activated factors XII XI IX X and II All available forms of heparin must be All available forms of heparin must be
administered administered parenterally since they are parenterally since they are highly charged and rapidlyhighly charged and rapidly hydrolyzed in the hydrolyzed in the GI tractGI tract
Heparin antagonist Protamine sulfate (Heparin antagonist Protamine sulfate (10mg for 10mg for 1000 unit of heparin)1000 unit of heparin)
Monitoring of heparin Monitoring of heparin
Subcutenous Subcutenous no monitoring requiredno monitoring required Intravenous Intravenous
Partial thromboplastin time (PTT normal value Partial thromboplastin time (PTT normal value ~30sec) ~30sec)
Activated clotting time ( ACT normal value ~90-Activated clotting time ( ACT normal value ~90-120sec)120sec)
Daily or more frequent if PTT ACT variesDaily or more frequent if PTT ACT varies
Mechanism Mechanism ndash measures intrinsic pathwayndash measures intrinsic pathway Therapeutic goal Therapeutic goal 2-25 times normal control value 2-25 times normal control value
ACT or aPTTACT or aPTT
Determine when to pull the femoral sheath Determine when to pull the femoral sheath Premature sheath pull can lead to bleedingPremature sheath pull can lead to bleeding Delayed removal can increase time in ICUDelayed removal can increase time in ICU Target set Target set at each siteat each site
ACT targets range from 150 ndash 220 ACT targets range from 150 ndash 220 secondsseconds
aPTT targets range from 40 ndash 70 seconds aPTT targets range from 40 ndash 70 seconds
During neuroangiography-During neuroangiography- Recommended therapeutic range of heparin in Recommended therapeutic range of heparin in
plasma is 02-08 uml ( corresponding to aPTT plasma is 02-08 uml ( corresponding to aPTT ACT values 15-25 times the baseline values)ACT values 15-25 times the baseline values)
Dose In diagnostic angiography bolus dose of Dose In diagnostic angiography bolus dose of 2500 iu is used followed by 1000 iu hour2500 iu is used followed by 1000 iu hour
Bolus dose is Bolus dose is 60 ukg to maintain the therapeutic 60 ukg to maintain the therapeutic range range If procedure continues for more than 75 If procedure continues for more than 75 minutes additional dose is required ( half of the minutes additional dose is required ( half of the initial dose for another 75 minutes) initial dose for another 75 minutes)
(AJNR 199415 51-54)
Mechanisms of HIT( Mechanisms of HIT( Heparin Heparin induced Thrombocytopeniainduced Thrombocytopenia))
Type 1Type 1 Fall in platelet count occurs within the first two Fall in platelet count occurs within the first two
days after heparin initiation often returns to days after heparin initiation often returns to normal with continued heparin administration normal with continued heparin administration and is of no clinical consequence and is of no clinical consequence
The mechanism of the thrombocytopenia is non-The mechanism of the thrombocytopenia is non-immune and appears to be due to a direct effect of immune and appears to be due to a direct effect of heparin on platelet activationheparin on platelet activation
Type 2Type 2 Approximately 03 to 3 percent of patients Approximately 03 to 3 percent of patients
receiving heparin develop an immune receiving heparin develop an immune thrombocytopenia mediated by antibodies to a thrombocytopenia mediated by antibodies to a heparin-platelet factor 4 complex heparin-platelet factor 4 complex
(AJNR 28155-158 2007)
Treatment of heparin-induced Treatment of heparin-induced thrombocytopeniathrombocytopenia
When HIT is diagnosed it is important to When HIT is diagnosed it is important to stop heparin mainly in type 2 and to avoid stop heparin mainly in type 2 and to avoid the use of LMWH the use of LMWH
Because of the increased risk of thrombosis Because of the increased risk of thrombosis however continuation of an anticoagulant however continuation of an anticoagulant must be considered must be considered
The drugs currently approved for the The drugs currently approved for the treatment of HIT in the United States are treatment of HIT in the United States are direct thrombin inhibitors argatroban and direct thrombin inhibitors argatroban and lepirudinlepirudin
WARFARIN MECHANISM OF ACTIONWARFARIN MECHANISM OF ACTION
Inactive factors II VII IX and X
Proteins S and C
Active factors II VII IX and X
Proteins S and C
Vitamin K epoxide
Vitamin K reduced
WA
RF
AR
IN
Prevents the reduction of vitamin K which is essential for Prevents the reduction of vitamin K which is essential for activation of certain factorsactivation of certain factors
Has no effect on previously formed thrombusHas no effect on previously formed thrombus
Antagonist is Vit KAntagonist is Vit K
OPTIMIZING WARFARIN THERAPYOPTIMIZING WARFARIN THERAPY
Use of large loading dose may lead to hemorrhage and Use of large loading dose may lead to hemorrhage and other complicationsother complications
Initial dose 2-5 mg once dailyInitial dose 2-5 mg once daily Maintenance dose 2-10 mg once dailyMaintenance dose 2-10 mg once daily If Immediate anticoagulation is requiredIf Immediate anticoagulation is required Heparin IS Heparin IS
started along with loading dose of warfarin 10 mg started along with loading dose of warfarin 10 mg Heparin is usually discontinued after 4-5 days Heparin is usually discontinued after 4-5 days Before Before discontinuing INR should be in therapeutic range for 2 discontinuing INR should be in therapeutic range for 2 consecutive daysconsecutive days
Daily monitoring of INR until INR is in therapeutic Daily monitoring of INR until INR is in therapeutic range then 3 times weekly for 1-2 weeks then less often range then 3 times weekly for 1-2 weeks then less often (every 4 to 6 weeks)(every 4 to 6 weeks)
OPTIMAL THERAPEUTIC RANGEOPTIMAL THERAPEUTIC RANGE
IndicationIndication INRINR
Prophylaxis of venous Prophylaxis of venous thromboembolismthromboembolism
20-3020-30
Treatment of venous Treatment of venous thromboembolismthromboembolism
20-3020-30
Atrial fibrillationAtrial fibrillation 20-3020-30
Mitral valve stenosisMitral valve stenosis 20-3020-30
Heart valve replacementHeart valve replacement
Bioprosthetic valveBioprosthetic valve
Mechanical valveMechanical valve
20-3020-30
25-3525-35
Myocardial infarctionMyocardial infarction 20-3020-30
25-35 25-35 (high risk patients)(high risk patients)
FACTORS INFLUENCING DOSE RESPONSEFACTORS INFLUENCING DOSE RESPONSE
Poor patient compliancePoor patient compliance Concomitant medicationsConcomitant medications Levels of dietary vitamin KLevels of dietary vitamin K Alcohol Inaccurate lab testingAlcohol Inaccurate lab testing Inaccurate lab testingInaccurate lab testing Hepatic dysfunctionHepatic dysfunction FeverFever
Contraindication for WarfarinContraindication for Warfarin
Hypersensitivity to warfarinHypersensitivity to warfarin Hemorrhagic tendencyHemorrhagic tendency Condition with risk of hemorrhageCondition with risk of hemorrhage Inadequate laboratory techniquesInadequate laboratory techniques Protein C amp S deficiencyProtein C amp S deficiency Vitamin K deficiencyVitamin K deficiency
SIDE EFFECTSSIDE EFFECTS
Hemorrhage Hemorrhage Skin necrosisSkin necrosis Purple toe syndromePurple toe syndrome Microembolization Microembolization TeratogenecityTeratogenecity Agranulocytosis leukopenia Agranulocytosis leukopenia Diarrhoeanausea anorexiaDiarrhoeanausea anorexia
MONITORING OF WARFARIN THERAPYMONITORING OF WARFARIN THERAPY
Prothrombin timeProthrombin time PT ratioPT ratio INR (International Normalized Ratio)INR (International Normalized Ratio)
PROTHROMBIN TIME (PT)PROTHROMBIN TIME (PT)
Time required for blood to coagulate Time required for blood to coagulate is called PT ( normal value ~10sec)is called PT ( normal value ~10sec)
Performed by adding a mixture of Performed by adding a mixture of calcium and thromboplastin to calcium and thromboplastin to citrated plasmacitrated plasma
As a control a normal blood sample is As a control a normal blood sample is tested continuouslytested continuously
PT ratio (PTR) = PT ratio (PTR) = Patientrsquos PTPatientrsquos PT Control PTControl PT
PROBLEMS WITH PTPTRPROBLEMS WITH PTPTR
Thromboplastins are extracts from Thromboplastins are extracts from brain lung or placenta of animalsbrain lung or placenta of animals
Thromboplastins from various Thromboplastins from various manufacturers differ in their manufacturers differ in their sensitivity to prolong PTsensitivity to prolong PT
May result in false control of May result in false control of anticoagulant therapyanticoagulant therapy
INTERNATIONAL NORMALISED RATIO (INR)INTERNATIONAL NORMALISED RATIO (INR)
International Normalized Ratio (INR) International Normalized Ratio (INR) a PT test with a a PT test with a formula based ratio to normalize the often variable source formula based ratio to normalize the often variable source of tissue factor (human rabbit recombinant)of tissue factor (human rabbit recombinant)
INR = [PTINR = [PTptpt] ] ISIISI
[PT[PTRefRef]]
PTPTpt pt ndash prothrombin time of patientndash prothrombin time of patient
PTPTRef Ref ndash prothrombin time of normal pooled samplendash prothrombin time of normal pooled sample
ISI ndash International Sensitivity IndexISI ndash International Sensitivity Index
Warfarin is given orally and titrated to achieve an INR of Warfarin is given orally and titrated to achieve an INR of typically 20 ndash 30typically 20 ndash 30
Heparin versus WarfarinHeparin versus Warfarin
Drug ActionMechan-ism
Moni-toring
Effective
HeparinDirect
Inhibition ofThrombin
ATIIIcofactor
APTTACT
Immediate
WarfarinDecreasesProductionof factors
Vitamin K PTDelay
3-5 days
INR
Recanalization or Antegrade Recanalization or Antegrade Reperfusion StrategiesReperfusion Strategies
Recanalization strategies focus on removing Recanalization strategies focus on removing andor dissolving the occlusive thrombus to re-andor dissolving the occlusive thrombus to re-establish antegrade flow Strategies may be establish antegrade flow Strategies may be classified into 7 different categories on the classified into 7 different categories on the basis of their primary mechanism of action basis of their primary mechanism of action 1) 1) IV andor intraarterial thrombolysis (IAT) IV andor intraarterial thrombolysis (IAT) 2) endovascular thrombectomy2) endovascular thrombectomy3) endovascular thromboaspiration 3) endovascular thromboaspiration 4) endovascular mechanical thrombus disruption or 4) endovascular mechanical thrombus disruption or
thromborrhexisthromborrhexis5) 5) transcranial or endovascular augmented transcranial or endovascular augmented
fibrinolysis fibrinolysis 6) endovascular thrombus entrapment and 6) endovascular thrombus entrapment and 7) temporary endovascular bypass7) temporary endovascular bypass
IAT in Acute Ischemic StrokeIAT in Acute Ischemic Stroke
IAT advantages over IV thrombolysisIAT advantages over IV thrombolysis Coaxial microcatheter techniques the occluded intracranial Coaxial microcatheter techniques the occluded intracranial
vessel is directly accessible and the fibrinolytic agent can be vessel is directly accessible and the fibrinolytic agent can be infused directly into the thrombusinfused directly into the thrombus
This permits a smaller dose of fibrinolytic agent to reach a This permits a smaller dose of fibrinolytic agent to reach a higher local concentration than that reached by systemic higher local concentration than that reached by systemic infusioninfusion
Allows more complete recanalization with lower total doses of Allows more complete recanalization with lower total doses of thrombolytic thrombolytic
With the smaller dose complications from systemic fibrinolytic With the smaller dose complications from systemic fibrinolytic effects including intracranial hemorrhage (ICH) can effects including intracranial hemorrhage (ICH) can theoretically be reduced theoretically be reduced
Treatment window for endovascular techniques can be Treatment window for endovascular techniques can be extended beyond the typical IV window of 3 hours extended beyond the typical IV window of 3 hours
IA techniques have led to higher recanalization rates than IV IA techniques have led to higher recanalization rates than IV thrombolysisthrombolysis
Major disadvantagesMajor disadvantages Relative complexity of the procedure the level Relative complexity of the procedure the level
of required technical expertise and its of required technical expertise and its relatively low availability relatively low availability
Delays in initiating treatmentDelays in initiating treatment InvasiveInvasive
ThrombolyticsThrombolytics
Plasminogen activators
Fibrinolytics
1 Plasminogen Activators 1 Plasminogen Activators drugs act by converting the inactive proenzyme drugs act by converting the inactive proenzyme plasminogen into the active enzyme plasmin Plasmin plasminogen into the active enzyme plasmin Plasmin digests fibrinogen fibrin monomers and cross-linked digests fibrinogen fibrin monomers and cross-linked fibrin (as found in a thrombus) into fibrin degradation fibrin (as found in a thrombus) into fibrin degradation productsproducts
First-Generation Agents First-Generation Agents StreptokinaseStreptokinase a protein derived from group C a protein derived from group C
szlig-hemolytic streptococci has a half-life of 16ndashszlig-hemolytic streptococci has a half-life of 16ndash90 minutes and low fibrin specificity This drug 90 minutes and low fibrin specificity This drug proved to have a very narrow therapeutic proved to have a very narrow therapeutic window and significant rates of ICH and window and significant rates of ICH and systemic hemorrhage18systemic hemorrhage18
UrokinaseUrokinase is a serine protease with a plasma is a serine protease with a plasma half life of 14 minutes and low fibrin specificity half life of 14 minutes and low fibrin specificity
The urokinase dose used in cerebral IAT has The urokinase dose used in cerebral IAT has ranged from 002 to 2 X106unitsranged from 002 to 2 X106units
Second-Generation Agents Second-Generation Agents Alteplase (rtPA) Alteplase (rtPA)
is a serine is a serine protease with a plasma half-life of 35 protease with a plasma half-life of 35 minutes and a high degree of fibrin affinity and minutes and a high degree of fibrin affinity and specificity specificity
Dose used in cerebral IAT has ranged between 20 Dose used in cerebral IAT has ranged between 20 and 60 mgand 60 mg
Disadvantages of alteplase include its relatively short Disadvantages of alteplase include its relatively short halflife and limited penetration into the clot matrix halflife and limited penetration into the clot matrix because of strong binding with surface fibrin which because of strong binding with surface fibrin which could delay recanalization and increase the risk of could delay recanalization and increase the risk of recurrent occlusion recurrent occlusion
Prourokinase (r-prourokinase) Prourokinase (r-prourokinase) is the proenzyme precursor of urokinase is the proenzyme precursor of urokinase T12 of 7 minutes and high fibrin specificity T12 of 7 minutes and high fibrin specificity
Third-Generation AgentsThird-Generation Agents
ReteplaseReteplase is a structurally modified is a structurally modified form of alteplase form of alteplase
with a longer half-life (15ndash18 minutes) In with a longer half-life (15ndash18 minutes) In addition it does not bind as highly to fibrin addition it does not bind as highly to fibrin unbound reteplase can thus theoretically better unbound reteplase can thus theoretically better penetrate the clot and potentially penetrate the clot and potentially improve in improve in vivo fibrinolytic activity vivo fibrinolytic activity
TenecteplaseTenecteplase is another modified form of rtPA with a longer is another modified form of rtPA with a longer
half-life (17 minutes)half-life (17 minutes) greater fibrin specificity and greater greater fibrin specificity and greater
resistance to plasminogen activator inhibitor-1 resistance to plasminogen activator inhibitor-1 IV tenecteplase in acute ischemic stroke IV tenecteplase in acute ischemic stroke
suggest that the drug is safe and promisingsuggest that the drug is safe and promising
Newer plasminogen activatorNewer plasminogen activator
DesmoteplaseDesmoteplase is a genetically engineered is a genetically engineered version of the clot-dissolving factor version of the clot-dissolving factor
found in the saliva found in the saliva of the vampire bat Desmodus rotundusof the vampire bat Desmodus rotundus moremore potent and more selective for fibrin-bound potent and more selective for fibrin-bound
plasminogen than any other known plasminogen plasminogen than any other known plasminogen activatoractivator
Unlike tissue plasminogen activator (tPA) desmoteplase Unlike tissue plasminogen activator (tPA) desmoteplase is not activated by fibrinogen or -amyloid proteins is not activated by fibrinogen or -amyloid proteins factors that may exacerbate the risk for ICH factors that may exacerbate the risk for ICH
The effect of IV administration of desmoteplase 3ndash9 The effect of IV administration of desmoteplase 3ndash9 hours after symptom onset in patients with stroke who hours after symptom onset in patients with stroke who present with mismatch on MR imaging or CT perfusion present with mismatch on MR imaging or CT perfusion
3 DefibrinogenatingFibrinogenolytic 3 DefibrinogenatingFibrinogenolytic Agents Agents
AncrodAncrod(Viprinex)(Viprinex) is is the purified fraction of the Malayan pit viper venomthe purified fraction of the Malayan pit viper venom It acts by directly cleaving and inactivating fibrinogen It acts by directly cleaving and inactivating fibrinogen
and thus indirectly promoting anticoagulation and thus indirectly promoting anticoagulation The reduction in the blood levels of fibrinogen also The reduction in the blood levels of fibrinogen also
leads to a reduced blood viscosity which may improve leads to a reduced blood viscosity which may improve blood flow to the affected areas of the brain blood flow to the affected areas of the brain
In the Stroke Treatment with Ancrod Trial 500 In the Stroke Treatment with Ancrod Trial 500 patients with stroke presenting within 3 hours of patients with stroke presenting within 3 hours of symptom onset were randomized to receive ancrod (symptom onset were randomized to receive ancrod (n n 248) or a placebo (n 252) Good outcome (Barthel 248) or a placebo (n 252) Good outcome (Barthel Index 95ndash100 at 3 months) was achieved in 4221 Index 95ndash100 at 3 months) was achieved in 4221 and 344 of the patients respectively and 344 of the patients respectively
2 Direct Fibrinolytics2 Direct Fibrinolytics
Microplasmin (Microplasmin (ThromboGenics Heverlee Belgium)ThromboGenics Heverlee Belgium) is a truncated form of plasmin that is more resistant to the effects is a truncated form of plasmin that is more resistant to the effects
of antiplasmin of antiplasmin microplasmin can be used upto 4ndash12 hours after stroke onset microplasmin can be used upto 4ndash12 hours after stroke onset There was no evidence of increased bleeding risk with There was no evidence of increased bleeding risk with
microplasminmicroplasmin
Alfimeprase (Nuvelo San Carlos Calif)Alfimeprase (Nuvelo San Carlos Calif) is a recombinant truncated form of fibrolase a fibrinolytic zinc metalloproteinase is a recombinant truncated form of fibrolase a fibrinolytic zinc metalloproteinase
isolated from the venom of the southern copperhead snake isolated from the venom of the southern copperhead snake It degrades fibrin directly and achieves thrombolysis independent It degrades fibrin directly and achieves thrombolysis independent
of plasmin formationof plasmin formation its thrombolytic activity appears to be localized to the site of its thrombolytic activity appears to be localized to the site of
delivery These properties should theoretically result in faster delivery These properties should theoretically result in faster recanalization and lower hemorrhagic conversion riskrecanalization and lower hemorrhagic conversion risk
Anti-fibrinolyticsAnti-fibrinolytics
to limit fibrinolytic activityto limit fibrinolytic activity -aminocaproic acid (EACA) -aminocaproic acid (EACA) competitively inhibitscompetitively inhibits plasminogen and plasminogen activators from plasminogen and plasminogen activators from
binding to fibrinbinding to fibrin
alpha2-antiplasminalpha2-antiplasmin a serine protease inhibitor that a serine protease inhibitor that neutralizes any free circulating plasminneutralizes any free circulating plasmin
Plasminogen activator inhibitor-1Plasminogen activator inhibitor-1 a serine protease a serine protease inhibitor that inhibits tissue-type plasminogen inhibitor that inhibits tissue-type plasminogen activatoractivator
Glycoprotein (GP) IIbIIIa antagonistsGlycoprotein (GP) IIbIIIa antagonists
such as ReoPro (abciximab) Integrilin such as ReoPro (abciximab) Integrilin (eptifibatide) or Aggrastat (tirofiban) in (eptifibatide) or Aggrastat (tirofiban) in ischemic stroke remains investigational ischemic stroke remains investigational Deshmukh et al38 reported 21 patients with Deshmukh et al38 reported 21 patients with large-vessel occlusion refractory to IAT with large-vessel occlusion refractory to IAT with rtPA who were treated with IV andor IA rtPA who were treated with IV andor IA abciximab eptifibatide or tirofiban abciximab eptifibatide or tirofiban
IA Mechanical Approaches in Acute Ischemic Stroke IA Mechanical Approaches in Acute Ischemic Stroke Mechanical strategies have several advantagesMechanical strategies have several advantages First they lessen and may even preclude the use of chemical First they lessen and may even preclude the use of chemical
thrombolytics in this manner very likely reducing the risk of ICHthrombolytics in this manner very likely reducing the risk of ICH Second by avoiding the use of chemical thrombolytics it is Second by avoiding the use of chemical thrombolytics it is
possible to extend the treatment window beyond the limit of 6ndash8 possible to extend the treatment window beyond the limit of 6ndash8 hours hours
Third mechanically fragmenting a clot increases the surface area Third mechanically fragmenting a clot increases the surface area accessible to fibrinolytic agents and allows inflow of fresh accessible to fibrinolytic agents and allows inflow of fresh plasminogen which in turn may increase the speed of plasminogen which in turn may increase the speed of thrombolysis thrombolysis
Finally clot-retrieval devices may provide faster recanalization Finally clot-retrieval devices may provide faster recanalization
The disadvantages of the mechanical The disadvantages of the mechanical approaches approaches technical difficulty of navigating mechanical technical difficulty of navigating mechanical
devices into the intracranial circulation excessive devices into the intracranial circulation excessive trauma to the vasculature (potentially leading to trauma to the vasculature (potentially leading to vasospasm vessel dissection perforation or vasospasm vessel dissection perforation or rupture) rupture)
fragmented thrombus causing distal embolization fragmented thrombus causing distal embolization into previously unaffected territories into previously unaffected territories
Nevertheless the advantages of mechanical stroke Nevertheless the advantages of mechanical stroke therapy appear to significantly outweigh its therapy appear to significantly outweigh its disadvantages and risksdisadvantages and risks
Contraindications to Thrombolytic Contraindications to Thrombolytic agents agents
Recent thoracic abdominal or Recent thoracic abdominal or intracranial surgeryintracranial surgery
Recent haemorrhagic CVA Head injury Recent haemorrhagic CVA Head injury or neoplasmor neoplasm
Bleeding ulcerBleeding ulcer Anticipated invasive procedures (arterial Anticipated invasive procedures (arterial
punctures biopsies)punctures biopsies) Concurrent hemostatic dysfunctionConcurrent hemostatic dysfunction
Monitoring of thrombolytic Monitoring of thrombolytic therapytherapy
Thrombin time Measures the availability of functional
fibrinogen Normal thrombin time is 10-14 sec Prolonged when fibrinogen level is below
75-100 mgdl
Half Life of ThrombolyticsHalf Life of ThrombolyticsAgent Administration Half Life
Streptokinase IA 60-80min
Urokinase IAIV 9-12min
rTPA IAIV 6min
Abciximab(Reopro) IAIV 12hour
Aspirin POIV 15-20min
Heparin IVSC 60min
Coumadin PO 15-25 days
Anti Platelet DrugsAnti Platelet DrugsDrug Drug Mechanism Mechanism UsesUsesAspirinAspirin Permanently inhibits Permanently inhibits
COX-1 and COX-2COX-1 and COX-2CADCAD
Stroke-TIAsStroke-TIAs
NSAIDsNSAIDs Reversibly inhibits Reversibly inhibits COX-1COX-1
LimitedLimited
DipyridamoleDipyridamole Inhibits PDE increases Inhibits PDE increases cAMPcAMP
TIAsTIAs
ThenopyridinesThenopyridines
(Ticlopidine(Ticlopidine
ClopidrgrelClopidrgrel))
Inhibits ADP Inhibits ADP
PlatAg PlatAg
TIAsStrokeTIAsStroke
CAD PVDCAD PVD
Abciximab (ReoPro)Abciximab (ReoPro)
Eptifibatide (Integrilin)Eptifibatide (Integrilin)
TirofibanTirofiban
GP IIBIIIA InhibitorsGP IIBIIIA Inhibitors
Stroke- TIAs Stroke- TIAs
MonitoringMonitoring
Bleeding timeBleeding time
Optical aggregometryOptical aggregometry
Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay
Bleeding timeBleeding time
Requires a skin incision (usually made on the ear lobe or Requires a skin incision (usually made on the ear lobe or forearm offorearm of
a depth that results in disruption of capillary loops and a depth that results in disruption of capillary loops and small vessels)small vessels)
AdvantagesAdvantages Universally availableUniversally available Relatively simple techniquesRelatively simple techniques Can be performed bedsideCan be performed bedside
DisadvantagesDisadvantages Insensitive inaccurate non-specific techniqueInsensitive inaccurate non-specific technique
Poorly reproducible (as depends on multiple variables)Poorly reproducible (as depends on multiple variables)
Optical aggregometryOptical aggregometry
Gold standard assay for platelet functionGold standard assay for platelet function Agonist induced aggregation is measuredAgonist induced aggregation is measured Different agonist are available for different Different agonist are available for different
agentsagents However require unique expertise and are not However require unique expertise and are not
universally availableuniversally available Aspirin measured with ADP or AA(gt70 Aspirin measured with ADP or AA(gt70
aggregation so resistance)aggregation so resistance) Clopidogrel( ADP gt 90 aggregation means Clopidogrel( ADP gt 90 aggregation means
resistance) resistance)
Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay
Can be performed bed sideCan be performed bed side Different assay devices with different Different assay devices with different
agonist are used for each of different agonist are used for each of different antiplatelet agents antiplatelet agents
For Aspirin AA is used (result is reported as aspirin For Aspirin AA is used (result is reported as aspirin reaction units [ARU] ARUgt 550 indicates non-reaction units [ARU] ARUgt 550 indicates non-responsiveness)responsiveness)
Verify IIbIIIa assay device uses TRAP as agonist for Verify IIbIIIa assay device uses TRAP as agonist for Abciximab and TirofibanAbciximab and Tirofiban
Practical Applications Practical Applications related to specific related to specific
Neurovascular Neurovascular interventionsinterventions
Acute ischemic StrokeAcute ischemic Stroke When an artery occludes neurons are affected When an artery occludes neurons are affected
differently depending upon the amount of residual blood differently depending upon the amount of residual blood flowflow
Normal cerebral blood flow is greater than 50 mL100 Normal cerebral blood flow is greater than 50 mL100 mgminmgmin
Once blood flow decreases to less than 20 mL100 Once blood flow decreases to less than 20 mL100 mgmin infarction occursmgmin infarction occurs
If blood flow decreases to less than 10 mL100 mgmin If blood flow decreases to less than 10 mL100 mgmin irreversible neuronal death occurs rapidly irreversible neuronal death occurs rapidly
Blood flow between 11 and 20 mL100 mgmin is thought Blood flow between 11 and 20 mL100 mgmin is thought to represent the ischemic penumbra an area where the to represent the ischemic penumbra an area where the cells are functionally silent because of ischemia but are cells are functionally silent because of ischemia but are still able to recover if blood flow is restored still able to recover if blood flow is restored
Many acute stroke therapies are targeted toward Many acute stroke therapies are targeted toward restoring flow or function to the ischemic penumbrarestoring flow or function to the ischemic penumbra
Therapeutic window in Therapeutic window in management of acute Ischemic management of acute Ischemic
StrokeStrokeThe early diagnosis of ischemic stroke is critical to the The early diagnosis of ischemic stroke is critical to the
with only a narrow therapeutic window in the first few with only a narrow therapeutic window in the first few hours following stroke ictushours following stroke ictus
Diagnosis in the first 3 hours postictus provides the Diagnosis in the first 3 hours postictus provides the opportunity for intravenous or intraarterial thrombolysis opportunity for intravenous or intraarterial thrombolysis and intra-arterial clot mechanical treatment which and intra-arterial clot mechanical treatment which improve the outcome improve the outcome
Diagnosis in the time period between 3 and 6 hours Diagnosis in the time period between 3 and 6 hours provides an opportunity for intra-arterial thrombolysis provides an opportunity for intra-arterial thrombolysis and mechanical treatment and mechanical treatment
Involvement of the posterior circulation especially the Involvement of the posterior circulation especially the basilar artery is treated by some regardless of time of basilar artery is treated by some regardless of time of onset or up until 12 to 24 hours in some practices This is onset or up until 12 to 24 hours in some practices This is related to the potentially high mortality and morbidity related to the potentially high mortality and morbidity associated with basilar artery thrombosisassociated with basilar artery thrombosis
Infarct evaluation on angiographyInfarct evaluation on angiography(CT angiography and catheter (CT angiography and catheter
angiography)angiography)CTA is an excellent first-line examination for CTA is an excellent first-line examination for
evaluation of the head and neck arteries evaluation of the head and neck arteries In comparison with catheter angiography In comparison with catheter angiography
what it gives up in resolution and dynamic what it gives up in resolution and dynamic properties it makes up for with rapid properties it makes up for with rapid acquisition of a 3-D dataset and the potential acquisition of a 3-D dataset and the potential for assessment of whole-brain perfusion and for assessment of whole-brain perfusion and better parenchymal evaluationbetter parenchymal evaluation
Moreover CTA illustrates not only arterial Moreover CTA illustrates not only arterial stenosis or occlusion but also the vessel wall stenosis or occlusion but also the vessel wall This factor is most important for evaluation of This factor is most important for evaluation of intramural dissection and thrombosed intramural dissection and thrombosed aneurysms which may both complicate aneurysms which may both complicate evaluation of stroke patientsevaluation of stroke patients
Early angiographic signs of strokes Early angiographic signs of strokes both CTA both CTA and DSA and DSA
Vessel occlusion or cutoff related to Vessel occlusion or cutoff related to thromboembolithromboemboli
aneurysms aneurysms arterial dissection arterial dissection Meniscus or flattened shape to clot Meniscus or flattened shape to clot
(recent) versus reverse meniscus (older)(recent) versus reverse meniscus (older) tram track (nonocclusive or recanalized tram track (nonocclusive or recanalized
clot) clot) delayed (antegrade) flow (manifest as delayed (antegrade) flow (manifest as
decreased whole-brain perfusion on CTA)decreased whole-brain perfusion on CTA) retrograde collateral flowretrograde collateral flow
Non-occlusive left MCA thrombus on 3-D imaging performed from CTA source data and was confirmed at catheter angiography
Therapy to be started within a 6-hr Therapy to be started within a 6-hr time to treatment (TTT) window time to treatment (TTT) window (while in case of IV thrombolysis (while in case of IV thrombolysis therapy to be started with in 3hrs)therapy to be started with in 3hrs)
Exclusion criteria Exclusion criteria Rapidly improving neurologic deficit or Rapidly improving neurologic deficit or Sustained blood pressure of gt180100 Sustained blood pressure of gt180100 Hemorrhage is detected on CTHemorrhage is detected on CT Infarct involving gt more than 13 rd Infarct involving gt more than 13 rd
territory of MCAterritory of MCA MRADWI-Perfusion mismatchlt 20MRADWI-Perfusion mismatchlt 20 Definite hypodensity on CTDefinite hypodensity on CT
Intra-arterial Thrombolysis
Fibrinolytics + AntiplateletsFibrinolytics + Antiplatelets
PlasminogenPlasminogen activators through fibrinolysis exposes activators through fibrinolysis exposes free thrombin and paradoxically stimulatesfree thrombin and paradoxically stimulates platelet platelet aggregation which leads to formation of aaggregation which leads to formation of a platelet platelet thrombus (white clot) thrombus (white clot)
This new thrombus is relatively resistant to This new thrombus is relatively resistant to fibrinolyticsfibrinolytics
So new regimen in case of acute stroke isSo new regimen in case of acute stroke is fibrinolytics + antiplatelet drugsfibrinolytics + antiplatelet drugs
rtPA + IIbIIIa inhibitors( tirofiban rtPA + IIbIIIa inhibitors( tirofiban abciximab) orabciximab) or
Urokinase + IIbIIIa Urokinase + IIbIIIa inhibitors( tirofiban abciximab)inhibitors( tirofiban abciximab)
Intra-arterial Thrombolysis Tirofiban (04 microgkgmin bolus for 3 min followed by Tirofiban (04 microgkgmin bolus for 3 min followed by
0125 ugkgmin)0125 ugkgmin)
++
Heparin (2000ndash3000 IU bolus followed by Heparin (2000ndash3000 IU bolus followed by 1000 IUhour infusion 1000 IUhour infusion
with ACT maintained bw 200-300) throughout the with ACT maintained bw 200-300) throughout the interventional procedure and for 24ndash48 hours thereafter when interventional procedure and for 24ndash48 hours thereafter when there is neither intraprocedural bleeding nor suspicion of there is neither intraprocedural bleeding nor suspicion of increased risk of bleeding increased risk of bleeding
Maximum dose of Urokinase Maximum dose of Urokinase Anterior circulation stroke - 500000 IU (mean 400000 Anterior circulation stroke - 500000 IU (mean 400000
IU range 300000ndash500000 IU)IU range 300000ndash500000 IU) Posterior circulation stroke -1000000 IU (mean 837000 Posterior circulation stroke -1000000 IU (mean 837000
IU range 300000ndash1000000 IU)IU range 300000ndash1000000 IU)American Journal of NeuroradiologyAmerican Journal of Neuroradiology 262595-2601 2005262595-2601 2005
Intravenous ThrombolysisIntravenous Thrombolysis
The first method to restore cerebral The first method to restore cerebral perfusion is clot lysis with the goal perfusion is clot lysis with the goal of re-establishing blood flow to the of re-establishing blood flow to the affected tissue affected tissue
IV thrombolysis rt-PA is the only IV thrombolysis rt-PA is the only FDA- approved treatment for AIS FDA- approved treatment for AIS
Fibrinolysis is enhanced powerfully Fibrinolysis is enhanced powerfully by rt-PAby rt-PA
Intravenous rTPA Intravenous rTPA administration administration protocolprotocol
Total dose of rt-PA 09 mgkg (maximum dose Total dose of rt-PA 09 mgkg (maximum dose 90 mg)90 mg)
Give 10 as initial IV bolusGive 10 as initial IV bolus Infuse remainder over 1 hourInfuse remainder over 1 hour Admit patient to an ICU or stroke unit for Admit patient to an ICU or stroke unit for
monitoringmonitoring Neurologic assessments every 15 minutes Neurologic assessments every 15 minutes
during infusion then every 30 minutes for next during infusion then every 30 minutes for next 6 hours then every hour until 24hours after 6 hours then every hour until 24hours after treatmenttreatment
Favorable Outcome vs Treatment Time Favorable Outcome vs Treatment Time with IV rTPAwith IV rTPA
Protocol limit = 3 hrs
Benefit ~ 45 hrs
Thromboembolism During coilingThromboembolism During coiling Most feared and frequent complication Most feared and frequent complication Reported incidence - Approx 7 Reported incidence - Approx 7 SourcesSources of Thromboembolism are of Thromboembolism are
- Clots at the aneurysmal neck during or immediately- Clots at the aneurysmal neck during or immediately after after embolization embolization
- Thrombus forming on catheters during- Thrombus forming on catheters during proceduresprocedures
- Stenosis of an adjacent artery dt coil mass- Stenosis of an adjacent artery dt coil mass or herniationor herniation
- Migration of intraaneurysmal- Migration of intraaneurysmal thrombus during coil thrombus during coil placement placement
- Slow flow dt vasospasm - Slow flow dt vasospasm
- Rare and unlikely causes are hypercoagulable- Rare and unlikely causes are hypercoagulable state such state such as antiphospholipid antibody syndrome or due to HITas antiphospholipid antibody syndrome or due to HIT
Occur more often with wide-necked aneurysms (dt Occur more often with wide-necked aneurysms (dt increased exposed surface area of thrombogenic coil increased exposed surface area of thrombogenic coil material)material)
Current regimen of endovascular Current regimen of endovascular managementmanagement
The The glycoprotein IIbIIIa antagonist tirofiban glycoprotein IIbIIIa antagonist tirofiban (04 (04 microgkgmin bolus for 30 minutes followed by infusion of microgkgmin bolus for 30 minutes followed by infusion of 0125 ugkgmin until the thrombus dissolved) 0125 ugkgmin until the thrombus dissolved)
Intraarterial thrombolysis with Intraarterial thrombolysis with urokinase or r- TPA urokinase or r- TPA increase of intravenous (IV) heparin (measured by increase of intravenous (IV) heparin (measured by
ACT) ACT) Intravenous aspirin Intravenous aspirin
Coil-related platelet aggregation (white clot) is Coil-related platelet aggregation (white clot) is unlikely to respond to fibrinolytics but has a high risk unlikely to respond to fibrinolytics but has a high risk of hemorrhage (In ISAT) all 5 patients who had of hemorrhage (In ISAT) all 5 patients who had received thrombolytic therapy with tPA to treat a received thrombolytic therapy with tPA to treat a thromboembolic complication after endovascular thromboembolic complication after endovascular treatment rebleed and all of these patients died)treatment rebleed and all of these patients died)
IntracranialIntracranial Stenting Stenting Metallic foreign body such as stent will accumulate Metallic foreign body such as stent will accumulate
thrombus in the absence of platelet inhibitionthrombus in the absence of platelet inhibition Antiplatelet drugs are important to prevent peri or Antiplatelet drugs are important to prevent peri or
post-interventional thromboembolic eventspost-interventional thromboembolic events Optimal treatment regimens has not been determined Optimal treatment regimens has not been determined
but usually but usually Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-
procedureprocedureOrOr
Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on
morning of proceduremorning of procedure
If need to use stent is not pre-planned thanIf need to use stent is not pre-planned than
Abciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkgAbciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkg IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)
Glycoprotein IIbIIIa inhibitor are not used routinely during elective Glycoprotein IIbIIIa inhibitor are not used routinely during elective stenting procedure dt increased risk of ICH stenting procedure dt increased risk of ICH
Carotid StentingCarotid Stenting
Pre-procedurePre-procedure
Double Antiplatelet therapy is routinely given Double Antiplatelet therapy is routinely given beginning at least 3beginning at least 3
days before the proceduredays before the procedure
Aspirin 325mgd+Clopidogrel 75mgdAspirin 325mgd+Clopidogrel 75mgd During procedureDuring procedure
Heparin is given with target clotting time of 250-Heparin is given with target clotting time of 250-300sec300sec
Post-procedure Post-procedure
Aspirin 325mg is continued indefinitely and Aspirin 325mg is continued indefinitely and
Clopidogrel 75mgd for at least 6 weeks Clopidogrel 75mgd for at least 6 weeks
Inclusion criteria for Local ThrombolysisInclusion criteria for Local Thrombolysis a)a) Patients in severe clinical grade on admission Patients in severe clinical grade on admission
with evidence of dural venous sinus with evidence of dural venous sinus thrombosis and restrictive venous outflow on thrombosis and restrictive venous outflow on cerebral angiogramcerebral angiogram
b)b) Patients in clinical grade 3 worsening on Patients in clinical grade 3 worsening on heparin therapy Restriction to venous heparin therapy Restriction to venous outflow was defined as an increase in brain outflow was defined as an increase in brain circulation time gt 12 s delay in the drainage circulation time gt 12 s delay in the drainage of cortical veins with cortical veins hanging of cortical veins with cortical veins hanging in spacein space
Treatment Options for Venous Thrombosis
CT Grading for Venous ThrombosisCT Grading for Venous Thrombosis Grade I no parenchymal change Grade I no parenchymal change
(hyperdense (hyperdense sinuses cortical veins empty sinuses cortical veins empty delta sign)delta sign)
Grade II non hemorrhagic venous infarct Grade II non hemorrhagic venous infarct without mass effect without mass effect
Grade III non-hemorrhagic infarct with Grade III non-hemorrhagic infarct with mass effectmass effect
Grade IV hemorrhagic venous infarct (max Grade IV hemorrhagic venous infarct (max diameter lt 3 cm) with no mass effectdiameter lt 3 cm) with no mass effect
Grade V hemorrhagic venous infarct (max Grade V hemorrhagic venous infarct (max diameter gt 3 cm) with mass effect diameter gt 3 cm) with mass effect
Local ThrombolysisLocal Thrombolysis
Femoral Jugular access was secured and a guiding Femoral Jugular access was secured and a guiding catheter was placed in the jugular bulb catheter was placed in the jugular bulb Mechanical Mechanical clot maceration clot maceration was done with the guidewire was done with the guidewire following which a microcatheter (was navigated and following which a microcatheter (was navigated and placed in the thrombosed segment of sinus confirmed placed in the thrombosed segment of sinus confirmed on a selective venogram on a selective venogram
Urokinase infusion Bolus dose of 2-6 lacs followed Urokinase infusion Bolus dose of 2-6 lacs followed by 60000 to 100000 units per hour along with by 60000 to 100000 units per hour along with periodic check venogram Along with maintenance periodic check venogram Along with maintenance systemic infusion of Heparinsystemic infusion of Heparin Other agents such as Other agents such as streptokinase altepase or rTPAstreptokinase altepase or rTPA can be also used can be also used
After thrombolysis patient should subjected to oral After thrombolysis patient should subjected to oral anticoagulation for six monthsanticoagulation for six months
Low-molecular-weight Low-molecular-weight heparinheparin
PharmacologyPharmacologyLMWH as its name suggests is a glycosaminoglycan that is approximatelyLMWH as its name suggests is a glycosaminoglycan that is approximately
one third the molecular weight of UFH It is derived from UFH through one third the molecular weight of UFH It is derived from UFH through variousvarious
depolymerization processes LMWH binds to antithrombin which in turn depolymerization processes LMWH binds to antithrombin which in turn
Neutralizes actors Xa and IIa Because LMWH lacks many of the longer Neutralizes actors Xa and IIa Because LMWH lacks many of the longer chains chains
required for binding to thrombin it has less ability to neutralize thrombin required for binding to thrombin it has less ability to neutralize thrombin
relativeto its ability to neutralize factor Xa LMWH also has less relativeto its ability to neutralize factor Xa LMWH also has less nonspecific nonspecific
binding to other proteins There is greater bioavailability with more binding to other proteins There is greater bioavailability with more predictable predictable
pharmacokinetics that eliminates the need for monitoring The smaller pharmacokinetics that eliminates the need for monitoring The smaller size also size also
allows for enhanced subcutaneous absorption when compared with UFHallows for enhanced subcutaneous absorption when compared with UFH
Three LMWH preparations are Three LMWH preparations are currently approved for use in the currently approved for use in the United States (1) enoxaparin (2) United States (1) enoxaparin (2) dalteparin and (3) tinzaparin dalteparin and (3) tinzaparin
They are all administered They are all administered subcutaneously at intervals of either subcutaneously at intervals of either once or twice daily for both once or twice daily for both prophylaxis and treatment dosesprophylaxis and treatment doses
Few Experiences of Few Experiences of ThrombolysisThrombolysis
Vickey 25 Yrs male patient presented Vickey 25 Yrs male patient presented with 12with 12thth day HO severe headache with day HO severe headache with right sided hemiplegiaright sided hemiplegia
MRI shows thrombosis of the superior MRI shows thrombosis of the superior sagittal left transverse left sigmoid sagittal left transverse left sigmoid sinuses and cortical veins in the fronto-sinuses and cortical veins in the fronto-parietal regions with eo haemorrhagic parietal regions with eo haemorrhagic infarct in the left cerebral hemisphere infarct in the left cerebral hemisphere with mass effect( Grade ndashV)with mass effect( Grade ndashV)
Sashi Srivastava 64 yrs FSashi Srivastava 64 yrs F In a follow up case of MRD with infra-renal In a follow up case of MRD with infra-renal
aortic abdominal and bilateral renal artery aortic abdominal and bilateral renal artery thrombosis renal angiogram shows filling thrombosis renal angiogram shows filling defects in the right Renal artery defects in the right Renal artery
Initially Renal angioplasty was done Initially Renal angioplasty was done Following angioplasty few thrombi are seem Following angioplasty few thrombi are seem to extends into the segmental branches and to extends into the segmental branches and causing blockage So Thrombolysis was causing blockage So Thrombolysis was plane to dissolve the run-out thrombi with plane to dissolve the run-out thrombi with urokinase urokinase
Rakesh 34yrsMRakesh 34yrsM Left SFA pseudoaneurysm with Left SFA pseudoaneurysm with
Covered stent placementCovered stent placement Pre operative antiplatelets with post Pre operative antiplatelets with post
procedure heparin Tirofiban procedure heparin Tirofiban followed by aspirin and clopidogrel followed by aspirin and clopidogrel were usedwere used
IAT may be a treatment option for selected patients IAT may be a treatment option for selected patients Possible selection criteria include Possible selection criteria include
presentation between 3 and 6 hours from symptom onsetpresentation between 3 and 6 hours from symptom onset major cerebral artery occlusion major cerebral artery occlusion severe neurologic deficits severe neurologic deficits high risk of systemic hemorrhage with IV rt-PA (eg recent high risk of systemic hemorrhage with IV rt-PA (eg recent
surgery) surgery) The MERCI (Mechanical Embolus Removal in Cerebral The MERCI (Mechanical Embolus Removal in Cerebral
Ischemia) retrievalIschemia) retrieval system system
Has been FDA-approved for recanalizing acutely occluded Has been FDA-approved for recanalizing acutely occluded cerebral arteries cerebral arteries
In the Multi-MERCI study patients who did not improve In the Multi-MERCI study patients who did not improve immediately after IV rt-PA underwent mechanical immediately after IV rt-PA underwent mechanical embolectomy within 8 hours of symptom onset embolectomy within 8 hours of symptom onset
Partial or complete recanalization occurred in 74 of Partial or complete recanalization occurred in 74 of patientspatients
with a symptomatic intracerebral hemorrhage (sICH) rate of with a symptomatic intracerebral hemorrhage (sICH) rate of 67 67
Mechanical embolectomy with the MERCI retriever may be a Mechanical embolectomy with the MERCI retriever may be a feasible and safe option for patients after IV rt-PAfeasible and safe option for patients after IV rt-PA
Penumbra stroke systemPenumbra stroke system This device combines two methods of clot This device combines two methods of clot
extraction aspiration and mechanical extraction aspiration and mechanical extraction extraction
First the clot is aspirated then a thrombus First the clot is aspirated then a thrombus removal ring can be used if necessary to removal ring can be used if necessary to remove remaining clot remove remaining clot
successful recanalizing 82successful recanalizing 82 Bridging therapyBridging therapy
06 mgkg IV rt-PA followed by IAT with IA rt-06 mgkg IV rt-PA followed by IAT with IA rt-PA (up to 20 mg)PA (up to 20 mg)
achieved a higher recanalization rateachieved a higher recanalization rate
Criteria for thrombolysis with rTPACriteria for thrombolysis with rTPA
Inclusion criteriaInclusion criteria Clinical signs and symptoms consistent with ischemic Clinical signs and symptoms consistent with ischemic
strokestroke Patient last seen normal within 3 hoursPatient last seen normal within 3 hours Measurable neurologic deficitMeasurable neurologic deficit
Exclusion criteriaExclusion criteria Any hemorrhage on neuroimaging (CT or MRI)Any hemorrhage on neuroimaging (CT or MRI) Symptoms suggestive of subarachnoid hemorrhageSymptoms suggestive of subarachnoid hemorrhage Seizure at stroke onset that is thought to contribute to Seizure at stroke onset that is thought to contribute to
neurologic deficitneurologic deficit Hypodensity greater than one third cerebral hemisphere Hypodensity greater than one third cerebral hemisphere
on CTon CT SBP greater than 185 mm Hg or DBP greater than 110 SBP greater than 185 mm Hg or DBP greater than 110
mm Hgmm Hg International normalized ratio (INR) greater than 17International normalized ratio (INR) greater than 17
Ischemic Stroke Ischemic Stroke Treatment ndash 2006Treatment ndash 2006
IV tissue plasminogen activator (tPA)IV tissue plasminogen activator (tPA) ndash ndash Only FDA-approved acute stroke drugOnly FDA-approved acute stroke drug ndash ndash 3 hour treatment window3 hour treatment window
MERCI - Concentric clot retrieval MERCI - Concentric clot retrieval devicedevice ndash ndash Rescue therapy - approved 2004Rescue therapy - approved 2004 ndash ndash Device approval (not outcomes-based)Device approval (not outcomes-based)
Off label approachesOff label approaches ndash ndash IV tPA after 3 hoursIV tPA after 3 hours ndash ndash IV-IA tPA sequential strategiesIV-IA tPA sequential strategies ndash ndash IA tPA clot angioplasty fragmentationIA tPA clot angioplasty fragmentation ndash ndash Ultrasound-assisted tPA lysisUltrasound-assisted tPA lysis
rt-PA Trials NINDSrt-PA Trials NINDS
Acute stroke - 624 patientsAcute stroke - 624 patients Treat within 3 hrsTreat within 3 hrs Intravenous 09 mgkg rt-PA vs placeboIntravenous 09 mgkg rt-PA vs placebo Hemorrhage 64 tPA 06 placeboHemorrhage 64 tPA 06 placebo Neurologic recovery better with tPA 30 Neurologic recovery better with tPA 30
more like to have minimal or no disabilitymore like to have minimal or no disability
First proven approved treatment for First proven approved treatment for strokestroke
Limitations of tPALimitations of tPA Only 4 of acute strokes receive tPAOnly 4 of acute strokes receive tPA (Kleindorfer et al Stroke 2004 35 e27-e29)(Kleindorfer et al Stroke 2004 35 e27-e29)
Only 22 of patients present within 3 hoursOnly 22 of patients present within 3 hours1048707 1048707 51 of these ineligible due to51 of these ineligible due to
bull bull Mild severityMild severity bull bull Medical or surgical historyMedical or surgical history bull bull Blood testsBlood tests
Sustained recanalization only 13Sustained recanalization only 13 (Alexandrov et al NEJM 2004 351 2170-8)(Alexandrov et al NEJM 2004 351 2170-8)
Concern for hemorrhageConcern for hemorrhage tPA potentiates apoptotic injury tPA potentiates apoptotic injury (Liu et al Nature Med 2004 101379-83)(Liu et al Nature Med 2004 101379-83)
PROACT II IA Lysis TrialPROACT II IA Lysis Trial Baseline 24 hours 8 days
Baseline 60 minutes 120 minutes
9mg IAProurokinase
Desmoteplase Trials DEDAS Desmoteplase Trials DEDAS DIASDIAS
Trial OverviewTrial Overview Double blind randomized placebo Double blind randomized placebo
controlled trialscontrolled trials IV delivery 3-9 hour time windowIV delivery 3-9 hour time window Plasminogen activator ndash from Plasminogen activator ndash from vampire bat vampire bat
salivasaliva Selection based on PWI-DWI MismatchSelection based on PWI-DWI Mismatch
MRI InclusionMRI Inclusion PWI defect at least 2 cm AND ~20 larger PWI defect at least 2 cm AND ~20 larger
than DWIthan DWI PWI should be obvious even visible on PWI should be obvious even visible on
raw imagesraw imagesMRI ExclusionMRI Exclusion
DWI gt 13 MCADWI gt 13 MCA MRA ICA occlusionMRA ICA occlusion
Desmoteplase ndash DIAS Desmoteplase ndash DIAS ResultsResults
Mechanical Thrombolysis Mechanical Thrombolysis devicesdevices
mechanical thrombolysis potentially extends the treatment mechanical thrombolysis potentially extends the treatment window because they act promptly at the site of the thrombuswindow because they act promptly at the site of the thrombus
The devices can retrieve large clots that pharmaceutical agents The devices can retrieve large clots that pharmaceutical agents may not successfully lysemay not successfully lyse
Patients treated with IV tPA may be considered for treatment of Patients treated with IV tPA may be considered for treatment of residual clot with some of these devicesresidual clot with some of these devices
suction-creating saline jets suction-creating saline jets laser energy ultrasound laser energy ultrasound a corkscrew apparatus to treat strokesa corkscrew apparatus to treat strokes The AngioJet systemThe AngioJet system uses saline jets that are directed back into the catheter to uses saline jets that are directed back into the catheter to
create a low-pressure zone around the catheter tip inducing create a low-pressure zone around the catheter tip inducing suction suction
The clot is pulled into the exhaust lumen and removed from the The clot is pulled into the exhaust lumen and removed from the vessel Although US Food and Drug Administration (FDA) has vessel Although US Food and Drug Administration (FDA) has approved this device for use in arteriovenous dialysis grafts and approved this device for use in arteriovenous dialysis grafts and fistulae and for the treatment of coronary arteries saphenous fistulae and for the treatment of coronary arteries saphenous vein grafts and peripheral vessels clinical trials for the vein grafts and peripheral vessels clinical trials for the treatment of acute stroke are no longer in progress treatment of acute stroke are no longer in progress
Most devices are used in cerebral vessels that 2-5 mm
The Latis laser device The Latis laser device used laser energy to ablate clots used laser energy to ablate clots Arteries 2-5 mm in diameter could be Arteries 2-5 mm in diameter could be
treated including the ICA M1 or M2 treated including the ICA M1 or M2 branch of the MCA A1 branch of the branch of the MCA A1 branch of the anterior cerebral artery (ACA) basilar anterior cerebral artery (ACA) basilar artery posterior cerebral artery (PCA) artery posterior cerebral artery (PCA) and vertebral and vertebral
Patients could receive treatment as late Patients could receive treatment as late as 8 hours after symptom onset in the as 8 hours after symptom onset in the anterior circulation and within 24 hours in anterior circulation and within 24 hours in the posterior circulation the posterior circulation
Endovascular Photo Acoustic Endovascular Photo Acoustic Recanalization (EPAR) Recanalization (EPAR)
A laser power source generated energy for the A laser power source generated energy for the systemsystem
The energy was delivered by means of The energy was delivered by means of fiberoptics to the tip of the catheter at the fiberoptics to the tip of the catheter at the treatment sitetreatment site
Absorption of laser light by darkly pigmented Absorption of laser light by darkly pigmented materials (ie the clot) occurred inside the 1-mm materials (ie the clot) occurred inside the 1-mm catheter tipcatheter tip
the system was designed to minimize scattering the system was designed to minimize scattering of laser light of laser light
Absorption converted photo energy to acoustic Absorption converted photo energy to acoustic energy which then emulsified the clot inside the energy which then emulsified the clot inside the catheter tip catheter tip
EKOS ultrasound( the EKOS ultrasound( the Ultrasound Thrombolytic Ultrasound Thrombolytic
Infusion Catheter) Infusion Catheter) combines the use of a distal ultrasound transducer with combines the use of a distal ultrasound transducer with
infusion of a thrombolytic agent through the infusion of a thrombolytic agent through the microcathetermicrocatheter
Ultrasound changes the structure of the clot to Ultrasound changes the structure of the clot to temporarily increase its permeability while providing an temporarily increase its permeability while providing an acoustic pressure gradient to move the drug into the clot acoustic pressure gradient to move the drug into the clot to speed its dissolution to speed its dissolution
The EKOS catheter is placed in the proximal portion of the The EKOS catheter is placed in the proximal portion of the clot clot
After a 2-mg bolus of tPA was injected through the After a 2-mg bolus of tPA was injected through the catheter catheter
the patient received a continuous infusion of IA tPA 03 the patient received a continuous infusion of IA tPA 03 mgmin to a maximum of 20 mg and simultaneous mgmin to a maximum of 20 mg and simultaneous ultrasound transmission for as long as 60 minutes ultrasound transmission for as long as 60 minutes
One patient was treated with a total of 4 units of One patient was treated with a total of 4 units of recombinant reteplase (Retavase) hand-injected over 60 recombinant reteplase (Retavase) hand-injected over 60 minutes minutes
Penumbra system Penumbra system The Penumbra system (Penumbra Inc) provides a dual The Penumbra system (Penumbra Inc) provides a dual
approach to clot extraction using aspiration followed by approach to clot extraction using aspiration followed by clot retrieval with a ring device if needed clot retrieval with a ring device if needed
Mechanical Embolus Removal in Cerebral Ischemia Mechanical Embolus Removal in Cerebral Ischemia (MERCI)(MERCI)
a corkscrew-like apparatus to remove blood clots from a corkscrew-like apparatus to remove blood clots from the brain in patients experiencing an ischemic stroke the brain in patients experiencing an ischemic stroke
The corkscrew itself resides in the catheter tip which The corkscrew itself resides in the catheter tip which shields it from the wall of the vessel until it is ready to be shields it from the wall of the vessel until it is ready to be burrowed into the clot Once lodged in the clot the device burrowed into the clot Once lodged in the clot the device and clot are withdrawn from the vessel and clot are withdrawn from the vessel
Snarelike devicesSnarelike devices Snares such as the Neuronet snare (Guidant Snares such as the Neuronet snare (Guidant
Endovascular Santa Clara CA) have been developed Endovascular Santa Clara CA) have been developed specifically for use in the treatment of strokes specifically for use in the treatment of strokes
These devices are simple in design and do not require the These devices are simple in design and do not require the clot to be amenable to emulsification clot to be amenable to emulsification
X-Sizer deviceX-Sizer device a device with small moving blades at the a device with small moving blades at the
catheter tip catheter tip This device the X-Sizer device (EndiCor Medical This device the X-Sizer device (EndiCor Medical
San Clemente CA) can be used to excise the San Clemente CA) can be used to excise the thrombus and aspirate it thrombus and aspirate it
The device was being evaluated in randomized The device was being evaluated in randomized studies of coronary vessels and in a registry of studies of coronary vessels and in a registry of patients with acute myocardial infarctionpatients with acute myocardial infarction
Although the manufacturer had modified the Although the manufacturer had modified the device for use in cerebral vessels a safety and device for use in cerebral vessels a safety and feasibility study was indefinitely suspended after feasibility study was indefinitely suspended after only 1 patient was treated with the device in only 1 patient was treated with the device in Europe Europe
Suction thrombectomySuction thrombectomy This method of mechanical thrombolysis is one of the This method of mechanical thrombolysis is one of the
simplestsimplest In this readily available technique suction is applied with In this readily available technique suction is applied with
a syringe to remove thrombus in the ICA a syringe to remove thrombus in the ICA It requires no other devicesIt requires no other devices A catheter with a large inner diameter (Brite Tip Cordis A catheter with a large inner diameter (Brite Tip Cordis
Corporation Miami FL) was placed in the symptomatic Corporation Miami FL) was placed in the symptomatic vessel and navigated over a guidewire into the thrombusvessel and navigated over a guidewire into the thrombus
A 60-mL syringe was used to aspirate the thrombus A 60-mL syringe was used to aspirate the thrombus Each patient required angioplasty and stenting of carotid Each patient required angioplasty and stenting of carotid
bifurcation stenosis and received daily aspirin and bifurcation stenosis and received daily aspirin and ticlopidine after the procedure No complications ticlopidine after the procedure No complications occurred occurred
Summary Acute Stroke Summary Acute Stroke ImagingImaging
PhysiologyPhysiology importance collaterals importance collaterals
ndash ndashGrowing role for perfusion Growing role for perfusion assessmentassessment
tPAtPA guidelines amp limitations guidelines amp limitations Signs on CT amp MRSigns on CT amp MR follow physiology follow physiology Stroke trialsStroke trials PWI-DWI mismatch PWI-DWI mismatch
ndash ndashTreat based on physiology not timeTreat based on physiology not time ProtocolsProtocols should be fast and should be fast and
comprehensivecomprehensive
WHY TO MONITOR ANTICOAGULANT THERAPYWHY TO MONITOR ANTICOAGULANT THERAPY
Narrow therapeutic rangeNarrow therapeutic range
Can increase risk of bleedingCan increase risk of bleeding
Coagulation TestingCoagulation Testing
Monitoring therapyMonitoring therapy
Intrinsic Pathway
Extrinsic Pathway
Common Pathway
CLOT
Heparin Coumadin
Monitor with
ACT aPTT
Monitor with PTINR
Thrombolytics
Monitor with TT Fibrinogen
Monitoring of Monitoring of Anti platelet drugsAnti platelet drugs
Bleeding timeBleeding time
Optical aggregometryOptical aggregometry
Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay
HeparinHeparin
Heterogeneous 3000-30000 dalton in Heterogeneous 3000-30000 dalton in molecular weight molecular weight
Average=15000 d (~45monosaccharide Average=15000 d (~45monosaccharide chains)chains)
About About 13 of dose binds to AT III and forms 13 of dose binds to AT III and forms the AT IIIHeparinClotting Factor Complexthe AT IIIHeparinClotting Factor Complex
Complex binds to clotting factors of the Complex binds to clotting factors of the intrinsic and common pathway (Xa IIa IXa intrinsic and common pathway (Xa IIa IXa XIa XIIa XIIIa) and inactivates themXIa XIIa XIIIa) and inactivates them
Anticoagulant of choice in pregnancy (not Anticoagulant of choice in pregnancy (not crosses placenta)crosses placenta)
Heparin and Low molecular weight heparinsHeparin and Low molecular weight heparins
Structure and sequence
O
OH
OH
O
COO
O
O
CH2OH
NHSO3
OH
_
_
O
O
CH2OSO3
NHSO3
OH
_
_
O
OH
OH
O
COOO
O
CH2OSO3
NHSO3
OH
_
_
O
OSO3
OHO
COOO
O
CH2OSO3
NHCOCH3
OH
_
_ _
_
_
O
OH
OH
O
COO
1
23
4
5
6
-D-glucosamine -L-iduronic acid -D-glucuronic acid
O
O
CH2OH
NH2
OH 12
3
4
5
6
O
OH
OHO
COO_
1
23
4
5
6
polymeric structure of heparin
Anticoagulant Properties of Anticoagulant Properties of HeparinHeparin
11 Inhibits the thrombin-mediated conversion of Inhibits the thrombin-mediated conversion of fibrinogen to fibrinfibrinogen to fibrin
22 Inhibits the aggregation of platelets by thrombin Inhibits the aggregation of platelets by thrombin (prolongs bleeding time)(prolongs bleeding time)
33 Inhibits activation of fibrin stabilizing enzymeInhibits activation of fibrin stabilizing enzyme
44 Inhibits activated factors XII XI IX X and IIInhibits activated factors XII XI IX X and II All available forms of heparin must be All available forms of heparin must be
administered administered parenterally since they are parenterally since they are highly charged and rapidlyhighly charged and rapidly hydrolyzed in the hydrolyzed in the GI tractGI tract
Heparin antagonist Protamine sulfate (Heparin antagonist Protamine sulfate (10mg for 10mg for 1000 unit of heparin)1000 unit of heparin)
Monitoring of heparin Monitoring of heparin
Subcutenous Subcutenous no monitoring requiredno monitoring required Intravenous Intravenous
Partial thromboplastin time (PTT normal value Partial thromboplastin time (PTT normal value ~30sec) ~30sec)
Activated clotting time ( ACT normal value ~90-Activated clotting time ( ACT normal value ~90-120sec)120sec)
Daily or more frequent if PTT ACT variesDaily or more frequent if PTT ACT varies
Mechanism Mechanism ndash measures intrinsic pathwayndash measures intrinsic pathway Therapeutic goal Therapeutic goal 2-25 times normal control value 2-25 times normal control value
ACT or aPTTACT or aPTT
Determine when to pull the femoral sheath Determine when to pull the femoral sheath Premature sheath pull can lead to bleedingPremature sheath pull can lead to bleeding Delayed removal can increase time in ICUDelayed removal can increase time in ICU Target set Target set at each siteat each site
ACT targets range from 150 ndash 220 ACT targets range from 150 ndash 220 secondsseconds
aPTT targets range from 40 ndash 70 seconds aPTT targets range from 40 ndash 70 seconds
During neuroangiography-During neuroangiography- Recommended therapeutic range of heparin in Recommended therapeutic range of heparin in
plasma is 02-08 uml ( corresponding to aPTT plasma is 02-08 uml ( corresponding to aPTT ACT values 15-25 times the baseline values)ACT values 15-25 times the baseline values)
Dose In diagnostic angiography bolus dose of Dose In diagnostic angiography bolus dose of 2500 iu is used followed by 1000 iu hour2500 iu is used followed by 1000 iu hour
Bolus dose is Bolus dose is 60 ukg to maintain the therapeutic 60 ukg to maintain the therapeutic range range If procedure continues for more than 75 If procedure continues for more than 75 minutes additional dose is required ( half of the minutes additional dose is required ( half of the initial dose for another 75 minutes) initial dose for another 75 minutes)
(AJNR 199415 51-54)
Mechanisms of HIT( Mechanisms of HIT( Heparin Heparin induced Thrombocytopeniainduced Thrombocytopenia))
Type 1Type 1 Fall in platelet count occurs within the first two Fall in platelet count occurs within the first two
days after heparin initiation often returns to days after heparin initiation often returns to normal with continued heparin administration normal with continued heparin administration and is of no clinical consequence and is of no clinical consequence
The mechanism of the thrombocytopenia is non-The mechanism of the thrombocytopenia is non-immune and appears to be due to a direct effect of immune and appears to be due to a direct effect of heparin on platelet activationheparin on platelet activation
Type 2Type 2 Approximately 03 to 3 percent of patients Approximately 03 to 3 percent of patients
receiving heparin develop an immune receiving heparin develop an immune thrombocytopenia mediated by antibodies to a thrombocytopenia mediated by antibodies to a heparin-platelet factor 4 complex heparin-platelet factor 4 complex
(AJNR 28155-158 2007)
Treatment of heparin-induced Treatment of heparin-induced thrombocytopeniathrombocytopenia
When HIT is diagnosed it is important to When HIT is diagnosed it is important to stop heparin mainly in type 2 and to avoid stop heparin mainly in type 2 and to avoid the use of LMWH the use of LMWH
Because of the increased risk of thrombosis Because of the increased risk of thrombosis however continuation of an anticoagulant however continuation of an anticoagulant must be considered must be considered
The drugs currently approved for the The drugs currently approved for the treatment of HIT in the United States are treatment of HIT in the United States are direct thrombin inhibitors argatroban and direct thrombin inhibitors argatroban and lepirudinlepirudin
WARFARIN MECHANISM OF ACTIONWARFARIN MECHANISM OF ACTION
Inactive factors II VII IX and X
Proteins S and C
Active factors II VII IX and X
Proteins S and C
Vitamin K epoxide
Vitamin K reduced
WA
RF
AR
IN
Prevents the reduction of vitamin K which is essential for Prevents the reduction of vitamin K which is essential for activation of certain factorsactivation of certain factors
Has no effect on previously formed thrombusHas no effect on previously formed thrombus
Antagonist is Vit KAntagonist is Vit K
OPTIMIZING WARFARIN THERAPYOPTIMIZING WARFARIN THERAPY
Use of large loading dose may lead to hemorrhage and Use of large loading dose may lead to hemorrhage and other complicationsother complications
Initial dose 2-5 mg once dailyInitial dose 2-5 mg once daily Maintenance dose 2-10 mg once dailyMaintenance dose 2-10 mg once daily If Immediate anticoagulation is requiredIf Immediate anticoagulation is required Heparin IS Heparin IS
started along with loading dose of warfarin 10 mg started along with loading dose of warfarin 10 mg Heparin is usually discontinued after 4-5 days Heparin is usually discontinued after 4-5 days Before Before discontinuing INR should be in therapeutic range for 2 discontinuing INR should be in therapeutic range for 2 consecutive daysconsecutive days
Daily monitoring of INR until INR is in therapeutic Daily monitoring of INR until INR is in therapeutic range then 3 times weekly for 1-2 weeks then less often range then 3 times weekly for 1-2 weeks then less often (every 4 to 6 weeks)(every 4 to 6 weeks)
OPTIMAL THERAPEUTIC RANGEOPTIMAL THERAPEUTIC RANGE
IndicationIndication INRINR
Prophylaxis of venous Prophylaxis of venous thromboembolismthromboembolism
20-3020-30
Treatment of venous Treatment of venous thromboembolismthromboembolism
20-3020-30
Atrial fibrillationAtrial fibrillation 20-3020-30
Mitral valve stenosisMitral valve stenosis 20-3020-30
Heart valve replacementHeart valve replacement
Bioprosthetic valveBioprosthetic valve
Mechanical valveMechanical valve
20-3020-30
25-3525-35
Myocardial infarctionMyocardial infarction 20-3020-30
25-35 25-35 (high risk patients)(high risk patients)
FACTORS INFLUENCING DOSE RESPONSEFACTORS INFLUENCING DOSE RESPONSE
Poor patient compliancePoor patient compliance Concomitant medicationsConcomitant medications Levels of dietary vitamin KLevels of dietary vitamin K Alcohol Inaccurate lab testingAlcohol Inaccurate lab testing Inaccurate lab testingInaccurate lab testing Hepatic dysfunctionHepatic dysfunction FeverFever
Contraindication for WarfarinContraindication for Warfarin
Hypersensitivity to warfarinHypersensitivity to warfarin Hemorrhagic tendencyHemorrhagic tendency Condition with risk of hemorrhageCondition with risk of hemorrhage Inadequate laboratory techniquesInadequate laboratory techniques Protein C amp S deficiencyProtein C amp S deficiency Vitamin K deficiencyVitamin K deficiency
SIDE EFFECTSSIDE EFFECTS
Hemorrhage Hemorrhage Skin necrosisSkin necrosis Purple toe syndromePurple toe syndrome Microembolization Microembolization TeratogenecityTeratogenecity Agranulocytosis leukopenia Agranulocytosis leukopenia Diarrhoeanausea anorexiaDiarrhoeanausea anorexia
MONITORING OF WARFARIN THERAPYMONITORING OF WARFARIN THERAPY
Prothrombin timeProthrombin time PT ratioPT ratio INR (International Normalized Ratio)INR (International Normalized Ratio)
PROTHROMBIN TIME (PT)PROTHROMBIN TIME (PT)
Time required for blood to coagulate Time required for blood to coagulate is called PT ( normal value ~10sec)is called PT ( normal value ~10sec)
Performed by adding a mixture of Performed by adding a mixture of calcium and thromboplastin to calcium and thromboplastin to citrated plasmacitrated plasma
As a control a normal blood sample is As a control a normal blood sample is tested continuouslytested continuously
PT ratio (PTR) = PT ratio (PTR) = Patientrsquos PTPatientrsquos PT Control PTControl PT
PROBLEMS WITH PTPTRPROBLEMS WITH PTPTR
Thromboplastins are extracts from Thromboplastins are extracts from brain lung or placenta of animalsbrain lung or placenta of animals
Thromboplastins from various Thromboplastins from various manufacturers differ in their manufacturers differ in their sensitivity to prolong PTsensitivity to prolong PT
May result in false control of May result in false control of anticoagulant therapyanticoagulant therapy
INTERNATIONAL NORMALISED RATIO (INR)INTERNATIONAL NORMALISED RATIO (INR)
International Normalized Ratio (INR) International Normalized Ratio (INR) a PT test with a a PT test with a formula based ratio to normalize the often variable source formula based ratio to normalize the often variable source of tissue factor (human rabbit recombinant)of tissue factor (human rabbit recombinant)
INR = [PTINR = [PTptpt] ] ISIISI
[PT[PTRefRef]]
PTPTpt pt ndash prothrombin time of patientndash prothrombin time of patient
PTPTRef Ref ndash prothrombin time of normal pooled samplendash prothrombin time of normal pooled sample
ISI ndash International Sensitivity IndexISI ndash International Sensitivity Index
Warfarin is given orally and titrated to achieve an INR of Warfarin is given orally and titrated to achieve an INR of typically 20 ndash 30typically 20 ndash 30
Heparin versus WarfarinHeparin versus Warfarin
Drug ActionMechan-ism
Moni-toring
Effective
HeparinDirect
Inhibition ofThrombin
ATIIIcofactor
APTTACT
Immediate
WarfarinDecreasesProductionof factors
Vitamin K PTDelay
3-5 days
INR
Recanalization or Antegrade Recanalization or Antegrade Reperfusion StrategiesReperfusion Strategies
Recanalization strategies focus on removing Recanalization strategies focus on removing andor dissolving the occlusive thrombus to re-andor dissolving the occlusive thrombus to re-establish antegrade flow Strategies may be establish antegrade flow Strategies may be classified into 7 different categories on the classified into 7 different categories on the basis of their primary mechanism of action basis of their primary mechanism of action 1) 1) IV andor intraarterial thrombolysis (IAT) IV andor intraarterial thrombolysis (IAT) 2) endovascular thrombectomy2) endovascular thrombectomy3) endovascular thromboaspiration 3) endovascular thromboaspiration 4) endovascular mechanical thrombus disruption or 4) endovascular mechanical thrombus disruption or
thromborrhexisthromborrhexis5) 5) transcranial or endovascular augmented transcranial or endovascular augmented
fibrinolysis fibrinolysis 6) endovascular thrombus entrapment and 6) endovascular thrombus entrapment and 7) temporary endovascular bypass7) temporary endovascular bypass
IAT in Acute Ischemic StrokeIAT in Acute Ischemic Stroke
IAT advantages over IV thrombolysisIAT advantages over IV thrombolysis Coaxial microcatheter techniques the occluded intracranial Coaxial microcatheter techniques the occluded intracranial
vessel is directly accessible and the fibrinolytic agent can be vessel is directly accessible and the fibrinolytic agent can be infused directly into the thrombusinfused directly into the thrombus
This permits a smaller dose of fibrinolytic agent to reach a This permits a smaller dose of fibrinolytic agent to reach a higher local concentration than that reached by systemic higher local concentration than that reached by systemic infusioninfusion
Allows more complete recanalization with lower total doses of Allows more complete recanalization with lower total doses of thrombolytic thrombolytic
With the smaller dose complications from systemic fibrinolytic With the smaller dose complications from systemic fibrinolytic effects including intracranial hemorrhage (ICH) can effects including intracranial hemorrhage (ICH) can theoretically be reduced theoretically be reduced
Treatment window for endovascular techniques can be Treatment window for endovascular techniques can be extended beyond the typical IV window of 3 hours extended beyond the typical IV window of 3 hours
IA techniques have led to higher recanalization rates than IV IA techniques have led to higher recanalization rates than IV thrombolysisthrombolysis
Major disadvantagesMajor disadvantages Relative complexity of the procedure the level Relative complexity of the procedure the level
of required technical expertise and its of required technical expertise and its relatively low availability relatively low availability
Delays in initiating treatmentDelays in initiating treatment InvasiveInvasive
ThrombolyticsThrombolytics
Plasminogen activators
Fibrinolytics
1 Plasminogen Activators 1 Plasminogen Activators drugs act by converting the inactive proenzyme drugs act by converting the inactive proenzyme plasminogen into the active enzyme plasmin Plasmin plasminogen into the active enzyme plasmin Plasmin digests fibrinogen fibrin monomers and cross-linked digests fibrinogen fibrin monomers and cross-linked fibrin (as found in a thrombus) into fibrin degradation fibrin (as found in a thrombus) into fibrin degradation productsproducts
First-Generation Agents First-Generation Agents StreptokinaseStreptokinase a protein derived from group C a protein derived from group C
szlig-hemolytic streptococci has a half-life of 16ndashszlig-hemolytic streptococci has a half-life of 16ndash90 minutes and low fibrin specificity This drug 90 minutes and low fibrin specificity This drug proved to have a very narrow therapeutic proved to have a very narrow therapeutic window and significant rates of ICH and window and significant rates of ICH and systemic hemorrhage18systemic hemorrhage18
UrokinaseUrokinase is a serine protease with a plasma is a serine protease with a plasma half life of 14 minutes and low fibrin specificity half life of 14 minutes and low fibrin specificity
The urokinase dose used in cerebral IAT has The urokinase dose used in cerebral IAT has ranged from 002 to 2 X106unitsranged from 002 to 2 X106units
Second-Generation Agents Second-Generation Agents Alteplase (rtPA) Alteplase (rtPA)
is a serine is a serine protease with a plasma half-life of 35 protease with a plasma half-life of 35 minutes and a high degree of fibrin affinity and minutes and a high degree of fibrin affinity and specificity specificity
Dose used in cerebral IAT has ranged between 20 Dose used in cerebral IAT has ranged between 20 and 60 mgand 60 mg
Disadvantages of alteplase include its relatively short Disadvantages of alteplase include its relatively short halflife and limited penetration into the clot matrix halflife and limited penetration into the clot matrix because of strong binding with surface fibrin which because of strong binding with surface fibrin which could delay recanalization and increase the risk of could delay recanalization and increase the risk of recurrent occlusion recurrent occlusion
Prourokinase (r-prourokinase) Prourokinase (r-prourokinase) is the proenzyme precursor of urokinase is the proenzyme precursor of urokinase T12 of 7 minutes and high fibrin specificity T12 of 7 minutes and high fibrin specificity
Third-Generation AgentsThird-Generation Agents
ReteplaseReteplase is a structurally modified is a structurally modified form of alteplase form of alteplase
with a longer half-life (15ndash18 minutes) In with a longer half-life (15ndash18 minutes) In addition it does not bind as highly to fibrin addition it does not bind as highly to fibrin unbound reteplase can thus theoretically better unbound reteplase can thus theoretically better penetrate the clot and potentially penetrate the clot and potentially improve in improve in vivo fibrinolytic activity vivo fibrinolytic activity
TenecteplaseTenecteplase is another modified form of rtPA with a longer is another modified form of rtPA with a longer
half-life (17 minutes)half-life (17 minutes) greater fibrin specificity and greater greater fibrin specificity and greater
resistance to plasminogen activator inhibitor-1 resistance to plasminogen activator inhibitor-1 IV tenecteplase in acute ischemic stroke IV tenecteplase in acute ischemic stroke
suggest that the drug is safe and promisingsuggest that the drug is safe and promising
Newer plasminogen activatorNewer plasminogen activator
DesmoteplaseDesmoteplase is a genetically engineered is a genetically engineered version of the clot-dissolving factor version of the clot-dissolving factor
found in the saliva found in the saliva of the vampire bat Desmodus rotundusof the vampire bat Desmodus rotundus moremore potent and more selective for fibrin-bound potent and more selective for fibrin-bound
plasminogen than any other known plasminogen plasminogen than any other known plasminogen activatoractivator
Unlike tissue plasminogen activator (tPA) desmoteplase Unlike tissue plasminogen activator (tPA) desmoteplase is not activated by fibrinogen or -amyloid proteins is not activated by fibrinogen or -amyloid proteins factors that may exacerbate the risk for ICH factors that may exacerbate the risk for ICH
The effect of IV administration of desmoteplase 3ndash9 The effect of IV administration of desmoteplase 3ndash9 hours after symptom onset in patients with stroke who hours after symptom onset in patients with stroke who present with mismatch on MR imaging or CT perfusion present with mismatch on MR imaging or CT perfusion
3 DefibrinogenatingFibrinogenolytic 3 DefibrinogenatingFibrinogenolytic Agents Agents
AncrodAncrod(Viprinex)(Viprinex) is is the purified fraction of the Malayan pit viper venomthe purified fraction of the Malayan pit viper venom It acts by directly cleaving and inactivating fibrinogen It acts by directly cleaving and inactivating fibrinogen
and thus indirectly promoting anticoagulation and thus indirectly promoting anticoagulation The reduction in the blood levels of fibrinogen also The reduction in the blood levels of fibrinogen also
leads to a reduced blood viscosity which may improve leads to a reduced blood viscosity which may improve blood flow to the affected areas of the brain blood flow to the affected areas of the brain
In the Stroke Treatment with Ancrod Trial 500 In the Stroke Treatment with Ancrod Trial 500 patients with stroke presenting within 3 hours of patients with stroke presenting within 3 hours of symptom onset were randomized to receive ancrod (symptom onset were randomized to receive ancrod (n n 248) or a placebo (n 252) Good outcome (Barthel 248) or a placebo (n 252) Good outcome (Barthel Index 95ndash100 at 3 months) was achieved in 4221 Index 95ndash100 at 3 months) was achieved in 4221 and 344 of the patients respectively and 344 of the patients respectively
2 Direct Fibrinolytics2 Direct Fibrinolytics
Microplasmin (Microplasmin (ThromboGenics Heverlee Belgium)ThromboGenics Heverlee Belgium) is a truncated form of plasmin that is more resistant to the effects is a truncated form of plasmin that is more resistant to the effects
of antiplasmin of antiplasmin microplasmin can be used upto 4ndash12 hours after stroke onset microplasmin can be used upto 4ndash12 hours after stroke onset There was no evidence of increased bleeding risk with There was no evidence of increased bleeding risk with
microplasminmicroplasmin
Alfimeprase (Nuvelo San Carlos Calif)Alfimeprase (Nuvelo San Carlos Calif) is a recombinant truncated form of fibrolase a fibrinolytic zinc metalloproteinase is a recombinant truncated form of fibrolase a fibrinolytic zinc metalloproteinase
isolated from the venom of the southern copperhead snake isolated from the venom of the southern copperhead snake It degrades fibrin directly and achieves thrombolysis independent It degrades fibrin directly and achieves thrombolysis independent
of plasmin formationof plasmin formation its thrombolytic activity appears to be localized to the site of its thrombolytic activity appears to be localized to the site of
delivery These properties should theoretically result in faster delivery These properties should theoretically result in faster recanalization and lower hemorrhagic conversion riskrecanalization and lower hemorrhagic conversion risk
Anti-fibrinolyticsAnti-fibrinolytics
to limit fibrinolytic activityto limit fibrinolytic activity -aminocaproic acid (EACA) -aminocaproic acid (EACA) competitively inhibitscompetitively inhibits plasminogen and plasminogen activators from plasminogen and plasminogen activators from
binding to fibrinbinding to fibrin
alpha2-antiplasminalpha2-antiplasmin a serine protease inhibitor that a serine protease inhibitor that neutralizes any free circulating plasminneutralizes any free circulating plasmin
Plasminogen activator inhibitor-1Plasminogen activator inhibitor-1 a serine protease a serine protease inhibitor that inhibits tissue-type plasminogen inhibitor that inhibits tissue-type plasminogen activatoractivator
Glycoprotein (GP) IIbIIIa antagonistsGlycoprotein (GP) IIbIIIa antagonists
such as ReoPro (abciximab) Integrilin such as ReoPro (abciximab) Integrilin (eptifibatide) or Aggrastat (tirofiban) in (eptifibatide) or Aggrastat (tirofiban) in ischemic stroke remains investigational ischemic stroke remains investigational Deshmukh et al38 reported 21 patients with Deshmukh et al38 reported 21 patients with large-vessel occlusion refractory to IAT with large-vessel occlusion refractory to IAT with rtPA who were treated with IV andor IA rtPA who were treated with IV andor IA abciximab eptifibatide or tirofiban abciximab eptifibatide or tirofiban
IA Mechanical Approaches in Acute Ischemic Stroke IA Mechanical Approaches in Acute Ischemic Stroke Mechanical strategies have several advantagesMechanical strategies have several advantages First they lessen and may even preclude the use of chemical First they lessen and may even preclude the use of chemical
thrombolytics in this manner very likely reducing the risk of ICHthrombolytics in this manner very likely reducing the risk of ICH Second by avoiding the use of chemical thrombolytics it is Second by avoiding the use of chemical thrombolytics it is
possible to extend the treatment window beyond the limit of 6ndash8 possible to extend the treatment window beyond the limit of 6ndash8 hours hours
Third mechanically fragmenting a clot increases the surface area Third mechanically fragmenting a clot increases the surface area accessible to fibrinolytic agents and allows inflow of fresh accessible to fibrinolytic agents and allows inflow of fresh plasminogen which in turn may increase the speed of plasminogen which in turn may increase the speed of thrombolysis thrombolysis
Finally clot-retrieval devices may provide faster recanalization Finally clot-retrieval devices may provide faster recanalization
The disadvantages of the mechanical The disadvantages of the mechanical approaches approaches technical difficulty of navigating mechanical technical difficulty of navigating mechanical
devices into the intracranial circulation excessive devices into the intracranial circulation excessive trauma to the vasculature (potentially leading to trauma to the vasculature (potentially leading to vasospasm vessel dissection perforation or vasospasm vessel dissection perforation or rupture) rupture)
fragmented thrombus causing distal embolization fragmented thrombus causing distal embolization into previously unaffected territories into previously unaffected territories
Nevertheless the advantages of mechanical stroke Nevertheless the advantages of mechanical stroke therapy appear to significantly outweigh its therapy appear to significantly outweigh its disadvantages and risksdisadvantages and risks
Contraindications to Thrombolytic Contraindications to Thrombolytic agents agents
Recent thoracic abdominal or Recent thoracic abdominal or intracranial surgeryintracranial surgery
Recent haemorrhagic CVA Head injury Recent haemorrhagic CVA Head injury or neoplasmor neoplasm
Bleeding ulcerBleeding ulcer Anticipated invasive procedures (arterial Anticipated invasive procedures (arterial
punctures biopsies)punctures biopsies) Concurrent hemostatic dysfunctionConcurrent hemostatic dysfunction
Monitoring of thrombolytic Monitoring of thrombolytic therapytherapy
Thrombin time Measures the availability of functional
fibrinogen Normal thrombin time is 10-14 sec Prolonged when fibrinogen level is below
75-100 mgdl
Half Life of ThrombolyticsHalf Life of ThrombolyticsAgent Administration Half Life
Streptokinase IA 60-80min
Urokinase IAIV 9-12min
rTPA IAIV 6min
Abciximab(Reopro) IAIV 12hour
Aspirin POIV 15-20min
Heparin IVSC 60min
Coumadin PO 15-25 days
Anti Platelet DrugsAnti Platelet DrugsDrug Drug Mechanism Mechanism UsesUsesAspirinAspirin Permanently inhibits Permanently inhibits
COX-1 and COX-2COX-1 and COX-2CADCAD
Stroke-TIAsStroke-TIAs
NSAIDsNSAIDs Reversibly inhibits Reversibly inhibits COX-1COX-1
LimitedLimited
DipyridamoleDipyridamole Inhibits PDE increases Inhibits PDE increases cAMPcAMP
TIAsTIAs
ThenopyridinesThenopyridines
(Ticlopidine(Ticlopidine
ClopidrgrelClopidrgrel))
Inhibits ADP Inhibits ADP
PlatAg PlatAg
TIAsStrokeTIAsStroke
CAD PVDCAD PVD
Abciximab (ReoPro)Abciximab (ReoPro)
Eptifibatide (Integrilin)Eptifibatide (Integrilin)
TirofibanTirofiban
GP IIBIIIA InhibitorsGP IIBIIIA Inhibitors
Stroke- TIAs Stroke- TIAs
MonitoringMonitoring
Bleeding timeBleeding time
Optical aggregometryOptical aggregometry
Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay
Bleeding timeBleeding time
Requires a skin incision (usually made on the ear lobe or Requires a skin incision (usually made on the ear lobe or forearm offorearm of
a depth that results in disruption of capillary loops and a depth that results in disruption of capillary loops and small vessels)small vessels)
AdvantagesAdvantages Universally availableUniversally available Relatively simple techniquesRelatively simple techniques Can be performed bedsideCan be performed bedside
DisadvantagesDisadvantages Insensitive inaccurate non-specific techniqueInsensitive inaccurate non-specific technique
Poorly reproducible (as depends on multiple variables)Poorly reproducible (as depends on multiple variables)
Optical aggregometryOptical aggregometry
Gold standard assay for platelet functionGold standard assay for platelet function Agonist induced aggregation is measuredAgonist induced aggregation is measured Different agonist are available for different Different agonist are available for different
agentsagents However require unique expertise and are not However require unique expertise and are not
universally availableuniversally available Aspirin measured with ADP or AA(gt70 Aspirin measured with ADP or AA(gt70
aggregation so resistance)aggregation so resistance) Clopidogrel( ADP gt 90 aggregation means Clopidogrel( ADP gt 90 aggregation means
resistance) resistance)
Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay
Can be performed bed sideCan be performed bed side Different assay devices with different Different assay devices with different
agonist are used for each of different agonist are used for each of different antiplatelet agents antiplatelet agents
For Aspirin AA is used (result is reported as aspirin For Aspirin AA is used (result is reported as aspirin reaction units [ARU] ARUgt 550 indicates non-reaction units [ARU] ARUgt 550 indicates non-responsiveness)responsiveness)
Verify IIbIIIa assay device uses TRAP as agonist for Verify IIbIIIa assay device uses TRAP as agonist for Abciximab and TirofibanAbciximab and Tirofiban
Practical Applications Practical Applications related to specific related to specific
Neurovascular Neurovascular interventionsinterventions
Acute ischemic StrokeAcute ischemic Stroke When an artery occludes neurons are affected When an artery occludes neurons are affected
differently depending upon the amount of residual blood differently depending upon the amount of residual blood flowflow
Normal cerebral blood flow is greater than 50 mL100 Normal cerebral blood flow is greater than 50 mL100 mgminmgmin
Once blood flow decreases to less than 20 mL100 Once blood flow decreases to less than 20 mL100 mgmin infarction occursmgmin infarction occurs
If blood flow decreases to less than 10 mL100 mgmin If blood flow decreases to less than 10 mL100 mgmin irreversible neuronal death occurs rapidly irreversible neuronal death occurs rapidly
Blood flow between 11 and 20 mL100 mgmin is thought Blood flow between 11 and 20 mL100 mgmin is thought to represent the ischemic penumbra an area where the to represent the ischemic penumbra an area where the cells are functionally silent because of ischemia but are cells are functionally silent because of ischemia but are still able to recover if blood flow is restored still able to recover if blood flow is restored
Many acute stroke therapies are targeted toward Many acute stroke therapies are targeted toward restoring flow or function to the ischemic penumbrarestoring flow or function to the ischemic penumbra
Therapeutic window in Therapeutic window in management of acute Ischemic management of acute Ischemic
StrokeStrokeThe early diagnosis of ischemic stroke is critical to the The early diagnosis of ischemic stroke is critical to the
with only a narrow therapeutic window in the first few with only a narrow therapeutic window in the first few hours following stroke ictushours following stroke ictus
Diagnosis in the first 3 hours postictus provides the Diagnosis in the first 3 hours postictus provides the opportunity for intravenous or intraarterial thrombolysis opportunity for intravenous or intraarterial thrombolysis and intra-arterial clot mechanical treatment which and intra-arterial clot mechanical treatment which improve the outcome improve the outcome
Diagnosis in the time period between 3 and 6 hours Diagnosis in the time period between 3 and 6 hours provides an opportunity for intra-arterial thrombolysis provides an opportunity for intra-arterial thrombolysis and mechanical treatment and mechanical treatment
Involvement of the posterior circulation especially the Involvement of the posterior circulation especially the basilar artery is treated by some regardless of time of basilar artery is treated by some regardless of time of onset or up until 12 to 24 hours in some practices This is onset or up until 12 to 24 hours in some practices This is related to the potentially high mortality and morbidity related to the potentially high mortality and morbidity associated with basilar artery thrombosisassociated with basilar artery thrombosis
Infarct evaluation on angiographyInfarct evaluation on angiography(CT angiography and catheter (CT angiography and catheter
angiography)angiography)CTA is an excellent first-line examination for CTA is an excellent first-line examination for
evaluation of the head and neck arteries evaluation of the head and neck arteries In comparison with catheter angiography In comparison with catheter angiography
what it gives up in resolution and dynamic what it gives up in resolution and dynamic properties it makes up for with rapid properties it makes up for with rapid acquisition of a 3-D dataset and the potential acquisition of a 3-D dataset and the potential for assessment of whole-brain perfusion and for assessment of whole-brain perfusion and better parenchymal evaluationbetter parenchymal evaluation
Moreover CTA illustrates not only arterial Moreover CTA illustrates not only arterial stenosis or occlusion but also the vessel wall stenosis or occlusion but also the vessel wall This factor is most important for evaluation of This factor is most important for evaluation of intramural dissection and thrombosed intramural dissection and thrombosed aneurysms which may both complicate aneurysms which may both complicate evaluation of stroke patientsevaluation of stroke patients
Early angiographic signs of strokes Early angiographic signs of strokes both CTA both CTA and DSA and DSA
Vessel occlusion or cutoff related to Vessel occlusion or cutoff related to thromboembolithromboemboli
aneurysms aneurysms arterial dissection arterial dissection Meniscus or flattened shape to clot Meniscus or flattened shape to clot
(recent) versus reverse meniscus (older)(recent) versus reverse meniscus (older) tram track (nonocclusive or recanalized tram track (nonocclusive or recanalized
clot) clot) delayed (antegrade) flow (manifest as delayed (antegrade) flow (manifest as
decreased whole-brain perfusion on CTA)decreased whole-brain perfusion on CTA) retrograde collateral flowretrograde collateral flow
Non-occlusive left MCA thrombus on 3-D imaging performed from CTA source data and was confirmed at catheter angiography
Therapy to be started within a 6-hr Therapy to be started within a 6-hr time to treatment (TTT) window time to treatment (TTT) window (while in case of IV thrombolysis (while in case of IV thrombolysis therapy to be started with in 3hrs)therapy to be started with in 3hrs)
Exclusion criteria Exclusion criteria Rapidly improving neurologic deficit or Rapidly improving neurologic deficit or Sustained blood pressure of gt180100 Sustained blood pressure of gt180100 Hemorrhage is detected on CTHemorrhage is detected on CT Infarct involving gt more than 13 rd Infarct involving gt more than 13 rd
territory of MCAterritory of MCA MRADWI-Perfusion mismatchlt 20MRADWI-Perfusion mismatchlt 20 Definite hypodensity on CTDefinite hypodensity on CT
Intra-arterial Thrombolysis
Fibrinolytics + AntiplateletsFibrinolytics + Antiplatelets
PlasminogenPlasminogen activators through fibrinolysis exposes activators through fibrinolysis exposes free thrombin and paradoxically stimulatesfree thrombin and paradoxically stimulates platelet platelet aggregation which leads to formation of aaggregation which leads to formation of a platelet platelet thrombus (white clot) thrombus (white clot)
This new thrombus is relatively resistant to This new thrombus is relatively resistant to fibrinolyticsfibrinolytics
So new regimen in case of acute stroke isSo new regimen in case of acute stroke is fibrinolytics + antiplatelet drugsfibrinolytics + antiplatelet drugs
rtPA + IIbIIIa inhibitors( tirofiban rtPA + IIbIIIa inhibitors( tirofiban abciximab) orabciximab) or
Urokinase + IIbIIIa Urokinase + IIbIIIa inhibitors( tirofiban abciximab)inhibitors( tirofiban abciximab)
Intra-arterial Thrombolysis Tirofiban (04 microgkgmin bolus for 3 min followed by Tirofiban (04 microgkgmin bolus for 3 min followed by
0125 ugkgmin)0125 ugkgmin)
++
Heparin (2000ndash3000 IU bolus followed by Heparin (2000ndash3000 IU bolus followed by 1000 IUhour infusion 1000 IUhour infusion
with ACT maintained bw 200-300) throughout the with ACT maintained bw 200-300) throughout the interventional procedure and for 24ndash48 hours thereafter when interventional procedure and for 24ndash48 hours thereafter when there is neither intraprocedural bleeding nor suspicion of there is neither intraprocedural bleeding nor suspicion of increased risk of bleeding increased risk of bleeding
Maximum dose of Urokinase Maximum dose of Urokinase Anterior circulation stroke - 500000 IU (mean 400000 Anterior circulation stroke - 500000 IU (mean 400000
IU range 300000ndash500000 IU)IU range 300000ndash500000 IU) Posterior circulation stroke -1000000 IU (mean 837000 Posterior circulation stroke -1000000 IU (mean 837000
IU range 300000ndash1000000 IU)IU range 300000ndash1000000 IU)American Journal of NeuroradiologyAmerican Journal of Neuroradiology 262595-2601 2005262595-2601 2005
Intravenous ThrombolysisIntravenous Thrombolysis
The first method to restore cerebral The first method to restore cerebral perfusion is clot lysis with the goal perfusion is clot lysis with the goal of re-establishing blood flow to the of re-establishing blood flow to the affected tissue affected tissue
IV thrombolysis rt-PA is the only IV thrombolysis rt-PA is the only FDA- approved treatment for AIS FDA- approved treatment for AIS
Fibrinolysis is enhanced powerfully Fibrinolysis is enhanced powerfully by rt-PAby rt-PA
Intravenous rTPA Intravenous rTPA administration administration protocolprotocol
Total dose of rt-PA 09 mgkg (maximum dose Total dose of rt-PA 09 mgkg (maximum dose 90 mg)90 mg)
Give 10 as initial IV bolusGive 10 as initial IV bolus Infuse remainder over 1 hourInfuse remainder over 1 hour Admit patient to an ICU or stroke unit for Admit patient to an ICU or stroke unit for
monitoringmonitoring Neurologic assessments every 15 minutes Neurologic assessments every 15 minutes
during infusion then every 30 minutes for next during infusion then every 30 minutes for next 6 hours then every hour until 24hours after 6 hours then every hour until 24hours after treatmenttreatment
Favorable Outcome vs Treatment Time Favorable Outcome vs Treatment Time with IV rTPAwith IV rTPA
Protocol limit = 3 hrs
Benefit ~ 45 hrs
Thromboembolism During coilingThromboembolism During coiling Most feared and frequent complication Most feared and frequent complication Reported incidence - Approx 7 Reported incidence - Approx 7 SourcesSources of Thromboembolism are of Thromboembolism are
- Clots at the aneurysmal neck during or immediately- Clots at the aneurysmal neck during or immediately after after embolization embolization
- Thrombus forming on catheters during- Thrombus forming on catheters during proceduresprocedures
- Stenosis of an adjacent artery dt coil mass- Stenosis of an adjacent artery dt coil mass or herniationor herniation
- Migration of intraaneurysmal- Migration of intraaneurysmal thrombus during coil thrombus during coil placement placement
- Slow flow dt vasospasm - Slow flow dt vasospasm
- Rare and unlikely causes are hypercoagulable- Rare and unlikely causes are hypercoagulable state such state such as antiphospholipid antibody syndrome or due to HITas antiphospholipid antibody syndrome or due to HIT
Occur more often with wide-necked aneurysms (dt Occur more often with wide-necked aneurysms (dt increased exposed surface area of thrombogenic coil increased exposed surface area of thrombogenic coil material)material)
Current regimen of endovascular Current regimen of endovascular managementmanagement
The The glycoprotein IIbIIIa antagonist tirofiban glycoprotein IIbIIIa antagonist tirofiban (04 (04 microgkgmin bolus for 30 minutes followed by infusion of microgkgmin bolus for 30 minutes followed by infusion of 0125 ugkgmin until the thrombus dissolved) 0125 ugkgmin until the thrombus dissolved)
Intraarterial thrombolysis with Intraarterial thrombolysis with urokinase or r- TPA urokinase or r- TPA increase of intravenous (IV) heparin (measured by increase of intravenous (IV) heparin (measured by
ACT) ACT) Intravenous aspirin Intravenous aspirin
Coil-related platelet aggregation (white clot) is Coil-related platelet aggregation (white clot) is unlikely to respond to fibrinolytics but has a high risk unlikely to respond to fibrinolytics but has a high risk of hemorrhage (In ISAT) all 5 patients who had of hemorrhage (In ISAT) all 5 patients who had received thrombolytic therapy with tPA to treat a received thrombolytic therapy with tPA to treat a thromboembolic complication after endovascular thromboembolic complication after endovascular treatment rebleed and all of these patients died)treatment rebleed and all of these patients died)
IntracranialIntracranial Stenting Stenting Metallic foreign body such as stent will accumulate Metallic foreign body such as stent will accumulate
thrombus in the absence of platelet inhibitionthrombus in the absence of platelet inhibition Antiplatelet drugs are important to prevent peri or Antiplatelet drugs are important to prevent peri or
post-interventional thromboembolic eventspost-interventional thromboembolic events Optimal treatment regimens has not been determined Optimal treatment regimens has not been determined
but usually but usually Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-
procedureprocedureOrOr
Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on
morning of proceduremorning of procedure
If need to use stent is not pre-planned thanIf need to use stent is not pre-planned than
Abciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkgAbciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkg IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)
Glycoprotein IIbIIIa inhibitor are not used routinely during elective Glycoprotein IIbIIIa inhibitor are not used routinely during elective stenting procedure dt increased risk of ICH stenting procedure dt increased risk of ICH
Carotid StentingCarotid Stenting
Pre-procedurePre-procedure
Double Antiplatelet therapy is routinely given Double Antiplatelet therapy is routinely given beginning at least 3beginning at least 3
days before the proceduredays before the procedure
Aspirin 325mgd+Clopidogrel 75mgdAspirin 325mgd+Clopidogrel 75mgd During procedureDuring procedure
Heparin is given with target clotting time of 250-Heparin is given with target clotting time of 250-300sec300sec
Post-procedure Post-procedure
Aspirin 325mg is continued indefinitely and Aspirin 325mg is continued indefinitely and
Clopidogrel 75mgd for at least 6 weeks Clopidogrel 75mgd for at least 6 weeks
Inclusion criteria for Local ThrombolysisInclusion criteria for Local Thrombolysis a)a) Patients in severe clinical grade on admission Patients in severe clinical grade on admission
with evidence of dural venous sinus with evidence of dural venous sinus thrombosis and restrictive venous outflow on thrombosis and restrictive venous outflow on cerebral angiogramcerebral angiogram
b)b) Patients in clinical grade 3 worsening on Patients in clinical grade 3 worsening on heparin therapy Restriction to venous heparin therapy Restriction to venous outflow was defined as an increase in brain outflow was defined as an increase in brain circulation time gt 12 s delay in the drainage circulation time gt 12 s delay in the drainage of cortical veins with cortical veins hanging of cortical veins with cortical veins hanging in spacein space
Treatment Options for Venous Thrombosis
CT Grading for Venous ThrombosisCT Grading for Venous Thrombosis Grade I no parenchymal change Grade I no parenchymal change
(hyperdense (hyperdense sinuses cortical veins empty sinuses cortical veins empty delta sign)delta sign)
Grade II non hemorrhagic venous infarct Grade II non hemorrhagic venous infarct without mass effect without mass effect
Grade III non-hemorrhagic infarct with Grade III non-hemorrhagic infarct with mass effectmass effect
Grade IV hemorrhagic venous infarct (max Grade IV hemorrhagic venous infarct (max diameter lt 3 cm) with no mass effectdiameter lt 3 cm) with no mass effect
Grade V hemorrhagic venous infarct (max Grade V hemorrhagic venous infarct (max diameter gt 3 cm) with mass effect diameter gt 3 cm) with mass effect
Local ThrombolysisLocal Thrombolysis
Femoral Jugular access was secured and a guiding Femoral Jugular access was secured and a guiding catheter was placed in the jugular bulb catheter was placed in the jugular bulb Mechanical Mechanical clot maceration clot maceration was done with the guidewire was done with the guidewire following which a microcatheter (was navigated and following which a microcatheter (was navigated and placed in the thrombosed segment of sinus confirmed placed in the thrombosed segment of sinus confirmed on a selective venogram on a selective venogram
Urokinase infusion Bolus dose of 2-6 lacs followed Urokinase infusion Bolus dose of 2-6 lacs followed by 60000 to 100000 units per hour along with by 60000 to 100000 units per hour along with periodic check venogram Along with maintenance periodic check venogram Along with maintenance systemic infusion of Heparinsystemic infusion of Heparin Other agents such as Other agents such as streptokinase altepase or rTPAstreptokinase altepase or rTPA can be also used can be also used
After thrombolysis patient should subjected to oral After thrombolysis patient should subjected to oral anticoagulation for six monthsanticoagulation for six months
Low-molecular-weight Low-molecular-weight heparinheparin
PharmacologyPharmacologyLMWH as its name suggests is a glycosaminoglycan that is approximatelyLMWH as its name suggests is a glycosaminoglycan that is approximately
one third the molecular weight of UFH It is derived from UFH through one third the molecular weight of UFH It is derived from UFH through variousvarious
depolymerization processes LMWH binds to antithrombin which in turn depolymerization processes LMWH binds to antithrombin which in turn
Neutralizes actors Xa and IIa Because LMWH lacks many of the longer Neutralizes actors Xa and IIa Because LMWH lacks many of the longer chains chains
required for binding to thrombin it has less ability to neutralize thrombin required for binding to thrombin it has less ability to neutralize thrombin
relativeto its ability to neutralize factor Xa LMWH also has less relativeto its ability to neutralize factor Xa LMWH also has less nonspecific nonspecific
binding to other proteins There is greater bioavailability with more binding to other proteins There is greater bioavailability with more predictable predictable
pharmacokinetics that eliminates the need for monitoring The smaller pharmacokinetics that eliminates the need for monitoring The smaller size also size also
allows for enhanced subcutaneous absorption when compared with UFHallows for enhanced subcutaneous absorption when compared with UFH
Three LMWH preparations are Three LMWH preparations are currently approved for use in the currently approved for use in the United States (1) enoxaparin (2) United States (1) enoxaparin (2) dalteparin and (3) tinzaparin dalteparin and (3) tinzaparin
They are all administered They are all administered subcutaneously at intervals of either subcutaneously at intervals of either once or twice daily for both once or twice daily for both prophylaxis and treatment dosesprophylaxis and treatment doses
Few Experiences of Few Experiences of ThrombolysisThrombolysis
Vickey 25 Yrs male patient presented Vickey 25 Yrs male patient presented with 12with 12thth day HO severe headache with day HO severe headache with right sided hemiplegiaright sided hemiplegia
MRI shows thrombosis of the superior MRI shows thrombosis of the superior sagittal left transverse left sigmoid sagittal left transverse left sigmoid sinuses and cortical veins in the fronto-sinuses and cortical veins in the fronto-parietal regions with eo haemorrhagic parietal regions with eo haemorrhagic infarct in the left cerebral hemisphere infarct in the left cerebral hemisphere with mass effect( Grade ndashV)with mass effect( Grade ndashV)
Sashi Srivastava 64 yrs FSashi Srivastava 64 yrs F In a follow up case of MRD with infra-renal In a follow up case of MRD with infra-renal
aortic abdominal and bilateral renal artery aortic abdominal and bilateral renal artery thrombosis renal angiogram shows filling thrombosis renal angiogram shows filling defects in the right Renal artery defects in the right Renal artery
Initially Renal angioplasty was done Initially Renal angioplasty was done Following angioplasty few thrombi are seem Following angioplasty few thrombi are seem to extends into the segmental branches and to extends into the segmental branches and causing blockage So Thrombolysis was causing blockage So Thrombolysis was plane to dissolve the run-out thrombi with plane to dissolve the run-out thrombi with urokinase urokinase
Rakesh 34yrsMRakesh 34yrsM Left SFA pseudoaneurysm with Left SFA pseudoaneurysm with
Covered stent placementCovered stent placement Pre operative antiplatelets with post Pre operative antiplatelets with post
procedure heparin Tirofiban procedure heparin Tirofiban followed by aspirin and clopidogrel followed by aspirin and clopidogrel were usedwere used
IAT may be a treatment option for selected patients IAT may be a treatment option for selected patients Possible selection criteria include Possible selection criteria include
presentation between 3 and 6 hours from symptom onsetpresentation between 3 and 6 hours from symptom onset major cerebral artery occlusion major cerebral artery occlusion severe neurologic deficits severe neurologic deficits high risk of systemic hemorrhage with IV rt-PA (eg recent high risk of systemic hemorrhage with IV rt-PA (eg recent
surgery) surgery) The MERCI (Mechanical Embolus Removal in Cerebral The MERCI (Mechanical Embolus Removal in Cerebral
Ischemia) retrievalIschemia) retrieval system system
Has been FDA-approved for recanalizing acutely occluded Has been FDA-approved for recanalizing acutely occluded cerebral arteries cerebral arteries
In the Multi-MERCI study patients who did not improve In the Multi-MERCI study patients who did not improve immediately after IV rt-PA underwent mechanical immediately after IV rt-PA underwent mechanical embolectomy within 8 hours of symptom onset embolectomy within 8 hours of symptom onset
Partial or complete recanalization occurred in 74 of Partial or complete recanalization occurred in 74 of patientspatients
with a symptomatic intracerebral hemorrhage (sICH) rate of with a symptomatic intracerebral hemorrhage (sICH) rate of 67 67
Mechanical embolectomy with the MERCI retriever may be a Mechanical embolectomy with the MERCI retriever may be a feasible and safe option for patients after IV rt-PAfeasible and safe option for patients after IV rt-PA
Penumbra stroke systemPenumbra stroke system This device combines two methods of clot This device combines two methods of clot
extraction aspiration and mechanical extraction aspiration and mechanical extraction extraction
First the clot is aspirated then a thrombus First the clot is aspirated then a thrombus removal ring can be used if necessary to removal ring can be used if necessary to remove remaining clot remove remaining clot
successful recanalizing 82successful recanalizing 82 Bridging therapyBridging therapy
06 mgkg IV rt-PA followed by IAT with IA rt-06 mgkg IV rt-PA followed by IAT with IA rt-PA (up to 20 mg)PA (up to 20 mg)
achieved a higher recanalization rateachieved a higher recanalization rate
Criteria for thrombolysis with rTPACriteria for thrombolysis with rTPA
Inclusion criteriaInclusion criteria Clinical signs and symptoms consistent with ischemic Clinical signs and symptoms consistent with ischemic
strokestroke Patient last seen normal within 3 hoursPatient last seen normal within 3 hours Measurable neurologic deficitMeasurable neurologic deficit
Exclusion criteriaExclusion criteria Any hemorrhage on neuroimaging (CT or MRI)Any hemorrhage on neuroimaging (CT or MRI) Symptoms suggestive of subarachnoid hemorrhageSymptoms suggestive of subarachnoid hemorrhage Seizure at stroke onset that is thought to contribute to Seizure at stroke onset that is thought to contribute to
neurologic deficitneurologic deficit Hypodensity greater than one third cerebral hemisphere Hypodensity greater than one third cerebral hemisphere
on CTon CT SBP greater than 185 mm Hg or DBP greater than 110 SBP greater than 185 mm Hg or DBP greater than 110
mm Hgmm Hg International normalized ratio (INR) greater than 17International normalized ratio (INR) greater than 17
Ischemic Stroke Ischemic Stroke Treatment ndash 2006Treatment ndash 2006
IV tissue plasminogen activator (tPA)IV tissue plasminogen activator (tPA) ndash ndash Only FDA-approved acute stroke drugOnly FDA-approved acute stroke drug ndash ndash 3 hour treatment window3 hour treatment window
MERCI - Concentric clot retrieval MERCI - Concentric clot retrieval devicedevice ndash ndash Rescue therapy - approved 2004Rescue therapy - approved 2004 ndash ndash Device approval (not outcomes-based)Device approval (not outcomes-based)
Off label approachesOff label approaches ndash ndash IV tPA after 3 hoursIV tPA after 3 hours ndash ndash IV-IA tPA sequential strategiesIV-IA tPA sequential strategies ndash ndash IA tPA clot angioplasty fragmentationIA tPA clot angioplasty fragmentation ndash ndash Ultrasound-assisted tPA lysisUltrasound-assisted tPA lysis
rt-PA Trials NINDSrt-PA Trials NINDS
Acute stroke - 624 patientsAcute stroke - 624 patients Treat within 3 hrsTreat within 3 hrs Intravenous 09 mgkg rt-PA vs placeboIntravenous 09 mgkg rt-PA vs placebo Hemorrhage 64 tPA 06 placeboHemorrhage 64 tPA 06 placebo Neurologic recovery better with tPA 30 Neurologic recovery better with tPA 30
more like to have minimal or no disabilitymore like to have minimal or no disability
First proven approved treatment for First proven approved treatment for strokestroke
Limitations of tPALimitations of tPA Only 4 of acute strokes receive tPAOnly 4 of acute strokes receive tPA (Kleindorfer et al Stroke 2004 35 e27-e29)(Kleindorfer et al Stroke 2004 35 e27-e29)
Only 22 of patients present within 3 hoursOnly 22 of patients present within 3 hours1048707 1048707 51 of these ineligible due to51 of these ineligible due to
bull bull Mild severityMild severity bull bull Medical or surgical historyMedical or surgical history bull bull Blood testsBlood tests
Sustained recanalization only 13Sustained recanalization only 13 (Alexandrov et al NEJM 2004 351 2170-8)(Alexandrov et al NEJM 2004 351 2170-8)
Concern for hemorrhageConcern for hemorrhage tPA potentiates apoptotic injury tPA potentiates apoptotic injury (Liu et al Nature Med 2004 101379-83)(Liu et al Nature Med 2004 101379-83)
PROACT II IA Lysis TrialPROACT II IA Lysis Trial Baseline 24 hours 8 days
Baseline 60 minutes 120 minutes
9mg IAProurokinase
Desmoteplase Trials DEDAS Desmoteplase Trials DEDAS DIASDIAS
Trial OverviewTrial Overview Double blind randomized placebo Double blind randomized placebo
controlled trialscontrolled trials IV delivery 3-9 hour time windowIV delivery 3-9 hour time window Plasminogen activator ndash from Plasminogen activator ndash from vampire bat vampire bat
salivasaliva Selection based on PWI-DWI MismatchSelection based on PWI-DWI Mismatch
MRI InclusionMRI Inclusion PWI defect at least 2 cm AND ~20 larger PWI defect at least 2 cm AND ~20 larger
than DWIthan DWI PWI should be obvious even visible on PWI should be obvious even visible on
raw imagesraw imagesMRI ExclusionMRI Exclusion
DWI gt 13 MCADWI gt 13 MCA MRA ICA occlusionMRA ICA occlusion
Desmoteplase ndash DIAS Desmoteplase ndash DIAS ResultsResults
Mechanical Thrombolysis Mechanical Thrombolysis devicesdevices
mechanical thrombolysis potentially extends the treatment mechanical thrombolysis potentially extends the treatment window because they act promptly at the site of the thrombuswindow because they act promptly at the site of the thrombus
The devices can retrieve large clots that pharmaceutical agents The devices can retrieve large clots that pharmaceutical agents may not successfully lysemay not successfully lyse
Patients treated with IV tPA may be considered for treatment of Patients treated with IV tPA may be considered for treatment of residual clot with some of these devicesresidual clot with some of these devices
suction-creating saline jets suction-creating saline jets laser energy ultrasound laser energy ultrasound a corkscrew apparatus to treat strokesa corkscrew apparatus to treat strokes The AngioJet systemThe AngioJet system uses saline jets that are directed back into the catheter to uses saline jets that are directed back into the catheter to
create a low-pressure zone around the catheter tip inducing create a low-pressure zone around the catheter tip inducing suction suction
The clot is pulled into the exhaust lumen and removed from the The clot is pulled into the exhaust lumen and removed from the vessel Although US Food and Drug Administration (FDA) has vessel Although US Food and Drug Administration (FDA) has approved this device for use in arteriovenous dialysis grafts and approved this device for use in arteriovenous dialysis grafts and fistulae and for the treatment of coronary arteries saphenous fistulae and for the treatment of coronary arteries saphenous vein grafts and peripheral vessels clinical trials for the vein grafts and peripheral vessels clinical trials for the treatment of acute stroke are no longer in progress treatment of acute stroke are no longer in progress
Most devices are used in cerebral vessels that 2-5 mm
The Latis laser device The Latis laser device used laser energy to ablate clots used laser energy to ablate clots Arteries 2-5 mm in diameter could be Arteries 2-5 mm in diameter could be
treated including the ICA M1 or M2 treated including the ICA M1 or M2 branch of the MCA A1 branch of the branch of the MCA A1 branch of the anterior cerebral artery (ACA) basilar anterior cerebral artery (ACA) basilar artery posterior cerebral artery (PCA) artery posterior cerebral artery (PCA) and vertebral and vertebral
Patients could receive treatment as late Patients could receive treatment as late as 8 hours after symptom onset in the as 8 hours after symptom onset in the anterior circulation and within 24 hours in anterior circulation and within 24 hours in the posterior circulation the posterior circulation
Endovascular Photo Acoustic Endovascular Photo Acoustic Recanalization (EPAR) Recanalization (EPAR)
A laser power source generated energy for the A laser power source generated energy for the systemsystem
The energy was delivered by means of The energy was delivered by means of fiberoptics to the tip of the catheter at the fiberoptics to the tip of the catheter at the treatment sitetreatment site
Absorption of laser light by darkly pigmented Absorption of laser light by darkly pigmented materials (ie the clot) occurred inside the 1-mm materials (ie the clot) occurred inside the 1-mm catheter tipcatheter tip
the system was designed to minimize scattering the system was designed to minimize scattering of laser light of laser light
Absorption converted photo energy to acoustic Absorption converted photo energy to acoustic energy which then emulsified the clot inside the energy which then emulsified the clot inside the catheter tip catheter tip
EKOS ultrasound( the EKOS ultrasound( the Ultrasound Thrombolytic Ultrasound Thrombolytic
Infusion Catheter) Infusion Catheter) combines the use of a distal ultrasound transducer with combines the use of a distal ultrasound transducer with
infusion of a thrombolytic agent through the infusion of a thrombolytic agent through the microcathetermicrocatheter
Ultrasound changes the structure of the clot to Ultrasound changes the structure of the clot to temporarily increase its permeability while providing an temporarily increase its permeability while providing an acoustic pressure gradient to move the drug into the clot acoustic pressure gradient to move the drug into the clot to speed its dissolution to speed its dissolution
The EKOS catheter is placed in the proximal portion of the The EKOS catheter is placed in the proximal portion of the clot clot
After a 2-mg bolus of tPA was injected through the After a 2-mg bolus of tPA was injected through the catheter catheter
the patient received a continuous infusion of IA tPA 03 the patient received a continuous infusion of IA tPA 03 mgmin to a maximum of 20 mg and simultaneous mgmin to a maximum of 20 mg and simultaneous ultrasound transmission for as long as 60 minutes ultrasound transmission for as long as 60 minutes
One patient was treated with a total of 4 units of One patient was treated with a total of 4 units of recombinant reteplase (Retavase) hand-injected over 60 recombinant reteplase (Retavase) hand-injected over 60 minutes minutes
Penumbra system Penumbra system The Penumbra system (Penumbra Inc) provides a dual The Penumbra system (Penumbra Inc) provides a dual
approach to clot extraction using aspiration followed by approach to clot extraction using aspiration followed by clot retrieval with a ring device if needed clot retrieval with a ring device if needed
Mechanical Embolus Removal in Cerebral Ischemia Mechanical Embolus Removal in Cerebral Ischemia (MERCI)(MERCI)
a corkscrew-like apparatus to remove blood clots from a corkscrew-like apparatus to remove blood clots from the brain in patients experiencing an ischemic stroke the brain in patients experiencing an ischemic stroke
The corkscrew itself resides in the catheter tip which The corkscrew itself resides in the catheter tip which shields it from the wall of the vessel until it is ready to be shields it from the wall of the vessel until it is ready to be burrowed into the clot Once lodged in the clot the device burrowed into the clot Once lodged in the clot the device and clot are withdrawn from the vessel and clot are withdrawn from the vessel
Snarelike devicesSnarelike devices Snares such as the Neuronet snare (Guidant Snares such as the Neuronet snare (Guidant
Endovascular Santa Clara CA) have been developed Endovascular Santa Clara CA) have been developed specifically for use in the treatment of strokes specifically for use in the treatment of strokes
These devices are simple in design and do not require the These devices are simple in design and do not require the clot to be amenable to emulsification clot to be amenable to emulsification
X-Sizer deviceX-Sizer device a device with small moving blades at the a device with small moving blades at the
catheter tip catheter tip This device the X-Sizer device (EndiCor Medical This device the X-Sizer device (EndiCor Medical
San Clemente CA) can be used to excise the San Clemente CA) can be used to excise the thrombus and aspirate it thrombus and aspirate it
The device was being evaluated in randomized The device was being evaluated in randomized studies of coronary vessels and in a registry of studies of coronary vessels and in a registry of patients with acute myocardial infarctionpatients with acute myocardial infarction
Although the manufacturer had modified the Although the manufacturer had modified the device for use in cerebral vessels a safety and device for use in cerebral vessels a safety and feasibility study was indefinitely suspended after feasibility study was indefinitely suspended after only 1 patient was treated with the device in only 1 patient was treated with the device in Europe Europe
Suction thrombectomySuction thrombectomy This method of mechanical thrombolysis is one of the This method of mechanical thrombolysis is one of the
simplestsimplest In this readily available technique suction is applied with In this readily available technique suction is applied with
a syringe to remove thrombus in the ICA a syringe to remove thrombus in the ICA It requires no other devicesIt requires no other devices A catheter with a large inner diameter (Brite Tip Cordis A catheter with a large inner diameter (Brite Tip Cordis
Corporation Miami FL) was placed in the symptomatic Corporation Miami FL) was placed in the symptomatic vessel and navigated over a guidewire into the thrombusvessel and navigated over a guidewire into the thrombus
A 60-mL syringe was used to aspirate the thrombus A 60-mL syringe was used to aspirate the thrombus Each patient required angioplasty and stenting of carotid Each patient required angioplasty and stenting of carotid
bifurcation stenosis and received daily aspirin and bifurcation stenosis and received daily aspirin and ticlopidine after the procedure No complications ticlopidine after the procedure No complications occurred occurred
Summary Acute Stroke Summary Acute Stroke ImagingImaging
PhysiologyPhysiology importance collaterals importance collaterals
ndash ndashGrowing role for perfusion Growing role for perfusion assessmentassessment
tPAtPA guidelines amp limitations guidelines amp limitations Signs on CT amp MRSigns on CT amp MR follow physiology follow physiology Stroke trialsStroke trials PWI-DWI mismatch PWI-DWI mismatch
ndash ndashTreat based on physiology not timeTreat based on physiology not time ProtocolsProtocols should be fast and should be fast and
comprehensivecomprehensive
Coagulation TestingCoagulation Testing
Monitoring therapyMonitoring therapy
Intrinsic Pathway
Extrinsic Pathway
Common Pathway
CLOT
Heparin Coumadin
Monitor with
ACT aPTT
Monitor with PTINR
Thrombolytics
Monitor with TT Fibrinogen
Monitoring of Monitoring of Anti platelet drugsAnti platelet drugs
Bleeding timeBleeding time
Optical aggregometryOptical aggregometry
Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay
HeparinHeparin
Heterogeneous 3000-30000 dalton in Heterogeneous 3000-30000 dalton in molecular weight molecular weight
Average=15000 d (~45monosaccharide Average=15000 d (~45monosaccharide chains)chains)
About About 13 of dose binds to AT III and forms 13 of dose binds to AT III and forms the AT IIIHeparinClotting Factor Complexthe AT IIIHeparinClotting Factor Complex
Complex binds to clotting factors of the Complex binds to clotting factors of the intrinsic and common pathway (Xa IIa IXa intrinsic and common pathway (Xa IIa IXa XIa XIIa XIIIa) and inactivates themXIa XIIa XIIIa) and inactivates them
Anticoagulant of choice in pregnancy (not Anticoagulant of choice in pregnancy (not crosses placenta)crosses placenta)
Heparin and Low molecular weight heparinsHeparin and Low molecular weight heparins
Structure and sequence
O
OH
OH
O
COO
O
O
CH2OH
NHSO3
OH
_
_
O
O
CH2OSO3
NHSO3
OH
_
_
O
OH
OH
O
COOO
O
CH2OSO3
NHSO3
OH
_
_
O
OSO3
OHO
COOO
O
CH2OSO3
NHCOCH3
OH
_
_ _
_
_
O
OH
OH
O
COO
1
23
4
5
6
-D-glucosamine -L-iduronic acid -D-glucuronic acid
O
O
CH2OH
NH2
OH 12
3
4
5
6
O
OH
OHO
COO_
1
23
4
5
6
polymeric structure of heparin
Anticoagulant Properties of Anticoagulant Properties of HeparinHeparin
11 Inhibits the thrombin-mediated conversion of Inhibits the thrombin-mediated conversion of fibrinogen to fibrinfibrinogen to fibrin
22 Inhibits the aggregation of platelets by thrombin Inhibits the aggregation of platelets by thrombin (prolongs bleeding time)(prolongs bleeding time)
33 Inhibits activation of fibrin stabilizing enzymeInhibits activation of fibrin stabilizing enzyme
44 Inhibits activated factors XII XI IX X and IIInhibits activated factors XII XI IX X and II All available forms of heparin must be All available forms of heparin must be
administered administered parenterally since they are parenterally since they are highly charged and rapidlyhighly charged and rapidly hydrolyzed in the hydrolyzed in the GI tractGI tract
Heparin antagonist Protamine sulfate (Heparin antagonist Protamine sulfate (10mg for 10mg for 1000 unit of heparin)1000 unit of heparin)
Monitoring of heparin Monitoring of heparin
Subcutenous Subcutenous no monitoring requiredno monitoring required Intravenous Intravenous
Partial thromboplastin time (PTT normal value Partial thromboplastin time (PTT normal value ~30sec) ~30sec)
Activated clotting time ( ACT normal value ~90-Activated clotting time ( ACT normal value ~90-120sec)120sec)
Daily or more frequent if PTT ACT variesDaily or more frequent if PTT ACT varies
Mechanism Mechanism ndash measures intrinsic pathwayndash measures intrinsic pathway Therapeutic goal Therapeutic goal 2-25 times normal control value 2-25 times normal control value
ACT or aPTTACT or aPTT
Determine when to pull the femoral sheath Determine when to pull the femoral sheath Premature sheath pull can lead to bleedingPremature sheath pull can lead to bleeding Delayed removal can increase time in ICUDelayed removal can increase time in ICU Target set Target set at each siteat each site
ACT targets range from 150 ndash 220 ACT targets range from 150 ndash 220 secondsseconds
aPTT targets range from 40 ndash 70 seconds aPTT targets range from 40 ndash 70 seconds
During neuroangiography-During neuroangiography- Recommended therapeutic range of heparin in Recommended therapeutic range of heparin in
plasma is 02-08 uml ( corresponding to aPTT plasma is 02-08 uml ( corresponding to aPTT ACT values 15-25 times the baseline values)ACT values 15-25 times the baseline values)
Dose In diagnostic angiography bolus dose of Dose In diagnostic angiography bolus dose of 2500 iu is used followed by 1000 iu hour2500 iu is used followed by 1000 iu hour
Bolus dose is Bolus dose is 60 ukg to maintain the therapeutic 60 ukg to maintain the therapeutic range range If procedure continues for more than 75 If procedure continues for more than 75 minutes additional dose is required ( half of the minutes additional dose is required ( half of the initial dose for another 75 minutes) initial dose for another 75 minutes)
(AJNR 199415 51-54)
Mechanisms of HIT( Mechanisms of HIT( Heparin Heparin induced Thrombocytopeniainduced Thrombocytopenia))
Type 1Type 1 Fall in platelet count occurs within the first two Fall in platelet count occurs within the first two
days after heparin initiation often returns to days after heparin initiation often returns to normal with continued heparin administration normal with continued heparin administration and is of no clinical consequence and is of no clinical consequence
The mechanism of the thrombocytopenia is non-The mechanism of the thrombocytopenia is non-immune and appears to be due to a direct effect of immune and appears to be due to a direct effect of heparin on platelet activationheparin on platelet activation
Type 2Type 2 Approximately 03 to 3 percent of patients Approximately 03 to 3 percent of patients
receiving heparin develop an immune receiving heparin develop an immune thrombocytopenia mediated by antibodies to a thrombocytopenia mediated by antibodies to a heparin-platelet factor 4 complex heparin-platelet factor 4 complex
(AJNR 28155-158 2007)
Treatment of heparin-induced Treatment of heparin-induced thrombocytopeniathrombocytopenia
When HIT is diagnosed it is important to When HIT is diagnosed it is important to stop heparin mainly in type 2 and to avoid stop heparin mainly in type 2 and to avoid the use of LMWH the use of LMWH
Because of the increased risk of thrombosis Because of the increased risk of thrombosis however continuation of an anticoagulant however continuation of an anticoagulant must be considered must be considered
The drugs currently approved for the The drugs currently approved for the treatment of HIT in the United States are treatment of HIT in the United States are direct thrombin inhibitors argatroban and direct thrombin inhibitors argatroban and lepirudinlepirudin
WARFARIN MECHANISM OF ACTIONWARFARIN MECHANISM OF ACTION
Inactive factors II VII IX and X
Proteins S and C
Active factors II VII IX and X
Proteins S and C
Vitamin K epoxide
Vitamin K reduced
WA
RF
AR
IN
Prevents the reduction of vitamin K which is essential for Prevents the reduction of vitamin K which is essential for activation of certain factorsactivation of certain factors
Has no effect on previously formed thrombusHas no effect on previously formed thrombus
Antagonist is Vit KAntagonist is Vit K
OPTIMIZING WARFARIN THERAPYOPTIMIZING WARFARIN THERAPY
Use of large loading dose may lead to hemorrhage and Use of large loading dose may lead to hemorrhage and other complicationsother complications
Initial dose 2-5 mg once dailyInitial dose 2-5 mg once daily Maintenance dose 2-10 mg once dailyMaintenance dose 2-10 mg once daily If Immediate anticoagulation is requiredIf Immediate anticoagulation is required Heparin IS Heparin IS
started along with loading dose of warfarin 10 mg started along with loading dose of warfarin 10 mg Heparin is usually discontinued after 4-5 days Heparin is usually discontinued after 4-5 days Before Before discontinuing INR should be in therapeutic range for 2 discontinuing INR should be in therapeutic range for 2 consecutive daysconsecutive days
Daily monitoring of INR until INR is in therapeutic Daily monitoring of INR until INR is in therapeutic range then 3 times weekly for 1-2 weeks then less often range then 3 times weekly for 1-2 weeks then less often (every 4 to 6 weeks)(every 4 to 6 weeks)
OPTIMAL THERAPEUTIC RANGEOPTIMAL THERAPEUTIC RANGE
IndicationIndication INRINR
Prophylaxis of venous Prophylaxis of venous thromboembolismthromboembolism
20-3020-30
Treatment of venous Treatment of venous thromboembolismthromboembolism
20-3020-30
Atrial fibrillationAtrial fibrillation 20-3020-30
Mitral valve stenosisMitral valve stenosis 20-3020-30
Heart valve replacementHeart valve replacement
Bioprosthetic valveBioprosthetic valve
Mechanical valveMechanical valve
20-3020-30
25-3525-35
Myocardial infarctionMyocardial infarction 20-3020-30
25-35 25-35 (high risk patients)(high risk patients)
FACTORS INFLUENCING DOSE RESPONSEFACTORS INFLUENCING DOSE RESPONSE
Poor patient compliancePoor patient compliance Concomitant medicationsConcomitant medications Levels of dietary vitamin KLevels of dietary vitamin K Alcohol Inaccurate lab testingAlcohol Inaccurate lab testing Inaccurate lab testingInaccurate lab testing Hepatic dysfunctionHepatic dysfunction FeverFever
Contraindication for WarfarinContraindication for Warfarin
Hypersensitivity to warfarinHypersensitivity to warfarin Hemorrhagic tendencyHemorrhagic tendency Condition with risk of hemorrhageCondition with risk of hemorrhage Inadequate laboratory techniquesInadequate laboratory techniques Protein C amp S deficiencyProtein C amp S deficiency Vitamin K deficiencyVitamin K deficiency
SIDE EFFECTSSIDE EFFECTS
Hemorrhage Hemorrhage Skin necrosisSkin necrosis Purple toe syndromePurple toe syndrome Microembolization Microembolization TeratogenecityTeratogenecity Agranulocytosis leukopenia Agranulocytosis leukopenia Diarrhoeanausea anorexiaDiarrhoeanausea anorexia
MONITORING OF WARFARIN THERAPYMONITORING OF WARFARIN THERAPY
Prothrombin timeProthrombin time PT ratioPT ratio INR (International Normalized Ratio)INR (International Normalized Ratio)
PROTHROMBIN TIME (PT)PROTHROMBIN TIME (PT)
Time required for blood to coagulate Time required for blood to coagulate is called PT ( normal value ~10sec)is called PT ( normal value ~10sec)
Performed by adding a mixture of Performed by adding a mixture of calcium and thromboplastin to calcium and thromboplastin to citrated plasmacitrated plasma
As a control a normal blood sample is As a control a normal blood sample is tested continuouslytested continuously
PT ratio (PTR) = PT ratio (PTR) = Patientrsquos PTPatientrsquos PT Control PTControl PT
PROBLEMS WITH PTPTRPROBLEMS WITH PTPTR
Thromboplastins are extracts from Thromboplastins are extracts from brain lung or placenta of animalsbrain lung or placenta of animals
Thromboplastins from various Thromboplastins from various manufacturers differ in their manufacturers differ in their sensitivity to prolong PTsensitivity to prolong PT
May result in false control of May result in false control of anticoagulant therapyanticoagulant therapy
INTERNATIONAL NORMALISED RATIO (INR)INTERNATIONAL NORMALISED RATIO (INR)
International Normalized Ratio (INR) International Normalized Ratio (INR) a PT test with a a PT test with a formula based ratio to normalize the often variable source formula based ratio to normalize the often variable source of tissue factor (human rabbit recombinant)of tissue factor (human rabbit recombinant)
INR = [PTINR = [PTptpt] ] ISIISI
[PT[PTRefRef]]
PTPTpt pt ndash prothrombin time of patientndash prothrombin time of patient
PTPTRef Ref ndash prothrombin time of normal pooled samplendash prothrombin time of normal pooled sample
ISI ndash International Sensitivity IndexISI ndash International Sensitivity Index
Warfarin is given orally and titrated to achieve an INR of Warfarin is given orally and titrated to achieve an INR of typically 20 ndash 30typically 20 ndash 30
Heparin versus WarfarinHeparin versus Warfarin
Drug ActionMechan-ism
Moni-toring
Effective
HeparinDirect
Inhibition ofThrombin
ATIIIcofactor
APTTACT
Immediate
WarfarinDecreasesProductionof factors
Vitamin K PTDelay
3-5 days
INR
Recanalization or Antegrade Recanalization or Antegrade Reperfusion StrategiesReperfusion Strategies
Recanalization strategies focus on removing Recanalization strategies focus on removing andor dissolving the occlusive thrombus to re-andor dissolving the occlusive thrombus to re-establish antegrade flow Strategies may be establish antegrade flow Strategies may be classified into 7 different categories on the classified into 7 different categories on the basis of their primary mechanism of action basis of their primary mechanism of action 1) 1) IV andor intraarterial thrombolysis (IAT) IV andor intraarterial thrombolysis (IAT) 2) endovascular thrombectomy2) endovascular thrombectomy3) endovascular thromboaspiration 3) endovascular thromboaspiration 4) endovascular mechanical thrombus disruption or 4) endovascular mechanical thrombus disruption or
thromborrhexisthromborrhexis5) 5) transcranial or endovascular augmented transcranial or endovascular augmented
fibrinolysis fibrinolysis 6) endovascular thrombus entrapment and 6) endovascular thrombus entrapment and 7) temporary endovascular bypass7) temporary endovascular bypass
IAT in Acute Ischemic StrokeIAT in Acute Ischemic Stroke
IAT advantages over IV thrombolysisIAT advantages over IV thrombolysis Coaxial microcatheter techniques the occluded intracranial Coaxial microcatheter techniques the occluded intracranial
vessel is directly accessible and the fibrinolytic agent can be vessel is directly accessible and the fibrinolytic agent can be infused directly into the thrombusinfused directly into the thrombus
This permits a smaller dose of fibrinolytic agent to reach a This permits a smaller dose of fibrinolytic agent to reach a higher local concentration than that reached by systemic higher local concentration than that reached by systemic infusioninfusion
Allows more complete recanalization with lower total doses of Allows more complete recanalization with lower total doses of thrombolytic thrombolytic
With the smaller dose complications from systemic fibrinolytic With the smaller dose complications from systemic fibrinolytic effects including intracranial hemorrhage (ICH) can effects including intracranial hemorrhage (ICH) can theoretically be reduced theoretically be reduced
Treatment window for endovascular techniques can be Treatment window for endovascular techniques can be extended beyond the typical IV window of 3 hours extended beyond the typical IV window of 3 hours
IA techniques have led to higher recanalization rates than IV IA techniques have led to higher recanalization rates than IV thrombolysisthrombolysis
Major disadvantagesMajor disadvantages Relative complexity of the procedure the level Relative complexity of the procedure the level
of required technical expertise and its of required technical expertise and its relatively low availability relatively low availability
Delays in initiating treatmentDelays in initiating treatment InvasiveInvasive
ThrombolyticsThrombolytics
Plasminogen activators
Fibrinolytics
1 Plasminogen Activators 1 Plasminogen Activators drugs act by converting the inactive proenzyme drugs act by converting the inactive proenzyme plasminogen into the active enzyme plasmin Plasmin plasminogen into the active enzyme plasmin Plasmin digests fibrinogen fibrin monomers and cross-linked digests fibrinogen fibrin monomers and cross-linked fibrin (as found in a thrombus) into fibrin degradation fibrin (as found in a thrombus) into fibrin degradation productsproducts
First-Generation Agents First-Generation Agents StreptokinaseStreptokinase a protein derived from group C a protein derived from group C
szlig-hemolytic streptococci has a half-life of 16ndashszlig-hemolytic streptococci has a half-life of 16ndash90 minutes and low fibrin specificity This drug 90 minutes and low fibrin specificity This drug proved to have a very narrow therapeutic proved to have a very narrow therapeutic window and significant rates of ICH and window and significant rates of ICH and systemic hemorrhage18systemic hemorrhage18
UrokinaseUrokinase is a serine protease with a plasma is a serine protease with a plasma half life of 14 minutes and low fibrin specificity half life of 14 minutes and low fibrin specificity
The urokinase dose used in cerebral IAT has The urokinase dose used in cerebral IAT has ranged from 002 to 2 X106unitsranged from 002 to 2 X106units
Second-Generation Agents Second-Generation Agents Alteplase (rtPA) Alteplase (rtPA)
is a serine is a serine protease with a plasma half-life of 35 protease with a plasma half-life of 35 minutes and a high degree of fibrin affinity and minutes and a high degree of fibrin affinity and specificity specificity
Dose used in cerebral IAT has ranged between 20 Dose used in cerebral IAT has ranged between 20 and 60 mgand 60 mg
Disadvantages of alteplase include its relatively short Disadvantages of alteplase include its relatively short halflife and limited penetration into the clot matrix halflife and limited penetration into the clot matrix because of strong binding with surface fibrin which because of strong binding with surface fibrin which could delay recanalization and increase the risk of could delay recanalization and increase the risk of recurrent occlusion recurrent occlusion
Prourokinase (r-prourokinase) Prourokinase (r-prourokinase) is the proenzyme precursor of urokinase is the proenzyme precursor of urokinase T12 of 7 minutes and high fibrin specificity T12 of 7 minutes and high fibrin specificity
Third-Generation AgentsThird-Generation Agents
ReteplaseReteplase is a structurally modified is a structurally modified form of alteplase form of alteplase
with a longer half-life (15ndash18 minutes) In with a longer half-life (15ndash18 minutes) In addition it does not bind as highly to fibrin addition it does not bind as highly to fibrin unbound reteplase can thus theoretically better unbound reteplase can thus theoretically better penetrate the clot and potentially penetrate the clot and potentially improve in improve in vivo fibrinolytic activity vivo fibrinolytic activity
TenecteplaseTenecteplase is another modified form of rtPA with a longer is another modified form of rtPA with a longer
half-life (17 minutes)half-life (17 minutes) greater fibrin specificity and greater greater fibrin specificity and greater
resistance to plasminogen activator inhibitor-1 resistance to plasminogen activator inhibitor-1 IV tenecteplase in acute ischemic stroke IV tenecteplase in acute ischemic stroke
suggest that the drug is safe and promisingsuggest that the drug is safe and promising
Newer plasminogen activatorNewer plasminogen activator
DesmoteplaseDesmoteplase is a genetically engineered is a genetically engineered version of the clot-dissolving factor version of the clot-dissolving factor
found in the saliva found in the saliva of the vampire bat Desmodus rotundusof the vampire bat Desmodus rotundus moremore potent and more selective for fibrin-bound potent and more selective for fibrin-bound
plasminogen than any other known plasminogen plasminogen than any other known plasminogen activatoractivator
Unlike tissue plasminogen activator (tPA) desmoteplase Unlike tissue plasminogen activator (tPA) desmoteplase is not activated by fibrinogen or -amyloid proteins is not activated by fibrinogen or -amyloid proteins factors that may exacerbate the risk for ICH factors that may exacerbate the risk for ICH
The effect of IV administration of desmoteplase 3ndash9 The effect of IV administration of desmoteplase 3ndash9 hours after symptom onset in patients with stroke who hours after symptom onset in patients with stroke who present with mismatch on MR imaging or CT perfusion present with mismatch on MR imaging or CT perfusion
3 DefibrinogenatingFibrinogenolytic 3 DefibrinogenatingFibrinogenolytic Agents Agents
AncrodAncrod(Viprinex)(Viprinex) is is the purified fraction of the Malayan pit viper venomthe purified fraction of the Malayan pit viper venom It acts by directly cleaving and inactivating fibrinogen It acts by directly cleaving and inactivating fibrinogen
and thus indirectly promoting anticoagulation and thus indirectly promoting anticoagulation The reduction in the blood levels of fibrinogen also The reduction in the blood levels of fibrinogen also
leads to a reduced blood viscosity which may improve leads to a reduced blood viscosity which may improve blood flow to the affected areas of the brain blood flow to the affected areas of the brain
In the Stroke Treatment with Ancrod Trial 500 In the Stroke Treatment with Ancrod Trial 500 patients with stroke presenting within 3 hours of patients with stroke presenting within 3 hours of symptom onset were randomized to receive ancrod (symptom onset were randomized to receive ancrod (n n 248) or a placebo (n 252) Good outcome (Barthel 248) or a placebo (n 252) Good outcome (Barthel Index 95ndash100 at 3 months) was achieved in 4221 Index 95ndash100 at 3 months) was achieved in 4221 and 344 of the patients respectively and 344 of the patients respectively
2 Direct Fibrinolytics2 Direct Fibrinolytics
Microplasmin (Microplasmin (ThromboGenics Heverlee Belgium)ThromboGenics Heverlee Belgium) is a truncated form of plasmin that is more resistant to the effects is a truncated form of plasmin that is more resistant to the effects
of antiplasmin of antiplasmin microplasmin can be used upto 4ndash12 hours after stroke onset microplasmin can be used upto 4ndash12 hours after stroke onset There was no evidence of increased bleeding risk with There was no evidence of increased bleeding risk with
microplasminmicroplasmin
Alfimeprase (Nuvelo San Carlos Calif)Alfimeprase (Nuvelo San Carlos Calif) is a recombinant truncated form of fibrolase a fibrinolytic zinc metalloproteinase is a recombinant truncated form of fibrolase a fibrinolytic zinc metalloproteinase
isolated from the venom of the southern copperhead snake isolated from the venom of the southern copperhead snake It degrades fibrin directly and achieves thrombolysis independent It degrades fibrin directly and achieves thrombolysis independent
of plasmin formationof plasmin formation its thrombolytic activity appears to be localized to the site of its thrombolytic activity appears to be localized to the site of
delivery These properties should theoretically result in faster delivery These properties should theoretically result in faster recanalization and lower hemorrhagic conversion riskrecanalization and lower hemorrhagic conversion risk
Anti-fibrinolyticsAnti-fibrinolytics
to limit fibrinolytic activityto limit fibrinolytic activity -aminocaproic acid (EACA) -aminocaproic acid (EACA) competitively inhibitscompetitively inhibits plasminogen and plasminogen activators from plasminogen and plasminogen activators from
binding to fibrinbinding to fibrin
alpha2-antiplasminalpha2-antiplasmin a serine protease inhibitor that a serine protease inhibitor that neutralizes any free circulating plasminneutralizes any free circulating plasmin
Plasminogen activator inhibitor-1Plasminogen activator inhibitor-1 a serine protease a serine protease inhibitor that inhibits tissue-type plasminogen inhibitor that inhibits tissue-type plasminogen activatoractivator
Glycoprotein (GP) IIbIIIa antagonistsGlycoprotein (GP) IIbIIIa antagonists
such as ReoPro (abciximab) Integrilin such as ReoPro (abciximab) Integrilin (eptifibatide) or Aggrastat (tirofiban) in (eptifibatide) or Aggrastat (tirofiban) in ischemic stroke remains investigational ischemic stroke remains investigational Deshmukh et al38 reported 21 patients with Deshmukh et al38 reported 21 patients with large-vessel occlusion refractory to IAT with large-vessel occlusion refractory to IAT with rtPA who were treated with IV andor IA rtPA who were treated with IV andor IA abciximab eptifibatide or tirofiban abciximab eptifibatide or tirofiban
IA Mechanical Approaches in Acute Ischemic Stroke IA Mechanical Approaches in Acute Ischemic Stroke Mechanical strategies have several advantagesMechanical strategies have several advantages First they lessen and may even preclude the use of chemical First they lessen and may even preclude the use of chemical
thrombolytics in this manner very likely reducing the risk of ICHthrombolytics in this manner very likely reducing the risk of ICH Second by avoiding the use of chemical thrombolytics it is Second by avoiding the use of chemical thrombolytics it is
possible to extend the treatment window beyond the limit of 6ndash8 possible to extend the treatment window beyond the limit of 6ndash8 hours hours
Third mechanically fragmenting a clot increases the surface area Third mechanically fragmenting a clot increases the surface area accessible to fibrinolytic agents and allows inflow of fresh accessible to fibrinolytic agents and allows inflow of fresh plasminogen which in turn may increase the speed of plasminogen which in turn may increase the speed of thrombolysis thrombolysis
Finally clot-retrieval devices may provide faster recanalization Finally clot-retrieval devices may provide faster recanalization
The disadvantages of the mechanical The disadvantages of the mechanical approaches approaches technical difficulty of navigating mechanical technical difficulty of navigating mechanical
devices into the intracranial circulation excessive devices into the intracranial circulation excessive trauma to the vasculature (potentially leading to trauma to the vasculature (potentially leading to vasospasm vessel dissection perforation or vasospasm vessel dissection perforation or rupture) rupture)
fragmented thrombus causing distal embolization fragmented thrombus causing distal embolization into previously unaffected territories into previously unaffected territories
Nevertheless the advantages of mechanical stroke Nevertheless the advantages of mechanical stroke therapy appear to significantly outweigh its therapy appear to significantly outweigh its disadvantages and risksdisadvantages and risks
Contraindications to Thrombolytic Contraindications to Thrombolytic agents agents
Recent thoracic abdominal or Recent thoracic abdominal or intracranial surgeryintracranial surgery
Recent haemorrhagic CVA Head injury Recent haemorrhagic CVA Head injury or neoplasmor neoplasm
Bleeding ulcerBleeding ulcer Anticipated invasive procedures (arterial Anticipated invasive procedures (arterial
punctures biopsies)punctures biopsies) Concurrent hemostatic dysfunctionConcurrent hemostatic dysfunction
Monitoring of thrombolytic Monitoring of thrombolytic therapytherapy
Thrombin time Measures the availability of functional
fibrinogen Normal thrombin time is 10-14 sec Prolonged when fibrinogen level is below
75-100 mgdl
Half Life of ThrombolyticsHalf Life of ThrombolyticsAgent Administration Half Life
Streptokinase IA 60-80min
Urokinase IAIV 9-12min
rTPA IAIV 6min
Abciximab(Reopro) IAIV 12hour
Aspirin POIV 15-20min
Heparin IVSC 60min
Coumadin PO 15-25 days
Anti Platelet DrugsAnti Platelet DrugsDrug Drug Mechanism Mechanism UsesUsesAspirinAspirin Permanently inhibits Permanently inhibits
COX-1 and COX-2COX-1 and COX-2CADCAD
Stroke-TIAsStroke-TIAs
NSAIDsNSAIDs Reversibly inhibits Reversibly inhibits COX-1COX-1
LimitedLimited
DipyridamoleDipyridamole Inhibits PDE increases Inhibits PDE increases cAMPcAMP
TIAsTIAs
ThenopyridinesThenopyridines
(Ticlopidine(Ticlopidine
ClopidrgrelClopidrgrel))
Inhibits ADP Inhibits ADP
PlatAg PlatAg
TIAsStrokeTIAsStroke
CAD PVDCAD PVD
Abciximab (ReoPro)Abciximab (ReoPro)
Eptifibatide (Integrilin)Eptifibatide (Integrilin)
TirofibanTirofiban
GP IIBIIIA InhibitorsGP IIBIIIA Inhibitors
Stroke- TIAs Stroke- TIAs
MonitoringMonitoring
Bleeding timeBleeding time
Optical aggregometryOptical aggregometry
Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay
Bleeding timeBleeding time
Requires a skin incision (usually made on the ear lobe or Requires a skin incision (usually made on the ear lobe or forearm offorearm of
a depth that results in disruption of capillary loops and a depth that results in disruption of capillary loops and small vessels)small vessels)
AdvantagesAdvantages Universally availableUniversally available Relatively simple techniquesRelatively simple techniques Can be performed bedsideCan be performed bedside
DisadvantagesDisadvantages Insensitive inaccurate non-specific techniqueInsensitive inaccurate non-specific technique
Poorly reproducible (as depends on multiple variables)Poorly reproducible (as depends on multiple variables)
Optical aggregometryOptical aggregometry
Gold standard assay for platelet functionGold standard assay for platelet function Agonist induced aggregation is measuredAgonist induced aggregation is measured Different agonist are available for different Different agonist are available for different
agentsagents However require unique expertise and are not However require unique expertise and are not
universally availableuniversally available Aspirin measured with ADP or AA(gt70 Aspirin measured with ADP or AA(gt70
aggregation so resistance)aggregation so resistance) Clopidogrel( ADP gt 90 aggregation means Clopidogrel( ADP gt 90 aggregation means
resistance) resistance)
Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay
Can be performed bed sideCan be performed bed side Different assay devices with different Different assay devices with different
agonist are used for each of different agonist are used for each of different antiplatelet agents antiplatelet agents
For Aspirin AA is used (result is reported as aspirin For Aspirin AA is used (result is reported as aspirin reaction units [ARU] ARUgt 550 indicates non-reaction units [ARU] ARUgt 550 indicates non-responsiveness)responsiveness)
Verify IIbIIIa assay device uses TRAP as agonist for Verify IIbIIIa assay device uses TRAP as agonist for Abciximab and TirofibanAbciximab and Tirofiban
Practical Applications Practical Applications related to specific related to specific
Neurovascular Neurovascular interventionsinterventions
Acute ischemic StrokeAcute ischemic Stroke When an artery occludes neurons are affected When an artery occludes neurons are affected
differently depending upon the amount of residual blood differently depending upon the amount of residual blood flowflow
Normal cerebral blood flow is greater than 50 mL100 Normal cerebral blood flow is greater than 50 mL100 mgminmgmin
Once blood flow decreases to less than 20 mL100 Once blood flow decreases to less than 20 mL100 mgmin infarction occursmgmin infarction occurs
If blood flow decreases to less than 10 mL100 mgmin If blood flow decreases to less than 10 mL100 mgmin irreversible neuronal death occurs rapidly irreversible neuronal death occurs rapidly
Blood flow between 11 and 20 mL100 mgmin is thought Blood flow between 11 and 20 mL100 mgmin is thought to represent the ischemic penumbra an area where the to represent the ischemic penumbra an area where the cells are functionally silent because of ischemia but are cells are functionally silent because of ischemia but are still able to recover if blood flow is restored still able to recover if blood flow is restored
Many acute stroke therapies are targeted toward Many acute stroke therapies are targeted toward restoring flow or function to the ischemic penumbrarestoring flow or function to the ischemic penumbra
Therapeutic window in Therapeutic window in management of acute Ischemic management of acute Ischemic
StrokeStrokeThe early diagnosis of ischemic stroke is critical to the The early diagnosis of ischemic stroke is critical to the
with only a narrow therapeutic window in the first few with only a narrow therapeutic window in the first few hours following stroke ictushours following stroke ictus
Diagnosis in the first 3 hours postictus provides the Diagnosis in the first 3 hours postictus provides the opportunity for intravenous or intraarterial thrombolysis opportunity for intravenous or intraarterial thrombolysis and intra-arterial clot mechanical treatment which and intra-arterial clot mechanical treatment which improve the outcome improve the outcome
Diagnosis in the time period between 3 and 6 hours Diagnosis in the time period between 3 and 6 hours provides an opportunity for intra-arterial thrombolysis provides an opportunity for intra-arterial thrombolysis and mechanical treatment and mechanical treatment
Involvement of the posterior circulation especially the Involvement of the posterior circulation especially the basilar artery is treated by some regardless of time of basilar artery is treated by some regardless of time of onset or up until 12 to 24 hours in some practices This is onset or up until 12 to 24 hours in some practices This is related to the potentially high mortality and morbidity related to the potentially high mortality and morbidity associated with basilar artery thrombosisassociated with basilar artery thrombosis
Infarct evaluation on angiographyInfarct evaluation on angiography(CT angiography and catheter (CT angiography and catheter
angiography)angiography)CTA is an excellent first-line examination for CTA is an excellent first-line examination for
evaluation of the head and neck arteries evaluation of the head and neck arteries In comparison with catheter angiography In comparison with catheter angiography
what it gives up in resolution and dynamic what it gives up in resolution and dynamic properties it makes up for with rapid properties it makes up for with rapid acquisition of a 3-D dataset and the potential acquisition of a 3-D dataset and the potential for assessment of whole-brain perfusion and for assessment of whole-brain perfusion and better parenchymal evaluationbetter parenchymal evaluation
Moreover CTA illustrates not only arterial Moreover CTA illustrates not only arterial stenosis or occlusion but also the vessel wall stenosis or occlusion but also the vessel wall This factor is most important for evaluation of This factor is most important for evaluation of intramural dissection and thrombosed intramural dissection and thrombosed aneurysms which may both complicate aneurysms which may both complicate evaluation of stroke patientsevaluation of stroke patients
Early angiographic signs of strokes Early angiographic signs of strokes both CTA both CTA and DSA and DSA
Vessel occlusion or cutoff related to Vessel occlusion or cutoff related to thromboembolithromboemboli
aneurysms aneurysms arterial dissection arterial dissection Meniscus or flattened shape to clot Meniscus or flattened shape to clot
(recent) versus reverse meniscus (older)(recent) versus reverse meniscus (older) tram track (nonocclusive or recanalized tram track (nonocclusive or recanalized
clot) clot) delayed (antegrade) flow (manifest as delayed (antegrade) flow (manifest as
decreased whole-brain perfusion on CTA)decreased whole-brain perfusion on CTA) retrograde collateral flowretrograde collateral flow
Non-occlusive left MCA thrombus on 3-D imaging performed from CTA source data and was confirmed at catheter angiography
Therapy to be started within a 6-hr Therapy to be started within a 6-hr time to treatment (TTT) window time to treatment (TTT) window (while in case of IV thrombolysis (while in case of IV thrombolysis therapy to be started with in 3hrs)therapy to be started with in 3hrs)
Exclusion criteria Exclusion criteria Rapidly improving neurologic deficit or Rapidly improving neurologic deficit or Sustained blood pressure of gt180100 Sustained blood pressure of gt180100 Hemorrhage is detected on CTHemorrhage is detected on CT Infarct involving gt more than 13 rd Infarct involving gt more than 13 rd
territory of MCAterritory of MCA MRADWI-Perfusion mismatchlt 20MRADWI-Perfusion mismatchlt 20 Definite hypodensity on CTDefinite hypodensity on CT
Intra-arterial Thrombolysis
Fibrinolytics + AntiplateletsFibrinolytics + Antiplatelets
PlasminogenPlasminogen activators through fibrinolysis exposes activators through fibrinolysis exposes free thrombin and paradoxically stimulatesfree thrombin and paradoxically stimulates platelet platelet aggregation which leads to formation of aaggregation which leads to formation of a platelet platelet thrombus (white clot) thrombus (white clot)
This new thrombus is relatively resistant to This new thrombus is relatively resistant to fibrinolyticsfibrinolytics
So new regimen in case of acute stroke isSo new regimen in case of acute stroke is fibrinolytics + antiplatelet drugsfibrinolytics + antiplatelet drugs
rtPA + IIbIIIa inhibitors( tirofiban rtPA + IIbIIIa inhibitors( tirofiban abciximab) orabciximab) or
Urokinase + IIbIIIa Urokinase + IIbIIIa inhibitors( tirofiban abciximab)inhibitors( tirofiban abciximab)
Intra-arterial Thrombolysis Tirofiban (04 microgkgmin bolus for 3 min followed by Tirofiban (04 microgkgmin bolus for 3 min followed by
0125 ugkgmin)0125 ugkgmin)
++
Heparin (2000ndash3000 IU bolus followed by Heparin (2000ndash3000 IU bolus followed by 1000 IUhour infusion 1000 IUhour infusion
with ACT maintained bw 200-300) throughout the with ACT maintained bw 200-300) throughout the interventional procedure and for 24ndash48 hours thereafter when interventional procedure and for 24ndash48 hours thereafter when there is neither intraprocedural bleeding nor suspicion of there is neither intraprocedural bleeding nor suspicion of increased risk of bleeding increased risk of bleeding
Maximum dose of Urokinase Maximum dose of Urokinase Anterior circulation stroke - 500000 IU (mean 400000 Anterior circulation stroke - 500000 IU (mean 400000
IU range 300000ndash500000 IU)IU range 300000ndash500000 IU) Posterior circulation stroke -1000000 IU (mean 837000 Posterior circulation stroke -1000000 IU (mean 837000
IU range 300000ndash1000000 IU)IU range 300000ndash1000000 IU)American Journal of NeuroradiologyAmerican Journal of Neuroradiology 262595-2601 2005262595-2601 2005
Intravenous ThrombolysisIntravenous Thrombolysis
The first method to restore cerebral The first method to restore cerebral perfusion is clot lysis with the goal perfusion is clot lysis with the goal of re-establishing blood flow to the of re-establishing blood flow to the affected tissue affected tissue
IV thrombolysis rt-PA is the only IV thrombolysis rt-PA is the only FDA- approved treatment for AIS FDA- approved treatment for AIS
Fibrinolysis is enhanced powerfully Fibrinolysis is enhanced powerfully by rt-PAby rt-PA
Intravenous rTPA Intravenous rTPA administration administration protocolprotocol
Total dose of rt-PA 09 mgkg (maximum dose Total dose of rt-PA 09 mgkg (maximum dose 90 mg)90 mg)
Give 10 as initial IV bolusGive 10 as initial IV bolus Infuse remainder over 1 hourInfuse remainder over 1 hour Admit patient to an ICU or stroke unit for Admit patient to an ICU or stroke unit for
monitoringmonitoring Neurologic assessments every 15 minutes Neurologic assessments every 15 minutes
during infusion then every 30 minutes for next during infusion then every 30 minutes for next 6 hours then every hour until 24hours after 6 hours then every hour until 24hours after treatmenttreatment
Favorable Outcome vs Treatment Time Favorable Outcome vs Treatment Time with IV rTPAwith IV rTPA
Protocol limit = 3 hrs
Benefit ~ 45 hrs
Thromboembolism During coilingThromboembolism During coiling Most feared and frequent complication Most feared and frequent complication Reported incidence - Approx 7 Reported incidence - Approx 7 SourcesSources of Thromboembolism are of Thromboembolism are
- Clots at the aneurysmal neck during or immediately- Clots at the aneurysmal neck during or immediately after after embolization embolization
- Thrombus forming on catheters during- Thrombus forming on catheters during proceduresprocedures
- Stenosis of an adjacent artery dt coil mass- Stenosis of an adjacent artery dt coil mass or herniationor herniation
- Migration of intraaneurysmal- Migration of intraaneurysmal thrombus during coil thrombus during coil placement placement
- Slow flow dt vasospasm - Slow flow dt vasospasm
- Rare and unlikely causes are hypercoagulable- Rare and unlikely causes are hypercoagulable state such state such as antiphospholipid antibody syndrome or due to HITas antiphospholipid antibody syndrome or due to HIT
Occur more often with wide-necked aneurysms (dt Occur more often with wide-necked aneurysms (dt increased exposed surface area of thrombogenic coil increased exposed surface area of thrombogenic coil material)material)
Current regimen of endovascular Current regimen of endovascular managementmanagement
The The glycoprotein IIbIIIa antagonist tirofiban glycoprotein IIbIIIa antagonist tirofiban (04 (04 microgkgmin bolus for 30 minutes followed by infusion of microgkgmin bolus for 30 minutes followed by infusion of 0125 ugkgmin until the thrombus dissolved) 0125 ugkgmin until the thrombus dissolved)
Intraarterial thrombolysis with Intraarterial thrombolysis with urokinase or r- TPA urokinase or r- TPA increase of intravenous (IV) heparin (measured by increase of intravenous (IV) heparin (measured by
ACT) ACT) Intravenous aspirin Intravenous aspirin
Coil-related platelet aggregation (white clot) is Coil-related platelet aggregation (white clot) is unlikely to respond to fibrinolytics but has a high risk unlikely to respond to fibrinolytics but has a high risk of hemorrhage (In ISAT) all 5 patients who had of hemorrhage (In ISAT) all 5 patients who had received thrombolytic therapy with tPA to treat a received thrombolytic therapy with tPA to treat a thromboembolic complication after endovascular thromboembolic complication after endovascular treatment rebleed and all of these patients died)treatment rebleed and all of these patients died)
IntracranialIntracranial Stenting Stenting Metallic foreign body such as stent will accumulate Metallic foreign body such as stent will accumulate
thrombus in the absence of platelet inhibitionthrombus in the absence of platelet inhibition Antiplatelet drugs are important to prevent peri or Antiplatelet drugs are important to prevent peri or
post-interventional thromboembolic eventspost-interventional thromboembolic events Optimal treatment regimens has not been determined Optimal treatment regimens has not been determined
but usually but usually Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-
procedureprocedureOrOr
Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on
morning of proceduremorning of procedure
If need to use stent is not pre-planned thanIf need to use stent is not pre-planned than
Abciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkgAbciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkg IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)
Glycoprotein IIbIIIa inhibitor are not used routinely during elective Glycoprotein IIbIIIa inhibitor are not used routinely during elective stenting procedure dt increased risk of ICH stenting procedure dt increased risk of ICH
Carotid StentingCarotid Stenting
Pre-procedurePre-procedure
Double Antiplatelet therapy is routinely given Double Antiplatelet therapy is routinely given beginning at least 3beginning at least 3
days before the proceduredays before the procedure
Aspirin 325mgd+Clopidogrel 75mgdAspirin 325mgd+Clopidogrel 75mgd During procedureDuring procedure
Heparin is given with target clotting time of 250-Heparin is given with target clotting time of 250-300sec300sec
Post-procedure Post-procedure
Aspirin 325mg is continued indefinitely and Aspirin 325mg is continued indefinitely and
Clopidogrel 75mgd for at least 6 weeks Clopidogrel 75mgd for at least 6 weeks
Inclusion criteria for Local ThrombolysisInclusion criteria for Local Thrombolysis a)a) Patients in severe clinical grade on admission Patients in severe clinical grade on admission
with evidence of dural venous sinus with evidence of dural venous sinus thrombosis and restrictive venous outflow on thrombosis and restrictive venous outflow on cerebral angiogramcerebral angiogram
b)b) Patients in clinical grade 3 worsening on Patients in clinical grade 3 worsening on heparin therapy Restriction to venous heparin therapy Restriction to venous outflow was defined as an increase in brain outflow was defined as an increase in brain circulation time gt 12 s delay in the drainage circulation time gt 12 s delay in the drainage of cortical veins with cortical veins hanging of cortical veins with cortical veins hanging in spacein space
Treatment Options for Venous Thrombosis
CT Grading for Venous ThrombosisCT Grading for Venous Thrombosis Grade I no parenchymal change Grade I no parenchymal change
(hyperdense (hyperdense sinuses cortical veins empty sinuses cortical veins empty delta sign)delta sign)
Grade II non hemorrhagic venous infarct Grade II non hemorrhagic venous infarct without mass effect without mass effect
Grade III non-hemorrhagic infarct with Grade III non-hemorrhagic infarct with mass effectmass effect
Grade IV hemorrhagic venous infarct (max Grade IV hemorrhagic venous infarct (max diameter lt 3 cm) with no mass effectdiameter lt 3 cm) with no mass effect
Grade V hemorrhagic venous infarct (max Grade V hemorrhagic venous infarct (max diameter gt 3 cm) with mass effect diameter gt 3 cm) with mass effect
Local ThrombolysisLocal Thrombolysis
Femoral Jugular access was secured and a guiding Femoral Jugular access was secured and a guiding catheter was placed in the jugular bulb catheter was placed in the jugular bulb Mechanical Mechanical clot maceration clot maceration was done with the guidewire was done with the guidewire following which a microcatheter (was navigated and following which a microcatheter (was navigated and placed in the thrombosed segment of sinus confirmed placed in the thrombosed segment of sinus confirmed on a selective venogram on a selective venogram
Urokinase infusion Bolus dose of 2-6 lacs followed Urokinase infusion Bolus dose of 2-6 lacs followed by 60000 to 100000 units per hour along with by 60000 to 100000 units per hour along with periodic check venogram Along with maintenance periodic check venogram Along with maintenance systemic infusion of Heparinsystemic infusion of Heparin Other agents such as Other agents such as streptokinase altepase or rTPAstreptokinase altepase or rTPA can be also used can be also used
After thrombolysis patient should subjected to oral After thrombolysis patient should subjected to oral anticoagulation for six monthsanticoagulation for six months
Low-molecular-weight Low-molecular-weight heparinheparin
PharmacologyPharmacologyLMWH as its name suggests is a glycosaminoglycan that is approximatelyLMWH as its name suggests is a glycosaminoglycan that is approximately
one third the molecular weight of UFH It is derived from UFH through one third the molecular weight of UFH It is derived from UFH through variousvarious
depolymerization processes LMWH binds to antithrombin which in turn depolymerization processes LMWH binds to antithrombin which in turn
Neutralizes actors Xa and IIa Because LMWH lacks many of the longer Neutralizes actors Xa and IIa Because LMWH lacks many of the longer chains chains
required for binding to thrombin it has less ability to neutralize thrombin required for binding to thrombin it has less ability to neutralize thrombin
relativeto its ability to neutralize factor Xa LMWH also has less relativeto its ability to neutralize factor Xa LMWH also has less nonspecific nonspecific
binding to other proteins There is greater bioavailability with more binding to other proteins There is greater bioavailability with more predictable predictable
pharmacokinetics that eliminates the need for monitoring The smaller pharmacokinetics that eliminates the need for monitoring The smaller size also size also
allows for enhanced subcutaneous absorption when compared with UFHallows for enhanced subcutaneous absorption when compared with UFH
Three LMWH preparations are Three LMWH preparations are currently approved for use in the currently approved for use in the United States (1) enoxaparin (2) United States (1) enoxaparin (2) dalteparin and (3) tinzaparin dalteparin and (3) tinzaparin
They are all administered They are all administered subcutaneously at intervals of either subcutaneously at intervals of either once or twice daily for both once or twice daily for both prophylaxis and treatment dosesprophylaxis and treatment doses
Few Experiences of Few Experiences of ThrombolysisThrombolysis
Vickey 25 Yrs male patient presented Vickey 25 Yrs male patient presented with 12with 12thth day HO severe headache with day HO severe headache with right sided hemiplegiaright sided hemiplegia
MRI shows thrombosis of the superior MRI shows thrombosis of the superior sagittal left transverse left sigmoid sagittal left transverse left sigmoid sinuses and cortical veins in the fronto-sinuses and cortical veins in the fronto-parietal regions with eo haemorrhagic parietal regions with eo haemorrhagic infarct in the left cerebral hemisphere infarct in the left cerebral hemisphere with mass effect( Grade ndashV)with mass effect( Grade ndashV)
Sashi Srivastava 64 yrs FSashi Srivastava 64 yrs F In a follow up case of MRD with infra-renal In a follow up case of MRD with infra-renal
aortic abdominal and bilateral renal artery aortic abdominal and bilateral renal artery thrombosis renal angiogram shows filling thrombosis renal angiogram shows filling defects in the right Renal artery defects in the right Renal artery
Initially Renal angioplasty was done Initially Renal angioplasty was done Following angioplasty few thrombi are seem Following angioplasty few thrombi are seem to extends into the segmental branches and to extends into the segmental branches and causing blockage So Thrombolysis was causing blockage So Thrombolysis was plane to dissolve the run-out thrombi with plane to dissolve the run-out thrombi with urokinase urokinase
Rakesh 34yrsMRakesh 34yrsM Left SFA pseudoaneurysm with Left SFA pseudoaneurysm with
Covered stent placementCovered stent placement Pre operative antiplatelets with post Pre operative antiplatelets with post
procedure heparin Tirofiban procedure heparin Tirofiban followed by aspirin and clopidogrel followed by aspirin and clopidogrel were usedwere used
IAT may be a treatment option for selected patients IAT may be a treatment option for selected patients Possible selection criteria include Possible selection criteria include
presentation between 3 and 6 hours from symptom onsetpresentation between 3 and 6 hours from symptom onset major cerebral artery occlusion major cerebral artery occlusion severe neurologic deficits severe neurologic deficits high risk of systemic hemorrhage with IV rt-PA (eg recent high risk of systemic hemorrhage with IV rt-PA (eg recent
surgery) surgery) The MERCI (Mechanical Embolus Removal in Cerebral The MERCI (Mechanical Embolus Removal in Cerebral
Ischemia) retrievalIschemia) retrieval system system
Has been FDA-approved for recanalizing acutely occluded Has been FDA-approved for recanalizing acutely occluded cerebral arteries cerebral arteries
In the Multi-MERCI study patients who did not improve In the Multi-MERCI study patients who did not improve immediately after IV rt-PA underwent mechanical immediately after IV rt-PA underwent mechanical embolectomy within 8 hours of symptom onset embolectomy within 8 hours of symptom onset
Partial or complete recanalization occurred in 74 of Partial or complete recanalization occurred in 74 of patientspatients
with a symptomatic intracerebral hemorrhage (sICH) rate of with a symptomatic intracerebral hemorrhage (sICH) rate of 67 67
Mechanical embolectomy with the MERCI retriever may be a Mechanical embolectomy with the MERCI retriever may be a feasible and safe option for patients after IV rt-PAfeasible and safe option for patients after IV rt-PA
Penumbra stroke systemPenumbra stroke system This device combines two methods of clot This device combines two methods of clot
extraction aspiration and mechanical extraction aspiration and mechanical extraction extraction
First the clot is aspirated then a thrombus First the clot is aspirated then a thrombus removal ring can be used if necessary to removal ring can be used if necessary to remove remaining clot remove remaining clot
successful recanalizing 82successful recanalizing 82 Bridging therapyBridging therapy
06 mgkg IV rt-PA followed by IAT with IA rt-06 mgkg IV rt-PA followed by IAT with IA rt-PA (up to 20 mg)PA (up to 20 mg)
achieved a higher recanalization rateachieved a higher recanalization rate
Criteria for thrombolysis with rTPACriteria for thrombolysis with rTPA
Inclusion criteriaInclusion criteria Clinical signs and symptoms consistent with ischemic Clinical signs and symptoms consistent with ischemic
strokestroke Patient last seen normal within 3 hoursPatient last seen normal within 3 hours Measurable neurologic deficitMeasurable neurologic deficit
Exclusion criteriaExclusion criteria Any hemorrhage on neuroimaging (CT or MRI)Any hemorrhage on neuroimaging (CT or MRI) Symptoms suggestive of subarachnoid hemorrhageSymptoms suggestive of subarachnoid hemorrhage Seizure at stroke onset that is thought to contribute to Seizure at stroke onset that is thought to contribute to
neurologic deficitneurologic deficit Hypodensity greater than one third cerebral hemisphere Hypodensity greater than one third cerebral hemisphere
on CTon CT SBP greater than 185 mm Hg or DBP greater than 110 SBP greater than 185 mm Hg or DBP greater than 110
mm Hgmm Hg International normalized ratio (INR) greater than 17International normalized ratio (INR) greater than 17
Ischemic Stroke Ischemic Stroke Treatment ndash 2006Treatment ndash 2006
IV tissue plasminogen activator (tPA)IV tissue plasminogen activator (tPA) ndash ndash Only FDA-approved acute stroke drugOnly FDA-approved acute stroke drug ndash ndash 3 hour treatment window3 hour treatment window
MERCI - Concentric clot retrieval MERCI - Concentric clot retrieval devicedevice ndash ndash Rescue therapy - approved 2004Rescue therapy - approved 2004 ndash ndash Device approval (not outcomes-based)Device approval (not outcomes-based)
Off label approachesOff label approaches ndash ndash IV tPA after 3 hoursIV tPA after 3 hours ndash ndash IV-IA tPA sequential strategiesIV-IA tPA sequential strategies ndash ndash IA tPA clot angioplasty fragmentationIA tPA clot angioplasty fragmentation ndash ndash Ultrasound-assisted tPA lysisUltrasound-assisted tPA lysis
rt-PA Trials NINDSrt-PA Trials NINDS
Acute stroke - 624 patientsAcute stroke - 624 patients Treat within 3 hrsTreat within 3 hrs Intravenous 09 mgkg rt-PA vs placeboIntravenous 09 mgkg rt-PA vs placebo Hemorrhage 64 tPA 06 placeboHemorrhage 64 tPA 06 placebo Neurologic recovery better with tPA 30 Neurologic recovery better with tPA 30
more like to have minimal or no disabilitymore like to have minimal or no disability
First proven approved treatment for First proven approved treatment for strokestroke
Limitations of tPALimitations of tPA Only 4 of acute strokes receive tPAOnly 4 of acute strokes receive tPA (Kleindorfer et al Stroke 2004 35 e27-e29)(Kleindorfer et al Stroke 2004 35 e27-e29)
Only 22 of patients present within 3 hoursOnly 22 of patients present within 3 hours1048707 1048707 51 of these ineligible due to51 of these ineligible due to
bull bull Mild severityMild severity bull bull Medical or surgical historyMedical or surgical history bull bull Blood testsBlood tests
Sustained recanalization only 13Sustained recanalization only 13 (Alexandrov et al NEJM 2004 351 2170-8)(Alexandrov et al NEJM 2004 351 2170-8)
Concern for hemorrhageConcern for hemorrhage tPA potentiates apoptotic injury tPA potentiates apoptotic injury (Liu et al Nature Med 2004 101379-83)(Liu et al Nature Med 2004 101379-83)
PROACT II IA Lysis TrialPROACT II IA Lysis Trial Baseline 24 hours 8 days
Baseline 60 minutes 120 minutes
9mg IAProurokinase
Desmoteplase Trials DEDAS Desmoteplase Trials DEDAS DIASDIAS
Trial OverviewTrial Overview Double blind randomized placebo Double blind randomized placebo
controlled trialscontrolled trials IV delivery 3-9 hour time windowIV delivery 3-9 hour time window Plasminogen activator ndash from Plasminogen activator ndash from vampire bat vampire bat
salivasaliva Selection based on PWI-DWI MismatchSelection based on PWI-DWI Mismatch
MRI InclusionMRI Inclusion PWI defect at least 2 cm AND ~20 larger PWI defect at least 2 cm AND ~20 larger
than DWIthan DWI PWI should be obvious even visible on PWI should be obvious even visible on
raw imagesraw imagesMRI ExclusionMRI Exclusion
DWI gt 13 MCADWI gt 13 MCA MRA ICA occlusionMRA ICA occlusion
Desmoteplase ndash DIAS Desmoteplase ndash DIAS ResultsResults
Mechanical Thrombolysis Mechanical Thrombolysis devicesdevices
mechanical thrombolysis potentially extends the treatment mechanical thrombolysis potentially extends the treatment window because they act promptly at the site of the thrombuswindow because they act promptly at the site of the thrombus
The devices can retrieve large clots that pharmaceutical agents The devices can retrieve large clots that pharmaceutical agents may not successfully lysemay not successfully lyse
Patients treated with IV tPA may be considered for treatment of Patients treated with IV tPA may be considered for treatment of residual clot with some of these devicesresidual clot with some of these devices
suction-creating saline jets suction-creating saline jets laser energy ultrasound laser energy ultrasound a corkscrew apparatus to treat strokesa corkscrew apparatus to treat strokes The AngioJet systemThe AngioJet system uses saline jets that are directed back into the catheter to uses saline jets that are directed back into the catheter to
create a low-pressure zone around the catheter tip inducing create a low-pressure zone around the catheter tip inducing suction suction
The clot is pulled into the exhaust lumen and removed from the The clot is pulled into the exhaust lumen and removed from the vessel Although US Food and Drug Administration (FDA) has vessel Although US Food and Drug Administration (FDA) has approved this device for use in arteriovenous dialysis grafts and approved this device for use in arteriovenous dialysis grafts and fistulae and for the treatment of coronary arteries saphenous fistulae and for the treatment of coronary arteries saphenous vein grafts and peripheral vessels clinical trials for the vein grafts and peripheral vessels clinical trials for the treatment of acute stroke are no longer in progress treatment of acute stroke are no longer in progress
Most devices are used in cerebral vessels that 2-5 mm
The Latis laser device The Latis laser device used laser energy to ablate clots used laser energy to ablate clots Arteries 2-5 mm in diameter could be Arteries 2-5 mm in diameter could be
treated including the ICA M1 or M2 treated including the ICA M1 or M2 branch of the MCA A1 branch of the branch of the MCA A1 branch of the anterior cerebral artery (ACA) basilar anterior cerebral artery (ACA) basilar artery posterior cerebral artery (PCA) artery posterior cerebral artery (PCA) and vertebral and vertebral
Patients could receive treatment as late Patients could receive treatment as late as 8 hours after symptom onset in the as 8 hours after symptom onset in the anterior circulation and within 24 hours in anterior circulation and within 24 hours in the posterior circulation the posterior circulation
Endovascular Photo Acoustic Endovascular Photo Acoustic Recanalization (EPAR) Recanalization (EPAR)
A laser power source generated energy for the A laser power source generated energy for the systemsystem
The energy was delivered by means of The energy was delivered by means of fiberoptics to the tip of the catheter at the fiberoptics to the tip of the catheter at the treatment sitetreatment site
Absorption of laser light by darkly pigmented Absorption of laser light by darkly pigmented materials (ie the clot) occurred inside the 1-mm materials (ie the clot) occurred inside the 1-mm catheter tipcatheter tip
the system was designed to minimize scattering the system was designed to minimize scattering of laser light of laser light
Absorption converted photo energy to acoustic Absorption converted photo energy to acoustic energy which then emulsified the clot inside the energy which then emulsified the clot inside the catheter tip catheter tip
EKOS ultrasound( the EKOS ultrasound( the Ultrasound Thrombolytic Ultrasound Thrombolytic
Infusion Catheter) Infusion Catheter) combines the use of a distal ultrasound transducer with combines the use of a distal ultrasound transducer with
infusion of a thrombolytic agent through the infusion of a thrombolytic agent through the microcathetermicrocatheter
Ultrasound changes the structure of the clot to Ultrasound changes the structure of the clot to temporarily increase its permeability while providing an temporarily increase its permeability while providing an acoustic pressure gradient to move the drug into the clot acoustic pressure gradient to move the drug into the clot to speed its dissolution to speed its dissolution
The EKOS catheter is placed in the proximal portion of the The EKOS catheter is placed in the proximal portion of the clot clot
After a 2-mg bolus of tPA was injected through the After a 2-mg bolus of tPA was injected through the catheter catheter
the patient received a continuous infusion of IA tPA 03 the patient received a continuous infusion of IA tPA 03 mgmin to a maximum of 20 mg and simultaneous mgmin to a maximum of 20 mg and simultaneous ultrasound transmission for as long as 60 minutes ultrasound transmission for as long as 60 minutes
One patient was treated with a total of 4 units of One patient was treated with a total of 4 units of recombinant reteplase (Retavase) hand-injected over 60 recombinant reteplase (Retavase) hand-injected over 60 minutes minutes
Penumbra system Penumbra system The Penumbra system (Penumbra Inc) provides a dual The Penumbra system (Penumbra Inc) provides a dual
approach to clot extraction using aspiration followed by approach to clot extraction using aspiration followed by clot retrieval with a ring device if needed clot retrieval with a ring device if needed
Mechanical Embolus Removal in Cerebral Ischemia Mechanical Embolus Removal in Cerebral Ischemia (MERCI)(MERCI)
a corkscrew-like apparatus to remove blood clots from a corkscrew-like apparatus to remove blood clots from the brain in patients experiencing an ischemic stroke the brain in patients experiencing an ischemic stroke
The corkscrew itself resides in the catheter tip which The corkscrew itself resides in the catheter tip which shields it from the wall of the vessel until it is ready to be shields it from the wall of the vessel until it is ready to be burrowed into the clot Once lodged in the clot the device burrowed into the clot Once lodged in the clot the device and clot are withdrawn from the vessel and clot are withdrawn from the vessel
Snarelike devicesSnarelike devices Snares such as the Neuronet snare (Guidant Snares such as the Neuronet snare (Guidant
Endovascular Santa Clara CA) have been developed Endovascular Santa Clara CA) have been developed specifically for use in the treatment of strokes specifically for use in the treatment of strokes
These devices are simple in design and do not require the These devices are simple in design and do not require the clot to be amenable to emulsification clot to be amenable to emulsification
X-Sizer deviceX-Sizer device a device with small moving blades at the a device with small moving blades at the
catheter tip catheter tip This device the X-Sizer device (EndiCor Medical This device the X-Sizer device (EndiCor Medical
San Clemente CA) can be used to excise the San Clemente CA) can be used to excise the thrombus and aspirate it thrombus and aspirate it
The device was being evaluated in randomized The device was being evaluated in randomized studies of coronary vessels and in a registry of studies of coronary vessels and in a registry of patients with acute myocardial infarctionpatients with acute myocardial infarction
Although the manufacturer had modified the Although the manufacturer had modified the device for use in cerebral vessels a safety and device for use in cerebral vessels a safety and feasibility study was indefinitely suspended after feasibility study was indefinitely suspended after only 1 patient was treated with the device in only 1 patient was treated with the device in Europe Europe
Suction thrombectomySuction thrombectomy This method of mechanical thrombolysis is one of the This method of mechanical thrombolysis is one of the
simplestsimplest In this readily available technique suction is applied with In this readily available technique suction is applied with
a syringe to remove thrombus in the ICA a syringe to remove thrombus in the ICA It requires no other devicesIt requires no other devices A catheter with a large inner diameter (Brite Tip Cordis A catheter with a large inner diameter (Brite Tip Cordis
Corporation Miami FL) was placed in the symptomatic Corporation Miami FL) was placed in the symptomatic vessel and navigated over a guidewire into the thrombusvessel and navigated over a guidewire into the thrombus
A 60-mL syringe was used to aspirate the thrombus A 60-mL syringe was used to aspirate the thrombus Each patient required angioplasty and stenting of carotid Each patient required angioplasty and stenting of carotid
bifurcation stenosis and received daily aspirin and bifurcation stenosis and received daily aspirin and ticlopidine after the procedure No complications ticlopidine after the procedure No complications occurred occurred
Summary Acute Stroke Summary Acute Stroke ImagingImaging
PhysiologyPhysiology importance collaterals importance collaterals
ndash ndashGrowing role for perfusion Growing role for perfusion assessmentassessment
tPAtPA guidelines amp limitations guidelines amp limitations Signs on CT amp MRSigns on CT amp MR follow physiology follow physiology Stroke trialsStroke trials PWI-DWI mismatch PWI-DWI mismatch
ndash ndashTreat based on physiology not timeTreat based on physiology not time ProtocolsProtocols should be fast and should be fast and
comprehensivecomprehensive
Monitoring of Monitoring of Anti platelet drugsAnti platelet drugs
Bleeding timeBleeding time
Optical aggregometryOptical aggregometry
Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay
HeparinHeparin
Heterogeneous 3000-30000 dalton in Heterogeneous 3000-30000 dalton in molecular weight molecular weight
Average=15000 d (~45monosaccharide Average=15000 d (~45monosaccharide chains)chains)
About About 13 of dose binds to AT III and forms 13 of dose binds to AT III and forms the AT IIIHeparinClotting Factor Complexthe AT IIIHeparinClotting Factor Complex
Complex binds to clotting factors of the Complex binds to clotting factors of the intrinsic and common pathway (Xa IIa IXa intrinsic and common pathway (Xa IIa IXa XIa XIIa XIIIa) and inactivates themXIa XIIa XIIIa) and inactivates them
Anticoagulant of choice in pregnancy (not Anticoagulant of choice in pregnancy (not crosses placenta)crosses placenta)
Heparin and Low molecular weight heparinsHeparin and Low molecular weight heparins
Structure and sequence
O
OH
OH
O
COO
O
O
CH2OH
NHSO3
OH
_
_
O
O
CH2OSO3
NHSO3
OH
_
_
O
OH
OH
O
COOO
O
CH2OSO3
NHSO3
OH
_
_
O
OSO3
OHO
COOO
O
CH2OSO3
NHCOCH3
OH
_
_ _
_
_
O
OH
OH
O
COO
1
23
4
5
6
-D-glucosamine -L-iduronic acid -D-glucuronic acid
O
O
CH2OH
NH2
OH 12
3
4
5
6
O
OH
OHO
COO_
1
23
4
5
6
polymeric structure of heparin
Anticoagulant Properties of Anticoagulant Properties of HeparinHeparin
11 Inhibits the thrombin-mediated conversion of Inhibits the thrombin-mediated conversion of fibrinogen to fibrinfibrinogen to fibrin
22 Inhibits the aggregation of platelets by thrombin Inhibits the aggregation of platelets by thrombin (prolongs bleeding time)(prolongs bleeding time)
33 Inhibits activation of fibrin stabilizing enzymeInhibits activation of fibrin stabilizing enzyme
44 Inhibits activated factors XII XI IX X and IIInhibits activated factors XII XI IX X and II All available forms of heparin must be All available forms of heparin must be
administered administered parenterally since they are parenterally since they are highly charged and rapidlyhighly charged and rapidly hydrolyzed in the hydrolyzed in the GI tractGI tract
Heparin antagonist Protamine sulfate (Heparin antagonist Protamine sulfate (10mg for 10mg for 1000 unit of heparin)1000 unit of heparin)
Monitoring of heparin Monitoring of heparin
Subcutenous Subcutenous no monitoring requiredno monitoring required Intravenous Intravenous
Partial thromboplastin time (PTT normal value Partial thromboplastin time (PTT normal value ~30sec) ~30sec)
Activated clotting time ( ACT normal value ~90-Activated clotting time ( ACT normal value ~90-120sec)120sec)
Daily or more frequent if PTT ACT variesDaily or more frequent if PTT ACT varies
Mechanism Mechanism ndash measures intrinsic pathwayndash measures intrinsic pathway Therapeutic goal Therapeutic goal 2-25 times normal control value 2-25 times normal control value
ACT or aPTTACT or aPTT
Determine when to pull the femoral sheath Determine when to pull the femoral sheath Premature sheath pull can lead to bleedingPremature sheath pull can lead to bleeding Delayed removal can increase time in ICUDelayed removal can increase time in ICU Target set Target set at each siteat each site
ACT targets range from 150 ndash 220 ACT targets range from 150 ndash 220 secondsseconds
aPTT targets range from 40 ndash 70 seconds aPTT targets range from 40 ndash 70 seconds
During neuroangiography-During neuroangiography- Recommended therapeutic range of heparin in Recommended therapeutic range of heparin in
plasma is 02-08 uml ( corresponding to aPTT plasma is 02-08 uml ( corresponding to aPTT ACT values 15-25 times the baseline values)ACT values 15-25 times the baseline values)
Dose In diagnostic angiography bolus dose of Dose In diagnostic angiography bolus dose of 2500 iu is used followed by 1000 iu hour2500 iu is used followed by 1000 iu hour
Bolus dose is Bolus dose is 60 ukg to maintain the therapeutic 60 ukg to maintain the therapeutic range range If procedure continues for more than 75 If procedure continues for more than 75 minutes additional dose is required ( half of the minutes additional dose is required ( half of the initial dose for another 75 minutes) initial dose for another 75 minutes)
(AJNR 199415 51-54)
Mechanisms of HIT( Mechanisms of HIT( Heparin Heparin induced Thrombocytopeniainduced Thrombocytopenia))
Type 1Type 1 Fall in platelet count occurs within the first two Fall in platelet count occurs within the first two
days after heparin initiation often returns to days after heparin initiation often returns to normal with continued heparin administration normal with continued heparin administration and is of no clinical consequence and is of no clinical consequence
The mechanism of the thrombocytopenia is non-The mechanism of the thrombocytopenia is non-immune and appears to be due to a direct effect of immune and appears to be due to a direct effect of heparin on platelet activationheparin on platelet activation
Type 2Type 2 Approximately 03 to 3 percent of patients Approximately 03 to 3 percent of patients
receiving heparin develop an immune receiving heparin develop an immune thrombocytopenia mediated by antibodies to a thrombocytopenia mediated by antibodies to a heparin-platelet factor 4 complex heparin-platelet factor 4 complex
(AJNR 28155-158 2007)
Treatment of heparin-induced Treatment of heparin-induced thrombocytopeniathrombocytopenia
When HIT is diagnosed it is important to When HIT is diagnosed it is important to stop heparin mainly in type 2 and to avoid stop heparin mainly in type 2 and to avoid the use of LMWH the use of LMWH
Because of the increased risk of thrombosis Because of the increased risk of thrombosis however continuation of an anticoagulant however continuation of an anticoagulant must be considered must be considered
The drugs currently approved for the The drugs currently approved for the treatment of HIT in the United States are treatment of HIT in the United States are direct thrombin inhibitors argatroban and direct thrombin inhibitors argatroban and lepirudinlepirudin
WARFARIN MECHANISM OF ACTIONWARFARIN MECHANISM OF ACTION
Inactive factors II VII IX and X
Proteins S and C
Active factors II VII IX and X
Proteins S and C
Vitamin K epoxide
Vitamin K reduced
WA
RF
AR
IN
Prevents the reduction of vitamin K which is essential for Prevents the reduction of vitamin K which is essential for activation of certain factorsactivation of certain factors
Has no effect on previously formed thrombusHas no effect on previously formed thrombus
Antagonist is Vit KAntagonist is Vit K
OPTIMIZING WARFARIN THERAPYOPTIMIZING WARFARIN THERAPY
Use of large loading dose may lead to hemorrhage and Use of large loading dose may lead to hemorrhage and other complicationsother complications
Initial dose 2-5 mg once dailyInitial dose 2-5 mg once daily Maintenance dose 2-10 mg once dailyMaintenance dose 2-10 mg once daily If Immediate anticoagulation is requiredIf Immediate anticoagulation is required Heparin IS Heparin IS
started along with loading dose of warfarin 10 mg started along with loading dose of warfarin 10 mg Heparin is usually discontinued after 4-5 days Heparin is usually discontinued after 4-5 days Before Before discontinuing INR should be in therapeutic range for 2 discontinuing INR should be in therapeutic range for 2 consecutive daysconsecutive days
Daily monitoring of INR until INR is in therapeutic Daily monitoring of INR until INR is in therapeutic range then 3 times weekly for 1-2 weeks then less often range then 3 times weekly for 1-2 weeks then less often (every 4 to 6 weeks)(every 4 to 6 weeks)
OPTIMAL THERAPEUTIC RANGEOPTIMAL THERAPEUTIC RANGE
IndicationIndication INRINR
Prophylaxis of venous Prophylaxis of venous thromboembolismthromboembolism
20-3020-30
Treatment of venous Treatment of venous thromboembolismthromboembolism
20-3020-30
Atrial fibrillationAtrial fibrillation 20-3020-30
Mitral valve stenosisMitral valve stenosis 20-3020-30
Heart valve replacementHeart valve replacement
Bioprosthetic valveBioprosthetic valve
Mechanical valveMechanical valve
20-3020-30
25-3525-35
Myocardial infarctionMyocardial infarction 20-3020-30
25-35 25-35 (high risk patients)(high risk patients)
FACTORS INFLUENCING DOSE RESPONSEFACTORS INFLUENCING DOSE RESPONSE
Poor patient compliancePoor patient compliance Concomitant medicationsConcomitant medications Levels of dietary vitamin KLevels of dietary vitamin K Alcohol Inaccurate lab testingAlcohol Inaccurate lab testing Inaccurate lab testingInaccurate lab testing Hepatic dysfunctionHepatic dysfunction FeverFever
Contraindication for WarfarinContraindication for Warfarin
Hypersensitivity to warfarinHypersensitivity to warfarin Hemorrhagic tendencyHemorrhagic tendency Condition with risk of hemorrhageCondition with risk of hemorrhage Inadequate laboratory techniquesInadequate laboratory techniques Protein C amp S deficiencyProtein C amp S deficiency Vitamin K deficiencyVitamin K deficiency
SIDE EFFECTSSIDE EFFECTS
Hemorrhage Hemorrhage Skin necrosisSkin necrosis Purple toe syndromePurple toe syndrome Microembolization Microembolization TeratogenecityTeratogenecity Agranulocytosis leukopenia Agranulocytosis leukopenia Diarrhoeanausea anorexiaDiarrhoeanausea anorexia
MONITORING OF WARFARIN THERAPYMONITORING OF WARFARIN THERAPY
Prothrombin timeProthrombin time PT ratioPT ratio INR (International Normalized Ratio)INR (International Normalized Ratio)
PROTHROMBIN TIME (PT)PROTHROMBIN TIME (PT)
Time required for blood to coagulate Time required for blood to coagulate is called PT ( normal value ~10sec)is called PT ( normal value ~10sec)
Performed by adding a mixture of Performed by adding a mixture of calcium and thromboplastin to calcium and thromboplastin to citrated plasmacitrated plasma
As a control a normal blood sample is As a control a normal blood sample is tested continuouslytested continuously
PT ratio (PTR) = PT ratio (PTR) = Patientrsquos PTPatientrsquos PT Control PTControl PT
PROBLEMS WITH PTPTRPROBLEMS WITH PTPTR
Thromboplastins are extracts from Thromboplastins are extracts from brain lung or placenta of animalsbrain lung or placenta of animals
Thromboplastins from various Thromboplastins from various manufacturers differ in their manufacturers differ in their sensitivity to prolong PTsensitivity to prolong PT
May result in false control of May result in false control of anticoagulant therapyanticoagulant therapy
INTERNATIONAL NORMALISED RATIO (INR)INTERNATIONAL NORMALISED RATIO (INR)
International Normalized Ratio (INR) International Normalized Ratio (INR) a PT test with a a PT test with a formula based ratio to normalize the often variable source formula based ratio to normalize the often variable source of tissue factor (human rabbit recombinant)of tissue factor (human rabbit recombinant)
INR = [PTINR = [PTptpt] ] ISIISI
[PT[PTRefRef]]
PTPTpt pt ndash prothrombin time of patientndash prothrombin time of patient
PTPTRef Ref ndash prothrombin time of normal pooled samplendash prothrombin time of normal pooled sample
ISI ndash International Sensitivity IndexISI ndash International Sensitivity Index
Warfarin is given orally and titrated to achieve an INR of Warfarin is given orally and titrated to achieve an INR of typically 20 ndash 30typically 20 ndash 30
Heparin versus WarfarinHeparin versus Warfarin
Drug ActionMechan-ism
Moni-toring
Effective
HeparinDirect
Inhibition ofThrombin
ATIIIcofactor
APTTACT
Immediate
WarfarinDecreasesProductionof factors
Vitamin K PTDelay
3-5 days
INR
Recanalization or Antegrade Recanalization or Antegrade Reperfusion StrategiesReperfusion Strategies
Recanalization strategies focus on removing Recanalization strategies focus on removing andor dissolving the occlusive thrombus to re-andor dissolving the occlusive thrombus to re-establish antegrade flow Strategies may be establish antegrade flow Strategies may be classified into 7 different categories on the classified into 7 different categories on the basis of their primary mechanism of action basis of their primary mechanism of action 1) 1) IV andor intraarterial thrombolysis (IAT) IV andor intraarterial thrombolysis (IAT) 2) endovascular thrombectomy2) endovascular thrombectomy3) endovascular thromboaspiration 3) endovascular thromboaspiration 4) endovascular mechanical thrombus disruption or 4) endovascular mechanical thrombus disruption or
thromborrhexisthromborrhexis5) 5) transcranial or endovascular augmented transcranial or endovascular augmented
fibrinolysis fibrinolysis 6) endovascular thrombus entrapment and 6) endovascular thrombus entrapment and 7) temporary endovascular bypass7) temporary endovascular bypass
IAT in Acute Ischemic StrokeIAT in Acute Ischemic Stroke
IAT advantages over IV thrombolysisIAT advantages over IV thrombolysis Coaxial microcatheter techniques the occluded intracranial Coaxial microcatheter techniques the occluded intracranial
vessel is directly accessible and the fibrinolytic agent can be vessel is directly accessible and the fibrinolytic agent can be infused directly into the thrombusinfused directly into the thrombus
This permits a smaller dose of fibrinolytic agent to reach a This permits a smaller dose of fibrinolytic agent to reach a higher local concentration than that reached by systemic higher local concentration than that reached by systemic infusioninfusion
Allows more complete recanalization with lower total doses of Allows more complete recanalization with lower total doses of thrombolytic thrombolytic
With the smaller dose complications from systemic fibrinolytic With the smaller dose complications from systemic fibrinolytic effects including intracranial hemorrhage (ICH) can effects including intracranial hemorrhage (ICH) can theoretically be reduced theoretically be reduced
Treatment window for endovascular techniques can be Treatment window for endovascular techniques can be extended beyond the typical IV window of 3 hours extended beyond the typical IV window of 3 hours
IA techniques have led to higher recanalization rates than IV IA techniques have led to higher recanalization rates than IV thrombolysisthrombolysis
Major disadvantagesMajor disadvantages Relative complexity of the procedure the level Relative complexity of the procedure the level
of required technical expertise and its of required technical expertise and its relatively low availability relatively low availability
Delays in initiating treatmentDelays in initiating treatment InvasiveInvasive
ThrombolyticsThrombolytics
Plasminogen activators
Fibrinolytics
1 Plasminogen Activators 1 Plasminogen Activators drugs act by converting the inactive proenzyme drugs act by converting the inactive proenzyme plasminogen into the active enzyme plasmin Plasmin plasminogen into the active enzyme plasmin Plasmin digests fibrinogen fibrin monomers and cross-linked digests fibrinogen fibrin monomers and cross-linked fibrin (as found in a thrombus) into fibrin degradation fibrin (as found in a thrombus) into fibrin degradation productsproducts
First-Generation Agents First-Generation Agents StreptokinaseStreptokinase a protein derived from group C a protein derived from group C
szlig-hemolytic streptococci has a half-life of 16ndashszlig-hemolytic streptococci has a half-life of 16ndash90 minutes and low fibrin specificity This drug 90 minutes and low fibrin specificity This drug proved to have a very narrow therapeutic proved to have a very narrow therapeutic window and significant rates of ICH and window and significant rates of ICH and systemic hemorrhage18systemic hemorrhage18
UrokinaseUrokinase is a serine protease with a plasma is a serine protease with a plasma half life of 14 minutes and low fibrin specificity half life of 14 minutes and low fibrin specificity
The urokinase dose used in cerebral IAT has The urokinase dose used in cerebral IAT has ranged from 002 to 2 X106unitsranged from 002 to 2 X106units
Second-Generation Agents Second-Generation Agents Alteplase (rtPA) Alteplase (rtPA)
is a serine is a serine protease with a plasma half-life of 35 protease with a plasma half-life of 35 minutes and a high degree of fibrin affinity and minutes and a high degree of fibrin affinity and specificity specificity
Dose used in cerebral IAT has ranged between 20 Dose used in cerebral IAT has ranged between 20 and 60 mgand 60 mg
Disadvantages of alteplase include its relatively short Disadvantages of alteplase include its relatively short halflife and limited penetration into the clot matrix halflife and limited penetration into the clot matrix because of strong binding with surface fibrin which because of strong binding with surface fibrin which could delay recanalization and increase the risk of could delay recanalization and increase the risk of recurrent occlusion recurrent occlusion
Prourokinase (r-prourokinase) Prourokinase (r-prourokinase) is the proenzyme precursor of urokinase is the proenzyme precursor of urokinase T12 of 7 minutes and high fibrin specificity T12 of 7 minutes and high fibrin specificity
Third-Generation AgentsThird-Generation Agents
ReteplaseReteplase is a structurally modified is a structurally modified form of alteplase form of alteplase
with a longer half-life (15ndash18 minutes) In with a longer half-life (15ndash18 minutes) In addition it does not bind as highly to fibrin addition it does not bind as highly to fibrin unbound reteplase can thus theoretically better unbound reteplase can thus theoretically better penetrate the clot and potentially penetrate the clot and potentially improve in improve in vivo fibrinolytic activity vivo fibrinolytic activity
TenecteplaseTenecteplase is another modified form of rtPA with a longer is another modified form of rtPA with a longer
half-life (17 minutes)half-life (17 minutes) greater fibrin specificity and greater greater fibrin specificity and greater
resistance to plasminogen activator inhibitor-1 resistance to plasminogen activator inhibitor-1 IV tenecteplase in acute ischemic stroke IV tenecteplase in acute ischemic stroke
suggest that the drug is safe and promisingsuggest that the drug is safe and promising
Newer plasminogen activatorNewer plasminogen activator
DesmoteplaseDesmoteplase is a genetically engineered is a genetically engineered version of the clot-dissolving factor version of the clot-dissolving factor
found in the saliva found in the saliva of the vampire bat Desmodus rotundusof the vampire bat Desmodus rotundus moremore potent and more selective for fibrin-bound potent and more selective for fibrin-bound
plasminogen than any other known plasminogen plasminogen than any other known plasminogen activatoractivator
Unlike tissue plasminogen activator (tPA) desmoteplase Unlike tissue plasminogen activator (tPA) desmoteplase is not activated by fibrinogen or -amyloid proteins is not activated by fibrinogen or -amyloid proteins factors that may exacerbate the risk for ICH factors that may exacerbate the risk for ICH
The effect of IV administration of desmoteplase 3ndash9 The effect of IV administration of desmoteplase 3ndash9 hours after symptom onset in patients with stroke who hours after symptom onset in patients with stroke who present with mismatch on MR imaging or CT perfusion present with mismatch on MR imaging or CT perfusion
3 DefibrinogenatingFibrinogenolytic 3 DefibrinogenatingFibrinogenolytic Agents Agents
AncrodAncrod(Viprinex)(Viprinex) is is the purified fraction of the Malayan pit viper venomthe purified fraction of the Malayan pit viper venom It acts by directly cleaving and inactivating fibrinogen It acts by directly cleaving and inactivating fibrinogen
and thus indirectly promoting anticoagulation and thus indirectly promoting anticoagulation The reduction in the blood levels of fibrinogen also The reduction in the blood levels of fibrinogen also
leads to a reduced blood viscosity which may improve leads to a reduced blood viscosity which may improve blood flow to the affected areas of the brain blood flow to the affected areas of the brain
In the Stroke Treatment with Ancrod Trial 500 In the Stroke Treatment with Ancrod Trial 500 patients with stroke presenting within 3 hours of patients with stroke presenting within 3 hours of symptom onset were randomized to receive ancrod (symptom onset were randomized to receive ancrod (n n 248) or a placebo (n 252) Good outcome (Barthel 248) or a placebo (n 252) Good outcome (Barthel Index 95ndash100 at 3 months) was achieved in 4221 Index 95ndash100 at 3 months) was achieved in 4221 and 344 of the patients respectively and 344 of the patients respectively
2 Direct Fibrinolytics2 Direct Fibrinolytics
Microplasmin (Microplasmin (ThromboGenics Heverlee Belgium)ThromboGenics Heverlee Belgium) is a truncated form of plasmin that is more resistant to the effects is a truncated form of plasmin that is more resistant to the effects
of antiplasmin of antiplasmin microplasmin can be used upto 4ndash12 hours after stroke onset microplasmin can be used upto 4ndash12 hours after stroke onset There was no evidence of increased bleeding risk with There was no evidence of increased bleeding risk with
microplasminmicroplasmin
Alfimeprase (Nuvelo San Carlos Calif)Alfimeprase (Nuvelo San Carlos Calif) is a recombinant truncated form of fibrolase a fibrinolytic zinc metalloproteinase is a recombinant truncated form of fibrolase a fibrinolytic zinc metalloproteinase
isolated from the venom of the southern copperhead snake isolated from the venom of the southern copperhead snake It degrades fibrin directly and achieves thrombolysis independent It degrades fibrin directly and achieves thrombolysis independent
of plasmin formationof plasmin formation its thrombolytic activity appears to be localized to the site of its thrombolytic activity appears to be localized to the site of
delivery These properties should theoretically result in faster delivery These properties should theoretically result in faster recanalization and lower hemorrhagic conversion riskrecanalization and lower hemorrhagic conversion risk
Anti-fibrinolyticsAnti-fibrinolytics
to limit fibrinolytic activityto limit fibrinolytic activity -aminocaproic acid (EACA) -aminocaproic acid (EACA) competitively inhibitscompetitively inhibits plasminogen and plasminogen activators from plasminogen and plasminogen activators from
binding to fibrinbinding to fibrin
alpha2-antiplasminalpha2-antiplasmin a serine protease inhibitor that a serine protease inhibitor that neutralizes any free circulating plasminneutralizes any free circulating plasmin
Plasminogen activator inhibitor-1Plasminogen activator inhibitor-1 a serine protease a serine protease inhibitor that inhibits tissue-type plasminogen inhibitor that inhibits tissue-type plasminogen activatoractivator
Glycoprotein (GP) IIbIIIa antagonistsGlycoprotein (GP) IIbIIIa antagonists
such as ReoPro (abciximab) Integrilin such as ReoPro (abciximab) Integrilin (eptifibatide) or Aggrastat (tirofiban) in (eptifibatide) or Aggrastat (tirofiban) in ischemic stroke remains investigational ischemic stroke remains investigational Deshmukh et al38 reported 21 patients with Deshmukh et al38 reported 21 patients with large-vessel occlusion refractory to IAT with large-vessel occlusion refractory to IAT with rtPA who were treated with IV andor IA rtPA who were treated with IV andor IA abciximab eptifibatide or tirofiban abciximab eptifibatide or tirofiban
IA Mechanical Approaches in Acute Ischemic Stroke IA Mechanical Approaches in Acute Ischemic Stroke Mechanical strategies have several advantagesMechanical strategies have several advantages First they lessen and may even preclude the use of chemical First they lessen and may even preclude the use of chemical
thrombolytics in this manner very likely reducing the risk of ICHthrombolytics in this manner very likely reducing the risk of ICH Second by avoiding the use of chemical thrombolytics it is Second by avoiding the use of chemical thrombolytics it is
possible to extend the treatment window beyond the limit of 6ndash8 possible to extend the treatment window beyond the limit of 6ndash8 hours hours
Third mechanically fragmenting a clot increases the surface area Third mechanically fragmenting a clot increases the surface area accessible to fibrinolytic agents and allows inflow of fresh accessible to fibrinolytic agents and allows inflow of fresh plasminogen which in turn may increase the speed of plasminogen which in turn may increase the speed of thrombolysis thrombolysis
Finally clot-retrieval devices may provide faster recanalization Finally clot-retrieval devices may provide faster recanalization
The disadvantages of the mechanical The disadvantages of the mechanical approaches approaches technical difficulty of navigating mechanical technical difficulty of navigating mechanical
devices into the intracranial circulation excessive devices into the intracranial circulation excessive trauma to the vasculature (potentially leading to trauma to the vasculature (potentially leading to vasospasm vessel dissection perforation or vasospasm vessel dissection perforation or rupture) rupture)
fragmented thrombus causing distal embolization fragmented thrombus causing distal embolization into previously unaffected territories into previously unaffected territories
Nevertheless the advantages of mechanical stroke Nevertheless the advantages of mechanical stroke therapy appear to significantly outweigh its therapy appear to significantly outweigh its disadvantages and risksdisadvantages and risks
Contraindications to Thrombolytic Contraindications to Thrombolytic agents agents
Recent thoracic abdominal or Recent thoracic abdominal or intracranial surgeryintracranial surgery
Recent haemorrhagic CVA Head injury Recent haemorrhagic CVA Head injury or neoplasmor neoplasm
Bleeding ulcerBleeding ulcer Anticipated invasive procedures (arterial Anticipated invasive procedures (arterial
punctures biopsies)punctures biopsies) Concurrent hemostatic dysfunctionConcurrent hemostatic dysfunction
Monitoring of thrombolytic Monitoring of thrombolytic therapytherapy
Thrombin time Measures the availability of functional
fibrinogen Normal thrombin time is 10-14 sec Prolonged when fibrinogen level is below
75-100 mgdl
Half Life of ThrombolyticsHalf Life of ThrombolyticsAgent Administration Half Life
Streptokinase IA 60-80min
Urokinase IAIV 9-12min
rTPA IAIV 6min
Abciximab(Reopro) IAIV 12hour
Aspirin POIV 15-20min
Heparin IVSC 60min
Coumadin PO 15-25 days
Anti Platelet DrugsAnti Platelet DrugsDrug Drug Mechanism Mechanism UsesUsesAspirinAspirin Permanently inhibits Permanently inhibits
COX-1 and COX-2COX-1 and COX-2CADCAD
Stroke-TIAsStroke-TIAs
NSAIDsNSAIDs Reversibly inhibits Reversibly inhibits COX-1COX-1
LimitedLimited
DipyridamoleDipyridamole Inhibits PDE increases Inhibits PDE increases cAMPcAMP
TIAsTIAs
ThenopyridinesThenopyridines
(Ticlopidine(Ticlopidine
ClopidrgrelClopidrgrel))
Inhibits ADP Inhibits ADP
PlatAg PlatAg
TIAsStrokeTIAsStroke
CAD PVDCAD PVD
Abciximab (ReoPro)Abciximab (ReoPro)
Eptifibatide (Integrilin)Eptifibatide (Integrilin)
TirofibanTirofiban
GP IIBIIIA InhibitorsGP IIBIIIA Inhibitors
Stroke- TIAs Stroke- TIAs
MonitoringMonitoring
Bleeding timeBleeding time
Optical aggregometryOptical aggregometry
Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay
Bleeding timeBleeding time
Requires a skin incision (usually made on the ear lobe or Requires a skin incision (usually made on the ear lobe or forearm offorearm of
a depth that results in disruption of capillary loops and a depth that results in disruption of capillary loops and small vessels)small vessels)
AdvantagesAdvantages Universally availableUniversally available Relatively simple techniquesRelatively simple techniques Can be performed bedsideCan be performed bedside
DisadvantagesDisadvantages Insensitive inaccurate non-specific techniqueInsensitive inaccurate non-specific technique
Poorly reproducible (as depends on multiple variables)Poorly reproducible (as depends on multiple variables)
Optical aggregometryOptical aggregometry
Gold standard assay for platelet functionGold standard assay for platelet function Agonist induced aggregation is measuredAgonist induced aggregation is measured Different agonist are available for different Different agonist are available for different
agentsagents However require unique expertise and are not However require unique expertise and are not
universally availableuniversally available Aspirin measured with ADP or AA(gt70 Aspirin measured with ADP or AA(gt70
aggregation so resistance)aggregation so resistance) Clopidogrel( ADP gt 90 aggregation means Clopidogrel( ADP gt 90 aggregation means
resistance) resistance)
Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay
Can be performed bed sideCan be performed bed side Different assay devices with different Different assay devices with different
agonist are used for each of different agonist are used for each of different antiplatelet agents antiplatelet agents
For Aspirin AA is used (result is reported as aspirin For Aspirin AA is used (result is reported as aspirin reaction units [ARU] ARUgt 550 indicates non-reaction units [ARU] ARUgt 550 indicates non-responsiveness)responsiveness)
Verify IIbIIIa assay device uses TRAP as agonist for Verify IIbIIIa assay device uses TRAP as agonist for Abciximab and TirofibanAbciximab and Tirofiban
Practical Applications Practical Applications related to specific related to specific
Neurovascular Neurovascular interventionsinterventions
Acute ischemic StrokeAcute ischemic Stroke When an artery occludes neurons are affected When an artery occludes neurons are affected
differently depending upon the amount of residual blood differently depending upon the amount of residual blood flowflow
Normal cerebral blood flow is greater than 50 mL100 Normal cerebral blood flow is greater than 50 mL100 mgminmgmin
Once blood flow decreases to less than 20 mL100 Once blood flow decreases to less than 20 mL100 mgmin infarction occursmgmin infarction occurs
If blood flow decreases to less than 10 mL100 mgmin If blood flow decreases to less than 10 mL100 mgmin irreversible neuronal death occurs rapidly irreversible neuronal death occurs rapidly
Blood flow between 11 and 20 mL100 mgmin is thought Blood flow between 11 and 20 mL100 mgmin is thought to represent the ischemic penumbra an area where the to represent the ischemic penumbra an area where the cells are functionally silent because of ischemia but are cells are functionally silent because of ischemia but are still able to recover if blood flow is restored still able to recover if blood flow is restored
Many acute stroke therapies are targeted toward Many acute stroke therapies are targeted toward restoring flow or function to the ischemic penumbrarestoring flow or function to the ischemic penumbra
Therapeutic window in Therapeutic window in management of acute Ischemic management of acute Ischemic
StrokeStrokeThe early diagnosis of ischemic stroke is critical to the The early diagnosis of ischemic stroke is critical to the
with only a narrow therapeutic window in the first few with only a narrow therapeutic window in the first few hours following stroke ictushours following stroke ictus
Diagnosis in the first 3 hours postictus provides the Diagnosis in the first 3 hours postictus provides the opportunity for intravenous or intraarterial thrombolysis opportunity for intravenous or intraarterial thrombolysis and intra-arterial clot mechanical treatment which and intra-arterial clot mechanical treatment which improve the outcome improve the outcome
Diagnosis in the time period between 3 and 6 hours Diagnosis in the time period between 3 and 6 hours provides an opportunity for intra-arterial thrombolysis provides an opportunity for intra-arterial thrombolysis and mechanical treatment and mechanical treatment
Involvement of the posterior circulation especially the Involvement of the posterior circulation especially the basilar artery is treated by some regardless of time of basilar artery is treated by some regardless of time of onset or up until 12 to 24 hours in some practices This is onset or up until 12 to 24 hours in some practices This is related to the potentially high mortality and morbidity related to the potentially high mortality and morbidity associated with basilar artery thrombosisassociated with basilar artery thrombosis
Infarct evaluation on angiographyInfarct evaluation on angiography(CT angiography and catheter (CT angiography and catheter
angiography)angiography)CTA is an excellent first-line examination for CTA is an excellent first-line examination for
evaluation of the head and neck arteries evaluation of the head and neck arteries In comparison with catheter angiography In comparison with catheter angiography
what it gives up in resolution and dynamic what it gives up in resolution and dynamic properties it makes up for with rapid properties it makes up for with rapid acquisition of a 3-D dataset and the potential acquisition of a 3-D dataset and the potential for assessment of whole-brain perfusion and for assessment of whole-brain perfusion and better parenchymal evaluationbetter parenchymal evaluation
Moreover CTA illustrates not only arterial Moreover CTA illustrates not only arterial stenosis or occlusion but also the vessel wall stenosis or occlusion but also the vessel wall This factor is most important for evaluation of This factor is most important for evaluation of intramural dissection and thrombosed intramural dissection and thrombosed aneurysms which may both complicate aneurysms which may both complicate evaluation of stroke patientsevaluation of stroke patients
Early angiographic signs of strokes Early angiographic signs of strokes both CTA both CTA and DSA and DSA
Vessel occlusion or cutoff related to Vessel occlusion or cutoff related to thromboembolithromboemboli
aneurysms aneurysms arterial dissection arterial dissection Meniscus or flattened shape to clot Meniscus or flattened shape to clot
(recent) versus reverse meniscus (older)(recent) versus reverse meniscus (older) tram track (nonocclusive or recanalized tram track (nonocclusive or recanalized
clot) clot) delayed (antegrade) flow (manifest as delayed (antegrade) flow (manifest as
decreased whole-brain perfusion on CTA)decreased whole-brain perfusion on CTA) retrograde collateral flowretrograde collateral flow
Non-occlusive left MCA thrombus on 3-D imaging performed from CTA source data and was confirmed at catheter angiography
Therapy to be started within a 6-hr Therapy to be started within a 6-hr time to treatment (TTT) window time to treatment (TTT) window (while in case of IV thrombolysis (while in case of IV thrombolysis therapy to be started with in 3hrs)therapy to be started with in 3hrs)
Exclusion criteria Exclusion criteria Rapidly improving neurologic deficit or Rapidly improving neurologic deficit or Sustained blood pressure of gt180100 Sustained blood pressure of gt180100 Hemorrhage is detected on CTHemorrhage is detected on CT Infarct involving gt more than 13 rd Infarct involving gt more than 13 rd
territory of MCAterritory of MCA MRADWI-Perfusion mismatchlt 20MRADWI-Perfusion mismatchlt 20 Definite hypodensity on CTDefinite hypodensity on CT
Intra-arterial Thrombolysis
Fibrinolytics + AntiplateletsFibrinolytics + Antiplatelets
PlasminogenPlasminogen activators through fibrinolysis exposes activators through fibrinolysis exposes free thrombin and paradoxically stimulatesfree thrombin and paradoxically stimulates platelet platelet aggregation which leads to formation of aaggregation which leads to formation of a platelet platelet thrombus (white clot) thrombus (white clot)
This new thrombus is relatively resistant to This new thrombus is relatively resistant to fibrinolyticsfibrinolytics
So new regimen in case of acute stroke isSo new regimen in case of acute stroke is fibrinolytics + antiplatelet drugsfibrinolytics + antiplatelet drugs
rtPA + IIbIIIa inhibitors( tirofiban rtPA + IIbIIIa inhibitors( tirofiban abciximab) orabciximab) or
Urokinase + IIbIIIa Urokinase + IIbIIIa inhibitors( tirofiban abciximab)inhibitors( tirofiban abciximab)
Intra-arterial Thrombolysis Tirofiban (04 microgkgmin bolus for 3 min followed by Tirofiban (04 microgkgmin bolus for 3 min followed by
0125 ugkgmin)0125 ugkgmin)
++
Heparin (2000ndash3000 IU bolus followed by Heparin (2000ndash3000 IU bolus followed by 1000 IUhour infusion 1000 IUhour infusion
with ACT maintained bw 200-300) throughout the with ACT maintained bw 200-300) throughout the interventional procedure and for 24ndash48 hours thereafter when interventional procedure and for 24ndash48 hours thereafter when there is neither intraprocedural bleeding nor suspicion of there is neither intraprocedural bleeding nor suspicion of increased risk of bleeding increased risk of bleeding
Maximum dose of Urokinase Maximum dose of Urokinase Anterior circulation stroke - 500000 IU (mean 400000 Anterior circulation stroke - 500000 IU (mean 400000
IU range 300000ndash500000 IU)IU range 300000ndash500000 IU) Posterior circulation stroke -1000000 IU (mean 837000 Posterior circulation stroke -1000000 IU (mean 837000
IU range 300000ndash1000000 IU)IU range 300000ndash1000000 IU)American Journal of NeuroradiologyAmerican Journal of Neuroradiology 262595-2601 2005262595-2601 2005
Intravenous ThrombolysisIntravenous Thrombolysis
The first method to restore cerebral The first method to restore cerebral perfusion is clot lysis with the goal perfusion is clot lysis with the goal of re-establishing blood flow to the of re-establishing blood flow to the affected tissue affected tissue
IV thrombolysis rt-PA is the only IV thrombolysis rt-PA is the only FDA- approved treatment for AIS FDA- approved treatment for AIS
Fibrinolysis is enhanced powerfully Fibrinolysis is enhanced powerfully by rt-PAby rt-PA
Intravenous rTPA Intravenous rTPA administration administration protocolprotocol
Total dose of rt-PA 09 mgkg (maximum dose Total dose of rt-PA 09 mgkg (maximum dose 90 mg)90 mg)
Give 10 as initial IV bolusGive 10 as initial IV bolus Infuse remainder over 1 hourInfuse remainder over 1 hour Admit patient to an ICU or stroke unit for Admit patient to an ICU or stroke unit for
monitoringmonitoring Neurologic assessments every 15 minutes Neurologic assessments every 15 minutes
during infusion then every 30 minutes for next during infusion then every 30 minutes for next 6 hours then every hour until 24hours after 6 hours then every hour until 24hours after treatmenttreatment
Favorable Outcome vs Treatment Time Favorable Outcome vs Treatment Time with IV rTPAwith IV rTPA
Protocol limit = 3 hrs
Benefit ~ 45 hrs
Thromboembolism During coilingThromboembolism During coiling Most feared and frequent complication Most feared and frequent complication Reported incidence - Approx 7 Reported incidence - Approx 7 SourcesSources of Thromboembolism are of Thromboembolism are
- Clots at the aneurysmal neck during or immediately- Clots at the aneurysmal neck during or immediately after after embolization embolization
- Thrombus forming on catheters during- Thrombus forming on catheters during proceduresprocedures
- Stenosis of an adjacent artery dt coil mass- Stenosis of an adjacent artery dt coil mass or herniationor herniation
- Migration of intraaneurysmal- Migration of intraaneurysmal thrombus during coil thrombus during coil placement placement
- Slow flow dt vasospasm - Slow flow dt vasospasm
- Rare and unlikely causes are hypercoagulable- Rare and unlikely causes are hypercoagulable state such state such as antiphospholipid antibody syndrome or due to HITas antiphospholipid antibody syndrome or due to HIT
Occur more often with wide-necked aneurysms (dt Occur more often with wide-necked aneurysms (dt increased exposed surface area of thrombogenic coil increased exposed surface area of thrombogenic coil material)material)
Current regimen of endovascular Current regimen of endovascular managementmanagement
The The glycoprotein IIbIIIa antagonist tirofiban glycoprotein IIbIIIa antagonist tirofiban (04 (04 microgkgmin bolus for 30 minutes followed by infusion of microgkgmin bolus for 30 minutes followed by infusion of 0125 ugkgmin until the thrombus dissolved) 0125 ugkgmin until the thrombus dissolved)
Intraarterial thrombolysis with Intraarterial thrombolysis with urokinase or r- TPA urokinase or r- TPA increase of intravenous (IV) heparin (measured by increase of intravenous (IV) heparin (measured by
ACT) ACT) Intravenous aspirin Intravenous aspirin
Coil-related platelet aggregation (white clot) is Coil-related platelet aggregation (white clot) is unlikely to respond to fibrinolytics but has a high risk unlikely to respond to fibrinolytics but has a high risk of hemorrhage (In ISAT) all 5 patients who had of hemorrhage (In ISAT) all 5 patients who had received thrombolytic therapy with tPA to treat a received thrombolytic therapy with tPA to treat a thromboembolic complication after endovascular thromboembolic complication after endovascular treatment rebleed and all of these patients died)treatment rebleed and all of these patients died)
IntracranialIntracranial Stenting Stenting Metallic foreign body such as stent will accumulate Metallic foreign body such as stent will accumulate
thrombus in the absence of platelet inhibitionthrombus in the absence of platelet inhibition Antiplatelet drugs are important to prevent peri or Antiplatelet drugs are important to prevent peri or
post-interventional thromboembolic eventspost-interventional thromboembolic events Optimal treatment regimens has not been determined Optimal treatment regimens has not been determined
but usually but usually Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-
procedureprocedureOrOr
Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on
morning of proceduremorning of procedure
If need to use stent is not pre-planned thanIf need to use stent is not pre-planned than
Abciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkgAbciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkg IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)
Glycoprotein IIbIIIa inhibitor are not used routinely during elective Glycoprotein IIbIIIa inhibitor are not used routinely during elective stenting procedure dt increased risk of ICH stenting procedure dt increased risk of ICH
Carotid StentingCarotid Stenting
Pre-procedurePre-procedure
Double Antiplatelet therapy is routinely given Double Antiplatelet therapy is routinely given beginning at least 3beginning at least 3
days before the proceduredays before the procedure
Aspirin 325mgd+Clopidogrel 75mgdAspirin 325mgd+Clopidogrel 75mgd During procedureDuring procedure
Heparin is given with target clotting time of 250-Heparin is given with target clotting time of 250-300sec300sec
Post-procedure Post-procedure
Aspirin 325mg is continued indefinitely and Aspirin 325mg is continued indefinitely and
Clopidogrel 75mgd for at least 6 weeks Clopidogrel 75mgd for at least 6 weeks
Inclusion criteria for Local ThrombolysisInclusion criteria for Local Thrombolysis a)a) Patients in severe clinical grade on admission Patients in severe clinical grade on admission
with evidence of dural venous sinus with evidence of dural venous sinus thrombosis and restrictive venous outflow on thrombosis and restrictive venous outflow on cerebral angiogramcerebral angiogram
b)b) Patients in clinical grade 3 worsening on Patients in clinical grade 3 worsening on heparin therapy Restriction to venous heparin therapy Restriction to venous outflow was defined as an increase in brain outflow was defined as an increase in brain circulation time gt 12 s delay in the drainage circulation time gt 12 s delay in the drainage of cortical veins with cortical veins hanging of cortical veins with cortical veins hanging in spacein space
Treatment Options for Venous Thrombosis
CT Grading for Venous ThrombosisCT Grading for Venous Thrombosis Grade I no parenchymal change Grade I no parenchymal change
(hyperdense (hyperdense sinuses cortical veins empty sinuses cortical veins empty delta sign)delta sign)
Grade II non hemorrhagic venous infarct Grade II non hemorrhagic venous infarct without mass effect without mass effect
Grade III non-hemorrhagic infarct with Grade III non-hemorrhagic infarct with mass effectmass effect
Grade IV hemorrhagic venous infarct (max Grade IV hemorrhagic venous infarct (max diameter lt 3 cm) with no mass effectdiameter lt 3 cm) with no mass effect
Grade V hemorrhagic venous infarct (max Grade V hemorrhagic venous infarct (max diameter gt 3 cm) with mass effect diameter gt 3 cm) with mass effect
Local ThrombolysisLocal Thrombolysis
Femoral Jugular access was secured and a guiding Femoral Jugular access was secured and a guiding catheter was placed in the jugular bulb catheter was placed in the jugular bulb Mechanical Mechanical clot maceration clot maceration was done with the guidewire was done with the guidewire following which a microcatheter (was navigated and following which a microcatheter (was navigated and placed in the thrombosed segment of sinus confirmed placed in the thrombosed segment of sinus confirmed on a selective venogram on a selective venogram
Urokinase infusion Bolus dose of 2-6 lacs followed Urokinase infusion Bolus dose of 2-6 lacs followed by 60000 to 100000 units per hour along with by 60000 to 100000 units per hour along with periodic check venogram Along with maintenance periodic check venogram Along with maintenance systemic infusion of Heparinsystemic infusion of Heparin Other agents such as Other agents such as streptokinase altepase or rTPAstreptokinase altepase or rTPA can be also used can be also used
After thrombolysis patient should subjected to oral After thrombolysis patient should subjected to oral anticoagulation for six monthsanticoagulation for six months
Low-molecular-weight Low-molecular-weight heparinheparin
PharmacologyPharmacologyLMWH as its name suggests is a glycosaminoglycan that is approximatelyLMWH as its name suggests is a glycosaminoglycan that is approximately
one third the molecular weight of UFH It is derived from UFH through one third the molecular weight of UFH It is derived from UFH through variousvarious
depolymerization processes LMWH binds to antithrombin which in turn depolymerization processes LMWH binds to antithrombin which in turn
Neutralizes actors Xa and IIa Because LMWH lacks many of the longer Neutralizes actors Xa and IIa Because LMWH lacks many of the longer chains chains
required for binding to thrombin it has less ability to neutralize thrombin required for binding to thrombin it has less ability to neutralize thrombin
relativeto its ability to neutralize factor Xa LMWH also has less relativeto its ability to neutralize factor Xa LMWH also has less nonspecific nonspecific
binding to other proteins There is greater bioavailability with more binding to other proteins There is greater bioavailability with more predictable predictable
pharmacokinetics that eliminates the need for monitoring The smaller pharmacokinetics that eliminates the need for monitoring The smaller size also size also
allows for enhanced subcutaneous absorption when compared with UFHallows for enhanced subcutaneous absorption when compared with UFH
Three LMWH preparations are Three LMWH preparations are currently approved for use in the currently approved for use in the United States (1) enoxaparin (2) United States (1) enoxaparin (2) dalteparin and (3) tinzaparin dalteparin and (3) tinzaparin
They are all administered They are all administered subcutaneously at intervals of either subcutaneously at intervals of either once or twice daily for both once or twice daily for both prophylaxis and treatment dosesprophylaxis and treatment doses
Few Experiences of Few Experiences of ThrombolysisThrombolysis
Vickey 25 Yrs male patient presented Vickey 25 Yrs male patient presented with 12with 12thth day HO severe headache with day HO severe headache with right sided hemiplegiaright sided hemiplegia
MRI shows thrombosis of the superior MRI shows thrombosis of the superior sagittal left transverse left sigmoid sagittal left transverse left sigmoid sinuses and cortical veins in the fronto-sinuses and cortical veins in the fronto-parietal regions with eo haemorrhagic parietal regions with eo haemorrhagic infarct in the left cerebral hemisphere infarct in the left cerebral hemisphere with mass effect( Grade ndashV)with mass effect( Grade ndashV)
Sashi Srivastava 64 yrs FSashi Srivastava 64 yrs F In a follow up case of MRD with infra-renal In a follow up case of MRD with infra-renal
aortic abdominal and bilateral renal artery aortic abdominal and bilateral renal artery thrombosis renal angiogram shows filling thrombosis renal angiogram shows filling defects in the right Renal artery defects in the right Renal artery
Initially Renal angioplasty was done Initially Renal angioplasty was done Following angioplasty few thrombi are seem Following angioplasty few thrombi are seem to extends into the segmental branches and to extends into the segmental branches and causing blockage So Thrombolysis was causing blockage So Thrombolysis was plane to dissolve the run-out thrombi with plane to dissolve the run-out thrombi with urokinase urokinase
Rakesh 34yrsMRakesh 34yrsM Left SFA pseudoaneurysm with Left SFA pseudoaneurysm with
Covered stent placementCovered stent placement Pre operative antiplatelets with post Pre operative antiplatelets with post
procedure heparin Tirofiban procedure heparin Tirofiban followed by aspirin and clopidogrel followed by aspirin and clopidogrel were usedwere used
IAT may be a treatment option for selected patients IAT may be a treatment option for selected patients Possible selection criteria include Possible selection criteria include
presentation between 3 and 6 hours from symptom onsetpresentation between 3 and 6 hours from symptom onset major cerebral artery occlusion major cerebral artery occlusion severe neurologic deficits severe neurologic deficits high risk of systemic hemorrhage with IV rt-PA (eg recent high risk of systemic hemorrhage with IV rt-PA (eg recent
surgery) surgery) The MERCI (Mechanical Embolus Removal in Cerebral The MERCI (Mechanical Embolus Removal in Cerebral
Ischemia) retrievalIschemia) retrieval system system
Has been FDA-approved for recanalizing acutely occluded Has been FDA-approved for recanalizing acutely occluded cerebral arteries cerebral arteries
In the Multi-MERCI study patients who did not improve In the Multi-MERCI study patients who did not improve immediately after IV rt-PA underwent mechanical immediately after IV rt-PA underwent mechanical embolectomy within 8 hours of symptom onset embolectomy within 8 hours of symptom onset
Partial or complete recanalization occurred in 74 of Partial or complete recanalization occurred in 74 of patientspatients
with a symptomatic intracerebral hemorrhage (sICH) rate of with a symptomatic intracerebral hemorrhage (sICH) rate of 67 67
Mechanical embolectomy with the MERCI retriever may be a Mechanical embolectomy with the MERCI retriever may be a feasible and safe option for patients after IV rt-PAfeasible and safe option for patients after IV rt-PA
Penumbra stroke systemPenumbra stroke system This device combines two methods of clot This device combines two methods of clot
extraction aspiration and mechanical extraction aspiration and mechanical extraction extraction
First the clot is aspirated then a thrombus First the clot is aspirated then a thrombus removal ring can be used if necessary to removal ring can be used if necessary to remove remaining clot remove remaining clot
successful recanalizing 82successful recanalizing 82 Bridging therapyBridging therapy
06 mgkg IV rt-PA followed by IAT with IA rt-06 mgkg IV rt-PA followed by IAT with IA rt-PA (up to 20 mg)PA (up to 20 mg)
achieved a higher recanalization rateachieved a higher recanalization rate
Criteria for thrombolysis with rTPACriteria for thrombolysis with rTPA
Inclusion criteriaInclusion criteria Clinical signs and symptoms consistent with ischemic Clinical signs and symptoms consistent with ischemic
strokestroke Patient last seen normal within 3 hoursPatient last seen normal within 3 hours Measurable neurologic deficitMeasurable neurologic deficit
Exclusion criteriaExclusion criteria Any hemorrhage on neuroimaging (CT or MRI)Any hemorrhage on neuroimaging (CT or MRI) Symptoms suggestive of subarachnoid hemorrhageSymptoms suggestive of subarachnoid hemorrhage Seizure at stroke onset that is thought to contribute to Seizure at stroke onset that is thought to contribute to
neurologic deficitneurologic deficit Hypodensity greater than one third cerebral hemisphere Hypodensity greater than one third cerebral hemisphere
on CTon CT SBP greater than 185 mm Hg or DBP greater than 110 SBP greater than 185 mm Hg or DBP greater than 110
mm Hgmm Hg International normalized ratio (INR) greater than 17International normalized ratio (INR) greater than 17
Ischemic Stroke Ischemic Stroke Treatment ndash 2006Treatment ndash 2006
IV tissue plasminogen activator (tPA)IV tissue plasminogen activator (tPA) ndash ndash Only FDA-approved acute stroke drugOnly FDA-approved acute stroke drug ndash ndash 3 hour treatment window3 hour treatment window
MERCI - Concentric clot retrieval MERCI - Concentric clot retrieval devicedevice ndash ndash Rescue therapy - approved 2004Rescue therapy - approved 2004 ndash ndash Device approval (not outcomes-based)Device approval (not outcomes-based)
Off label approachesOff label approaches ndash ndash IV tPA after 3 hoursIV tPA after 3 hours ndash ndash IV-IA tPA sequential strategiesIV-IA tPA sequential strategies ndash ndash IA tPA clot angioplasty fragmentationIA tPA clot angioplasty fragmentation ndash ndash Ultrasound-assisted tPA lysisUltrasound-assisted tPA lysis
rt-PA Trials NINDSrt-PA Trials NINDS
Acute stroke - 624 patientsAcute stroke - 624 patients Treat within 3 hrsTreat within 3 hrs Intravenous 09 mgkg rt-PA vs placeboIntravenous 09 mgkg rt-PA vs placebo Hemorrhage 64 tPA 06 placeboHemorrhage 64 tPA 06 placebo Neurologic recovery better with tPA 30 Neurologic recovery better with tPA 30
more like to have minimal or no disabilitymore like to have minimal or no disability
First proven approved treatment for First proven approved treatment for strokestroke
Limitations of tPALimitations of tPA Only 4 of acute strokes receive tPAOnly 4 of acute strokes receive tPA (Kleindorfer et al Stroke 2004 35 e27-e29)(Kleindorfer et al Stroke 2004 35 e27-e29)
Only 22 of patients present within 3 hoursOnly 22 of patients present within 3 hours1048707 1048707 51 of these ineligible due to51 of these ineligible due to
bull bull Mild severityMild severity bull bull Medical or surgical historyMedical or surgical history bull bull Blood testsBlood tests
Sustained recanalization only 13Sustained recanalization only 13 (Alexandrov et al NEJM 2004 351 2170-8)(Alexandrov et al NEJM 2004 351 2170-8)
Concern for hemorrhageConcern for hemorrhage tPA potentiates apoptotic injury tPA potentiates apoptotic injury (Liu et al Nature Med 2004 101379-83)(Liu et al Nature Med 2004 101379-83)
PROACT II IA Lysis TrialPROACT II IA Lysis Trial Baseline 24 hours 8 days
Baseline 60 minutes 120 minutes
9mg IAProurokinase
Desmoteplase Trials DEDAS Desmoteplase Trials DEDAS DIASDIAS
Trial OverviewTrial Overview Double blind randomized placebo Double blind randomized placebo
controlled trialscontrolled trials IV delivery 3-9 hour time windowIV delivery 3-9 hour time window Plasminogen activator ndash from Plasminogen activator ndash from vampire bat vampire bat
salivasaliva Selection based on PWI-DWI MismatchSelection based on PWI-DWI Mismatch
MRI InclusionMRI Inclusion PWI defect at least 2 cm AND ~20 larger PWI defect at least 2 cm AND ~20 larger
than DWIthan DWI PWI should be obvious even visible on PWI should be obvious even visible on
raw imagesraw imagesMRI ExclusionMRI Exclusion
DWI gt 13 MCADWI gt 13 MCA MRA ICA occlusionMRA ICA occlusion
Desmoteplase ndash DIAS Desmoteplase ndash DIAS ResultsResults
Mechanical Thrombolysis Mechanical Thrombolysis devicesdevices
mechanical thrombolysis potentially extends the treatment mechanical thrombolysis potentially extends the treatment window because they act promptly at the site of the thrombuswindow because they act promptly at the site of the thrombus
The devices can retrieve large clots that pharmaceutical agents The devices can retrieve large clots that pharmaceutical agents may not successfully lysemay not successfully lyse
Patients treated with IV tPA may be considered for treatment of Patients treated with IV tPA may be considered for treatment of residual clot with some of these devicesresidual clot with some of these devices
suction-creating saline jets suction-creating saline jets laser energy ultrasound laser energy ultrasound a corkscrew apparatus to treat strokesa corkscrew apparatus to treat strokes The AngioJet systemThe AngioJet system uses saline jets that are directed back into the catheter to uses saline jets that are directed back into the catheter to
create a low-pressure zone around the catheter tip inducing create a low-pressure zone around the catheter tip inducing suction suction
The clot is pulled into the exhaust lumen and removed from the The clot is pulled into the exhaust lumen and removed from the vessel Although US Food and Drug Administration (FDA) has vessel Although US Food and Drug Administration (FDA) has approved this device for use in arteriovenous dialysis grafts and approved this device for use in arteriovenous dialysis grafts and fistulae and for the treatment of coronary arteries saphenous fistulae and for the treatment of coronary arteries saphenous vein grafts and peripheral vessels clinical trials for the vein grafts and peripheral vessels clinical trials for the treatment of acute stroke are no longer in progress treatment of acute stroke are no longer in progress
Most devices are used in cerebral vessels that 2-5 mm
The Latis laser device The Latis laser device used laser energy to ablate clots used laser energy to ablate clots Arteries 2-5 mm in diameter could be Arteries 2-5 mm in diameter could be
treated including the ICA M1 or M2 treated including the ICA M1 or M2 branch of the MCA A1 branch of the branch of the MCA A1 branch of the anterior cerebral artery (ACA) basilar anterior cerebral artery (ACA) basilar artery posterior cerebral artery (PCA) artery posterior cerebral artery (PCA) and vertebral and vertebral
Patients could receive treatment as late Patients could receive treatment as late as 8 hours after symptom onset in the as 8 hours after symptom onset in the anterior circulation and within 24 hours in anterior circulation and within 24 hours in the posterior circulation the posterior circulation
Endovascular Photo Acoustic Endovascular Photo Acoustic Recanalization (EPAR) Recanalization (EPAR)
A laser power source generated energy for the A laser power source generated energy for the systemsystem
The energy was delivered by means of The energy was delivered by means of fiberoptics to the tip of the catheter at the fiberoptics to the tip of the catheter at the treatment sitetreatment site
Absorption of laser light by darkly pigmented Absorption of laser light by darkly pigmented materials (ie the clot) occurred inside the 1-mm materials (ie the clot) occurred inside the 1-mm catheter tipcatheter tip
the system was designed to minimize scattering the system was designed to minimize scattering of laser light of laser light
Absorption converted photo energy to acoustic Absorption converted photo energy to acoustic energy which then emulsified the clot inside the energy which then emulsified the clot inside the catheter tip catheter tip
EKOS ultrasound( the EKOS ultrasound( the Ultrasound Thrombolytic Ultrasound Thrombolytic
Infusion Catheter) Infusion Catheter) combines the use of a distal ultrasound transducer with combines the use of a distal ultrasound transducer with
infusion of a thrombolytic agent through the infusion of a thrombolytic agent through the microcathetermicrocatheter
Ultrasound changes the structure of the clot to Ultrasound changes the structure of the clot to temporarily increase its permeability while providing an temporarily increase its permeability while providing an acoustic pressure gradient to move the drug into the clot acoustic pressure gradient to move the drug into the clot to speed its dissolution to speed its dissolution
The EKOS catheter is placed in the proximal portion of the The EKOS catheter is placed in the proximal portion of the clot clot
After a 2-mg bolus of tPA was injected through the After a 2-mg bolus of tPA was injected through the catheter catheter
the patient received a continuous infusion of IA tPA 03 the patient received a continuous infusion of IA tPA 03 mgmin to a maximum of 20 mg and simultaneous mgmin to a maximum of 20 mg and simultaneous ultrasound transmission for as long as 60 minutes ultrasound transmission for as long as 60 minutes
One patient was treated with a total of 4 units of One patient was treated with a total of 4 units of recombinant reteplase (Retavase) hand-injected over 60 recombinant reteplase (Retavase) hand-injected over 60 minutes minutes
Penumbra system Penumbra system The Penumbra system (Penumbra Inc) provides a dual The Penumbra system (Penumbra Inc) provides a dual
approach to clot extraction using aspiration followed by approach to clot extraction using aspiration followed by clot retrieval with a ring device if needed clot retrieval with a ring device if needed
Mechanical Embolus Removal in Cerebral Ischemia Mechanical Embolus Removal in Cerebral Ischemia (MERCI)(MERCI)
a corkscrew-like apparatus to remove blood clots from a corkscrew-like apparatus to remove blood clots from the brain in patients experiencing an ischemic stroke the brain in patients experiencing an ischemic stroke
The corkscrew itself resides in the catheter tip which The corkscrew itself resides in the catheter tip which shields it from the wall of the vessel until it is ready to be shields it from the wall of the vessel until it is ready to be burrowed into the clot Once lodged in the clot the device burrowed into the clot Once lodged in the clot the device and clot are withdrawn from the vessel and clot are withdrawn from the vessel
Snarelike devicesSnarelike devices Snares such as the Neuronet snare (Guidant Snares such as the Neuronet snare (Guidant
Endovascular Santa Clara CA) have been developed Endovascular Santa Clara CA) have been developed specifically for use in the treatment of strokes specifically for use in the treatment of strokes
These devices are simple in design and do not require the These devices are simple in design and do not require the clot to be amenable to emulsification clot to be amenable to emulsification
X-Sizer deviceX-Sizer device a device with small moving blades at the a device with small moving blades at the
catheter tip catheter tip This device the X-Sizer device (EndiCor Medical This device the X-Sizer device (EndiCor Medical
San Clemente CA) can be used to excise the San Clemente CA) can be used to excise the thrombus and aspirate it thrombus and aspirate it
The device was being evaluated in randomized The device was being evaluated in randomized studies of coronary vessels and in a registry of studies of coronary vessels and in a registry of patients with acute myocardial infarctionpatients with acute myocardial infarction
Although the manufacturer had modified the Although the manufacturer had modified the device for use in cerebral vessels a safety and device for use in cerebral vessels a safety and feasibility study was indefinitely suspended after feasibility study was indefinitely suspended after only 1 patient was treated with the device in only 1 patient was treated with the device in Europe Europe
Suction thrombectomySuction thrombectomy This method of mechanical thrombolysis is one of the This method of mechanical thrombolysis is one of the
simplestsimplest In this readily available technique suction is applied with In this readily available technique suction is applied with
a syringe to remove thrombus in the ICA a syringe to remove thrombus in the ICA It requires no other devicesIt requires no other devices A catheter with a large inner diameter (Brite Tip Cordis A catheter with a large inner diameter (Brite Tip Cordis
Corporation Miami FL) was placed in the symptomatic Corporation Miami FL) was placed in the symptomatic vessel and navigated over a guidewire into the thrombusvessel and navigated over a guidewire into the thrombus
A 60-mL syringe was used to aspirate the thrombus A 60-mL syringe was used to aspirate the thrombus Each patient required angioplasty and stenting of carotid Each patient required angioplasty and stenting of carotid
bifurcation stenosis and received daily aspirin and bifurcation stenosis and received daily aspirin and ticlopidine after the procedure No complications ticlopidine after the procedure No complications occurred occurred
Summary Acute Stroke Summary Acute Stroke ImagingImaging
PhysiologyPhysiology importance collaterals importance collaterals
ndash ndashGrowing role for perfusion Growing role for perfusion assessmentassessment
tPAtPA guidelines amp limitations guidelines amp limitations Signs on CT amp MRSigns on CT amp MR follow physiology follow physiology Stroke trialsStroke trials PWI-DWI mismatch PWI-DWI mismatch
ndash ndashTreat based on physiology not timeTreat based on physiology not time ProtocolsProtocols should be fast and should be fast and
comprehensivecomprehensive
HeparinHeparin
Heterogeneous 3000-30000 dalton in Heterogeneous 3000-30000 dalton in molecular weight molecular weight
Average=15000 d (~45monosaccharide Average=15000 d (~45monosaccharide chains)chains)
About About 13 of dose binds to AT III and forms 13 of dose binds to AT III and forms the AT IIIHeparinClotting Factor Complexthe AT IIIHeparinClotting Factor Complex
Complex binds to clotting factors of the Complex binds to clotting factors of the intrinsic and common pathway (Xa IIa IXa intrinsic and common pathway (Xa IIa IXa XIa XIIa XIIIa) and inactivates themXIa XIIa XIIIa) and inactivates them
Anticoagulant of choice in pregnancy (not Anticoagulant of choice in pregnancy (not crosses placenta)crosses placenta)
Heparin and Low molecular weight heparinsHeparin and Low molecular weight heparins
Structure and sequence
O
OH
OH
O
COO
O
O
CH2OH
NHSO3
OH
_
_
O
O
CH2OSO3
NHSO3
OH
_
_
O
OH
OH
O
COOO
O
CH2OSO3
NHSO3
OH
_
_
O
OSO3
OHO
COOO
O
CH2OSO3
NHCOCH3
OH
_
_ _
_
_
O
OH
OH
O
COO
1
23
4
5
6
-D-glucosamine -L-iduronic acid -D-glucuronic acid
O
O
CH2OH
NH2
OH 12
3
4
5
6
O
OH
OHO
COO_
1
23
4
5
6
polymeric structure of heparin
Anticoagulant Properties of Anticoagulant Properties of HeparinHeparin
11 Inhibits the thrombin-mediated conversion of Inhibits the thrombin-mediated conversion of fibrinogen to fibrinfibrinogen to fibrin
22 Inhibits the aggregation of platelets by thrombin Inhibits the aggregation of platelets by thrombin (prolongs bleeding time)(prolongs bleeding time)
33 Inhibits activation of fibrin stabilizing enzymeInhibits activation of fibrin stabilizing enzyme
44 Inhibits activated factors XII XI IX X and IIInhibits activated factors XII XI IX X and II All available forms of heparin must be All available forms of heparin must be
administered administered parenterally since they are parenterally since they are highly charged and rapidlyhighly charged and rapidly hydrolyzed in the hydrolyzed in the GI tractGI tract
Heparin antagonist Protamine sulfate (Heparin antagonist Protamine sulfate (10mg for 10mg for 1000 unit of heparin)1000 unit of heparin)
Monitoring of heparin Monitoring of heparin
Subcutenous Subcutenous no monitoring requiredno monitoring required Intravenous Intravenous
Partial thromboplastin time (PTT normal value Partial thromboplastin time (PTT normal value ~30sec) ~30sec)
Activated clotting time ( ACT normal value ~90-Activated clotting time ( ACT normal value ~90-120sec)120sec)
Daily or more frequent if PTT ACT variesDaily or more frequent if PTT ACT varies
Mechanism Mechanism ndash measures intrinsic pathwayndash measures intrinsic pathway Therapeutic goal Therapeutic goal 2-25 times normal control value 2-25 times normal control value
ACT or aPTTACT or aPTT
Determine when to pull the femoral sheath Determine when to pull the femoral sheath Premature sheath pull can lead to bleedingPremature sheath pull can lead to bleeding Delayed removal can increase time in ICUDelayed removal can increase time in ICU Target set Target set at each siteat each site
ACT targets range from 150 ndash 220 ACT targets range from 150 ndash 220 secondsseconds
aPTT targets range from 40 ndash 70 seconds aPTT targets range from 40 ndash 70 seconds
During neuroangiography-During neuroangiography- Recommended therapeutic range of heparin in Recommended therapeutic range of heparin in
plasma is 02-08 uml ( corresponding to aPTT plasma is 02-08 uml ( corresponding to aPTT ACT values 15-25 times the baseline values)ACT values 15-25 times the baseline values)
Dose In diagnostic angiography bolus dose of Dose In diagnostic angiography bolus dose of 2500 iu is used followed by 1000 iu hour2500 iu is used followed by 1000 iu hour
Bolus dose is Bolus dose is 60 ukg to maintain the therapeutic 60 ukg to maintain the therapeutic range range If procedure continues for more than 75 If procedure continues for more than 75 minutes additional dose is required ( half of the minutes additional dose is required ( half of the initial dose for another 75 minutes) initial dose for another 75 minutes)
(AJNR 199415 51-54)
Mechanisms of HIT( Mechanisms of HIT( Heparin Heparin induced Thrombocytopeniainduced Thrombocytopenia))
Type 1Type 1 Fall in platelet count occurs within the first two Fall in platelet count occurs within the first two
days after heparin initiation often returns to days after heparin initiation often returns to normal with continued heparin administration normal with continued heparin administration and is of no clinical consequence and is of no clinical consequence
The mechanism of the thrombocytopenia is non-The mechanism of the thrombocytopenia is non-immune and appears to be due to a direct effect of immune and appears to be due to a direct effect of heparin on platelet activationheparin on platelet activation
Type 2Type 2 Approximately 03 to 3 percent of patients Approximately 03 to 3 percent of patients
receiving heparin develop an immune receiving heparin develop an immune thrombocytopenia mediated by antibodies to a thrombocytopenia mediated by antibodies to a heparin-platelet factor 4 complex heparin-platelet factor 4 complex
(AJNR 28155-158 2007)
Treatment of heparin-induced Treatment of heparin-induced thrombocytopeniathrombocytopenia
When HIT is diagnosed it is important to When HIT is diagnosed it is important to stop heparin mainly in type 2 and to avoid stop heparin mainly in type 2 and to avoid the use of LMWH the use of LMWH
Because of the increased risk of thrombosis Because of the increased risk of thrombosis however continuation of an anticoagulant however continuation of an anticoagulant must be considered must be considered
The drugs currently approved for the The drugs currently approved for the treatment of HIT in the United States are treatment of HIT in the United States are direct thrombin inhibitors argatroban and direct thrombin inhibitors argatroban and lepirudinlepirudin
WARFARIN MECHANISM OF ACTIONWARFARIN MECHANISM OF ACTION
Inactive factors II VII IX and X
Proteins S and C
Active factors II VII IX and X
Proteins S and C
Vitamin K epoxide
Vitamin K reduced
WA
RF
AR
IN
Prevents the reduction of vitamin K which is essential for Prevents the reduction of vitamin K which is essential for activation of certain factorsactivation of certain factors
Has no effect on previously formed thrombusHas no effect on previously formed thrombus
Antagonist is Vit KAntagonist is Vit K
OPTIMIZING WARFARIN THERAPYOPTIMIZING WARFARIN THERAPY
Use of large loading dose may lead to hemorrhage and Use of large loading dose may lead to hemorrhage and other complicationsother complications
Initial dose 2-5 mg once dailyInitial dose 2-5 mg once daily Maintenance dose 2-10 mg once dailyMaintenance dose 2-10 mg once daily If Immediate anticoagulation is requiredIf Immediate anticoagulation is required Heparin IS Heparin IS
started along with loading dose of warfarin 10 mg started along with loading dose of warfarin 10 mg Heparin is usually discontinued after 4-5 days Heparin is usually discontinued after 4-5 days Before Before discontinuing INR should be in therapeutic range for 2 discontinuing INR should be in therapeutic range for 2 consecutive daysconsecutive days
Daily monitoring of INR until INR is in therapeutic Daily monitoring of INR until INR is in therapeutic range then 3 times weekly for 1-2 weeks then less often range then 3 times weekly for 1-2 weeks then less often (every 4 to 6 weeks)(every 4 to 6 weeks)
OPTIMAL THERAPEUTIC RANGEOPTIMAL THERAPEUTIC RANGE
IndicationIndication INRINR
Prophylaxis of venous Prophylaxis of venous thromboembolismthromboembolism
20-3020-30
Treatment of venous Treatment of venous thromboembolismthromboembolism
20-3020-30
Atrial fibrillationAtrial fibrillation 20-3020-30
Mitral valve stenosisMitral valve stenosis 20-3020-30
Heart valve replacementHeart valve replacement
Bioprosthetic valveBioprosthetic valve
Mechanical valveMechanical valve
20-3020-30
25-3525-35
Myocardial infarctionMyocardial infarction 20-3020-30
25-35 25-35 (high risk patients)(high risk patients)
FACTORS INFLUENCING DOSE RESPONSEFACTORS INFLUENCING DOSE RESPONSE
Poor patient compliancePoor patient compliance Concomitant medicationsConcomitant medications Levels of dietary vitamin KLevels of dietary vitamin K Alcohol Inaccurate lab testingAlcohol Inaccurate lab testing Inaccurate lab testingInaccurate lab testing Hepatic dysfunctionHepatic dysfunction FeverFever
Contraindication for WarfarinContraindication for Warfarin
Hypersensitivity to warfarinHypersensitivity to warfarin Hemorrhagic tendencyHemorrhagic tendency Condition with risk of hemorrhageCondition with risk of hemorrhage Inadequate laboratory techniquesInadequate laboratory techniques Protein C amp S deficiencyProtein C amp S deficiency Vitamin K deficiencyVitamin K deficiency
SIDE EFFECTSSIDE EFFECTS
Hemorrhage Hemorrhage Skin necrosisSkin necrosis Purple toe syndromePurple toe syndrome Microembolization Microembolization TeratogenecityTeratogenecity Agranulocytosis leukopenia Agranulocytosis leukopenia Diarrhoeanausea anorexiaDiarrhoeanausea anorexia
MONITORING OF WARFARIN THERAPYMONITORING OF WARFARIN THERAPY
Prothrombin timeProthrombin time PT ratioPT ratio INR (International Normalized Ratio)INR (International Normalized Ratio)
PROTHROMBIN TIME (PT)PROTHROMBIN TIME (PT)
Time required for blood to coagulate Time required for blood to coagulate is called PT ( normal value ~10sec)is called PT ( normal value ~10sec)
Performed by adding a mixture of Performed by adding a mixture of calcium and thromboplastin to calcium and thromboplastin to citrated plasmacitrated plasma
As a control a normal blood sample is As a control a normal blood sample is tested continuouslytested continuously
PT ratio (PTR) = PT ratio (PTR) = Patientrsquos PTPatientrsquos PT Control PTControl PT
PROBLEMS WITH PTPTRPROBLEMS WITH PTPTR
Thromboplastins are extracts from Thromboplastins are extracts from brain lung or placenta of animalsbrain lung or placenta of animals
Thromboplastins from various Thromboplastins from various manufacturers differ in their manufacturers differ in their sensitivity to prolong PTsensitivity to prolong PT
May result in false control of May result in false control of anticoagulant therapyanticoagulant therapy
INTERNATIONAL NORMALISED RATIO (INR)INTERNATIONAL NORMALISED RATIO (INR)
International Normalized Ratio (INR) International Normalized Ratio (INR) a PT test with a a PT test with a formula based ratio to normalize the often variable source formula based ratio to normalize the often variable source of tissue factor (human rabbit recombinant)of tissue factor (human rabbit recombinant)
INR = [PTINR = [PTptpt] ] ISIISI
[PT[PTRefRef]]
PTPTpt pt ndash prothrombin time of patientndash prothrombin time of patient
PTPTRef Ref ndash prothrombin time of normal pooled samplendash prothrombin time of normal pooled sample
ISI ndash International Sensitivity IndexISI ndash International Sensitivity Index
Warfarin is given orally and titrated to achieve an INR of Warfarin is given orally and titrated to achieve an INR of typically 20 ndash 30typically 20 ndash 30
Heparin versus WarfarinHeparin versus Warfarin
Drug ActionMechan-ism
Moni-toring
Effective
HeparinDirect
Inhibition ofThrombin
ATIIIcofactor
APTTACT
Immediate
WarfarinDecreasesProductionof factors
Vitamin K PTDelay
3-5 days
INR
Recanalization or Antegrade Recanalization or Antegrade Reperfusion StrategiesReperfusion Strategies
Recanalization strategies focus on removing Recanalization strategies focus on removing andor dissolving the occlusive thrombus to re-andor dissolving the occlusive thrombus to re-establish antegrade flow Strategies may be establish antegrade flow Strategies may be classified into 7 different categories on the classified into 7 different categories on the basis of their primary mechanism of action basis of their primary mechanism of action 1) 1) IV andor intraarterial thrombolysis (IAT) IV andor intraarterial thrombolysis (IAT) 2) endovascular thrombectomy2) endovascular thrombectomy3) endovascular thromboaspiration 3) endovascular thromboaspiration 4) endovascular mechanical thrombus disruption or 4) endovascular mechanical thrombus disruption or
thromborrhexisthromborrhexis5) 5) transcranial or endovascular augmented transcranial or endovascular augmented
fibrinolysis fibrinolysis 6) endovascular thrombus entrapment and 6) endovascular thrombus entrapment and 7) temporary endovascular bypass7) temporary endovascular bypass
IAT in Acute Ischemic StrokeIAT in Acute Ischemic Stroke
IAT advantages over IV thrombolysisIAT advantages over IV thrombolysis Coaxial microcatheter techniques the occluded intracranial Coaxial microcatheter techniques the occluded intracranial
vessel is directly accessible and the fibrinolytic agent can be vessel is directly accessible and the fibrinolytic agent can be infused directly into the thrombusinfused directly into the thrombus
This permits a smaller dose of fibrinolytic agent to reach a This permits a smaller dose of fibrinolytic agent to reach a higher local concentration than that reached by systemic higher local concentration than that reached by systemic infusioninfusion
Allows more complete recanalization with lower total doses of Allows more complete recanalization with lower total doses of thrombolytic thrombolytic
With the smaller dose complications from systemic fibrinolytic With the smaller dose complications from systemic fibrinolytic effects including intracranial hemorrhage (ICH) can effects including intracranial hemorrhage (ICH) can theoretically be reduced theoretically be reduced
Treatment window for endovascular techniques can be Treatment window for endovascular techniques can be extended beyond the typical IV window of 3 hours extended beyond the typical IV window of 3 hours
IA techniques have led to higher recanalization rates than IV IA techniques have led to higher recanalization rates than IV thrombolysisthrombolysis
Major disadvantagesMajor disadvantages Relative complexity of the procedure the level Relative complexity of the procedure the level
of required technical expertise and its of required technical expertise and its relatively low availability relatively low availability
Delays in initiating treatmentDelays in initiating treatment InvasiveInvasive
ThrombolyticsThrombolytics
Plasminogen activators
Fibrinolytics
1 Plasminogen Activators 1 Plasminogen Activators drugs act by converting the inactive proenzyme drugs act by converting the inactive proenzyme plasminogen into the active enzyme plasmin Plasmin plasminogen into the active enzyme plasmin Plasmin digests fibrinogen fibrin monomers and cross-linked digests fibrinogen fibrin monomers and cross-linked fibrin (as found in a thrombus) into fibrin degradation fibrin (as found in a thrombus) into fibrin degradation productsproducts
First-Generation Agents First-Generation Agents StreptokinaseStreptokinase a protein derived from group C a protein derived from group C
szlig-hemolytic streptococci has a half-life of 16ndashszlig-hemolytic streptococci has a half-life of 16ndash90 minutes and low fibrin specificity This drug 90 minutes and low fibrin specificity This drug proved to have a very narrow therapeutic proved to have a very narrow therapeutic window and significant rates of ICH and window and significant rates of ICH and systemic hemorrhage18systemic hemorrhage18
UrokinaseUrokinase is a serine protease with a plasma is a serine protease with a plasma half life of 14 minutes and low fibrin specificity half life of 14 minutes and low fibrin specificity
The urokinase dose used in cerebral IAT has The urokinase dose used in cerebral IAT has ranged from 002 to 2 X106unitsranged from 002 to 2 X106units
Second-Generation Agents Second-Generation Agents Alteplase (rtPA) Alteplase (rtPA)
is a serine is a serine protease with a plasma half-life of 35 protease with a plasma half-life of 35 minutes and a high degree of fibrin affinity and minutes and a high degree of fibrin affinity and specificity specificity
Dose used in cerebral IAT has ranged between 20 Dose used in cerebral IAT has ranged between 20 and 60 mgand 60 mg
Disadvantages of alteplase include its relatively short Disadvantages of alteplase include its relatively short halflife and limited penetration into the clot matrix halflife and limited penetration into the clot matrix because of strong binding with surface fibrin which because of strong binding with surface fibrin which could delay recanalization and increase the risk of could delay recanalization and increase the risk of recurrent occlusion recurrent occlusion
Prourokinase (r-prourokinase) Prourokinase (r-prourokinase) is the proenzyme precursor of urokinase is the proenzyme precursor of urokinase T12 of 7 minutes and high fibrin specificity T12 of 7 minutes and high fibrin specificity
Third-Generation AgentsThird-Generation Agents
ReteplaseReteplase is a structurally modified is a structurally modified form of alteplase form of alteplase
with a longer half-life (15ndash18 minutes) In with a longer half-life (15ndash18 minutes) In addition it does not bind as highly to fibrin addition it does not bind as highly to fibrin unbound reteplase can thus theoretically better unbound reteplase can thus theoretically better penetrate the clot and potentially penetrate the clot and potentially improve in improve in vivo fibrinolytic activity vivo fibrinolytic activity
TenecteplaseTenecteplase is another modified form of rtPA with a longer is another modified form of rtPA with a longer
half-life (17 minutes)half-life (17 minutes) greater fibrin specificity and greater greater fibrin specificity and greater
resistance to plasminogen activator inhibitor-1 resistance to plasminogen activator inhibitor-1 IV tenecteplase in acute ischemic stroke IV tenecteplase in acute ischemic stroke
suggest that the drug is safe and promisingsuggest that the drug is safe and promising
Newer plasminogen activatorNewer plasminogen activator
DesmoteplaseDesmoteplase is a genetically engineered is a genetically engineered version of the clot-dissolving factor version of the clot-dissolving factor
found in the saliva found in the saliva of the vampire bat Desmodus rotundusof the vampire bat Desmodus rotundus moremore potent and more selective for fibrin-bound potent and more selective for fibrin-bound
plasminogen than any other known plasminogen plasminogen than any other known plasminogen activatoractivator
Unlike tissue plasminogen activator (tPA) desmoteplase Unlike tissue plasminogen activator (tPA) desmoteplase is not activated by fibrinogen or -amyloid proteins is not activated by fibrinogen or -amyloid proteins factors that may exacerbate the risk for ICH factors that may exacerbate the risk for ICH
The effect of IV administration of desmoteplase 3ndash9 The effect of IV administration of desmoteplase 3ndash9 hours after symptom onset in patients with stroke who hours after symptom onset in patients with stroke who present with mismatch on MR imaging or CT perfusion present with mismatch on MR imaging or CT perfusion
3 DefibrinogenatingFibrinogenolytic 3 DefibrinogenatingFibrinogenolytic Agents Agents
AncrodAncrod(Viprinex)(Viprinex) is is the purified fraction of the Malayan pit viper venomthe purified fraction of the Malayan pit viper venom It acts by directly cleaving and inactivating fibrinogen It acts by directly cleaving and inactivating fibrinogen
and thus indirectly promoting anticoagulation and thus indirectly promoting anticoagulation The reduction in the blood levels of fibrinogen also The reduction in the blood levels of fibrinogen also
leads to a reduced blood viscosity which may improve leads to a reduced blood viscosity which may improve blood flow to the affected areas of the brain blood flow to the affected areas of the brain
In the Stroke Treatment with Ancrod Trial 500 In the Stroke Treatment with Ancrod Trial 500 patients with stroke presenting within 3 hours of patients with stroke presenting within 3 hours of symptom onset were randomized to receive ancrod (symptom onset were randomized to receive ancrod (n n 248) or a placebo (n 252) Good outcome (Barthel 248) or a placebo (n 252) Good outcome (Barthel Index 95ndash100 at 3 months) was achieved in 4221 Index 95ndash100 at 3 months) was achieved in 4221 and 344 of the patients respectively and 344 of the patients respectively
2 Direct Fibrinolytics2 Direct Fibrinolytics
Microplasmin (Microplasmin (ThromboGenics Heverlee Belgium)ThromboGenics Heverlee Belgium) is a truncated form of plasmin that is more resistant to the effects is a truncated form of plasmin that is more resistant to the effects
of antiplasmin of antiplasmin microplasmin can be used upto 4ndash12 hours after stroke onset microplasmin can be used upto 4ndash12 hours after stroke onset There was no evidence of increased bleeding risk with There was no evidence of increased bleeding risk with
microplasminmicroplasmin
Alfimeprase (Nuvelo San Carlos Calif)Alfimeprase (Nuvelo San Carlos Calif) is a recombinant truncated form of fibrolase a fibrinolytic zinc metalloproteinase is a recombinant truncated form of fibrolase a fibrinolytic zinc metalloproteinase
isolated from the venom of the southern copperhead snake isolated from the venom of the southern copperhead snake It degrades fibrin directly and achieves thrombolysis independent It degrades fibrin directly and achieves thrombolysis independent
of plasmin formationof plasmin formation its thrombolytic activity appears to be localized to the site of its thrombolytic activity appears to be localized to the site of
delivery These properties should theoretically result in faster delivery These properties should theoretically result in faster recanalization and lower hemorrhagic conversion riskrecanalization and lower hemorrhagic conversion risk
Anti-fibrinolyticsAnti-fibrinolytics
to limit fibrinolytic activityto limit fibrinolytic activity -aminocaproic acid (EACA) -aminocaproic acid (EACA) competitively inhibitscompetitively inhibits plasminogen and plasminogen activators from plasminogen and plasminogen activators from
binding to fibrinbinding to fibrin
alpha2-antiplasminalpha2-antiplasmin a serine protease inhibitor that a serine protease inhibitor that neutralizes any free circulating plasminneutralizes any free circulating plasmin
Plasminogen activator inhibitor-1Plasminogen activator inhibitor-1 a serine protease a serine protease inhibitor that inhibits tissue-type plasminogen inhibitor that inhibits tissue-type plasminogen activatoractivator
Glycoprotein (GP) IIbIIIa antagonistsGlycoprotein (GP) IIbIIIa antagonists
such as ReoPro (abciximab) Integrilin such as ReoPro (abciximab) Integrilin (eptifibatide) or Aggrastat (tirofiban) in (eptifibatide) or Aggrastat (tirofiban) in ischemic stroke remains investigational ischemic stroke remains investigational Deshmukh et al38 reported 21 patients with Deshmukh et al38 reported 21 patients with large-vessel occlusion refractory to IAT with large-vessel occlusion refractory to IAT with rtPA who were treated with IV andor IA rtPA who were treated with IV andor IA abciximab eptifibatide or tirofiban abciximab eptifibatide or tirofiban
IA Mechanical Approaches in Acute Ischemic Stroke IA Mechanical Approaches in Acute Ischemic Stroke Mechanical strategies have several advantagesMechanical strategies have several advantages First they lessen and may even preclude the use of chemical First they lessen and may even preclude the use of chemical
thrombolytics in this manner very likely reducing the risk of ICHthrombolytics in this manner very likely reducing the risk of ICH Second by avoiding the use of chemical thrombolytics it is Second by avoiding the use of chemical thrombolytics it is
possible to extend the treatment window beyond the limit of 6ndash8 possible to extend the treatment window beyond the limit of 6ndash8 hours hours
Third mechanically fragmenting a clot increases the surface area Third mechanically fragmenting a clot increases the surface area accessible to fibrinolytic agents and allows inflow of fresh accessible to fibrinolytic agents and allows inflow of fresh plasminogen which in turn may increase the speed of plasminogen which in turn may increase the speed of thrombolysis thrombolysis
Finally clot-retrieval devices may provide faster recanalization Finally clot-retrieval devices may provide faster recanalization
The disadvantages of the mechanical The disadvantages of the mechanical approaches approaches technical difficulty of navigating mechanical technical difficulty of navigating mechanical
devices into the intracranial circulation excessive devices into the intracranial circulation excessive trauma to the vasculature (potentially leading to trauma to the vasculature (potentially leading to vasospasm vessel dissection perforation or vasospasm vessel dissection perforation or rupture) rupture)
fragmented thrombus causing distal embolization fragmented thrombus causing distal embolization into previously unaffected territories into previously unaffected territories
Nevertheless the advantages of mechanical stroke Nevertheless the advantages of mechanical stroke therapy appear to significantly outweigh its therapy appear to significantly outweigh its disadvantages and risksdisadvantages and risks
Contraindications to Thrombolytic Contraindications to Thrombolytic agents agents
Recent thoracic abdominal or Recent thoracic abdominal or intracranial surgeryintracranial surgery
Recent haemorrhagic CVA Head injury Recent haemorrhagic CVA Head injury or neoplasmor neoplasm
Bleeding ulcerBleeding ulcer Anticipated invasive procedures (arterial Anticipated invasive procedures (arterial
punctures biopsies)punctures biopsies) Concurrent hemostatic dysfunctionConcurrent hemostatic dysfunction
Monitoring of thrombolytic Monitoring of thrombolytic therapytherapy
Thrombin time Measures the availability of functional
fibrinogen Normal thrombin time is 10-14 sec Prolonged when fibrinogen level is below
75-100 mgdl
Half Life of ThrombolyticsHalf Life of ThrombolyticsAgent Administration Half Life
Streptokinase IA 60-80min
Urokinase IAIV 9-12min
rTPA IAIV 6min
Abciximab(Reopro) IAIV 12hour
Aspirin POIV 15-20min
Heparin IVSC 60min
Coumadin PO 15-25 days
Anti Platelet DrugsAnti Platelet DrugsDrug Drug Mechanism Mechanism UsesUsesAspirinAspirin Permanently inhibits Permanently inhibits
COX-1 and COX-2COX-1 and COX-2CADCAD
Stroke-TIAsStroke-TIAs
NSAIDsNSAIDs Reversibly inhibits Reversibly inhibits COX-1COX-1
LimitedLimited
DipyridamoleDipyridamole Inhibits PDE increases Inhibits PDE increases cAMPcAMP
TIAsTIAs
ThenopyridinesThenopyridines
(Ticlopidine(Ticlopidine
ClopidrgrelClopidrgrel))
Inhibits ADP Inhibits ADP
PlatAg PlatAg
TIAsStrokeTIAsStroke
CAD PVDCAD PVD
Abciximab (ReoPro)Abciximab (ReoPro)
Eptifibatide (Integrilin)Eptifibatide (Integrilin)
TirofibanTirofiban
GP IIBIIIA InhibitorsGP IIBIIIA Inhibitors
Stroke- TIAs Stroke- TIAs
MonitoringMonitoring
Bleeding timeBleeding time
Optical aggregometryOptical aggregometry
Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay
Bleeding timeBleeding time
Requires a skin incision (usually made on the ear lobe or Requires a skin incision (usually made on the ear lobe or forearm offorearm of
a depth that results in disruption of capillary loops and a depth that results in disruption of capillary loops and small vessels)small vessels)
AdvantagesAdvantages Universally availableUniversally available Relatively simple techniquesRelatively simple techniques Can be performed bedsideCan be performed bedside
DisadvantagesDisadvantages Insensitive inaccurate non-specific techniqueInsensitive inaccurate non-specific technique
Poorly reproducible (as depends on multiple variables)Poorly reproducible (as depends on multiple variables)
Optical aggregometryOptical aggregometry
Gold standard assay for platelet functionGold standard assay for platelet function Agonist induced aggregation is measuredAgonist induced aggregation is measured Different agonist are available for different Different agonist are available for different
agentsagents However require unique expertise and are not However require unique expertise and are not
universally availableuniversally available Aspirin measured with ADP or AA(gt70 Aspirin measured with ADP or AA(gt70
aggregation so resistance)aggregation so resistance) Clopidogrel( ADP gt 90 aggregation means Clopidogrel( ADP gt 90 aggregation means
resistance) resistance)
Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay
Can be performed bed sideCan be performed bed side Different assay devices with different Different assay devices with different
agonist are used for each of different agonist are used for each of different antiplatelet agents antiplatelet agents
For Aspirin AA is used (result is reported as aspirin For Aspirin AA is used (result is reported as aspirin reaction units [ARU] ARUgt 550 indicates non-reaction units [ARU] ARUgt 550 indicates non-responsiveness)responsiveness)
Verify IIbIIIa assay device uses TRAP as agonist for Verify IIbIIIa assay device uses TRAP as agonist for Abciximab and TirofibanAbciximab and Tirofiban
Practical Applications Practical Applications related to specific related to specific
Neurovascular Neurovascular interventionsinterventions
Acute ischemic StrokeAcute ischemic Stroke When an artery occludes neurons are affected When an artery occludes neurons are affected
differently depending upon the amount of residual blood differently depending upon the amount of residual blood flowflow
Normal cerebral blood flow is greater than 50 mL100 Normal cerebral blood flow is greater than 50 mL100 mgminmgmin
Once blood flow decreases to less than 20 mL100 Once blood flow decreases to less than 20 mL100 mgmin infarction occursmgmin infarction occurs
If blood flow decreases to less than 10 mL100 mgmin If blood flow decreases to less than 10 mL100 mgmin irreversible neuronal death occurs rapidly irreversible neuronal death occurs rapidly
Blood flow between 11 and 20 mL100 mgmin is thought Blood flow between 11 and 20 mL100 mgmin is thought to represent the ischemic penumbra an area where the to represent the ischemic penumbra an area where the cells are functionally silent because of ischemia but are cells are functionally silent because of ischemia but are still able to recover if blood flow is restored still able to recover if blood flow is restored
Many acute stroke therapies are targeted toward Many acute stroke therapies are targeted toward restoring flow or function to the ischemic penumbrarestoring flow or function to the ischemic penumbra
Therapeutic window in Therapeutic window in management of acute Ischemic management of acute Ischemic
StrokeStrokeThe early diagnosis of ischemic stroke is critical to the The early diagnosis of ischemic stroke is critical to the
with only a narrow therapeutic window in the first few with only a narrow therapeutic window in the first few hours following stroke ictushours following stroke ictus
Diagnosis in the first 3 hours postictus provides the Diagnosis in the first 3 hours postictus provides the opportunity for intravenous or intraarterial thrombolysis opportunity for intravenous or intraarterial thrombolysis and intra-arterial clot mechanical treatment which and intra-arterial clot mechanical treatment which improve the outcome improve the outcome
Diagnosis in the time period between 3 and 6 hours Diagnosis in the time period between 3 and 6 hours provides an opportunity for intra-arterial thrombolysis provides an opportunity for intra-arterial thrombolysis and mechanical treatment and mechanical treatment
Involvement of the posterior circulation especially the Involvement of the posterior circulation especially the basilar artery is treated by some regardless of time of basilar artery is treated by some regardless of time of onset or up until 12 to 24 hours in some practices This is onset or up until 12 to 24 hours in some practices This is related to the potentially high mortality and morbidity related to the potentially high mortality and morbidity associated with basilar artery thrombosisassociated with basilar artery thrombosis
Infarct evaluation on angiographyInfarct evaluation on angiography(CT angiography and catheter (CT angiography and catheter
angiography)angiography)CTA is an excellent first-line examination for CTA is an excellent first-line examination for
evaluation of the head and neck arteries evaluation of the head and neck arteries In comparison with catheter angiography In comparison with catheter angiography
what it gives up in resolution and dynamic what it gives up in resolution and dynamic properties it makes up for with rapid properties it makes up for with rapid acquisition of a 3-D dataset and the potential acquisition of a 3-D dataset and the potential for assessment of whole-brain perfusion and for assessment of whole-brain perfusion and better parenchymal evaluationbetter parenchymal evaluation
Moreover CTA illustrates not only arterial Moreover CTA illustrates not only arterial stenosis or occlusion but also the vessel wall stenosis or occlusion but also the vessel wall This factor is most important for evaluation of This factor is most important for evaluation of intramural dissection and thrombosed intramural dissection and thrombosed aneurysms which may both complicate aneurysms which may both complicate evaluation of stroke patientsevaluation of stroke patients
Early angiographic signs of strokes Early angiographic signs of strokes both CTA both CTA and DSA and DSA
Vessel occlusion or cutoff related to Vessel occlusion or cutoff related to thromboembolithromboemboli
aneurysms aneurysms arterial dissection arterial dissection Meniscus or flattened shape to clot Meniscus or flattened shape to clot
(recent) versus reverse meniscus (older)(recent) versus reverse meniscus (older) tram track (nonocclusive or recanalized tram track (nonocclusive or recanalized
clot) clot) delayed (antegrade) flow (manifest as delayed (antegrade) flow (manifest as
decreased whole-brain perfusion on CTA)decreased whole-brain perfusion on CTA) retrograde collateral flowretrograde collateral flow
Non-occlusive left MCA thrombus on 3-D imaging performed from CTA source data and was confirmed at catheter angiography
Therapy to be started within a 6-hr Therapy to be started within a 6-hr time to treatment (TTT) window time to treatment (TTT) window (while in case of IV thrombolysis (while in case of IV thrombolysis therapy to be started with in 3hrs)therapy to be started with in 3hrs)
Exclusion criteria Exclusion criteria Rapidly improving neurologic deficit or Rapidly improving neurologic deficit or Sustained blood pressure of gt180100 Sustained blood pressure of gt180100 Hemorrhage is detected on CTHemorrhage is detected on CT Infarct involving gt more than 13 rd Infarct involving gt more than 13 rd
territory of MCAterritory of MCA MRADWI-Perfusion mismatchlt 20MRADWI-Perfusion mismatchlt 20 Definite hypodensity on CTDefinite hypodensity on CT
Intra-arterial Thrombolysis
Fibrinolytics + AntiplateletsFibrinolytics + Antiplatelets
PlasminogenPlasminogen activators through fibrinolysis exposes activators through fibrinolysis exposes free thrombin and paradoxically stimulatesfree thrombin and paradoxically stimulates platelet platelet aggregation which leads to formation of aaggregation which leads to formation of a platelet platelet thrombus (white clot) thrombus (white clot)
This new thrombus is relatively resistant to This new thrombus is relatively resistant to fibrinolyticsfibrinolytics
So new regimen in case of acute stroke isSo new regimen in case of acute stroke is fibrinolytics + antiplatelet drugsfibrinolytics + antiplatelet drugs
rtPA + IIbIIIa inhibitors( tirofiban rtPA + IIbIIIa inhibitors( tirofiban abciximab) orabciximab) or
Urokinase + IIbIIIa Urokinase + IIbIIIa inhibitors( tirofiban abciximab)inhibitors( tirofiban abciximab)
Intra-arterial Thrombolysis Tirofiban (04 microgkgmin bolus for 3 min followed by Tirofiban (04 microgkgmin bolus for 3 min followed by
0125 ugkgmin)0125 ugkgmin)
++
Heparin (2000ndash3000 IU bolus followed by Heparin (2000ndash3000 IU bolus followed by 1000 IUhour infusion 1000 IUhour infusion
with ACT maintained bw 200-300) throughout the with ACT maintained bw 200-300) throughout the interventional procedure and for 24ndash48 hours thereafter when interventional procedure and for 24ndash48 hours thereafter when there is neither intraprocedural bleeding nor suspicion of there is neither intraprocedural bleeding nor suspicion of increased risk of bleeding increased risk of bleeding
Maximum dose of Urokinase Maximum dose of Urokinase Anterior circulation stroke - 500000 IU (mean 400000 Anterior circulation stroke - 500000 IU (mean 400000
IU range 300000ndash500000 IU)IU range 300000ndash500000 IU) Posterior circulation stroke -1000000 IU (mean 837000 Posterior circulation stroke -1000000 IU (mean 837000
IU range 300000ndash1000000 IU)IU range 300000ndash1000000 IU)American Journal of NeuroradiologyAmerican Journal of Neuroradiology 262595-2601 2005262595-2601 2005
Intravenous ThrombolysisIntravenous Thrombolysis
The first method to restore cerebral The first method to restore cerebral perfusion is clot lysis with the goal perfusion is clot lysis with the goal of re-establishing blood flow to the of re-establishing blood flow to the affected tissue affected tissue
IV thrombolysis rt-PA is the only IV thrombolysis rt-PA is the only FDA- approved treatment for AIS FDA- approved treatment for AIS
Fibrinolysis is enhanced powerfully Fibrinolysis is enhanced powerfully by rt-PAby rt-PA
Intravenous rTPA Intravenous rTPA administration administration protocolprotocol
Total dose of rt-PA 09 mgkg (maximum dose Total dose of rt-PA 09 mgkg (maximum dose 90 mg)90 mg)
Give 10 as initial IV bolusGive 10 as initial IV bolus Infuse remainder over 1 hourInfuse remainder over 1 hour Admit patient to an ICU or stroke unit for Admit patient to an ICU or stroke unit for
monitoringmonitoring Neurologic assessments every 15 minutes Neurologic assessments every 15 minutes
during infusion then every 30 minutes for next during infusion then every 30 minutes for next 6 hours then every hour until 24hours after 6 hours then every hour until 24hours after treatmenttreatment
Favorable Outcome vs Treatment Time Favorable Outcome vs Treatment Time with IV rTPAwith IV rTPA
Protocol limit = 3 hrs
Benefit ~ 45 hrs
Thromboembolism During coilingThromboembolism During coiling Most feared and frequent complication Most feared and frequent complication Reported incidence - Approx 7 Reported incidence - Approx 7 SourcesSources of Thromboembolism are of Thromboembolism are
- Clots at the aneurysmal neck during or immediately- Clots at the aneurysmal neck during or immediately after after embolization embolization
- Thrombus forming on catheters during- Thrombus forming on catheters during proceduresprocedures
- Stenosis of an adjacent artery dt coil mass- Stenosis of an adjacent artery dt coil mass or herniationor herniation
- Migration of intraaneurysmal- Migration of intraaneurysmal thrombus during coil thrombus during coil placement placement
- Slow flow dt vasospasm - Slow flow dt vasospasm
- Rare and unlikely causes are hypercoagulable- Rare and unlikely causes are hypercoagulable state such state such as antiphospholipid antibody syndrome or due to HITas antiphospholipid antibody syndrome or due to HIT
Occur more often with wide-necked aneurysms (dt Occur more often with wide-necked aneurysms (dt increased exposed surface area of thrombogenic coil increased exposed surface area of thrombogenic coil material)material)
Current regimen of endovascular Current regimen of endovascular managementmanagement
The The glycoprotein IIbIIIa antagonist tirofiban glycoprotein IIbIIIa antagonist tirofiban (04 (04 microgkgmin bolus for 30 minutes followed by infusion of microgkgmin bolus for 30 minutes followed by infusion of 0125 ugkgmin until the thrombus dissolved) 0125 ugkgmin until the thrombus dissolved)
Intraarterial thrombolysis with Intraarterial thrombolysis with urokinase or r- TPA urokinase or r- TPA increase of intravenous (IV) heparin (measured by increase of intravenous (IV) heparin (measured by
ACT) ACT) Intravenous aspirin Intravenous aspirin
Coil-related platelet aggregation (white clot) is Coil-related platelet aggregation (white clot) is unlikely to respond to fibrinolytics but has a high risk unlikely to respond to fibrinolytics but has a high risk of hemorrhage (In ISAT) all 5 patients who had of hemorrhage (In ISAT) all 5 patients who had received thrombolytic therapy with tPA to treat a received thrombolytic therapy with tPA to treat a thromboembolic complication after endovascular thromboembolic complication after endovascular treatment rebleed and all of these patients died)treatment rebleed and all of these patients died)
IntracranialIntracranial Stenting Stenting Metallic foreign body such as stent will accumulate Metallic foreign body such as stent will accumulate
thrombus in the absence of platelet inhibitionthrombus in the absence of platelet inhibition Antiplatelet drugs are important to prevent peri or Antiplatelet drugs are important to prevent peri or
post-interventional thromboembolic eventspost-interventional thromboembolic events Optimal treatment regimens has not been determined Optimal treatment regimens has not been determined
but usually but usually Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-
procedureprocedureOrOr
Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on
morning of proceduremorning of procedure
If need to use stent is not pre-planned thanIf need to use stent is not pre-planned than
Abciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkgAbciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkg IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)
Glycoprotein IIbIIIa inhibitor are not used routinely during elective Glycoprotein IIbIIIa inhibitor are not used routinely during elective stenting procedure dt increased risk of ICH stenting procedure dt increased risk of ICH
Carotid StentingCarotid Stenting
Pre-procedurePre-procedure
Double Antiplatelet therapy is routinely given Double Antiplatelet therapy is routinely given beginning at least 3beginning at least 3
days before the proceduredays before the procedure
Aspirin 325mgd+Clopidogrel 75mgdAspirin 325mgd+Clopidogrel 75mgd During procedureDuring procedure
Heparin is given with target clotting time of 250-Heparin is given with target clotting time of 250-300sec300sec
Post-procedure Post-procedure
Aspirin 325mg is continued indefinitely and Aspirin 325mg is continued indefinitely and
Clopidogrel 75mgd for at least 6 weeks Clopidogrel 75mgd for at least 6 weeks
Inclusion criteria for Local ThrombolysisInclusion criteria for Local Thrombolysis a)a) Patients in severe clinical grade on admission Patients in severe clinical grade on admission
with evidence of dural venous sinus with evidence of dural venous sinus thrombosis and restrictive venous outflow on thrombosis and restrictive venous outflow on cerebral angiogramcerebral angiogram
b)b) Patients in clinical grade 3 worsening on Patients in clinical grade 3 worsening on heparin therapy Restriction to venous heparin therapy Restriction to venous outflow was defined as an increase in brain outflow was defined as an increase in brain circulation time gt 12 s delay in the drainage circulation time gt 12 s delay in the drainage of cortical veins with cortical veins hanging of cortical veins with cortical veins hanging in spacein space
Treatment Options for Venous Thrombosis
CT Grading for Venous ThrombosisCT Grading for Venous Thrombosis Grade I no parenchymal change Grade I no parenchymal change
(hyperdense (hyperdense sinuses cortical veins empty sinuses cortical veins empty delta sign)delta sign)
Grade II non hemorrhagic venous infarct Grade II non hemorrhagic venous infarct without mass effect without mass effect
Grade III non-hemorrhagic infarct with Grade III non-hemorrhagic infarct with mass effectmass effect
Grade IV hemorrhagic venous infarct (max Grade IV hemorrhagic venous infarct (max diameter lt 3 cm) with no mass effectdiameter lt 3 cm) with no mass effect
Grade V hemorrhagic venous infarct (max Grade V hemorrhagic venous infarct (max diameter gt 3 cm) with mass effect diameter gt 3 cm) with mass effect
Local ThrombolysisLocal Thrombolysis
Femoral Jugular access was secured and a guiding Femoral Jugular access was secured and a guiding catheter was placed in the jugular bulb catheter was placed in the jugular bulb Mechanical Mechanical clot maceration clot maceration was done with the guidewire was done with the guidewire following which a microcatheter (was navigated and following which a microcatheter (was navigated and placed in the thrombosed segment of sinus confirmed placed in the thrombosed segment of sinus confirmed on a selective venogram on a selective venogram
Urokinase infusion Bolus dose of 2-6 lacs followed Urokinase infusion Bolus dose of 2-6 lacs followed by 60000 to 100000 units per hour along with by 60000 to 100000 units per hour along with periodic check venogram Along with maintenance periodic check venogram Along with maintenance systemic infusion of Heparinsystemic infusion of Heparin Other agents such as Other agents such as streptokinase altepase or rTPAstreptokinase altepase or rTPA can be also used can be also used
After thrombolysis patient should subjected to oral After thrombolysis patient should subjected to oral anticoagulation for six monthsanticoagulation for six months
Low-molecular-weight Low-molecular-weight heparinheparin
PharmacologyPharmacologyLMWH as its name suggests is a glycosaminoglycan that is approximatelyLMWH as its name suggests is a glycosaminoglycan that is approximately
one third the molecular weight of UFH It is derived from UFH through one third the molecular weight of UFH It is derived from UFH through variousvarious
depolymerization processes LMWH binds to antithrombin which in turn depolymerization processes LMWH binds to antithrombin which in turn
Neutralizes actors Xa and IIa Because LMWH lacks many of the longer Neutralizes actors Xa and IIa Because LMWH lacks many of the longer chains chains
required for binding to thrombin it has less ability to neutralize thrombin required for binding to thrombin it has less ability to neutralize thrombin
relativeto its ability to neutralize factor Xa LMWH also has less relativeto its ability to neutralize factor Xa LMWH also has less nonspecific nonspecific
binding to other proteins There is greater bioavailability with more binding to other proteins There is greater bioavailability with more predictable predictable
pharmacokinetics that eliminates the need for monitoring The smaller pharmacokinetics that eliminates the need for monitoring The smaller size also size also
allows for enhanced subcutaneous absorption when compared with UFHallows for enhanced subcutaneous absorption when compared with UFH
Three LMWH preparations are Three LMWH preparations are currently approved for use in the currently approved for use in the United States (1) enoxaparin (2) United States (1) enoxaparin (2) dalteparin and (3) tinzaparin dalteparin and (3) tinzaparin
They are all administered They are all administered subcutaneously at intervals of either subcutaneously at intervals of either once or twice daily for both once or twice daily for both prophylaxis and treatment dosesprophylaxis and treatment doses
Few Experiences of Few Experiences of ThrombolysisThrombolysis
Vickey 25 Yrs male patient presented Vickey 25 Yrs male patient presented with 12with 12thth day HO severe headache with day HO severe headache with right sided hemiplegiaright sided hemiplegia
MRI shows thrombosis of the superior MRI shows thrombosis of the superior sagittal left transverse left sigmoid sagittal left transverse left sigmoid sinuses and cortical veins in the fronto-sinuses and cortical veins in the fronto-parietal regions with eo haemorrhagic parietal regions with eo haemorrhagic infarct in the left cerebral hemisphere infarct in the left cerebral hemisphere with mass effect( Grade ndashV)with mass effect( Grade ndashV)
Sashi Srivastava 64 yrs FSashi Srivastava 64 yrs F In a follow up case of MRD with infra-renal In a follow up case of MRD with infra-renal
aortic abdominal and bilateral renal artery aortic abdominal and bilateral renal artery thrombosis renal angiogram shows filling thrombosis renal angiogram shows filling defects in the right Renal artery defects in the right Renal artery
Initially Renal angioplasty was done Initially Renal angioplasty was done Following angioplasty few thrombi are seem Following angioplasty few thrombi are seem to extends into the segmental branches and to extends into the segmental branches and causing blockage So Thrombolysis was causing blockage So Thrombolysis was plane to dissolve the run-out thrombi with plane to dissolve the run-out thrombi with urokinase urokinase
Rakesh 34yrsMRakesh 34yrsM Left SFA pseudoaneurysm with Left SFA pseudoaneurysm with
Covered stent placementCovered stent placement Pre operative antiplatelets with post Pre operative antiplatelets with post
procedure heparin Tirofiban procedure heparin Tirofiban followed by aspirin and clopidogrel followed by aspirin and clopidogrel were usedwere used
IAT may be a treatment option for selected patients IAT may be a treatment option for selected patients Possible selection criteria include Possible selection criteria include
presentation between 3 and 6 hours from symptom onsetpresentation between 3 and 6 hours from symptom onset major cerebral artery occlusion major cerebral artery occlusion severe neurologic deficits severe neurologic deficits high risk of systemic hemorrhage with IV rt-PA (eg recent high risk of systemic hemorrhage with IV rt-PA (eg recent
surgery) surgery) The MERCI (Mechanical Embolus Removal in Cerebral The MERCI (Mechanical Embolus Removal in Cerebral
Ischemia) retrievalIschemia) retrieval system system
Has been FDA-approved for recanalizing acutely occluded Has been FDA-approved for recanalizing acutely occluded cerebral arteries cerebral arteries
In the Multi-MERCI study patients who did not improve In the Multi-MERCI study patients who did not improve immediately after IV rt-PA underwent mechanical immediately after IV rt-PA underwent mechanical embolectomy within 8 hours of symptom onset embolectomy within 8 hours of symptom onset
Partial or complete recanalization occurred in 74 of Partial or complete recanalization occurred in 74 of patientspatients
with a symptomatic intracerebral hemorrhage (sICH) rate of with a symptomatic intracerebral hemorrhage (sICH) rate of 67 67
Mechanical embolectomy with the MERCI retriever may be a Mechanical embolectomy with the MERCI retriever may be a feasible and safe option for patients after IV rt-PAfeasible and safe option for patients after IV rt-PA
Penumbra stroke systemPenumbra stroke system This device combines two methods of clot This device combines two methods of clot
extraction aspiration and mechanical extraction aspiration and mechanical extraction extraction
First the clot is aspirated then a thrombus First the clot is aspirated then a thrombus removal ring can be used if necessary to removal ring can be used if necessary to remove remaining clot remove remaining clot
successful recanalizing 82successful recanalizing 82 Bridging therapyBridging therapy
06 mgkg IV rt-PA followed by IAT with IA rt-06 mgkg IV rt-PA followed by IAT with IA rt-PA (up to 20 mg)PA (up to 20 mg)
achieved a higher recanalization rateachieved a higher recanalization rate
Criteria for thrombolysis with rTPACriteria for thrombolysis with rTPA
Inclusion criteriaInclusion criteria Clinical signs and symptoms consistent with ischemic Clinical signs and symptoms consistent with ischemic
strokestroke Patient last seen normal within 3 hoursPatient last seen normal within 3 hours Measurable neurologic deficitMeasurable neurologic deficit
Exclusion criteriaExclusion criteria Any hemorrhage on neuroimaging (CT or MRI)Any hemorrhage on neuroimaging (CT or MRI) Symptoms suggestive of subarachnoid hemorrhageSymptoms suggestive of subarachnoid hemorrhage Seizure at stroke onset that is thought to contribute to Seizure at stroke onset that is thought to contribute to
neurologic deficitneurologic deficit Hypodensity greater than one third cerebral hemisphere Hypodensity greater than one third cerebral hemisphere
on CTon CT SBP greater than 185 mm Hg or DBP greater than 110 SBP greater than 185 mm Hg or DBP greater than 110
mm Hgmm Hg International normalized ratio (INR) greater than 17International normalized ratio (INR) greater than 17
Ischemic Stroke Ischemic Stroke Treatment ndash 2006Treatment ndash 2006
IV tissue plasminogen activator (tPA)IV tissue plasminogen activator (tPA) ndash ndash Only FDA-approved acute stroke drugOnly FDA-approved acute stroke drug ndash ndash 3 hour treatment window3 hour treatment window
MERCI - Concentric clot retrieval MERCI - Concentric clot retrieval devicedevice ndash ndash Rescue therapy - approved 2004Rescue therapy - approved 2004 ndash ndash Device approval (not outcomes-based)Device approval (not outcomes-based)
Off label approachesOff label approaches ndash ndash IV tPA after 3 hoursIV tPA after 3 hours ndash ndash IV-IA tPA sequential strategiesIV-IA tPA sequential strategies ndash ndash IA tPA clot angioplasty fragmentationIA tPA clot angioplasty fragmentation ndash ndash Ultrasound-assisted tPA lysisUltrasound-assisted tPA lysis
rt-PA Trials NINDSrt-PA Trials NINDS
Acute stroke - 624 patientsAcute stroke - 624 patients Treat within 3 hrsTreat within 3 hrs Intravenous 09 mgkg rt-PA vs placeboIntravenous 09 mgkg rt-PA vs placebo Hemorrhage 64 tPA 06 placeboHemorrhage 64 tPA 06 placebo Neurologic recovery better with tPA 30 Neurologic recovery better with tPA 30
more like to have minimal or no disabilitymore like to have minimal or no disability
First proven approved treatment for First proven approved treatment for strokestroke
Limitations of tPALimitations of tPA Only 4 of acute strokes receive tPAOnly 4 of acute strokes receive tPA (Kleindorfer et al Stroke 2004 35 e27-e29)(Kleindorfer et al Stroke 2004 35 e27-e29)
Only 22 of patients present within 3 hoursOnly 22 of patients present within 3 hours1048707 1048707 51 of these ineligible due to51 of these ineligible due to
bull bull Mild severityMild severity bull bull Medical or surgical historyMedical or surgical history bull bull Blood testsBlood tests
Sustained recanalization only 13Sustained recanalization only 13 (Alexandrov et al NEJM 2004 351 2170-8)(Alexandrov et al NEJM 2004 351 2170-8)
Concern for hemorrhageConcern for hemorrhage tPA potentiates apoptotic injury tPA potentiates apoptotic injury (Liu et al Nature Med 2004 101379-83)(Liu et al Nature Med 2004 101379-83)
PROACT II IA Lysis TrialPROACT II IA Lysis Trial Baseline 24 hours 8 days
Baseline 60 minutes 120 minutes
9mg IAProurokinase
Desmoteplase Trials DEDAS Desmoteplase Trials DEDAS DIASDIAS
Trial OverviewTrial Overview Double blind randomized placebo Double blind randomized placebo
controlled trialscontrolled trials IV delivery 3-9 hour time windowIV delivery 3-9 hour time window Plasminogen activator ndash from Plasminogen activator ndash from vampire bat vampire bat
salivasaliva Selection based on PWI-DWI MismatchSelection based on PWI-DWI Mismatch
MRI InclusionMRI Inclusion PWI defect at least 2 cm AND ~20 larger PWI defect at least 2 cm AND ~20 larger
than DWIthan DWI PWI should be obvious even visible on PWI should be obvious even visible on
raw imagesraw imagesMRI ExclusionMRI Exclusion
DWI gt 13 MCADWI gt 13 MCA MRA ICA occlusionMRA ICA occlusion
Desmoteplase ndash DIAS Desmoteplase ndash DIAS ResultsResults
Mechanical Thrombolysis Mechanical Thrombolysis devicesdevices
mechanical thrombolysis potentially extends the treatment mechanical thrombolysis potentially extends the treatment window because they act promptly at the site of the thrombuswindow because they act promptly at the site of the thrombus
The devices can retrieve large clots that pharmaceutical agents The devices can retrieve large clots that pharmaceutical agents may not successfully lysemay not successfully lyse
Patients treated with IV tPA may be considered for treatment of Patients treated with IV tPA may be considered for treatment of residual clot with some of these devicesresidual clot with some of these devices
suction-creating saline jets suction-creating saline jets laser energy ultrasound laser energy ultrasound a corkscrew apparatus to treat strokesa corkscrew apparatus to treat strokes The AngioJet systemThe AngioJet system uses saline jets that are directed back into the catheter to uses saline jets that are directed back into the catheter to
create a low-pressure zone around the catheter tip inducing create a low-pressure zone around the catheter tip inducing suction suction
The clot is pulled into the exhaust lumen and removed from the The clot is pulled into the exhaust lumen and removed from the vessel Although US Food and Drug Administration (FDA) has vessel Although US Food and Drug Administration (FDA) has approved this device for use in arteriovenous dialysis grafts and approved this device for use in arteriovenous dialysis grafts and fistulae and for the treatment of coronary arteries saphenous fistulae and for the treatment of coronary arteries saphenous vein grafts and peripheral vessels clinical trials for the vein grafts and peripheral vessels clinical trials for the treatment of acute stroke are no longer in progress treatment of acute stroke are no longer in progress
Most devices are used in cerebral vessels that 2-5 mm
The Latis laser device The Latis laser device used laser energy to ablate clots used laser energy to ablate clots Arteries 2-5 mm in diameter could be Arteries 2-5 mm in diameter could be
treated including the ICA M1 or M2 treated including the ICA M1 or M2 branch of the MCA A1 branch of the branch of the MCA A1 branch of the anterior cerebral artery (ACA) basilar anterior cerebral artery (ACA) basilar artery posterior cerebral artery (PCA) artery posterior cerebral artery (PCA) and vertebral and vertebral
Patients could receive treatment as late Patients could receive treatment as late as 8 hours after symptom onset in the as 8 hours after symptom onset in the anterior circulation and within 24 hours in anterior circulation and within 24 hours in the posterior circulation the posterior circulation
Endovascular Photo Acoustic Endovascular Photo Acoustic Recanalization (EPAR) Recanalization (EPAR)
A laser power source generated energy for the A laser power source generated energy for the systemsystem
The energy was delivered by means of The energy was delivered by means of fiberoptics to the tip of the catheter at the fiberoptics to the tip of the catheter at the treatment sitetreatment site
Absorption of laser light by darkly pigmented Absorption of laser light by darkly pigmented materials (ie the clot) occurred inside the 1-mm materials (ie the clot) occurred inside the 1-mm catheter tipcatheter tip
the system was designed to minimize scattering the system was designed to minimize scattering of laser light of laser light
Absorption converted photo energy to acoustic Absorption converted photo energy to acoustic energy which then emulsified the clot inside the energy which then emulsified the clot inside the catheter tip catheter tip
EKOS ultrasound( the EKOS ultrasound( the Ultrasound Thrombolytic Ultrasound Thrombolytic
Infusion Catheter) Infusion Catheter) combines the use of a distal ultrasound transducer with combines the use of a distal ultrasound transducer with
infusion of a thrombolytic agent through the infusion of a thrombolytic agent through the microcathetermicrocatheter
Ultrasound changes the structure of the clot to Ultrasound changes the structure of the clot to temporarily increase its permeability while providing an temporarily increase its permeability while providing an acoustic pressure gradient to move the drug into the clot acoustic pressure gradient to move the drug into the clot to speed its dissolution to speed its dissolution
The EKOS catheter is placed in the proximal portion of the The EKOS catheter is placed in the proximal portion of the clot clot
After a 2-mg bolus of tPA was injected through the After a 2-mg bolus of tPA was injected through the catheter catheter
the patient received a continuous infusion of IA tPA 03 the patient received a continuous infusion of IA tPA 03 mgmin to a maximum of 20 mg and simultaneous mgmin to a maximum of 20 mg and simultaneous ultrasound transmission for as long as 60 minutes ultrasound transmission for as long as 60 minutes
One patient was treated with a total of 4 units of One patient was treated with a total of 4 units of recombinant reteplase (Retavase) hand-injected over 60 recombinant reteplase (Retavase) hand-injected over 60 minutes minutes
Penumbra system Penumbra system The Penumbra system (Penumbra Inc) provides a dual The Penumbra system (Penumbra Inc) provides a dual
approach to clot extraction using aspiration followed by approach to clot extraction using aspiration followed by clot retrieval with a ring device if needed clot retrieval with a ring device if needed
Mechanical Embolus Removal in Cerebral Ischemia Mechanical Embolus Removal in Cerebral Ischemia (MERCI)(MERCI)
a corkscrew-like apparatus to remove blood clots from a corkscrew-like apparatus to remove blood clots from the brain in patients experiencing an ischemic stroke the brain in patients experiencing an ischemic stroke
The corkscrew itself resides in the catheter tip which The corkscrew itself resides in the catheter tip which shields it from the wall of the vessel until it is ready to be shields it from the wall of the vessel until it is ready to be burrowed into the clot Once lodged in the clot the device burrowed into the clot Once lodged in the clot the device and clot are withdrawn from the vessel and clot are withdrawn from the vessel
Snarelike devicesSnarelike devices Snares such as the Neuronet snare (Guidant Snares such as the Neuronet snare (Guidant
Endovascular Santa Clara CA) have been developed Endovascular Santa Clara CA) have been developed specifically for use in the treatment of strokes specifically for use in the treatment of strokes
These devices are simple in design and do not require the These devices are simple in design and do not require the clot to be amenable to emulsification clot to be amenable to emulsification
X-Sizer deviceX-Sizer device a device with small moving blades at the a device with small moving blades at the
catheter tip catheter tip This device the X-Sizer device (EndiCor Medical This device the X-Sizer device (EndiCor Medical
San Clemente CA) can be used to excise the San Clemente CA) can be used to excise the thrombus and aspirate it thrombus and aspirate it
The device was being evaluated in randomized The device was being evaluated in randomized studies of coronary vessels and in a registry of studies of coronary vessels and in a registry of patients with acute myocardial infarctionpatients with acute myocardial infarction
Although the manufacturer had modified the Although the manufacturer had modified the device for use in cerebral vessels a safety and device for use in cerebral vessels a safety and feasibility study was indefinitely suspended after feasibility study was indefinitely suspended after only 1 patient was treated with the device in only 1 patient was treated with the device in Europe Europe
Suction thrombectomySuction thrombectomy This method of mechanical thrombolysis is one of the This method of mechanical thrombolysis is one of the
simplestsimplest In this readily available technique suction is applied with In this readily available technique suction is applied with
a syringe to remove thrombus in the ICA a syringe to remove thrombus in the ICA It requires no other devicesIt requires no other devices A catheter with a large inner diameter (Brite Tip Cordis A catheter with a large inner diameter (Brite Tip Cordis
Corporation Miami FL) was placed in the symptomatic Corporation Miami FL) was placed in the symptomatic vessel and navigated over a guidewire into the thrombusvessel and navigated over a guidewire into the thrombus
A 60-mL syringe was used to aspirate the thrombus A 60-mL syringe was used to aspirate the thrombus Each patient required angioplasty and stenting of carotid Each patient required angioplasty and stenting of carotid
bifurcation stenosis and received daily aspirin and bifurcation stenosis and received daily aspirin and ticlopidine after the procedure No complications ticlopidine after the procedure No complications occurred occurred
Summary Acute Stroke Summary Acute Stroke ImagingImaging
PhysiologyPhysiology importance collaterals importance collaterals
ndash ndashGrowing role for perfusion Growing role for perfusion assessmentassessment
tPAtPA guidelines amp limitations guidelines amp limitations Signs on CT amp MRSigns on CT amp MR follow physiology follow physiology Stroke trialsStroke trials PWI-DWI mismatch PWI-DWI mismatch
ndash ndashTreat based on physiology not timeTreat based on physiology not time ProtocolsProtocols should be fast and should be fast and
comprehensivecomprehensive
Heparin and Low molecular weight heparinsHeparin and Low molecular weight heparins
Structure and sequence
O
OH
OH
O
COO
O
O
CH2OH
NHSO3
OH
_
_
O
O
CH2OSO3
NHSO3
OH
_
_
O
OH
OH
O
COOO
O
CH2OSO3
NHSO3
OH
_
_
O
OSO3
OHO
COOO
O
CH2OSO3
NHCOCH3
OH
_
_ _
_
_
O
OH
OH
O
COO
1
23
4
5
6
-D-glucosamine -L-iduronic acid -D-glucuronic acid
O
O
CH2OH
NH2
OH 12
3
4
5
6
O
OH
OHO
COO_
1
23
4
5
6
polymeric structure of heparin
Anticoagulant Properties of Anticoagulant Properties of HeparinHeparin
11 Inhibits the thrombin-mediated conversion of Inhibits the thrombin-mediated conversion of fibrinogen to fibrinfibrinogen to fibrin
22 Inhibits the aggregation of platelets by thrombin Inhibits the aggregation of platelets by thrombin (prolongs bleeding time)(prolongs bleeding time)
33 Inhibits activation of fibrin stabilizing enzymeInhibits activation of fibrin stabilizing enzyme
44 Inhibits activated factors XII XI IX X and IIInhibits activated factors XII XI IX X and II All available forms of heparin must be All available forms of heparin must be
administered administered parenterally since they are parenterally since they are highly charged and rapidlyhighly charged and rapidly hydrolyzed in the hydrolyzed in the GI tractGI tract
Heparin antagonist Protamine sulfate (Heparin antagonist Protamine sulfate (10mg for 10mg for 1000 unit of heparin)1000 unit of heparin)
Monitoring of heparin Monitoring of heparin
Subcutenous Subcutenous no monitoring requiredno monitoring required Intravenous Intravenous
Partial thromboplastin time (PTT normal value Partial thromboplastin time (PTT normal value ~30sec) ~30sec)
Activated clotting time ( ACT normal value ~90-Activated clotting time ( ACT normal value ~90-120sec)120sec)
Daily or more frequent if PTT ACT variesDaily or more frequent if PTT ACT varies
Mechanism Mechanism ndash measures intrinsic pathwayndash measures intrinsic pathway Therapeutic goal Therapeutic goal 2-25 times normal control value 2-25 times normal control value
ACT or aPTTACT or aPTT
Determine when to pull the femoral sheath Determine when to pull the femoral sheath Premature sheath pull can lead to bleedingPremature sheath pull can lead to bleeding Delayed removal can increase time in ICUDelayed removal can increase time in ICU Target set Target set at each siteat each site
ACT targets range from 150 ndash 220 ACT targets range from 150 ndash 220 secondsseconds
aPTT targets range from 40 ndash 70 seconds aPTT targets range from 40 ndash 70 seconds
During neuroangiography-During neuroangiography- Recommended therapeutic range of heparin in Recommended therapeutic range of heparin in
plasma is 02-08 uml ( corresponding to aPTT plasma is 02-08 uml ( corresponding to aPTT ACT values 15-25 times the baseline values)ACT values 15-25 times the baseline values)
Dose In diagnostic angiography bolus dose of Dose In diagnostic angiography bolus dose of 2500 iu is used followed by 1000 iu hour2500 iu is used followed by 1000 iu hour
Bolus dose is Bolus dose is 60 ukg to maintain the therapeutic 60 ukg to maintain the therapeutic range range If procedure continues for more than 75 If procedure continues for more than 75 minutes additional dose is required ( half of the minutes additional dose is required ( half of the initial dose for another 75 minutes) initial dose for another 75 minutes)
(AJNR 199415 51-54)
Mechanisms of HIT( Mechanisms of HIT( Heparin Heparin induced Thrombocytopeniainduced Thrombocytopenia))
Type 1Type 1 Fall in platelet count occurs within the first two Fall in platelet count occurs within the first two
days after heparin initiation often returns to days after heparin initiation often returns to normal with continued heparin administration normal with continued heparin administration and is of no clinical consequence and is of no clinical consequence
The mechanism of the thrombocytopenia is non-The mechanism of the thrombocytopenia is non-immune and appears to be due to a direct effect of immune and appears to be due to a direct effect of heparin on platelet activationheparin on platelet activation
Type 2Type 2 Approximately 03 to 3 percent of patients Approximately 03 to 3 percent of patients
receiving heparin develop an immune receiving heparin develop an immune thrombocytopenia mediated by antibodies to a thrombocytopenia mediated by antibodies to a heparin-platelet factor 4 complex heparin-platelet factor 4 complex
(AJNR 28155-158 2007)
Treatment of heparin-induced Treatment of heparin-induced thrombocytopeniathrombocytopenia
When HIT is diagnosed it is important to When HIT is diagnosed it is important to stop heparin mainly in type 2 and to avoid stop heparin mainly in type 2 and to avoid the use of LMWH the use of LMWH
Because of the increased risk of thrombosis Because of the increased risk of thrombosis however continuation of an anticoagulant however continuation of an anticoagulant must be considered must be considered
The drugs currently approved for the The drugs currently approved for the treatment of HIT in the United States are treatment of HIT in the United States are direct thrombin inhibitors argatroban and direct thrombin inhibitors argatroban and lepirudinlepirudin
WARFARIN MECHANISM OF ACTIONWARFARIN MECHANISM OF ACTION
Inactive factors II VII IX and X
Proteins S and C
Active factors II VII IX and X
Proteins S and C
Vitamin K epoxide
Vitamin K reduced
WA
RF
AR
IN
Prevents the reduction of vitamin K which is essential for Prevents the reduction of vitamin K which is essential for activation of certain factorsactivation of certain factors
Has no effect on previously formed thrombusHas no effect on previously formed thrombus
Antagonist is Vit KAntagonist is Vit K
OPTIMIZING WARFARIN THERAPYOPTIMIZING WARFARIN THERAPY
Use of large loading dose may lead to hemorrhage and Use of large loading dose may lead to hemorrhage and other complicationsother complications
Initial dose 2-5 mg once dailyInitial dose 2-5 mg once daily Maintenance dose 2-10 mg once dailyMaintenance dose 2-10 mg once daily If Immediate anticoagulation is requiredIf Immediate anticoagulation is required Heparin IS Heparin IS
started along with loading dose of warfarin 10 mg started along with loading dose of warfarin 10 mg Heparin is usually discontinued after 4-5 days Heparin is usually discontinued after 4-5 days Before Before discontinuing INR should be in therapeutic range for 2 discontinuing INR should be in therapeutic range for 2 consecutive daysconsecutive days
Daily monitoring of INR until INR is in therapeutic Daily monitoring of INR until INR is in therapeutic range then 3 times weekly for 1-2 weeks then less often range then 3 times weekly for 1-2 weeks then less often (every 4 to 6 weeks)(every 4 to 6 weeks)
OPTIMAL THERAPEUTIC RANGEOPTIMAL THERAPEUTIC RANGE
IndicationIndication INRINR
Prophylaxis of venous Prophylaxis of venous thromboembolismthromboembolism
20-3020-30
Treatment of venous Treatment of venous thromboembolismthromboembolism
20-3020-30
Atrial fibrillationAtrial fibrillation 20-3020-30
Mitral valve stenosisMitral valve stenosis 20-3020-30
Heart valve replacementHeart valve replacement
Bioprosthetic valveBioprosthetic valve
Mechanical valveMechanical valve
20-3020-30
25-3525-35
Myocardial infarctionMyocardial infarction 20-3020-30
25-35 25-35 (high risk patients)(high risk patients)
FACTORS INFLUENCING DOSE RESPONSEFACTORS INFLUENCING DOSE RESPONSE
Poor patient compliancePoor patient compliance Concomitant medicationsConcomitant medications Levels of dietary vitamin KLevels of dietary vitamin K Alcohol Inaccurate lab testingAlcohol Inaccurate lab testing Inaccurate lab testingInaccurate lab testing Hepatic dysfunctionHepatic dysfunction FeverFever
Contraindication for WarfarinContraindication for Warfarin
Hypersensitivity to warfarinHypersensitivity to warfarin Hemorrhagic tendencyHemorrhagic tendency Condition with risk of hemorrhageCondition with risk of hemorrhage Inadequate laboratory techniquesInadequate laboratory techniques Protein C amp S deficiencyProtein C amp S deficiency Vitamin K deficiencyVitamin K deficiency
SIDE EFFECTSSIDE EFFECTS
Hemorrhage Hemorrhage Skin necrosisSkin necrosis Purple toe syndromePurple toe syndrome Microembolization Microembolization TeratogenecityTeratogenecity Agranulocytosis leukopenia Agranulocytosis leukopenia Diarrhoeanausea anorexiaDiarrhoeanausea anorexia
MONITORING OF WARFARIN THERAPYMONITORING OF WARFARIN THERAPY
Prothrombin timeProthrombin time PT ratioPT ratio INR (International Normalized Ratio)INR (International Normalized Ratio)
PROTHROMBIN TIME (PT)PROTHROMBIN TIME (PT)
Time required for blood to coagulate Time required for blood to coagulate is called PT ( normal value ~10sec)is called PT ( normal value ~10sec)
Performed by adding a mixture of Performed by adding a mixture of calcium and thromboplastin to calcium and thromboplastin to citrated plasmacitrated plasma
As a control a normal blood sample is As a control a normal blood sample is tested continuouslytested continuously
PT ratio (PTR) = PT ratio (PTR) = Patientrsquos PTPatientrsquos PT Control PTControl PT
PROBLEMS WITH PTPTRPROBLEMS WITH PTPTR
Thromboplastins are extracts from Thromboplastins are extracts from brain lung or placenta of animalsbrain lung or placenta of animals
Thromboplastins from various Thromboplastins from various manufacturers differ in their manufacturers differ in their sensitivity to prolong PTsensitivity to prolong PT
May result in false control of May result in false control of anticoagulant therapyanticoagulant therapy
INTERNATIONAL NORMALISED RATIO (INR)INTERNATIONAL NORMALISED RATIO (INR)
International Normalized Ratio (INR) International Normalized Ratio (INR) a PT test with a a PT test with a formula based ratio to normalize the often variable source formula based ratio to normalize the often variable source of tissue factor (human rabbit recombinant)of tissue factor (human rabbit recombinant)
INR = [PTINR = [PTptpt] ] ISIISI
[PT[PTRefRef]]
PTPTpt pt ndash prothrombin time of patientndash prothrombin time of patient
PTPTRef Ref ndash prothrombin time of normal pooled samplendash prothrombin time of normal pooled sample
ISI ndash International Sensitivity IndexISI ndash International Sensitivity Index
Warfarin is given orally and titrated to achieve an INR of Warfarin is given orally and titrated to achieve an INR of typically 20 ndash 30typically 20 ndash 30
Heparin versus WarfarinHeparin versus Warfarin
Drug ActionMechan-ism
Moni-toring
Effective
HeparinDirect
Inhibition ofThrombin
ATIIIcofactor
APTTACT
Immediate
WarfarinDecreasesProductionof factors
Vitamin K PTDelay
3-5 days
INR
Recanalization or Antegrade Recanalization or Antegrade Reperfusion StrategiesReperfusion Strategies
Recanalization strategies focus on removing Recanalization strategies focus on removing andor dissolving the occlusive thrombus to re-andor dissolving the occlusive thrombus to re-establish antegrade flow Strategies may be establish antegrade flow Strategies may be classified into 7 different categories on the classified into 7 different categories on the basis of their primary mechanism of action basis of their primary mechanism of action 1) 1) IV andor intraarterial thrombolysis (IAT) IV andor intraarterial thrombolysis (IAT) 2) endovascular thrombectomy2) endovascular thrombectomy3) endovascular thromboaspiration 3) endovascular thromboaspiration 4) endovascular mechanical thrombus disruption or 4) endovascular mechanical thrombus disruption or
thromborrhexisthromborrhexis5) 5) transcranial or endovascular augmented transcranial or endovascular augmented
fibrinolysis fibrinolysis 6) endovascular thrombus entrapment and 6) endovascular thrombus entrapment and 7) temporary endovascular bypass7) temporary endovascular bypass
IAT in Acute Ischemic StrokeIAT in Acute Ischemic Stroke
IAT advantages over IV thrombolysisIAT advantages over IV thrombolysis Coaxial microcatheter techniques the occluded intracranial Coaxial microcatheter techniques the occluded intracranial
vessel is directly accessible and the fibrinolytic agent can be vessel is directly accessible and the fibrinolytic agent can be infused directly into the thrombusinfused directly into the thrombus
This permits a smaller dose of fibrinolytic agent to reach a This permits a smaller dose of fibrinolytic agent to reach a higher local concentration than that reached by systemic higher local concentration than that reached by systemic infusioninfusion
Allows more complete recanalization with lower total doses of Allows more complete recanalization with lower total doses of thrombolytic thrombolytic
With the smaller dose complications from systemic fibrinolytic With the smaller dose complications from systemic fibrinolytic effects including intracranial hemorrhage (ICH) can effects including intracranial hemorrhage (ICH) can theoretically be reduced theoretically be reduced
Treatment window for endovascular techniques can be Treatment window for endovascular techniques can be extended beyond the typical IV window of 3 hours extended beyond the typical IV window of 3 hours
IA techniques have led to higher recanalization rates than IV IA techniques have led to higher recanalization rates than IV thrombolysisthrombolysis
Major disadvantagesMajor disadvantages Relative complexity of the procedure the level Relative complexity of the procedure the level
of required technical expertise and its of required technical expertise and its relatively low availability relatively low availability
Delays in initiating treatmentDelays in initiating treatment InvasiveInvasive
ThrombolyticsThrombolytics
Plasminogen activators
Fibrinolytics
1 Plasminogen Activators 1 Plasminogen Activators drugs act by converting the inactive proenzyme drugs act by converting the inactive proenzyme plasminogen into the active enzyme plasmin Plasmin plasminogen into the active enzyme plasmin Plasmin digests fibrinogen fibrin monomers and cross-linked digests fibrinogen fibrin monomers and cross-linked fibrin (as found in a thrombus) into fibrin degradation fibrin (as found in a thrombus) into fibrin degradation productsproducts
First-Generation Agents First-Generation Agents StreptokinaseStreptokinase a protein derived from group C a protein derived from group C
szlig-hemolytic streptococci has a half-life of 16ndashszlig-hemolytic streptococci has a half-life of 16ndash90 minutes and low fibrin specificity This drug 90 minutes and low fibrin specificity This drug proved to have a very narrow therapeutic proved to have a very narrow therapeutic window and significant rates of ICH and window and significant rates of ICH and systemic hemorrhage18systemic hemorrhage18
UrokinaseUrokinase is a serine protease with a plasma is a serine protease with a plasma half life of 14 minutes and low fibrin specificity half life of 14 minutes and low fibrin specificity
The urokinase dose used in cerebral IAT has The urokinase dose used in cerebral IAT has ranged from 002 to 2 X106unitsranged from 002 to 2 X106units
Second-Generation Agents Second-Generation Agents Alteplase (rtPA) Alteplase (rtPA)
is a serine is a serine protease with a plasma half-life of 35 protease with a plasma half-life of 35 minutes and a high degree of fibrin affinity and minutes and a high degree of fibrin affinity and specificity specificity
Dose used in cerebral IAT has ranged between 20 Dose used in cerebral IAT has ranged between 20 and 60 mgand 60 mg
Disadvantages of alteplase include its relatively short Disadvantages of alteplase include its relatively short halflife and limited penetration into the clot matrix halflife and limited penetration into the clot matrix because of strong binding with surface fibrin which because of strong binding with surface fibrin which could delay recanalization and increase the risk of could delay recanalization and increase the risk of recurrent occlusion recurrent occlusion
Prourokinase (r-prourokinase) Prourokinase (r-prourokinase) is the proenzyme precursor of urokinase is the proenzyme precursor of urokinase T12 of 7 minutes and high fibrin specificity T12 of 7 minutes and high fibrin specificity
Third-Generation AgentsThird-Generation Agents
ReteplaseReteplase is a structurally modified is a structurally modified form of alteplase form of alteplase
with a longer half-life (15ndash18 minutes) In with a longer half-life (15ndash18 minutes) In addition it does not bind as highly to fibrin addition it does not bind as highly to fibrin unbound reteplase can thus theoretically better unbound reteplase can thus theoretically better penetrate the clot and potentially penetrate the clot and potentially improve in improve in vivo fibrinolytic activity vivo fibrinolytic activity
TenecteplaseTenecteplase is another modified form of rtPA with a longer is another modified form of rtPA with a longer
half-life (17 minutes)half-life (17 minutes) greater fibrin specificity and greater greater fibrin specificity and greater
resistance to plasminogen activator inhibitor-1 resistance to plasminogen activator inhibitor-1 IV tenecteplase in acute ischemic stroke IV tenecteplase in acute ischemic stroke
suggest that the drug is safe and promisingsuggest that the drug is safe and promising
Newer plasminogen activatorNewer plasminogen activator
DesmoteplaseDesmoteplase is a genetically engineered is a genetically engineered version of the clot-dissolving factor version of the clot-dissolving factor
found in the saliva found in the saliva of the vampire bat Desmodus rotundusof the vampire bat Desmodus rotundus moremore potent and more selective for fibrin-bound potent and more selective for fibrin-bound
plasminogen than any other known plasminogen plasminogen than any other known plasminogen activatoractivator
Unlike tissue plasminogen activator (tPA) desmoteplase Unlike tissue plasminogen activator (tPA) desmoteplase is not activated by fibrinogen or -amyloid proteins is not activated by fibrinogen or -amyloid proteins factors that may exacerbate the risk for ICH factors that may exacerbate the risk for ICH
The effect of IV administration of desmoteplase 3ndash9 The effect of IV administration of desmoteplase 3ndash9 hours after symptom onset in patients with stroke who hours after symptom onset in patients with stroke who present with mismatch on MR imaging or CT perfusion present with mismatch on MR imaging or CT perfusion
3 DefibrinogenatingFibrinogenolytic 3 DefibrinogenatingFibrinogenolytic Agents Agents
AncrodAncrod(Viprinex)(Viprinex) is is the purified fraction of the Malayan pit viper venomthe purified fraction of the Malayan pit viper venom It acts by directly cleaving and inactivating fibrinogen It acts by directly cleaving and inactivating fibrinogen
and thus indirectly promoting anticoagulation and thus indirectly promoting anticoagulation The reduction in the blood levels of fibrinogen also The reduction in the blood levels of fibrinogen also
leads to a reduced blood viscosity which may improve leads to a reduced blood viscosity which may improve blood flow to the affected areas of the brain blood flow to the affected areas of the brain
In the Stroke Treatment with Ancrod Trial 500 In the Stroke Treatment with Ancrod Trial 500 patients with stroke presenting within 3 hours of patients with stroke presenting within 3 hours of symptom onset were randomized to receive ancrod (symptom onset were randomized to receive ancrod (n n 248) or a placebo (n 252) Good outcome (Barthel 248) or a placebo (n 252) Good outcome (Barthel Index 95ndash100 at 3 months) was achieved in 4221 Index 95ndash100 at 3 months) was achieved in 4221 and 344 of the patients respectively and 344 of the patients respectively
2 Direct Fibrinolytics2 Direct Fibrinolytics
Microplasmin (Microplasmin (ThromboGenics Heverlee Belgium)ThromboGenics Heverlee Belgium) is a truncated form of plasmin that is more resistant to the effects is a truncated form of plasmin that is more resistant to the effects
of antiplasmin of antiplasmin microplasmin can be used upto 4ndash12 hours after stroke onset microplasmin can be used upto 4ndash12 hours after stroke onset There was no evidence of increased bleeding risk with There was no evidence of increased bleeding risk with
microplasminmicroplasmin
Alfimeprase (Nuvelo San Carlos Calif)Alfimeprase (Nuvelo San Carlos Calif) is a recombinant truncated form of fibrolase a fibrinolytic zinc metalloproteinase is a recombinant truncated form of fibrolase a fibrinolytic zinc metalloproteinase
isolated from the venom of the southern copperhead snake isolated from the venom of the southern copperhead snake It degrades fibrin directly and achieves thrombolysis independent It degrades fibrin directly and achieves thrombolysis independent
of plasmin formationof plasmin formation its thrombolytic activity appears to be localized to the site of its thrombolytic activity appears to be localized to the site of
delivery These properties should theoretically result in faster delivery These properties should theoretically result in faster recanalization and lower hemorrhagic conversion riskrecanalization and lower hemorrhagic conversion risk
Anti-fibrinolyticsAnti-fibrinolytics
to limit fibrinolytic activityto limit fibrinolytic activity -aminocaproic acid (EACA) -aminocaproic acid (EACA) competitively inhibitscompetitively inhibits plasminogen and plasminogen activators from plasminogen and plasminogen activators from
binding to fibrinbinding to fibrin
alpha2-antiplasminalpha2-antiplasmin a serine protease inhibitor that a serine protease inhibitor that neutralizes any free circulating plasminneutralizes any free circulating plasmin
Plasminogen activator inhibitor-1Plasminogen activator inhibitor-1 a serine protease a serine protease inhibitor that inhibits tissue-type plasminogen inhibitor that inhibits tissue-type plasminogen activatoractivator
Glycoprotein (GP) IIbIIIa antagonistsGlycoprotein (GP) IIbIIIa antagonists
such as ReoPro (abciximab) Integrilin such as ReoPro (abciximab) Integrilin (eptifibatide) or Aggrastat (tirofiban) in (eptifibatide) or Aggrastat (tirofiban) in ischemic stroke remains investigational ischemic stroke remains investigational Deshmukh et al38 reported 21 patients with Deshmukh et al38 reported 21 patients with large-vessel occlusion refractory to IAT with large-vessel occlusion refractory to IAT with rtPA who were treated with IV andor IA rtPA who were treated with IV andor IA abciximab eptifibatide or tirofiban abciximab eptifibatide or tirofiban
IA Mechanical Approaches in Acute Ischemic Stroke IA Mechanical Approaches in Acute Ischemic Stroke Mechanical strategies have several advantagesMechanical strategies have several advantages First they lessen and may even preclude the use of chemical First they lessen and may even preclude the use of chemical
thrombolytics in this manner very likely reducing the risk of ICHthrombolytics in this manner very likely reducing the risk of ICH Second by avoiding the use of chemical thrombolytics it is Second by avoiding the use of chemical thrombolytics it is
possible to extend the treatment window beyond the limit of 6ndash8 possible to extend the treatment window beyond the limit of 6ndash8 hours hours
Third mechanically fragmenting a clot increases the surface area Third mechanically fragmenting a clot increases the surface area accessible to fibrinolytic agents and allows inflow of fresh accessible to fibrinolytic agents and allows inflow of fresh plasminogen which in turn may increase the speed of plasminogen which in turn may increase the speed of thrombolysis thrombolysis
Finally clot-retrieval devices may provide faster recanalization Finally clot-retrieval devices may provide faster recanalization
The disadvantages of the mechanical The disadvantages of the mechanical approaches approaches technical difficulty of navigating mechanical technical difficulty of navigating mechanical
devices into the intracranial circulation excessive devices into the intracranial circulation excessive trauma to the vasculature (potentially leading to trauma to the vasculature (potentially leading to vasospasm vessel dissection perforation or vasospasm vessel dissection perforation or rupture) rupture)
fragmented thrombus causing distal embolization fragmented thrombus causing distal embolization into previously unaffected territories into previously unaffected territories
Nevertheless the advantages of mechanical stroke Nevertheless the advantages of mechanical stroke therapy appear to significantly outweigh its therapy appear to significantly outweigh its disadvantages and risksdisadvantages and risks
Contraindications to Thrombolytic Contraindications to Thrombolytic agents agents
Recent thoracic abdominal or Recent thoracic abdominal or intracranial surgeryintracranial surgery
Recent haemorrhagic CVA Head injury Recent haemorrhagic CVA Head injury or neoplasmor neoplasm
Bleeding ulcerBleeding ulcer Anticipated invasive procedures (arterial Anticipated invasive procedures (arterial
punctures biopsies)punctures biopsies) Concurrent hemostatic dysfunctionConcurrent hemostatic dysfunction
Monitoring of thrombolytic Monitoring of thrombolytic therapytherapy
Thrombin time Measures the availability of functional
fibrinogen Normal thrombin time is 10-14 sec Prolonged when fibrinogen level is below
75-100 mgdl
Half Life of ThrombolyticsHalf Life of ThrombolyticsAgent Administration Half Life
Streptokinase IA 60-80min
Urokinase IAIV 9-12min
rTPA IAIV 6min
Abciximab(Reopro) IAIV 12hour
Aspirin POIV 15-20min
Heparin IVSC 60min
Coumadin PO 15-25 days
Anti Platelet DrugsAnti Platelet DrugsDrug Drug Mechanism Mechanism UsesUsesAspirinAspirin Permanently inhibits Permanently inhibits
COX-1 and COX-2COX-1 and COX-2CADCAD
Stroke-TIAsStroke-TIAs
NSAIDsNSAIDs Reversibly inhibits Reversibly inhibits COX-1COX-1
LimitedLimited
DipyridamoleDipyridamole Inhibits PDE increases Inhibits PDE increases cAMPcAMP
TIAsTIAs
ThenopyridinesThenopyridines
(Ticlopidine(Ticlopidine
ClopidrgrelClopidrgrel))
Inhibits ADP Inhibits ADP
PlatAg PlatAg
TIAsStrokeTIAsStroke
CAD PVDCAD PVD
Abciximab (ReoPro)Abciximab (ReoPro)
Eptifibatide (Integrilin)Eptifibatide (Integrilin)
TirofibanTirofiban
GP IIBIIIA InhibitorsGP IIBIIIA Inhibitors
Stroke- TIAs Stroke- TIAs
MonitoringMonitoring
Bleeding timeBleeding time
Optical aggregometryOptical aggregometry
Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay
Bleeding timeBleeding time
Requires a skin incision (usually made on the ear lobe or Requires a skin incision (usually made on the ear lobe or forearm offorearm of
a depth that results in disruption of capillary loops and a depth that results in disruption of capillary loops and small vessels)small vessels)
AdvantagesAdvantages Universally availableUniversally available Relatively simple techniquesRelatively simple techniques Can be performed bedsideCan be performed bedside
DisadvantagesDisadvantages Insensitive inaccurate non-specific techniqueInsensitive inaccurate non-specific technique
Poorly reproducible (as depends on multiple variables)Poorly reproducible (as depends on multiple variables)
Optical aggregometryOptical aggregometry
Gold standard assay for platelet functionGold standard assay for platelet function Agonist induced aggregation is measuredAgonist induced aggregation is measured Different agonist are available for different Different agonist are available for different
agentsagents However require unique expertise and are not However require unique expertise and are not
universally availableuniversally available Aspirin measured with ADP or AA(gt70 Aspirin measured with ADP or AA(gt70
aggregation so resistance)aggregation so resistance) Clopidogrel( ADP gt 90 aggregation means Clopidogrel( ADP gt 90 aggregation means
resistance) resistance)
Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay
Can be performed bed sideCan be performed bed side Different assay devices with different Different assay devices with different
agonist are used for each of different agonist are used for each of different antiplatelet agents antiplatelet agents
For Aspirin AA is used (result is reported as aspirin For Aspirin AA is used (result is reported as aspirin reaction units [ARU] ARUgt 550 indicates non-reaction units [ARU] ARUgt 550 indicates non-responsiveness)responsiveness)
Verify IIbIIIa assay device uses TRAP as agonist for Verify IIbIIIa assay device uses TRAP as agonist for Abciximab and TirofibanAbciximab and Tirofiban
Practical Applications Practical Applications related to specific related to specific
Neurovascular Neurovascular interventionsinterventions
Acute ischemic StrokeAcute ischemic Stroke When an artery occludes neurons are affected When an artery occludes neurons are affected
differently depending upon the amount of residual blood differently depending upon the amount of residual blood flowflow
Normal cerebral blood flow is greater than 50 mL100 Normal cerebral blood flow is greater than 50 mL100 mgminmgmin
Once blood flow decreases to less than 20 mL100 Once blood flow decreases to less than 20 mL100 mgmin infarction occursmgmin infarction occurs
If blood flow decreases to less than 10 mL100 mgmin If blood flow decreases to less than 10 mL100 mgmin irreversible neuronal death occurs rapidly irreversible neuronal death occurs rapidly
Blood flow between 11 and 20 mL100 mgmin is thought Blood flow between 11 and 20 mL100 mgmin is thought to represent the ischemic penumbra an area where the to represent the ischemic penumbra an area where the cells are functionally silent because of ischemia but are cells are functionally silent because of ischemia but are still able to recover if blood flow is restored still able to recover if blood flow is restored
Many acute stroke therapies are targeted toward Many acute stroke therapies are targeted toward restoring flow or function to the ischemic penumbrarestoring flow or function to the ischemic penumbra
Therapeutic window in Therapeutic window in management of acute Ischemic management of acute Ischemic
StrokeStrokeThe early diagnosis of ischemic stroke is critical to the The early diagnosis of ischemic stroke is critical to the
with only a narrow therapeutic window in the first few with only a narrow therapeutic window in the first few hours following stroke ictushours following stroke ictus
Diagnosis in the first 3 hours postictus provides the Diagnosis in the first 3 hours postictus provides the opportunity for intravenous or intraarterial thrombolysis opportunity for intravenous or intraarterial thrombolysis and intra-arterial clot mechanical treatment which and intra-arterial clot mechanical treatment which improve the outcome improve the outcome
Diagnosis in the time period between 3 and 6 hours Diagnosis in the time period between 3 and 6 hours provides an opportunity for intra-arterial thrombolysis provides an opportunity for intra-arterial thrombolysis and mechanical treatment and mechanical treatment
Involvement of the posterior circulation especially the Involvement of the posterior circulation especially the basilar artery is treated by some regardless of time of basilar artery is treated by some regardless of time of onset or up until 12 to 24 hours in some practices This is onset or up until 12 to 24 hours in some practices This is related to the potentially high mortality and morbidity related to the potentially high mortality and morbidity associated with basilar artery thrombosisassociated with basilar artery thrombosis
Infarct evaluation on angiographyInfarct evaluation on angiography(CT angiography and catheter (CT angiography and catheter
angiography)angiography)CTA is an excellent first-line examination for CTA is an excellent first-line examination for
evaluation of the head and neck arteries evaluation of the head and neck arteries In comparison with catheter angiography In comparison with catheter angiography
what it gives up in resolution and dynamic what it gives up in resolution and dynamic properties it makes up for with rapid properties it makes up for with rapid acquisition of a 3-D dataset and the potential acquisition of a 3-D dataset and the potential for assessment of whole-brain perfusion and for assessment of whole-brain perfusion and better parenchymal evaluationbetter parenchymal evaluation
Moreover CTA illustrates not only arterial Moreover CTA illustrates not only arterial stenosis or occlusion but also the vessel wall stenosis or occlusion but also the vessel wall This factor is most important for evaluation of This factor is most important for evaluation of intramural dissection and thrombosed intramural dissection and thrombosed aneurysms which may both complicate aneurysms which may both complicate evaluation of stroke patientsevaluation of stroke patients
Early angiographic signs of strokes Early angiographic signs of strokes both CTA both CTA and DSA and DSA
Vessel occlusion or cutoff related to Vessel occlusion or cutoff related to thromboembolithromboemboli
aneurysms aneurysms arterial dissection arterial dissection Meniscus or flattened shape to clot Meniscus or flattened shape to clot
(recent) versus reverse meniscus (older)(recent) versus reverse meniscus (older) tram track (nonocclusive or recanalized tram track (nonocclusive or recanalized
clot) clot) delayed (antegrade) flow (manifest as delayed (antegrade) flow (manifest as
decreased whole-brain perfusion on CTA)decreased whole-brain perfusion on CTA) retrograde collateral flowretrograde collateral flow
Non-occlusive left MCA thrombus on 3-D imaging performed from CTA source data and was confirmed at catheter angiography
Therapy to be started within a 6-hr Therapy to be started within a 6-hr time to treatment (TTT) window time to treatment (TTT) window (while in case of IV thrombolysis (while in case of IV thrombolysis therapy to be started with in 3hrs)therapy to be started with in 3hrs)
Exclusion criteria Exclusion criteria Rapidly improving neurologic deficit or Rapidly improving neurologic deficit or Sustained blood pressure of gt180100 Sustained blood pressure of gt180100 Hemorrhage is detected on CTHemorrhage is detected on CT Infarct involving gt more than 13 rd Infarct involving gt more than 13 rd
territory of MCAterritory of MCA MRADWI-Perfusion mismatchlt 20MRADWI-Perfusion mismatchlt 20 Definite hypodensity on CTDefinite hypodensity on CT
Intra-arterial Thrombolysis
Fibrinolytics + AntiplateletsFibrinolytics + Antiplatelets
PlasminogenPlasminogen activators through fibrinolysis exposes activators through fibrinolysis exposes free thrombin and paradoxically stimulatesfree thrombin and paradoxically stimulates platelet platelet aggregation which leads to formation of aaggregation which leads to formation of a platelet platelet thrombus (white clot) thrombus (white clot)
This new thrombus is relatively resistant to This new thrombus is relatively resistant to fibrinolyticsfibrinolytics
So new regimen in case of acute stroke isSo new regimen in case of acute stroke is fibrinolytics + antiplatelet drugsfibrinolytics + antiplatelet drugs
rtPA + IIbIIIa inhibitors( tirofiban rtPA + IIbIIIa inhibitors( tirofiban abciximab) orabciximab) or
Urokinase + IIbIIIa Urokinase + IIbIIIa inhibitors( tirofiban abciximab)inhibitors( tirofiban abciximab)
Intra-arterial Thrombolysis Tirofiban (04 microgkgmin bolus for 3 min followed by Tirofiban (04 microgkgmin bolus for 3 min followed by
0125 ugkgmin)0125 ugkgmin)
++
Heparin (2000ndash3000 IU bolus followed by Heparin (2000ndash3000 IU bolus followed by 1000 IUhour infusion 1000 IUhour infusion
with ACT maintained bw 200-300) throughout the with ACT maintained bw 200-300) throughout the interventional procedure and for 24ndash48 hours thereafter when interventional procedure and for 24ndash48 hours thereafter when there is neither intraprocedural bleeding nor suspicion of there is neither intraprocedural bleeding nor suspicion of increased risk of bleeding increased risk of bleeding
Maximum dose of Urokinase Maximum dose of Urokinase Anterior circulation stroke - 500000 IU (mean 400000 Anterior circulation stroke - 500000 IU (mean 400000
IU range 300000ndash500000 IU)IU range 300000ndash500000 IU) Posterior circulation stroke -1000000 IU (mean 837000 Posterior circulation stroke -1000000 IU (mean 837000
IU range 300000ndash1000000 IU)IU range 300000ndash1000000 IU)American Journal of NeuroradiologyAmerican Journal of Neuroradiology 262595-2601 2005262595-2601 2005
Intravenous ThrombolysisIntravenous Thrombolysis
The first method to restore cerebral The first method to restore cerebral perfusion is clot lysis with the goal perfusion is clot lysis with the goal of re-establishing blood flow to the of re-establishing blood flow to the affected tissue affected tissue
IV thrombolysis rt-PA is the only IV thrombolysis rt-PA is the only FDA- approved treatment for AIS FDA- approved treatment for AIS
Fibrinolysis is enhanced powerfully Fibrinolysis is enhanced powerfully by rt-PAby rt-PA
Intravenous rTPA Intravenous rTPA administration administration protocolprotocol
Total dose of rt-PA 09 mgkg (maximum dose Total dose of rt-PA 09 mgkg (maximum dose 90 mg)90 mg)
Give 10 as initial IV bolusGive 10 as initial IV bolus Infuse remainder over 1 hourInfuse remainder over 1 hour Admit patient to an ICU or stroke unit for Admit patient to an ICU or stroke unit for
monitoringmonitoring Neurologic assessments every 15 minutes Neurologic assessments every 15 minutes
during infusion then every 30 minutes for next during infusion then every 30 minutes for next 6 hours then every hour until 24hours after 6 hours then every hour until 24hours after treatmenttreatment
Favorable Outcome vs Treatment Time Favorable Outcome vs Treatment Time with IV rTPAwith IV rTPA
Protocol limit = 3 hrs
Benefit ~ 45 hrs
Thromboembolism During coilingThromboembolism During coiling Most feared and frequent complication Most feared and frequent complication Reported incidence - Approx 7 Reported incidence - Approx 7 SourcesSources of Thromboembolism are of Thromboembolism are
- Clots at the aneurysmal neck during or immediately- Clots at the aneurysmal neck during or immediately after after embolization embolization
- Thrombus forming on catheters during- Thrombus forming on catheters during proceduresprocedures
- Stenosis of an adjacent artery dt coil mass- Stenosis of an adjacent artery dt coil mass or herniationor herniation
- Migration of intraaneurysmal- Migration of intraaneurysmal thrombus during coil thrombus during coil placement placement
- Slow flow dt vasospasm - Slow flow dt vasospasm
- Rare and unlikely causes are hypercoagulable- Rare and unlikely causes are hypercoagulable state such state such as antiphospholipid antibody syndrome or due to HITas antiphospholipid antibody syndrome or due to HIT
Occur more often with wide-necked aneurysms (dt Occur more often with wide-necked aneurysms (dt increased exposed surface area of thrombogenic coil increased exposed surface area of thrombogenic coil material)material)
Current regimen of endovascular Current regimen of endovascular managementmanagement
The The glycoprotein IIbIIIa antagonist tirofiban glycoprotein IIbIIIa antagonist tirofiban (04 (04 microgkgmin bolus for 30 minutes followed by infusion of microgkgmin bolus for 30 minutes followed by infusion of 0125 ugkgmin until the thrombus dissolved) 0125 ugkgmin until the thrombus dissolved)
Intraarterial thrombolysis with Intraarterial thrombolysis with urokinase or r- TPA urokinase or r- TPA increase of intravenous (IV) heparin (measured by increase of intravenous (IV) heparin (measured by
ACT) ACT) Intravenous aspirin Intravenous aspirin
Coil-related platelet aggregation (white clot) is Coil-related platelet aggregation (white clot) is unlikely to respond to fibrinolytics but has a high risk unlikely to respond to fibrinolytics but has a high risk of hemorrhage (In ISAT) all 5 patients who had of hemorrhage (In ISAT) all 5 patients who had received thrombolytic therapy with tPA to treat a received thrombolytic therapy with tPA to treat a thromboembolic complication after endovascular thromboembolic complication after endovascular treatment rebleed and all of these patients died)treatment rebleed and all of these patients died)
IntracranialIntracranial Stenting Stenting Metallic foreign body such as stent will accumulate Metallic foreign body such as stent will accumulate
thrombus in the absence of platelet inhibitionthrombus in the absence of platelet inhibition Antiplatelet drugs are important to prevent peri or Antiplatelet drugs are important to prevent peri or
post-interventional thromboembolic eventspost-interventional thromboembolic events Optimal treatment regimens has not been determined Optimal treatment regimens has not been determined
but usually but usually Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-
procedureprocedureOrOr
Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on
morning of proceduremorning of procedure
If need to use stent is not pre-planned thanIf need to use stent is not pre-planned than
Abciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkgAbciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkg IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)
Glycoprotein IIbIIIa inhibitor are not used routinely during elective Glycoprotein IIbIIIa inhibitor are not used routinely during elective stenting procedure dt increased risk of ICH stenting procedure dt increased risk of ICH
Carotid StentingCarotid Stenting
Pre-procedurePre-procedure
Double Antiplatelet therapy is routinely given Double Antiplatelet therapy is routinely given beginning at least 3beginning at least 3
days before the proceduredays before the procedure
Aspirin 325mgd+Clopidogrel 75mgdAspirin 325mgd+Clopidogrel 75mgd During procedureDuring procedure
Heparin is given with target clotting time of 250-Heparin is given with target clotting time of 250-300sec300sec
Post-procedure Post-procedure
Aspirin 325mg is continued indefinitely and Aspirin 325mg is continued indefinitely and
Clopidogrel 75mgd for at least 6 weeks Clopidogrel 75mgd for at least 6 weeks
Inclusion criteria for Local ThrombolysisInclusion criteria for Local Thrombolysis a)a) Patients in severe clinical grade on admission Patients in severe clinical grade on admission
with evidence of dural venous sinus with evidence of dural venous sinus thrombosis and restrictive venous outflow on thrombosis and restrictive venous outflow on cerebral angiogramcerebral angiogram
b)b) Patients in clinical grade 3 worsening on Patients in clinical grade 3 worsening on heparin therapy Restriction to venous heparin therapy Restriction to venous outflow was defined as an increase in brain outflow was defined as an increase in brain circulation time gt 12 s delay in the drainage circulation time gt 12 s delay in the drainage of cortical veins with cortical veins hanging of cortical veins with cortical veins hanging in spacein space
Treatment Options for Venous Thrombosis
CT Grading for Venous ThrombosisCT Grading for Venous Thrombosis Grade I no parenchymal change Grade I no parenchymal change
(hyperdense (hyperdense sinuses cortical veins empty sinuses cortical veins empty delta sign)delta sign)
Grade II non hemorrhagic venous infarct Grade II non hemorrhagic venous infarct without mass effect without mass effect
Grade III non-hemorrhagic infarct with Grade III non-hemorrhagic infarct with mass effectmass effect
Grade IV hemorrhagic venous infarct (max Grade IV hemorrhagic venous infarct (max diameter lt 3 cm) with no mass effectdiameter lt 3 cm) with no mass effect
Grade V hemorrhagic venous infarct (max Grade V hemorrhagic venous infarct (max diameter gt 3 cm) with mass effect diameter gt 3 cm) with mass effect
Local ThrombolysisLocal Thrombolysis
Femoral Jugular access was secured and a guiding Femoral Jugular access was secured and a guiding catheter was placed in the jugular bulb catheter was placed in the jugular bulb Mechanical Mechanical clot maceration clot maceration was done with the guidewire was done with the guidewire following which a microcatheter (was navigated and following which a microcatheter (was navigated and placed in the thrombosed segment of sinus confirmed placed in the thrombosed segment of sinus confirmed on a selective venogram on a selective venogram
Urokinase infusion Bolus dose of 2-6 lacs followed Urokinase infusion Bolus dose of 2-6 lacs followed by 60000 to 100000 units per hour along with by 60000 to 100000 units per hour along with periodic check venogram Along with maintenance periodic check venogram Along with maintenance systemic infusion of Heparinsystemic infusion of Heparin Other agents such as Other agents such as streptokinase altepase or rTPAstreptokinase altepase or rTPA can be also used can be also used
After thrombolysis patient should subjected to oral After thrombolysis patient should subjected to oral anticoagulation for six monthsanticoagulation for six months
Low-molecular-weight Low-molecular-weight heparinheparin
PharmacologyPharmacologyLMWH as its name suggests is a glycosaminoglycan that is approximatelyLMWH as its name suggests is a glycosaminoglycan that is approximately
one third the molecular weight of UFH It is derived from UFH through one third the molecular weight of UFH It is derived from UFH through variousvarious
depolymerization processes LMWH binds to antithrombin which in turn depolymerization processes LMWH binds to antithrombin which in turn
Neutralizes actors Xa and IIa Because LMWH lacks many of the longer Neutralizes actors Xa and IIa Because LMWH lacks many of the longer chains chains
required for binding to thrombin it has less ability to neutralize thrombin required for binding to thrombin it has less ability to neutralize thrombin
relativeto its ability to neutralize factor Xa LMWH also has less relativeto its ability to neutralize factor Xa LMWH also has less nonspecific nonspecific
binding to other proteins There is greater bioavailability with more binding to other proteins There is greater bioavailability with more predictable predictable
pharmacokinetics that eliminates the need for monitoring The smaller pharmacokinetics that eliminates the need for monitoring The smaller size also size also
allows for enhanced subcutaneous absorption when compared with UFHallows for enhanced subcutaneous absorption when compared with UFH
Three LMWH preparations are Three LMWH preparations are currently approved for use in the currently approved for use in the United States (1) enoxaparin (2) United States (1) enoxaparin (2) dalteparin and (3) tinzaparin dalteparin and (3) tinzaparin
They are all administered They are all administered subcutaneously at intervals of either subcutaneously at intervals of either once or twice daily for both once or twice daily for both prophylaxis and treatment dosesprophylaxis and treatment doses
Few Experiences of Few Experiences of ThrombolysisThrombolysis
Vickey 25 Yrs male patient presented Vickey 25 Yrs male patient presented with 12with 12thth day HO severe headache with day HO severe headache with right sided hemiplegiaright sided hemiplegia
MRI shows thrombosis of the superior MRI shows thrombosis of the superior sagittal left transverse left sigmoid sagittal left transverse left sigmoid sinuses and cortical veins in the fronto-sinuses and cortical veins in the fronto-parietal regions with eo haemorrhagic parietal regions with eo haemorrhagic infarct in the left cerebral hemisphere infarct in the left cerebral hemisphere with mass effect( Grade ndashV)with mass effect( Grade ndashV)
Sashi Srivastava 64 yrs FSashi Srivastava 64 yrs F In a follow up case of MRD with infra-renal In a follow up case of MRD with infra-renal
aortic abdominal and bilateral renal artery aortic abdominal and bilateral renal artery thrombosis renal angiogram shows filling thrombosis renal angiogram shows filling defects in the right Renal artery defects in the right Renal artery
Initially Renal angioplasty was done Initially Renal angioplasty was done Following angioplasty few thrombi are seem Following angioplasty few thrombi are seem to extends into the segmental branches and to extends into the segmental branches and causing blockage So Thrombolysis was causing blockage So Thrombolysis was plane to dissolve the run-out thrombi with plane to dissolve the run-out thrombi with urokinase urokinase
Rakesh 34yrsMRakesh 34yrsM Left SFA pseudoaneurysm with Left SFA pseudoaneurysm with
Covered stent placementCovered stent placement Pre operative antiplatelets with post Pre operative antiplatelets with post
procedure heparin Tirofiban procedure heparin Tirofiban followed by aspirin and clopidogrel followed by aspirin and clopidogrel were usedwere used
IAT may be a treatment option for selected patients IAT may be a treatment option for selected patients Possible selection criteria include Possible selection criteria include
presentation between 3 and 6 hours from symptom onsetpresentation between 3 and 6 hours from symptom onset major cerebral artery occlusion major cerebral artery occlusion severe neurologic deficits severe neurologic deficits high risk of systemic hemorrhage with IV rt-PA (eg recent high risk of systemic hemorrhage with IV rt-PA (eg recent
surgery) surgery) The MERCI (Mechanical Embolus Removal in Cerebral The MERCI (Mechanical Embolus Removal in Cerebral
Ischemia) retrievalIschemia) retrieval system system
Has been FDA-approved for recanalizing acutely occluded Has been FDA-approved for recanalizing acutely occluded cerebral arteries cerebral arteries
In the Multi-MERCI study patients who did not improve In the Multi-MERCI study patients who did not improve immediately after IV rt-PA underwent mechanical immediately after IV rt-PA underwent mechanical embolectomy within 8 hours of symptom onset embolectomy within 8 hours of symptom onset
Partial or complete recanalization occurred in 74 of Partial or complete recanalization occurred in 74 of patientspatients
with a symptomatic intracerebral hemorrhage (sICH) rate of with a symptomatic intracerebral hemorrhage (sICH) rate of 67 67
Mechanical embolectomy with the MERCI retriever may be a Mechanical embolectomy with the MERCI retriever may be a feasible and safe option for patients after IV rt-PAfeasible and safe option for patients after IV rt-PA
Penumbra stroke systemPenumbra stroke system This device combines two methods of clot This device combines two methods of clot
extraction aspiration and mechanical extraction aspiration and mechanical extraction extraction
First the clot is aspirated then a thrombus First the clot is aspirated then a thrombus removal ring can be used if necessary to removal ring can be used if necessary to remove remaining clot remove remaining clot
successful recanalizing 82successful recanalizing 82 Bridging therapyBridging therapy
06 mgkg IV rt-PA followed by IAT with IA rt-06 mgkg IV rt-PA followed by IAT with IA rt-PA (up to 20 mg)PA (up to 20 mg)
achieved a higher recanalization rateachieved a higher recanalization rate
Criteria for thrombolysis with rTPACriteria for thrombolysis with rTPA
Inclusion criteriaInclusion criteria Clinical signs and symptoms consistent with ischemic Clinical signs and symptoms consistent with ischemic
strokestroke Patient last seen normal within 3 hoursPatient last seen normal within 3 hours Measurable neurologic deficitMeasurable neurologic deficit
Exclusion criteriaExclusion criteria Any hemorrhage on neuroimaging (CT or MRI)Any hemorrhage on neuroimaging (CT or MRI) Symptoms suggestive of subarachnoid hemorrhageSymptoms suggestive of subarachnoid hemorrhage Seizure at stroke onset that is thought to contribute to Seizure at stroke onset that is thought to contribute to
neurologic deficitneurologic deficit Hypodensity greater than one third cerebral hemisphere Hypodensity greater than one third cerebral hemisphere
on CTon CT SBP greater than 185 mm Hg or DBP greater than 110 SBP greater than 185 mm Hg or DBP greater than 110
mm Hgmm Hg International normalized ratio (INR) greater than 17International normalized ratio (INR) greater than 17
Ischemic Stroke Ischemic Stroke Treatment ndash 2006Treatment ndash 2006
IV tissue plasminogen activator (tPA)IV tissue plasminogen activator (tPA) ndash ndash Only FDA-approved acute stroke drugOnly FDA-approved acute stroke drug ndash ndash 3 hour treatment window3 hour treatment window
MERCI - Concentric clot retrieval MERCI - Concentric clot retrieval devicedevice ndash ndash Rescue therapy - approved 2004Rescue therapy - approved 2004 ndash ndash Device approval (not outcomes-based)Device approval (not outcomes-based)
Off label approachesOff label approaches ndash ndash IV tPA after 3 hoursIV tPA after 3 hours ndash ndash IV-IA tPA sequential strategiesIV-IA tPA sequential strategies ndash ndash IA tPA clot angioplasty fragmentationIA tPA clot angioplasty fragmentation ndash ndash Ultrasound-assisted tPA lysisUltrasound-assisted tPA lysis
rt-PA Trials NINDSrt-PA Trials NINDS
Acute stroke - 624 patientsAcute stroke - 624 patients Treat within 3 hrsTreat within 3 hrs Intravenous 09 mgkg rt-PA vs placeboIntravenous 09 mgkg rt-PA vs placebo Hemorrhage 64 tPA 06 placeboHemorrhage 64 tPA 06 placebo Neurologic recovery better with tPA 30 Neurologic recovery better with tPA 30
more like to have minimal or no disabilitymore like to have minimal or no disability
First proven approved treatment for First proven approved treatment for strokestroke
Limitations of tPALimitations of tPA Only 4 of acute strokes receive tPAOnly 4 of acute strokes receive tPA (Kleindorfer et al Stroke 2004 35 e27-e29)(Kleindorfer et al Stroke 2004 35 e27-e29)
Only 22 of patients present within 3 hoursOnly 22 of patients present within 3 hours1048707 1048707 51 of these ineligible due to51 of these ineligible due to
bull bull Mild severityMild severity bull bull Medical or surgical historyMedical or surgical history bull bull Blood testsBlood tests
Sustained recanalization only 13Sustained recanalization only 13 (Alexandrov et al NEJM 2004 351 2170-8)(Alexandrov et al NEJM 2004 351 2170-8)
Concern for hemorrhageConcern for hemorrhage tPA potentiates apoptotic injury tPA potentiates apoptotic injury (Liu et al Nature Med 2004 101379-83)(Liu et al Nature Med 2004 101379-83)
PROACT II IA Lysis TrialPROACT II IA Lysis Trial Baseline 24 hours 8 days
Baseline 60 minutes 120 minutes
9mg IAProurokinase
Desmoteplase Trials DEDAS Desmoteplase Trials DEDAS DIASDIAS
Trial OverviewTrial Overview Double blind randomized placebo Double blind randomized placebo
controlled trialscontrolled trials IV delivery 3-9 hour time windowIV delivery 3-9 hour time window Plasminogen activator ndash from Plasminogen activator ndash from vampire bat vampire bat
salivasaliva Selection based on PWI-DWI MismatchSelection based on PWI-DWI Mismatch
MRI InclusionMRI Inclusion PWI defect at least 2 cm AND ~20 larger PWI defect at least 2 cm AND ~20 larger
than DWIthan DWI PWI should be obvious even visible on PWI should be obvious even visible on
raw imagesraw imagesMRI ExclusionMRI Exclusion
DWI gt 13 MCADWI gt 13 MCA MRA ICA occlusionMRA ICA occlusion
Desmoteplase ndash DIAS Desmoteplase ndash DIAS ResultsResults
Mechanical Thrombolysis Mechanical Thrombolysis devicesdevices
mechanical thrombolysis potentially extends the treatment mechanical thrombolysis potentially extends the treatment window because they act promptly at the site of the thrombuswindow because they act promptly at the site of the thrombus
The devices can retrieve large clots that pharmaceutical agents The devices can retrieve large clots that pharmaceutical agents may not successfully lysemay not successfully lyse
Patients treated with IV tPA may be considered for treatment of Patients treated with IV tPA may be considered for treatment of residual clot with some of these devicesresidual clot with some of these devices
suction-creating saline jets suction-creating saline jets laser energy ultrasound laser energy ultrasound a corkscrew apparatus to treat strokesa corkscrew apparatus to treat strokes The AngioJet systemThe AngioJet system uses saline jets that are directed back into the catheter to uses saline jets that are directed back into the catheter to
create a low-pressure zone around the catheter tip inducing create a low-pressure zone around the catheter tip inducing suction suction
The clot is pulled into the exhaust lumen and removed from the The clot is pulled into the exhaust lumen and removed from the vessel Although US Food and Drug Administration (FDA) has vessel Although US Food and Drug Administration (FDA) has approved this device for use in arteriovenous dialysis grafts and approved this device for use in arteriovenous dialysis grafts and fistulae and for the treatment of coronary arteries saphenous fistulae and for the treatment of coronary arteries saphenous vein grafts and peripheral vessels clinical trials for the vein grafts and peripheral vessels clinical trials for the treatment of acute stroke are no longer in progress treatment of acute stroke are no longer in progress
Most devices are used in cerebral vessels that 2-5 mm
The Latis laser device The Latis laser device used laser energy to ablate clots used laser energy to ablate clots Arteries 2-5 mm in diameter could be Arteries 2-5 mm in diameter could be
treated including the ICA M1 or M2 treated including the ICA M1 or M2 branch of the MCA A1 branch of the branch of the MCA A1 branch of the anterior cerebral artery (ACA) basilar anterior cerebral artery (ACA) basilar artery posterior cerebral artery (PCA) artery posterior cerebral artery (PCA) and vertebral and vertebral
Patients could receive treatment as late Patients could receive treatment as late as 8 hours after symptom onset in the as 8 hours after symptom onset in the anterior circulation and within 24 hours in anterior circulation and within 24 hours in the posterior circulation the posterior circulation
Endovascular Photo Acoustic Endovascular Photo Acoustic Recanalization (EPAR) Recanalization (EPAR)
A laser power source generated energy for the A laser power source generated energy for the systemsystem
The energy was delivered by means of The energy was delivered by means of fiberoptics to the tip of the catheter at the fiberoptics to the tip of the catheter at the treatment sitetreatment site
Absorption of laser light by darkly pigmented Absorption of laser light by darkly pigmented materials (ie the clot) occurred inside the 1-mm materials (ie the clot) occurred inside the 1-mm catheter tipcatheter tip
the system was designed to minimize scattering the system was designed to minimize scattering of laser light of laser light
Absorption converted photo energy to acoustic Absorption converted photo energy to acoustic energy which then emulsified the clot inside the energy which then emulsified the clot inside the catheter tip catheter tip
EKOS ultrasound( the EKOS ultrasound( the Ultrasound Thrombolytic Ultrasound Thrombolytic
Infusion Catheter) Infusion Catheter) combines the use of a distal ultrasound transducer with combines the use of a distal ultrasound transducer with
infusion of a thrombolytic agent through the infusion of a thrombolytic agent through the microcathetermicrocatheter
Ultrasound changes the structure of the clot to Ultrasound changes the structure of the clot to temporarily increase its permeability while providing an temporarily increase its permeability while providing an acoustic pressure gradient to move the drug into the clot acoustic pressure gradient to move the drug into the clot to speed its dissolution to speed its dissolution
The EKOS catheter is placed in the proximal portion of the The EKOS catheter is placed in the proximal portion of the clot clot
After a 2-mg bolus of tPA was injected through the After a 2-mg bolus of tPA was injected through the catheter catheter
the patient received a continuous infusion of IA tPA 03 the patient received a continuous infusion of IA tPA 03 mgmin to a maximum of 20 mg and simultaneous mgmin to a maximum of 20 mg and simultaneous ultrasound transmission for as long as 60 minutes ultrasound transmission for as long as 60 minutes
One patient was treated with a total of 4 units of One patient was treated with a total of 4 units of recombinant reteplase (Retavase) hand-injected over 60 recombinant reteplase (Retavase) hand-injected over 60 minutes minutes
Penumbra system Penumbra system The Penumbra system (Penumbra Inc) provides a dual The Penumbra system (Penumbra Inc) provides a dual
approach to clot extraction using aspiration followed by approach to clot extraction using aspiration followed by clot retrieval with a ring device if needed clot retrieval with a ring device if needed
Mechanical Embolus Removal in Cerebral Ischemia Mechanical Embolus Removal in Cerebral Ischemia (MERCI)(MERCI)
a corkscrew-like apparatus to remove blood clots from a corkscrew-like apparatus to remove blood clots from the brain in patients experiencing an ischemic stroke the brain in patients experiencing an ischemic stroke
The corkscrew itself resides in the catheter tip which The corkscrew itself resides in the catheter tip which shields it from the wall of the vessel until it is ready to be shields it from the wall of the vessel until it is ready to be burrowed into the clot Once lodged in the clot the device burrowed into the clot Once lodged in the clot the device and clot are withdrawn from the vessel and clot are withdrawn from the vessel
Snarelike devicesSnarelike devices Snares such as the Neuronet snare (Guidant Snares such as the Neuronet snare (Guidant
Endovascular Santa Clara CA) have been developed Endovascular Santa Clara CA) have been developed specifically for use in the treatment of strokes specifically for use in the treatment of strokes
These devices are simple in design and do not require the These devices are simple in design and do not require the clot to be amenable to emulsification clot to be amenable to emulsification
X-Sizer deviceX-Sizer device a device with small moving blades at the a device with small moving blades at the
catheter tip catheter tip This device the X-Sizer device (EndiCor Medical This device the X-Sizer device (EndiCor Medical
San Clemente CA) can be used to excise the San Clemente CA) can be used to excise the thrombus and aspirate it thrombus and aspirate it
The device was being evaluated in randomized The device was being evaluated in randomized studies of coronary vessels and in a registry of studies of coronary vessels and in a registry of patients with acute myocardial infarctionpatients with acute myocardial infarction
Although the manufacturer had modified the Although the manufacturer had modified the device for use in cerebral vessels a safety and device for use in cerebral vessels a safety and feasibility study was indefinitely suspended after feasibility study was indefinitely suspended after only 1 patient was treated with the device in only 1 patient was treated with the device in Europe Europe
Suction thrombectomySuction thrombectomy This method of mechanical thrombolysis is one of the This method of mechanical thrombolysis is one of the
simplestsimplest In this readily available technique suction is applied with In this readily available technique suction is applied with
a syringe to remove thrombus in the ICA a syringe to remove thrombus in the ICA It requires no other devicesIt requires no other devices A catheter with a large inner diameter (Brite Tip Cordis A catheter with a large inner diameter (Brite Tip Cordis
Corporation Miami FL) was placed in the symptomatic Corporation Miami FL) was placed in the symptomatic vessel and navigated over a guidewire into the thrombusvessel and navigated over a guidewire into the thrombus
A 60-mL syringe was used to aspirate the thrombus A 60-mL syringe was used to aspirate the thrombus Each patient required angioplasty and stenting of carotid Each patient required angioplasty and stenting of carotid
bifurcation stenosis and received daily aspirin and bifurcation stenosis and received daily aspirin and ticlopidine after the procedure No complications ticlopidine after the procedure No complications occurred occurred
Summary Acute Stroke Summary Acute Stroke ImagingImaging
PhysiologyPhysiology importance collaterals importance collaterals
ndash ndashGrowing role for perfusion Growing role for perfusion assessmentassessment
tPAtPA guidelines amp limitations guidelines amp limitations Signs on CT amp MRSigns on CT amp MR follow physiology follow physiology Stroke trialsStroke trials PWI-DWI mismatch PWI-DWI mismatch
ndash ndashTreat based on physiology not timeTreat based on physiology not time ProtocolsProtocols should be fast and should be fast and
comprehensivecomprehensive
Anticoagulant Properties of Anticoagulant Properties of HeparinHeparin
11 Inhibits the thrombin-mediated conversion of Inhibits the thrombin-mediated conversion of fibrinogen to fibrinfibrinogen to fibrin
22 Inhibits the aggregation of platelets by thrombin Inhibits the aggregation of platelets by thrombin (prolongs bleeding time)(prolongs bleeding time)
33 Inhibits activation of fibrin stabilizing enzymeInhibits activation of fibrin stabilizing enzyme
44 Inhibits activated factors XII XI IX X and IIInhibits activated factors XII XI IX X and II All available forms of heparin must be All available forms of heparin must be
administered administered parenterally since they are parenterally since they are highly charged and rapidlyhighly charged and rapidly hydrolyzed in the hydrolyzed in the GI tractGI tract
Heparin antagonist Protamine sulfate (Heparin antagonist Protamine sulfate (10mg for 10mg for 1000 unit of heparin)1000 unit of heparin)
Monitoring of heparin Monitoring of heparin
Subcutenous Subcutenous no monitoring requiredno monitoring required Intravenous Intravenous
Partial thromboplastin time (PTT normal value Partial thromboplastin time (PTT normal value ~30sec) ~30sec)
Activated clotting time ( ACT normal value ~90-Activated clotting time ( ACT normal value ~90-120sec)120sec)
Daily or more frequent if PTT ACT variesDaily or more frequent if PTT ACT varies
Mechanism Mechanism ndash measures intrinsic pathwayndash measures intrinsic pathway Therapeutic goal Therapeutic goal 2-25 times normal control value 2-25 times normal control value
ACT or aPTTACT or aPTT
Determine when to pull the femoral sheath Determine when to pull the femoral sheath Premature sheath pull can lead to bleedingPremature sheath pull can lead to bleeding Delayed removal can increase time in ICUDelayed removal can increase time in ICU Target set Target set at each siteat each site
ACT targets range from 150 ndash 220 ACT targets range from 150 ndash 220 secondsseconds
aPTT targets range from 40 ndash 70 seconds aPTT targets range from 40 ndash 70 seconds
During neuroangiography-During neuroangiography- Recommended therapeutic range of heparin in Recommended therapeutic range of heparin in
plasma is 02-08 uml ( corresponding to aPTT plasma is 02-08 uml ( corresponding to aPTT ACT values 15-25 times the baseline values)ACT values 15-25 times the baseline values)
Dose In diagnostic angiography bolus dose of Dose In diagnostic angiography bolus dose of 2500 iu is used followed by 1000 iu hour2500 iu is used followed by 1000 iu hour
Bolus dose is Bolus dose is 60 ukg to maintain the therapeutic 60 ukg to maintain the therapeutic range range If procedure continues for more than 75 If procedure continues for more than 75 minutes additional dose is required ( half of the minutes additional dose is required ( half of the initial dose for another 75 minutes) initial dose for another 75 minutes)
(AJNR 199415 51-54)
Mechanisms of HIT( Mechanisms of HIT( Heparin Heparin induced Thrombocytopeniainduced Thrombocytopenia))
Type 1Type 1 Fall in platelet count occurs within the first two Fall in platelet count occurs within the first two
days after heparin initiation often returns to days after heparin initiation often returns to normal with continued heparin administration normal with continued heparin administration and is of no clinical consequence and is of no clinical consequence
The mechanism of the thrombocytopenia is non-The mechanism of the thrombocytopenia is non-immune and appears to be due to a direct effect of immune and appears to be due to a direct effect of heparin on platelet activationheparin on platelet activation
Type 2Type 2 Approximately 03 to 3 percent of patients Approximately 03 to 3 percent of patients
receiving heparin develop an immune receiving heparin develop an immune thrombocytopenia mediated by antibodies to a thrombocytopenia mediated by antibodies to a heparin-platelet factor 4 complex heparin-platelet factor 4 complex
(AJNR 28155-158 2007)
Treatment of heparin-induced Treatment of heparin-induced thrombocytopeniathrombocytopenia
When HIT is diagnosed it is important to When HIT is diagnosed it is important to stop heparin mainly in type 2 and to avoid stop heparin mainly in type 2 and to avoid the use of LMWH the use of LMWH
Because of the increased risk of thrombosis Because of the increased risk of thrombosis however continuation of an anticoagulant however continuation of an anticoagulant must be considered must be considered
The drugs currently approved for the The drugs currently approved for the treatment of HIT in the United States are treatment of HIT in the United States are direct thrombin inhibitors argatroban and direct thrombin inhibitors argatroban and lepirudinlepirudin
WARFARIN MECHANISM OF ACTIONWARFARIN MECHANISM OF ACTION
Inactive factors II VII IX and X
Proteins S and C
Active factors II VII IX and X
Proteins S and C
Vitamin K epoxide
Vitamin K reduced
WA
RF
AR
IN
Prevents the reduction of vitamin K which is essential for Prevents the reduction of vitamin K which is essential for activation of certain factorsactivation of certain factors
Has no effect on previously formed thrombusHas no effect on previously formed thrombus
Antagonist is Vit KAntagonist is Vit K
OPTIMIZING WARFARIN THERAPYOPTIMIZING WARFARIN THERAPY
Use of large loading dose may lead to hemorrhage and Use of large loading dose may lead to hemorrhage and other complicationsother complications
Initial dose 2-5 mg once dailyInitial dose 2-5 mg once daily Maintenance dose 2-10 mg once dailyMaintenance dose 2-10 mg once daily If Immediate anticoagulation is requiredIf Immediate anticoagulation is required Heparin IS Heparin IS
started along with loading dose of warfarin 10 mg started along with loading dose of warfarin 10 mg Heparin is usually discontinued after 4-5 days Heparin is usually discontinued after 4-5 days Before Before discontinuing INR should be in therapeutic range for 2 discontinuing INR should be in therapeutic range for 2 consecutive daysconsecutive days
Daily monitoring of INR until INR is in therapeutic Daily monitoring of INR until INR is in therapeutic range then 3 times weekly for 1-2 weeks then less often range then 3 times weekly for 1-2 weeks then less often (every 4 to 6 weeks)(every 4 to 6 weeks)
OPTIMAL THERAPEUTIC RANGEOPTIMAL THERAPEUTIC RANGE
IndicationIndication INRINR
Prophylaxis of venous Prophylaxis of venous thromboembolismthromboembolism
20-3020-30
Treatment of venous Treatment of venous thromboembolismthromboembolism
20-3020-30
Atrial fibrillationAtrial fibrillation 20-3020-30
Mitral valve stenosisMitral valve stenosis 20-3020-30
Heart valve replacementHeart valve replacement
Bioprosthetic valveBioprosthetic valve
Mechanical valveMechanical valve
20-3020-30
25-3525-35
Myocardial infarctionMyocardial infarction 20-3020-30
25-35 25-35 (high risk patients)(high risk patients)
FACTORS INFLUENCING DOSE RESPONSEFACTORS INFLUENCING DOSE RESPONSE
Poor patient compliancePoor patient compliance Concomitant medicationsConcomitant medications Levels of dietary vitamin KLevels of dietary vitamin K Alcohol Inaccurate lab testingAlcohol Inaccurate lab testing Inaccurate lab testingInaccurate lab testing Hepatic dysfunctionHepatic dysfunction FeverFever
Contraindication for WarfarinContraindication for Warfarin
Hypersensitivity to warfarinHypersensitivity to warfarin Hemorrhagic tendencyHemorrhagic tendency Condition with risk of hemorrhageCondition with risk of hemorrhage Inadequate laboratory techniquesInadequate laboratory techniques Protein C amp S deficiencyProtein C amp S deficiency Vitamin K deficiencyVitamin K deficiency
SIDE EFFECTSSIDE EFFECTS
Hemorrhage Hemorrhage Skin necrosisSkin necrosis Purple toe syndromePurple toe syndrome Microembolization Microembolization TeratogenecityTeratogenecity Agranulocytosis leukopenia Agranulocytosis leukopenia Diarrhoeanausea anorexiaDiarrhoeanausea anorexia
MONITORING OF WARFARIN THERAPYMONITORING OF WARFARIN THERAPY
Prothrombin timeProthrombin time PT ratioPT ratio INR (International Normalized Ratio)INR (International Normalized Ratio)
PROTHROMBIN TIME (PT)PROTHROMBIN TIME (PT)
Time required for blood to coagulate Time required for blood to coagulate is called PT ( normal value ~10sec)is called PT ( normal value ~10sec)
Performed by adding a mixture of Performed by adding a mixture of calcium and thromboplastin to calcium and thromboplastin to citrated plasmacitrated plasma
As a control a normal blood sample is As a control a normal blood sample is tested continuouslytested continuously
PT ratio (PTR) = PT ratio (PTR) = Patientrsquos PTPatientrsquos PT Control PTControl PT
PROBLEMS WITH PTPTRPROBLEMS WITH PTPTR
Thromboplastins are extracts from Thromboplastins are extracts from brain lung or placenta of animalsbrain lung or placenta of animals
Thromboplastins from various Thromboplastins from various manufacturers differ in their manufacturers differ in their sensitivity to prolong PTsensitivity to prolong PT
May result in false control of May result in false control of anticoagulant therapyanticoagulant therapy
INTERNATIONAL NORMALISED RATIO (INR)INTERNATIONAL NORMALISED RATIO (INR)
International Normalized Ratio (INR) International Normalized Ratio (INR) a PT test with a a PT test with a formula based ratio to normalize the often variable source formula based ratio to normalize the often variable source of tissue factor (human rabbit recombinant)of tissue factor (human rabbit recombinant)
INR = [PTINR = [PTptpt] ] ISIISI
[PT[PTRefRef]]
PTPTpt pt ndash prothrombin time of patientndash prothrombin time of patient
PTPTRef Ref ndash prothrombin time of normal pooled samplendash prothrombin time of normal pooled sample
ISI ndash International Sensitivity IndexISI ndash International Sensitivity Index
Warfarin is given orally and titrated to achieve an INR of Warfarin is given orally and titrated to achieve an INR of typically 20 ndash 30typically 20 ndash 30
Heparin versus WarfarinHeparin versus Warfarin
Drug ActionMechan-ism
Moni-toring
Effective
HeparinDirect
Inhibition ofThrombin
ATIIIcofactor
APTTACT
Immediate
WarfarinDecreasesProductionof factors
Vitamin K PTDelay
3-5 days
INR
Recanalization or Antegrade Recanalization or Antegrade Reperfusion StrategiesReperfusion Strategies
Recanalization strategies focus on removing Recanalization strategies focus on removing andor dissolving the occlusive thrombus to re-andor dissolving the occlusive thrombus to re-establish antegrade flow Strategies may be establish antegrade flow Strategies may be classified into 7 different categories on the classified into 7 different categories on the basis of their primary mechanism of action basis of their primary mechanism of action 1) 1) IV andor intraarterial thrombolysis (IAT) IV andor intraarterial thrombolysis (IAT) 2) endovascular thrombectomy2) endovascular thrombectomy3) endovascular thromboaspiration 3) endovascular thromboaspiration 4) endovascular mechanical thrombus disruption or 4) endovascular mechanical thrombus disruption or
thromborrhexisthromborrhexis5) 5) transcranial or endovascular augmented transcranial or endovascular augmented
fibrinolysis fibrinolysis 6) endovascular thrombus entrapment and 6) endovascular thrombus entrapment and 7) temporary endovascular bypass7) temporary endovascular bypass
IAT in Acute Ischemic StrokeIAT in Acute Ischemic Stroke
IAT advantages over IV thrombolysisIAT advantages over IV thrombolysis Coaxial microcatheter techniques the occluded intracranial Coaxial microcatheter techniques the occluded intracranial
vessel is directly accessible and the fibrinolytic agent can be vessel is directly accessible and the fibrinolytic agent can be infused directly into the thrombusinfused directly into the thrombus
This permits a smaller dose of fibrinolytic agent to reach a This permits a smaller dose of fibrinolytic agent to reach a higher local concentration than that reached by systemic higher local concentration than that reached by systemic infusioninfusion
Allows more complete recanalization with lower total doses of Allows more complete recanalization with lower total doses of thrombolytic thrombolytic
With the smaller dose complications from systemic fibrinolytic With the smaller dose complications from systemic fibrinolytic effects including intracranial hemorrhage (ICH) can effects including intracranial hemorrhage (ICH) can theoretically be reduced theoretically be reduced
Treatment window for endovascular techniques can be Treatment window for endovascular techniques can be extended beyond the typical IV window of 3 hours extended beyond the typical IV window of 3 hours
IA techniques have led to higher recanalization rates than IV IA techniques have led to higher recanalization rates than IV thrombolysisthrombolysis
Major disadvantagesMajor disadvantages Relative complexity of the procedure the level Relative complexity of the procedure the level
of required technical expertise and its of required technical expertise and its relatively low availability relatively low availability
Delays in initiating treatmentDelays in initiating treatment InvasiveInvasive
ThrombolyticsThrombolytics
Plasminogen activators
Fibrinolytics
1 Plasminogen Activators 1 Plasminogen Activators drugs act by converting the inactive proenzyme drugs act by converting the inactive proenzyme plasminogen into the active enzyme plasmin Plasmin plasminogen into the active enzyme plasmin Plasmin digests fibrinogen fibrin monomers and cross-linked digests fibrinogen fibrin monomers and cross-linked fibrin (as found in a thrombus) into fibrin degradation fibrin (as found in a thrombus) into fibrin degradation productsproducts
First-Generation Agents First-Generation Agents StreptokinaseStreptokinase a protein derived from group C a protein derived from group C
szlig-hemolytic streptococci has a half-life of 16ndashszlig-hemolytic streptococci has a half-life of 16ndash90 minutes and low fibrin specificity This drug 90 minutes and low fibrin specificity This drug proved to have a very narrow therapeutic proved to have a very narrow therapeutic window and significant rates of ICH and window and significant rates of ICH and systemic hemorrhage18systemic hemorrhage18
UrokinaseUrokinase is a serine protease with a plasma is a serine protease with a plasma half life of 14 minutes and low fibrin specificity half life of 14 minutes and low fibrin specificity
The urokinase dose used in cerebral IAT has The urokinase dose used in cerebral IAT has ranged from 002 to 2 X106unitsranged from 002 to 2 X106units
Second-Generation Agents Second-Generation Agents Alteplase (rtPA) Alteplase (rtPA)
is a serine is a serine protease with a plasma half-life of 35 protease with a plasma half-life of 35 minutes and a high degree of fibrin affinity and minutes and a high degree of fibrin affinity and specificity specificity
Dose used in cerebral IAT has ranged between 20 Dose used in cerebral IAT has ranged between 20 and 60 mgand 60 mg
Disadvantages of alteplase include its relatively short Disadvantages of alteplase include its relatively short halflife and limited penetration into the clot matrix halflife and limited penetration into the clot matrix because of strong binding with surface fibrin which because of strong binding with surface fibrin which could delay recanalization and increase the risk of could delay recanalization and increase the risk of recurrent occlusion recurrent occlusion
Prourokinase (r-prourokinase) Prourokinase (r-prourokinase) is the proenzyme precursor of urokinase is the proenzyme precursor of urokinase T12 of 7 minutes and high fibrin specificity T12 of 7 minutes and high fibrin specificity
Third-Generation AgentsThird-Generation Agents
ReteplaseReteplase is a structurally modified is a structurally modified form of alteplase form of alteplase
with a longer half-life (15ndash18 minutes) In with a longer half-life (15ndash18 minutes) In addition it does not bind as highly to fibrin addition it does not bind as highly to fibrin unbound reteplase can thus theoretically better unbound reteplase can thus theoretically better penetrate the clot and potentially penetrate the clot and potentially improve in improve in vivo fibrinolytic activity vivo fibrinolytic activity
TenecteplaseTenecteplase is another modified form of rtPA with a longer is another modified form of rtPA with a longer
half-life (17 minutes)half-life (17 minutes) greater fibrin specificity and greater greater fibrin specificity and greater
resistance to plasminogen activator inhibitor-1 resistance to plasminogen activator inhibitor-1 IV tenecteplase in acute ischemic stroke IV tenecteplase in acute ischemic stroke
suggest that the drug is safe and promisingsuggest that the drug is safe and promising
Newer plasminogen activatorNewer plasminogen activator
DesmoteplaseDesmoteplase is a genetically engineered is a genetically engineered version of the clot-dissolving factor version of the clot-dissolving factor
found in the saliva found in the saliva of the vampire bat Desmodus rotundusof the vampire bat Desmodus rotundus moremore potent and more selective for fibrin-bound potent and more selective for fibrin-bound
plasminogen than any other known plasminogen plasminogen than any other known plasminogen activatoractivator
Unlike tissue plasminogen activator (tPA) desmoteplase Unlike tissue plasminogen activator (tPA) desmoteplase is not activated by fibrinogen or -amyloid proteins is not activated by fibrinogen or -amyloid proteins factors that may exacerbate the risk for ICH factors that may exacerbate the risk for ICH
The effect of IV administration of desmoteplase 3ndash9 The effect of IV administration of desmoteplase 3ndash9 hours after symptom onset in patients with stroke who hours after symptom onset in patients with stroke who present with mismatch on MR imaging or CT perfusion present with mismatch on MR imaging or CT perfusion
3 DefibrinogenatingFibrinogenolytic 3 DefibrinogenatingFibrinogenolytic Agents Agents
AncrodAncrod(Viprinex)(Viprinex) is is the purified fraction of the Malayan pit viper venomthe purified fraction of the Malayan pit viper venom It acts by directly cleaving and inactivating fibrinogen It acts by directly cleaving and inactivating fibrinogen
and thus indirectly promoting anticoagulation and thus indirectly promoting anticoagulation The reduction in the blood levels of fibrinogen also The reduction in the blood levels of fibrinogen also
leads to a reduced blood viscosity which may improve leads to a reduced blood viscosity which may improve blood flow to the affected areas of the brain blood flow to the affected areas of the brain
In the Stroke Treatment with Ancrod Trial 500 In the Stroke Treatment with Ancrod Trial 500 patients with stroke presenting within 3 hours of patients with stroke presenting within 3 hours of symptom onset were randomized to receive ancrod (symptom onset were randomized to receive ancrod (n n 248) or a placebo (n 252) Good outcome (Barthel 248) or a placebo (n 252) Good outcome (Barthel Index 95ndash100 at 3 months) was achieved in 4221 Index 95ndash100 at 3 months) was achieved in 4221 and 344 of the patients respectively and 344 of the patients respectively
2 Direct Fibrinolytics2 Direct Fibrinolytics
Microplasmin (Microplasmin (ThromboGenics Heverlee Belgium)ThromboGenics Heverlee Belgium) is a truncated form of plasmin that is more resistant to the effects is a truncated form of plasmin that is more resistant to the effects
of antiplasmin of antiplasmin microplasmin can be used upto 4ndash12 hours after stroke onset microplasmin can be used upto 4ndash12 hours after stroke onset There was no evidence of increased bleeding risk with There was no evidence of increased bleeding risk with
microplasminmicroplasmin
Alfimeprase (Nuvelo San Carlos Calif)Alfimeprase (Nuvelo San Carlos Calif) is a recombinant truncated form of fibrolase a fibrinolytic zinc metalloproteinase is a recombinant truncated form of fibrolase a fibrinolytic zinc metalloproteinase
isolated from the venom of the southern copperhead snake isolated from the venom of the southern copperhead snake It degrades fibrin directly and achieves thrombolysis independent It degrades fibrin directly and achieves thrombolysis independent
of plasmin formationof plasmin formation its thrombolytic activity appears to be localized to the site of its thrombolytic activity appears to be localized to the site of
delivery These properties should theoretically result in faster delivery These properties should theoretically result in faster recanalization and lower hemorrhagic conversion riskrecanalization and lower hemorrhagic conversion risk
Anti-fibrinolyticsAnti-fibrinolytics
to limit fibrinolytic activityto limit fibrinolytic activity -aminocaproic acid (EACA) -aminocaproic acid (EACA) competitively inhibitscompetitively inhibits plasminogen and plasminogen activators from plasminogen and plasminogen activators from
binding to fibrinbinding to fibrin
alpha2-antiplasminalpha2-antiplasmin a serine protease inhibitor that a serine protease inhibitor that neutralizes any free circulating plasminneutralizes any free circulating plasmin
Plasminogen activator inhibitor-1Plasminogen activator inhibitor-1 a serine protease a serine protease inhibitor that inhibits tissue-type plasminogen inhibitor that inhibits tissue-type plasminogen activatoractivator
Glycoprotein (GP) IIbIIIa antagonistsGlycoprotein (GP) IIbIIIa antagonists
such as ReoPro (abciximab) Integrilin such as ReoPro (abciximab) Integrilin (eptifibatide) or Aggrastat (tirofiban) in (eptifibatide) or Aggrastat (tirofiban) in ischemic stroke remains investigational ischemic stroke remains investigational Deshmukh et al38 reported 21 patients with Deshmukh et al38 reported 21 patients with large-vessel occlusion refractory to IAT with large-vessel occlusion refractory to IAT with rtPA who were treated with IV andor IA rtPA who were treated with IV andor IA abciximab eptifibatide or tirofiban abciximab eptifibatide or tirofiban
IA Mechanical Approaches in Acute Ischemic Stroke IA Mechanical Approaches in Acute Ischemic Stroke Mechanical strategies have several advantagesMechanical strategies have several advantages First they lessen and may even preclude the use of chemical First they lessen and may even preclude the use of chemical
thrombolytics in this manner very likely reducing the risk of ICHthrombolytics in this manner very likely reducing the risk of ICH Second by avoiding the use of chemical thrombolytics it is Second by avoiding the use of chemical thrombolytics it is
possible to extend the treatment window beyond the limit of 6ndash8 possible to extend the treatment window beyond the limit of 6ndash8 hours hours
Third mechanically fragmenting a clot increases the surface area Third mechanically fragmenting a clot increases the surface area accessible to fibrinolytic agents and allows inflow of fresh accessible to fibrinolytic agents and allows inflow of fresh plasminogen which in turn may increase the speed of plasminogen which in turn may increase the speed of thrombolysis thrombolysis
Finally clot-retrieval devices may provide faster recanalization Finally clot-retrieval devices may provide faster recanalization
The disadvantages of the mechanical The disadvantages of the mechanical approaches approaches technical difficulty of navigating mechanical technical difficulty of navigating mechanical
devices into the intracranial circulation excessive devices into the intracranial circulation excessive trauma to the vasculature (potentially leading to trauma to the vasculature (potentially leading to vasospasm vessel dissection perforation or vasospasm vessel dissection perforation or rupture) rupture)
fragmented thrombus causing distal embolization fragmented thrombus causing distal embolization into previously unaffected territories into previously unaffected territories
Nevertheless the advantages of mechanical stroke Nevertheless the advantages of mechanical stroke therapy appear to significantly outweigh its therapy appear to significantly outweigh its disadvantages and risksdisadvantages and risks
Contraindications to Thrombolytic Contraindications to Thrombolytic agents agents
Recent thoracic abdominal or Recent thoracic abdominal or intracranial surgeryintracranial surgery
Recent haemorrhagic CVA Head injury Recent haemorrhagic CVA Head injury or neoplasmor neoplasm
Bleeding ulcerBleeding ulcer Anticipated invasive procedures (arterial Anticipated invasive procedures (arterial
punctures biopsies)punctures biopsies) Concurrent hemostatic dysfunctionConcurrent hemostatic dysfunction
Monitoring of thrombolytic Monitoring of thrombolytic therapytherapy
Thrombin time Measures the availability of functional
fibrinogen Normal thrombin time is 10-14 sec Prolonged when fibrinogen level is below
75-100 mgdl
Half Life of ThrombolyticsHalf Life of ThrombolyticsAgent Administration Half Life
Streptokinase IA 60-80min
Urokinase IAIV 9-12min
rTPA IAIV 6min
Abciximab(Reopro) IAIV 12hour
Aspirin POIV 15-20min
Heparin IVSC 60min
Coumadin PO 15-25 days
Anti Platelet DrugsAnti Platelet DrugsDrug Drug Mechanism Mechanism UsesUsesAspirinAspirin Permanently inhibits Permanently inhibits
COX-1 and COX-2COX-1 and COX-2CADCAD
Stroke-TIAsStroke-TIAs
NSAIDsNSAIDs Reversibly inhibits Reversibly inhibits COX-1COX-1
LimitedLimited
DipyridamoleDipyridamole Inhibits PDE increases Inhibits PDE increases cAMPcAMP
TIAsTIAs
ThenopyridinesThenopyridines
(Ticlopidine(Ticlopidine
ClopidrgrelClopidrgrel))
Inhibits ADP Inhibits ADP
PlatAg PlatAg
TIAsStrokeTIAsStroke
CAD PVDCAD PVD
Abciximab (ReoPro)Abciximab (ReoPro)
Eptifibatide (Integrilin)Eptifibatide (Integrilin)
TirofibanTirofiban
GP IIBIIIA InhibitorsGP IIBIIIA Inhibitors
Stroke- TIAs Stroke- TIAs
MonitoringMonitoring
Bleeding timeBleeding time
Optical aggregometryOptical aggregometry
Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay
Bleeding timeBleeding time
Requires a skin incision (usually made on the ear lobe or Requires a skin incision (usually made on the ear lobe or forearm offorearm of
a depth that results in disruption of capillary loops and a depth that results in disruption of capillary loops and small vessels)small vessels)
AdvantagesAdvantages Universally availableUniversally available Relatively simple techniquesRelatively simple techniques Can be performed bedsideCan be performed bedside
DisadvantagesDisadvantages Insensitive inaccurate non-specific techniqueInsensitive inaccurate non-specific technique
Poorly reproducible (as depends on multiple variables)Poorly reproducible (as depends on multiple variables)
Optical aggregometryOptical aggregometry
Gold standard assay for platelet functionGold standard assay for platelet function Agonist induced aggregation is measuredAgonist induced aggregation is measured Different agonist are available for different Different agonist are available for different
agentsagents However require unique expertise and are not However require unique expertise and are not
universally availableuniversally available Aspirin measured with ADP or AA(gt70 Aspirin measured with ADP or AA(gt70
aggregation so resistance)aggregation so resistance) Clopidogrel( ADP gt 90 aggregation means Clopidogrel( ADP gt 90 aggregation means
resistance) resistance)
Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay
Can be performed bed sideCan be performed bed side Different assay devices with different Different assay devices with different
agonist are used for each of different agonist are used for each of different antiplatelet agents antiplatelet agents
For Aspirin AA is used (result is reported as aspirin For Aspirin AA is used (result is reported as aspirin reaction units [ARU] ARUgt 550 indicates non-reaction units [ARU] ARUgt 550 indicates non-responsiveness)responsiveness)
Verify IIbIIIa assay device uses TRAP as agonist for Verify IIbIIIa assay device uses TRAP as agonist for Abciximab and TirofibanAbciximab and Tirofiban
Practical Applications Practical Applications related to specific related to specific
Neurovascular Neurovascular interventionsinterventions
Acute ischemic StrokeAcute ischemic Stroke When an artery occludes neurons are affected When an artery occludes neurons are affected
differently depending upon the amount of residual blood differently depending upon the amount of residual blood flowflow
Normal cerebral blood flow is greater than 50 mL100 Normal cerebral blood flow is greater than 50 mL100 mgminmgmin
Once blood flow decreases to less than 20 mL100 Once blood flow decreases to less than 20 mL100 mgmin infarction occursmgmin infarction occurs
If blood flow decreases to less than 10 mL100 mgmin If blood flow decreases to less than 10 mL100 mgmin irreversible neuronal death occurs rapidly irreversible neuronal death occurs rapidly
Blood flow between 11 and 20 mL100 mgmin is thought Blood flow between 11 and 20 mL100 mgmin is thought to represent the ischemic penumbra an area where the to represent the ischemic penumbra an area where the cells are functionally silent because of ischemia but are cells are functionally silent because of ischemia but are still able to recover if blood flow is restored still able to recover if blood flow is restored
Many acute stroke therapies are targeted toward Many acute stroke therapies are targeted toward restoring flow or function to the ischemic penumbrarestoring flow or function to the ischemic penumbra
Therapeutic window in Therapeutic window in management of acute Ischemic management of acute Ischemic
StrokeStrokeThe early diagnosis of ischemic stroke is critical to the The early diagnosis of ischemic stroke is critical to the
with only a narrow therapeutic window in the first few with only a narrow therapeutic window in the first few hours following stroke ictushours following stroke ictus
Diagnosis in the first 3 hours postictus provides the Diagnosis in the first 3 hours postictus provides the opportunity for intravenous or intraarterial thrombolysis opportunity for intravenous or intraarterial thrombolysis and intra-arterial clot mechanical treatment which and intra-arterial clot mechanical treatment which improve the outcome improve the outcome
Diagnosis in the time period between 3 and 6 hours Diagnosis in the time period between 3 and 6 hours provides an opportunity for intra-arterial thrombolysis provides an opportunity for intra-arterial thrombolysis and mechanical treatment and mechanical treatment
Involvement of the posterior circulation especially the Involvement of the posterior circulation especially the basilar artery is treated by some regardless of time of basilar artery is treated by some regardless of time of onset or up until 12 to 24 hours in some practices This is onset or up until 12 to 24 hours in some practices This is related to the potentially high mortality and morbidity related to the potentially high mortality and morbidity associated with basilar artery thrombosisassociated with basilar artery thrombosis
Infarct evaluation on angiographyInfarct evaluation on angiography(CT angiography and catheter (CT angiography and catheter
angiography)angiography)CTA is an excellent first-line examination for CTA is an excellent first-line examination for
evaluation of the head and neck arteries evaluation of the head and neck arteries In comparison with catheter angiography In comparison with catheter angiography
what it gives up in resolution and dynamic what it gives up in resolution and dynamic properties it makes up for with rapid properties it makes up for with rapid acquisition of a 3-D dataset and the potential acquisition of a 3-D dataset and the potential for assessment of whole-brain perfusion and for assessment of whole-brain perfusion and better parenchymal evaluationbetter parenchymal evaluation
Moreover CTA illustrates not only arterial Moreover CTA illustrates not only arterial stenosis or occlusion but also the vessel wall stenosis or occlusion but also the vessel wall This factor is most important for evaluation of This factor is most important for evaluation of intramural dissection and thrombosed intramural dissection and thrombosed aneurysms which may both complicate aneurysms which may both complicate evaluation of stroke patientsevaluation of stroke patients
Early angiographic signs of strokes Early angiographic signs of strokes both CTA both CTA and DSA and DSA
Vessel occlusion or cutoff related to Vessel occlusion or cutoff related to thromboembolithromboemboli
aneurysms aneurysms arterial dissection arterial dissection Meniscus or flattened shape to clot Meniscus or flattened shape to clot
(recent) versus reverse meniscus (older)(recent) versus reverse meniscus (older) tram track (nonocclusive or recanalized tram track (nonocclusive or recanalized
clot) clot) delayed (antegrade) flow (manifest as delayed (antegrade) flow (manifest as
decreased whole-brain perfusion on CTA)decreased whole-brain perfusion on CTA) retrograde collateral flowretrograde collateral flow
Non-occlusive left MCA thrombus on 3-D imaging performed from CTA source data and was confirmed at catheter angiography
Therapy to be started within a 6-hr Therapy to be started within a 6-hr time to treatment (TTT) window time to treatment (TTT) window (while in case of IV thrombolysis (while in case of IV thrombolysis therapy to be started with in 3hrs)therapy to be started with in 3hrs)
Exclusion criteria Exclusion criteria Rapidly improving neurologic deficit or Rapidly improving neurologic deficit or Sustained blood pressure of gt180100 Sustained blood pressure of gt180100 Hemorrhage is detected on CTHemorrhage is detected on CT Infarct involving gt more than 13 rd Infarct involving gt more than 13 rd
territory of MCAterritory of MCA MRADWI-Perfusion mismatchlt 20MRADWI-Perfusion mismatchlt 20 Definite hypodensity on CTDefinite hypodensity on CT
Intra-arterial Thrombolysis
Fibrinolytics + AntiplateletsFibrinolytics + Antiplatelets
PlasminogenPlasminogen activators through fibrinolysis exposes activators through fibrinolysis exposes free thrombin and paradoxically stimulatesfree thrombin and paradoxically stimulates platelet platelet aggregation which leads to formation of aaggregation which leads to formation of a platelet platelet thrombus (white clot) thrombus (white clot)
This new thrombus is relatively resistant to This new thrombus is relatively resistant to fibrinolyticsfibrinolytics
So new regimen in case of acute stroke isSo new regimen in case of acute stroke is fibrinolytics + antiplatelet drugsfibrinolytics + antiplatelet drugs
rtPA + IIbIIIa inhibitors( tirofiban rtPA + IIbIIIa inhibitors( tirofiban abciximab) orabciximab) or
Urokinase + IIbIIIa Urokinase + IIbIIIa inhibitors( tirofiban abciximab)inhibitors( tirofiban abciximab)
Intra-arterial Thrombolysis Tirofiban (04 microgkgmin bolus for 3 min followed by Tirofiban (04 microgkgmin bolus for 3 min followed by
0125 ugkgmin)0125 ugkgmin)
++
Heparin (2000ndash3000 IU bolus followed by Heparin (2000ndash3000 IU bolus followed by 1000 IUhour infusion 1000 IUhour infusion
with ACT maintained bw 200-300) throughout the with ACT maintained bw 200-300) throughout the interventional procedure and for 24ndash48 hours thereafter when interventional procedure and for 24ndash48 hours thereafter when there is neither intraprocedural bleeding nor suspicion of there is neither intraprocedural bleeding nor suspicion of increased risk of bleeding increased risk of bleeding
Maximum dose of Urokinase Maximum dose of Urokinase Anterior circulation stroke - 500000 IU (mean 400000 Anterior circulation stroke - 500000 IU (mean 400000
IU range 300000ndash500000 IU)IU range 300000ndash500000 IU) Posterior circulation stroke -1000000 IU (mean 837000 Posterior circulation stroke -1000000 IU (mean 837000
IU range 300000ndash1000000 IU)IU range 300000ndash1000000 IU)American Journal of NeuroradiologyAmerican Journal of Neuroradiology 262595-2601 2005262595-2601 2005
Intravenous ThrombolysisIntravenous Thrombolysis
The first method to restore cerebral The first method to restore cerebral perfusion is clot lysis with the goal perfusion is clot lysis with the goal of re-establishing blood flow to the of re-establishing blood flow to the affected tissue affected tissue
IV thrombolysis rt-PA is the only IV thrombolysis rt-PA is the only FDA- approved treatment for AIS FDA- approved treatment for AIS
Fibrinolysis is enhanced powerfully Fibrinolysis is enhanced powerfully by rt-PAby rt-PA
Intravenous rTPA Intravenous rTPA administration administration protocolprotocol
Total dose of rt-PA 09 mgkg (maximum dose Total dose of rt-PA 09 mgkg (maximum dose 90 mg)90 mg)
Give 10 as initial IV bolusGive 10 as initial IV bolus Infuse remainder over 1 hourInfuse remainder over 1 hour Admit patient to an ICU or stroke unit for Admit patient to an ICU or stroke unit for
monitoringmonitoring Neurologic assessments every 15 minutes Neurologic assessments every 15 minutes
during infusion then every 30 minutes for next during infusion then every 30 minutes for next 6 hours then every hour until 24hours after 6 hours then every hour until 24hours after treatmenttreatment
Favorable Outcome vs Treatment Time Favorable Outcome vs Treatment Time with IV rTPAwith IV rTPA
Protocol limit = 3 hrs
Benefit ~ 45 hrs
Thromboembolism During coilingThromboembolism During coiling Most feared and frequent complication Most feared and frequent complication Reported incidence - Approx 7 Reported incidence - Approx 7 SourcesSources of Thromboembolism are of Thromboembolism are
- Clots at the aneurysmal neck during or immediately- Clots at the aneurysmal neck during or immediately after after embolization embolization
- Thrombus forming on catheters during- Thrombus forming on catheters during proceduresprocedures
- Stenosis of an adjacent artery dt coil mass- Stenosis of an adjacent artery dt coil mass or herniationor herniation
- Migration of intraaneurysmal- Migration of intraaneurysmal thrombus during coil thrombus during coil placement placement
- Slow flow dt vasospasm - Slow flow dt vasospasm
- Rare and unlikely causes are hypercoagulable- Rare and unlikely causes are hypercoagulable state such state such as antiphospholipid antibody syndrome or due to HITas antiphospholipid antibody syndrome or due to HIT
Occur more often with wide-necked aneurysms (dt Occur more often with wide-necked aneurysms (dt increased exposed surface area of thrombogenic coil increased exposed surface area of thrombogenic coil material)material)
Current regimen of endovascular Current regimen of endovascular managementmanagement
The The glycoprotein IIbIIIa antagonist tirofiban glycoprotein IIbIIIa antagonist tirofiban (04 (04 microgkgmin bolus for 30 minutes followed by infusion of microgkgmin bolus for 30 minutes followed by infusion of 0125 ugkgmin until the thrombus dissolved) 0125 ugkgmin until the thrombus dissolved)
Intraarterial thrombolysis with Intraarterial thrombolysis with urokinase or r- TPA urokinase or r- TPA increase of intravenous (IV) heparin (measured by increase of intravenous (IV) heparin (measured by
ACT) ACT) Intravenous aspirin Intravenous aspirin
Coil-related platelet aggregation (white clot) is Coil-related platelet aggregation (white clot) is unlikely to respond to fibrinolytics but has a high risk unlikely to respond to fibrinolytics but has a high risk of hemorrhage (In ISAT) all 5 patients who had of hemorrhage (In ISAT) all 5 patients who had received thrombolytic therapy with tPA to treat a received thrombolytic therapy with tPA to treat a thromboembolic complication after endovascular thromboembolic complication after endovascular treatment rebleed and all of these patients died)treatment rebleed and all of these patients died)
IntracranialIntracranial Stenting Stenting Metallic foreign body such as stent will accumulate Metallic foreign body such as stent will accumulate
thrombus in the absence of platelet inhibitionthrombus in the absence of platelet inhibition Antiplatelet drugs are important to prevent peri or Antiplatelet drugs are important to prevent peri or
post-interventional thromboembolic eventspost-interventional thromboembolic events Optimal treatment regimens has not been determined Optimal treatment regimens has not been determined
but usually but usually Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-
procedureprocedureOrOr
Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on
morning of proceduremorning of procedure
If need to use stent is not pre-planned thanIf need to use stent is not pre-planned than
Abciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkgAbciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkg IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)
Glycoprotein IIbIIIa inhibitor are not used routinely during elective Glycoprotein IIbIIIa inhibitor are not used routinely during elective stenting procedure dt increased risk of ICH stenting procedure dt increased risk of ICH
Carotid StentingCarotid Stenting
Pre-procedurePre-procedure
Double Antiplatelet therapy is routinely given Double Antiplatelet therapy is routinely given beginning at least 3beginning at least 3
days before the proceduredays before the procedure
Aspirin 325mgd+Clopidogrel 75mgdAspirin 325mgd+Clopidogrel 75mgd During procedureDuring procedure
Heparin is given with target clotting time of 250-Heparin is given with target clotting time of 250-300sec300sec
Post-procedure Post-procedure
Aspirin 325mg is continued indefinitely and Aspirin 325mg is continued indefinitely and
Clopidogrel 75mgd for at least 6 weeks Clopidogrel 75mgd for at least 6 weeks
Inclusion criteria for Local ThrombolysisInclusion criteria for Local Thrombolysis a)a) Patients in severe clinical grade on admission Patients in severe clinical grade on admission
with evidence of dural venous sinus with evidence of dural venous sinus thrombosis and restrictive venous outflow on thrombosis and restrictive venous outflow on cerebral angiogramcerebral angiogram
b)b) Patients in clinical grade 3 worsening on Patients in clinical grade 3 worsening on heparin therapy Restriction to venous heparin therapy Restriction to venous outflow was defined as an increase in brain outflow was defined as an increase in brain circulation time gt 12 s delay in the drainage circulation time gt 12 s delay in the drainage of cortical veins with cortical veins hanging of cortical veins with cortical veins hanging in spacein space
Treatment Options for Venous Thrombosis
CT Grading for Venous ThrombosisCT Grading for Venous Thrombosis Grade I no parenchymal change Grade I no parenchymal change
(hyperdense (hyperdense sinuses cortical veins empty sinuses cortical veins empty delta sign)delta sign)
Grade II non hemorrhagic venous infarct Grade II non hemorrhagic venous infarct without mass effect without mass effect
Grade III non-hemorrhagic infarct with Grade III non-hemorrhagic infarct with mass effectmass effect
Grade IV hemorrhagic venous infarct (max Grade IV hemorrhagic venous infarct (max diameter lt 3 cm) with no mass effectdiameter lt 3 cm) with no mass effect
Grade V hemorrhagic venous infarct (max Grade V hemorrhagic venous infarct (max diameter gt 3 cm) with mass effect diameter gt 3 cm) with mass effect
Local ThrombolysisLocal Thrombolysis
Femoral Jugular access was secured and a guiding Femoral Jugular access was secured and a guiding catheter was placed in the jugular bulb catheter was placed in the jugular bulb Mechanical Mechanical clot maceration clot maceration was done with the guidewire was done with the guidewire following which a microcatheter (was navigated and following which a microcatheter (was navigated and placed in the thrombosed segment of sinus confirmed placed in the thrombosed segment of sinus confirmed on a selective venogram on a selective venogram
Urokinase infusion Bolus dose of 2-6 lacs followed Urokinase infusion Bolus dose of 2-6 lacs followed by 60000 to 100000 units per hour along with by 60000 to 100000 units per hour along with periodic check venogram Along with maintenance periodic check venogram Along with maintenance systemic infusion of Heparinsystemic infusion of Heparin Other agents such as Other agents such as streptokinase altepase or rTPAstreptokinase altepase or rTPA can be also used can be also used
After thrombolysis patient should subjected to oral After thrombolysis patient should subjected to oral anticoagulation for six monthsanticoagulation for six months
Low-molecular-weight Low-molecular-weight heparinheparin
PharmacologyPharmacologyLMWH as its name suggests is a glycosaminoglycan that is approximatelyLMWH as its name suggests is a glycosaminoglycan that is approximately
one third the molecular weight of UFH It is derived from UFH through one third the molecular weight of UFH It is derived from UFH through variousvarious
depolymerization processes LMWH binds to antithrombin which in turn depolymerization processes LMWH binds to antithrombin which in turn
Neutralizes actors Xa and IIa Because LMWH lacks many of the longer Neutralizes actors Xa and IIa Because LMWH lacks many of the longer chains chains
required for binding to thrombin it has less ability to neutralize thrombin required for binding to thrombin it has less ability to neutralize thrombin
relativeto its ability to neutralize factor Xa LMWH also has less relativeto its ability to neutralize factor Xa LMWH also has less nonspecific nonspecific
binding to other proteins There is greater bioavailability with more binding to other proteins There is greater bioavailability with more predictable predictable
pharmacokinetics that eliminates the need for monitoring The smaller pharmacokinetics that eliminates the need for monitoring The smaller size also size also
allows for enhanced subcutaneous absorption when compared with UFHallows for enhanced subcutaneous absorption when compared with UFH
Three LMWH preparations are Three LMWH preparations are currently approved for use in the currently approved for use in the United States (1) enoxaparin (2) United States (1) enoxaparin (2) dalteparin and (3) tinzaparin dalteparin and (3) tinzaparin
They are all administered They are all administered subcutaneously at intervals of either subcutaneously at intervals of either once or twice daily for both once or twice daily for both prophylaxis and treatment dosesprophylaxis and treatment doses
Few Experiences of Few Experiences of ThrombolysisThrombolysis
Vickey 25 Yrs male patient presented Vickey 25 Yrs male patient presented with 12with 12thth day HO severe headache with day HO severe headache with right sided hemiplegiaright sided hemiplegia
MRI shows thrombosis of the superior MRI shows thrombosis of the superior sagittal left transverse left sigmoid sagittal left transverse left sigmoid sinuses and cortical veins in the fronto-sinuses and cortical veins in the fronto-parietal regions with eo haemorrhagic parietal regions with eo haemorrhagic infarct in the left cerebral hemisphere infarct in the left cerebral hemisphere with mass effect( Grade ndashV)with mass effect( Grade ndashV)
Sashi Srivastava 64 yrs FSashi Srivastava 64 yrs F In a follow up case of MRD with infra-renal In a follow up case of MRD with infra-renal
aortic abdominal and bilateral renal artery aortic abdominal and bilateral renal artery thrombosis renal angiogram shows filling thrombosis renal angiogram shows filling defects in the right Renal artery defects in the right Renal artery
Initially Renal angioplasty was done Initially Renal angioplasty was done Following angioplasty few thrombi are seem Following angioplasty few thrombi are seem to extends into the segmental branches and to extends into the segmental branches and causing blockage So Thrombolysis was causing blockage So Thrombolysis was plane to dissolve the run-out thrombi with plane to dissolve the run-out thrombi with urokinase urokinase
Rakesh 34yrsMRakesh 34yrsM Left SFA pseudoaneurysm with Left SFA pseudoaneurysm with
Covered stent placementCovered stent placement Pre operative antiplatelets with post Pre operative antiplatelets with post
procedure heparin Tirofiban procedure heparin Tirofiban followed by aspirin and clopidogrel followed by aspirin and clopidogrel were usedwere used
IAT may be a treatment option for selected patients IAT may be a treatment option for selected patients Possible selection criteria include Possible selection criteria include
presentation between 3 and 6 hours from symptom onsetpresentation between 3 and 6 hours from symptom onset major cerebral artery occlusion major cerebral artery occlusion severe neurologic deficits severe neurologic deficits high risk of systemic hemorrhage with IV rt-PA (eg recent high risk of systemic hemorrhage with IV rt-PA (eg recent
surgery) surgery) The MERCI (Mechanical Embolus Removal in Cerebral The MERCI (Mechanical Embolus Removal in Cerebral
Ischemia) retrievalIschemia) retrieval system system
Has been FDA-approved for recanalizing acutely occluded Has been FDA-approved for recanalizing acutely occluded cerebral arteries cerebral arteries
In the Multi-MERCI study patients who did not improve In the Multi-MERCI study patients who did not improve immediately after IV rt-PA underwent mechanical immediately after IV rt-PA underwent mechanical embolectomy within 8 hours of symptom onset embolectomy within 8 hours of symptom onset
Partial or complete recanalization occurred in 74 of Partial or complete recanalization occurred in 74 of patientspatients
with a symptomatic intracerebral hemorrhage (sICH) rate of with a symptomatic intracerebral hemorrhage (sICH) rate of 67 67
Mechanical embolectomy with the MERCI retriever may be a Mechanical embolectomy with the MERCI retriever may be a feasible and safe option for patients after IV rt-PAfeasible and safe option for patients after IV rt-PA
Penumbra stroke systemPenumbra stroke system This device combines two methods of clot This device combines two methods of clot
extraction aspiration and mechanical extraction aspiration and mechanical extraction extraction
First the clot is aspirated then a thrombus First the clot is aspirated then a thrombus removal ring can be used if necessary to removal ring can be used if necessary to remove remaining clot remove remaining clot
successful recanalizing 82successful recanalizing 82 Bridging therapyBridging therapy
06 mgkg IV rt-PA followed by IAT with IA rt-06 mgkg IV rt-PA followed by IAT with IA rt-PA (up to 20 mg)PA (up to 20 mg)
achieved a higher recanalization rateachieved a higher recanalization rate
Criteria for thrombolysis with rTPACriteria for thrombolysis with rTPA
Inclusion criteriaInclusion criteria Clinical signs and symptoms consistent with ischemic Clinical signs and symptoms consistent with ischemic
strokestroke Patient last seen normal within 3 hoursPatient last seen normal within 3 hours Measurable neurologic deficitMeasurable neurologic deficit
Exclusion criteriaExclusion criteria Any hemorrhage on neuroimaging (CT or MRI)Any hemorrhage on neuroimaging (CT or MRI) Symptoms suggestive of subarachnoid hemorrhageSymptoms suggestive of subarachnoid hemorrhage Seizure at stroke onset that is thought to contribute to Seizure at stroke onset that is thought to contribute to
neurologic deficitneurologic deficit Hypodensity greater than one third cerebral hemisphere Hypodensity greater than one third cerebral hemisphere
on CTon CT SBP greater than 185 mm Hg or DBP greater than 110 SBP greater than 185 mm Hg or DBP greater than 110
mm Hgmm Hg International normalized ratio (INR) greater than 17International normalized ratio (INR) greater than 17
Ischemic Stroke Ischemic Stroke Treatment ndash 2006Treatment ndash 2006
IV tissue plasminogen activator (tPA)IV tissue plasminogen activator (tPA) ndash ndash Only FDA-approved acute stroke drugOnly FDA-approved acute stroke drug ndash ndash 3 hour treatment window3 hour treatment window
MERCI - Concentric clot retrieval MERCI - Concentric clot retrieval devicedevice ndash ndash Rescue therapy - approved 2004Rescue therapy - approved 2004 ndash ndash Device approval (not outcomes-based)Device approval (not outcomes-based)
Off label approachesOff label approaches ndash ndash IV tPA after 3 hoursIV tPA after 3 hours ndash ndash IV-IA tPA sequential strategiesIV-IA tPA sequential strategies ndash ndash IA tPA clot angioplasty fragmentationIA tPA clot angioplasty fragmentation ndash ndash Ultrasound-assisted tPA lysisUltrasound-assisted tPA lysis
rt-PA Trials NINDSrt-PA Trials NINDS
Acute stroke - 624 patientsAcute stroke - 624 patients Treat within 3 hrsTreat within 3 hrs Intravenous 09 mgkg rt-PA vs placeboIntravenous 09 mgkg rt-PA vs placebo Hemorrhage 64 tPA 06 placeboHemorrhage 64 tPA 06 placebo Neurologic recovery better with tPA 30 Neurologic recovery better with tPA 30
more like to have minimal or no disabilitymore like to have minimal or no disability
First proven approved treatment for First proven approved treatment for strokestroke
Limitations of tPALimitations of tPA Only 4 of acute strokes receive tPAOnly 4 of acute strokes receive tPA (Kleindorfer et al Stroke 2004 35 e27-e29)(Kleindorfer et al Stroke 2004 35 e27-e29)
Only 22 of patients present within 3 hoursOnly 22 of patients present within 3 hours1048707 1048707 51 of these ineligible due to51 of these ineligible due to
bull bull Mild severityMild severity bull bull Medical or surgical historyMedical or surgical history bull bull Blood testsBlood tests
Sustained recanalization only 13Sustained recanalization only 13 (Alexandrov et al NEJM 2004 351 2170-8)(Alexandrov et al NEJM 2004 351 2170-8)
Concern for hemorrhageConcern for hemorrhage tPA potentiates apoptotic injury tPA potentiates apoptotic injury (Liu et al Nature Med 2004 101379-83)(Liu et al Nature Med 2004 101379-83)
PROACT II IA Lysis TrialPROACT II IA Lysis Trial Baseline 24 hours 8 days
Baseline 60 minutes 120 minutes
9mg IAProurokinase
Desmoteplase Trials DEDAS Desmoteplase Trials DEDAS DIASDIAS
Trial OverviewTrial Overview Double blind randomized placebo Double blind randomized placebo
controlled trialscontrolled trials IV delivery 3-9 hour time windowIV delivery 3-9 hour time window Plasminogen activator ndash from Plasminogen activator ndash from vampire bat vampire bat
salivasaliva Selection based on PWI-DWI MismatchSelection based on PWI-DWI Mismatch
MRI InclusionMRI Inclusion PWI defect at least 2 cm AND ~20 larger PWI defect at least 2 cm AND ~20 larger
than DWIthan DWI PWI should be obvious even visible on PWI should be obvious even visible on
raw imagesraw imagesMRI ExclusionMRI Exclusion
DWI gt 13 MCADWI gt 13 MCA MRA ICA occlusionMRA ICA occlusion
Desmoteplase ndash DIAS Desmoteplase ndash DIAS ResultsResults
Mechanical Thrombolysis Mechanical Thrombolysis devicesdevices
mechanical thrombolysis potentially extends the treatment mechanical thrombolysis potentially extends the treatment window because they act promptly at the site of the thrombuswindow because they act promptly at the site of the thrombus
The devices can retrieve large clots that pharmaceutical agents The devices can retrieve large clots that pharmaceutical agents may not successfully lysemay not successfully lyse
Patients treated with IV tPA may be considered for treatment of Patients treated with IV tPA may be considered for treatment of residual clot with some of these devicesresidual clot with some of these devices
suction-creating saline jets suction-creating saline jets laser energy ultrasound laser energy ultrasound a corkscrew apparatus to treat strokesa corkscrew apparatus to treat strokes The AngioJet systemThe AngioJet system uses saline jets that are directed back into the catheter to uses saline jets that are directed back into the catheter to
create a low-pressure zone around the catheter tip inducing create a low-pressure zone around the catheter tip inducing suction suction
The clot is pulled into the exhaust lumen and removed from the The clot is pulled into the exhaust lumen and removed from the vessel Although US Food and Drug Administration (FDA) has vessel Although US Food and Drug Administration (FDA) has approved this device for use in arteriovenous dialysis grafts and approved this device for use in arteriovenous dialysis grafts and fistulae and for the treatment of coronary arteries saphenous fistulae and for the treatment of coronary arteries saphenous vein grafts and peripheral vessels clinical trials for the vein grafts and peripheral vessels clinical trials for the treatment of acute stroke are no longer in progress treatment of acute stroke are no longer in progress
Most devices are used in cerebral vessels that 2-5 mm
The Latis laser device The Latis laser device used laser energy to ablate clots used laser energy to ablate clots Arteries 2-5 mm in diameter could be Arteries 2-5 mm in diameter could be
treated including the ICA M1 or M2 treated including the ICA M1 or M2 branch of the MCA A1 branch of the branch of the MCA A1 branch of the anterior cerebral artery (ACA) basilar anterior cerebral artery (ACA) basilar artery posterior cerebral artery (PCA) artery posterior cerebral artery (PCA) and vertebral and vertebral
Patients could receive treatment as late Patients could receive treatment as late as 8 hours after symptom onset in the as 8 hours after symptom onset in the anterior circulation and within 24 hours in anterior circulation and within 24 hours in the posterior circulation the posterior circulation
Endovascular Photo Acoustic Endovascular Photo Acoustic Recanalization (EPAR) Recanalization (EPAR)
A laser power source generated energy for the A laser power source generated energy for the systemsystem
The energy was delivered by means of The energy was delivered by means of fiberoptics to the tip of the catheter at the fiberoptics to the tip of the catheter at the treatment sitetreatment site
Absorption of laser light by darkly pigmented Absorption of laser light by darkly pigmented materials (ie the clot) occurred inside the 1-mm materials (ie the clot) occurred inside the 1-mm catheter tipcatheter tip
the system was designed to minimize scattering the system was designed to minimize scattering of laser light of laser light
Absorption converted photo energy to acoustic Absorption converted photo energy to acoustic energy which then emulsified the clot inside the energy which then emulsified the clot inside the catheter tip catheter tip
EKOS ultrasound( the EKOS ultrasound( the Ultrasound Thrombolytic Ultrasound Thrombolytic
Infusion Catheter) Infusion Catheter) combines the use of a distal ultrasound transducer with combines the use of a distal ultrasound transducer with
infusion of a thrombolytic agent through the infusion of a thrombolytic agent through the microcathetermicrocatheter
Ultrasound changes the structure of the clot to Ultrasound changes the structure of the clot to temporarily increase its permeability while providing an temporarily increase its permeability while providing an acoustic pressure gradient to move the drug into the clot acoustic pressure gradient to move the drug into the clot to speed its dissolution to speed its dissolution
The EKOS catheter is placed in the proximal portion of the The EKOS catheter is placed in the proximal portion of the clot clot
After a 2-mg bolus of tPA was injected through the After a 2-mg bolus of tPA was injected through the catheter catheter
the patient received a continuous infusion of IA tPA 03 the patient received a continuous infusion of IA tPA 03 mgmin to a maximum of 20 mg and simultaneous mgmin to a maximum of 20 mg and simultaneous ultrasound transmission for as long as 60 minutes ultrasound transmission for as long as 60 minutes
One patient was treated with a total of 4 units of One patient was treated with a total of 4 units of recombinant reteplase (Retavase) hand-injected over 60 recombinant reteplase (Retavase) hand-injected over 60 minutes minutes
Penumbra system Penumbra system The Penumbra system (Penumbra Inc) provides a dual The Penumbra system (Penumbra Inc) provides a dual
approach to clot extraction using aspiration followed by approach to clot extraction using aspiration followed by clot retrieval with a ring device if needed clot retrieval with a ring device if needed
Mechanical Embolus Removal in Cerebral Ischemia Mechanical Embolus Removal in Cerebral Ischemia (MERCI)(MERCI)
a corkscrew-like apparatus to remove blood clots from a corkscrew-like apparatus to remove blood clots from the brain in patients experiencing an ischemic stroke the brain in patients experiencing an ischemic stroke
The corkscrew itself resides in the catheter tip which The corkscrew itself resides in the catheter tip which shields it from the wall of the vessel until it is ready to be shields it from the wall of the vessel until it is ready to be burrowed into the clot Once lodged in the clot the device burrowed into the clot Once lodged in the clot the device and clot are withdrawn from the vessel and clot are withdrawn from the vessel
Snarelike devicesSnarelike devices Snares such as the Neuronet snare (Guidant Snares such as the Neuronet snare (Guidant
Endovascular Santa Clara CA) have been developed Endovascular Santa Clara CA) have been developed specifically for use in the treatment of strokes specifically for use in the treatment of strokes
These devices are simple in design and do not require the These devices are simple in design and do not require the clot to be amenable to emulsification clot to be amenable to emulsification
X-Sizer deviceX-Sizer device a device with small moving blades at the a device with small moving blades at the
catheter tip catheter tip This device the X-Sizer device (EndiCor Medical This device the X-Sizer device (EndiCor Medical
San Clemente CA) can be used to excise the San Clemente CA) can be used to excise the thrombus and aspirate it thrombus and aspirate it
The device was being evaluated in randomized The device was being evaluated in randomized studies of coronary vessels and in a registry of studies of coronary vessels and in a registry of patients with acute myocardial infarctionpatients with acute myocardial infarction
Although the manufacturer had modified the Although the manufacturer had modified the device for use in cerebral vessels a safety and device for use in cerebral vessels a safety and feasibility study was indefinitely suspended after feasibility study was indefinitely suspended after only 1 patient was treated with the device in only 1 patient was treated with the device in Europe Europe
Suction thrombectomySuction thrombectomy This method of mechanical thrombolysis is one of the This method of mechanical thrombolysis is one of the
simplestsimplest In this readily available technique suction is applied with In this readily available technique suction is applied with
a syringe to remove thrombus in the ICA a syringe to remove thrombus in the ICA It requires no other devicesIt requires no other devices A catheter with a large inner diameter (Brite Tip Cordis A catheter with a large inner diameter (Brite Tip Cordis
Corporation Miami FL) was placed in the symptomatic Corporation Miami FL) was placed in the symptomatic vessel and navigated over a guidewire into the thrombusvessel and navigated over a guidewire into the thrombus
A 60-mL syringe was used to aspirate the thrombus A 60-mL syringe was used to aspirate the thrombus Each patient required angioplasty and stenting of carotid Each patient required angioplasty and stenting of carotid
bifurcation stenosis and received daily aspirin and bifurcation stenosis and received daily aspirin and ticlopidine after the procedure No complications ticlopidine after the procedure No complications occurred occurred
Summary Acute Stroke Summary Acute Stroke ImagingImaging
PhysiologyPhysiology importance collaterals importance collaterals
ndash ndashGrowing role for perfusion Growing role for perfusion assessmentassessment
tPAtPA guidelines amp limitations guidelines amp limitations Signs on CT amp MRSigns on CT amp MR follow physiology follow physiology Stroke trialsStroke trials PWI-DWI mismatch PWI-DWI mismatch
ndash ndashTreat based on physiology not timeTreat based on physiology not time ProtocolsProtocols should be fast and should be fast and
comprehensivecomprehensive
Monitoring of heparin Monitoring of heparin
Subcutenous Subcutenous no monitoring requiredno monitoring required Intravenous Intravenous
Partial thromboplastin time (PTT normal value Partial thromboplastin time (PTT normal value ~30sec) ~30sec)
Activated clotting time ( ACT normal value ~90-Activated clotting time ( ACT normal value ~90-120sec)120sec)
Daily or more frequent if PTT ACT variesDaily or more frequent if PTT ACT varies
Mechanism Mechanism ndash measures intrinsic pathwayndash measures intrinsic pathway Therapeutic goal Therapeutic goal 2-25 times normal control value 2-25 times normal control value
ACT or aPTTACT or aPTT
Determine when to pull the femoral sheath Determine when to pull the femoral sheath Premature sheath pull can lead to bleedingPremature sheath pull can lead to bleeding Delayed removal can increase time in ICUDelayed removal can increase time in ICU Target set Target set at each siteat each site
ACT targets range from 150 ndash 220 ACT targets range from 150 ndash 220 secondsseconds
aPTT targets range from 40 ndash 70 seconds aPTT targets range from 40 ndash 70 seconds
During neuroangiography-During neuroangiography- Recommended therapeutic range of heparin in Recommended therapeutic range of heparin in
plasma is 02-08 uml ( corresponding to aPTT plasma is 02-08 uml ( corresponding to aPTT ACT values 15-25 times the baseline values)ACT values 15-25 times the baseline values)
Dose In diagnostic angiography bolus dose of Dose In diagnostic angiography bolus dose of 2500 iu is used followed by 1000 iu hour2500 iu is used followed by 1000 iu hour
Bolus dose is Bolus dose is 60 ukg to maintain the therapeutic 60 ukg to maintain the therapeutic range range If procedure continues for more than 75 If procedure continues for more than 75 minutes additional dose is required ( half of the minutes additional dose is required ( half of the initial dose for another 75 minutes) initial dose for another 75 minutes)
(AJNR 199415 51-54)
Mechanisms of HIT( Mechanisms of HIT( Heparin Heparin induced Thrombocytopeniainduced Thrombocytopenia))
Type 1Type 1 Fall in platelet count occurs within the first two Fall in platelet count occurs within the first two
days after heparin initiation often returns to days after heparin initiation often returns to normal with continued heparin administration normal with continued heparin administration and is of no clinical consequence and is of no clinical consequence
The mechanism of the thrombocytopenia is non-The mechanism of the thrombocytopenia is non-immune and appears to be due to a direct effect of immune and appears to be due to a direct effect of heparin on platelet activationheparin on platelet activation
Type 2Type 2 Approximately 03 to 3 percent of patients Approximately 03 to 3 percent of patients
receiving heparin develop an immune receiving heparin develop an immune thrombocytopenia mediated by antibodies to a thrombocytopenia mediated by antibodies to a heparin-platelet factor 4 complex heparin-platelet factor 4 complex
(AJNR 28155-158 2007)
Treatment of heparin-induced Treatment of heparin-induced thrombocytopeniathrombocytopenia
When HIT is diagnosed it is important to When HIT is diagnosed it is important to stop heparin mainly in type 2 and to avoid stop heparin mainly in type 2 and to avoid the use of LMWH the use of LMWH
Because of the increased risk of thrombosis Because of the increased risk of thrombosis however continuation of an anticoagulant however continuation of an anticoagulant must be considered must be considered
The drugs currently approved for the The drugs currently approved for the treatment of HIT in the United States are treatment of HIT in the United States are direct thrombin inhibitors argatroban and direct thrombin inhibitors argatroban and lepirudinlepirudin
WARFARIN MECHANISM OF ACTIONWARFARIN MECHANISM OF ACTION
Inactive factors II VII IX and X
Proteins S and C
Active factors II VII IX and X
Proteins S and C
Vitamin K epoxide
Vitamin K reduced
WA
RF
AR
IN
Prevents the reduction of vitamin K which is essential for Prevents the reduction of vitamin K which is essential for activation of certain factorsactivation of certain factors
Has no effect on previously formed thrombusHas no effect on previously formed thrombus
Antagonist is Vit KAntagonist is Vit K
OPTIMIZING WARFARIN THERAPYOPTIMIZING WARFARIN THERAPY
Use of large loading dose may lead to hemorrhage and Use of large loading dose may lead to hemorrhage and other complicationsother complications
Initial dose 2-5 mg once dailyInitial dose 2-5 mg once daily Maintenance dose 2-10 mg once dailyMaintenance dose 2-10 mg once daily If Immediate anticoagulation is requiredIf Immediate anticoagulation is required Heparin IS Heparin IS
started along with loading dose of warfarin 10 mg started along with loading dose of warfarin 10 mg Heparin is usually discontinued after 4-5 days Heparin is usually discontinued after 4-5 days Before Before discontinuing INR should be in therapeutic range for 2 discontinuing INR should be in therapeutic range for 2 consecutive daysconsecutive days
Daily monitoring of INR until INR is in therapeutic Daily monitoring of INR until INR is in therapeutic range then 3 times weekly for 1-2 weeks then less often range then 3 times weekly for 1-2 weeks then less often (every 4 to 6 weeks)(every 4 to 6 weeks)
OPTIMAL THERAPEUTIC RANGEOPTIMAL THERAPEUTIC RANGE
IndicationIndication INRINR
Prophylaxis of venous Prophylaxis of venous thromboembolismthromboembolism
20-3020-30
Treatment of venous Treatment of venous thromboembolismthromboembolism
20-3020-30
Atrial fibrillationAtrial fibrillation 20-3020-30
Mitral valve stenosisMitral valve stenosis 20-3020-30
Heart valve replacementHeart valve replacement
Bioprosthetic valveBioprosthetic valve
Mechanical valveMechanical valve
20-3020-30
25-3525-35
Myocardial infarctionMyocardial infarction 20-3020-30
25-35 25-35 (high risk patients)(high risk patients)
FACTORS INFLUENCING DOSE RESPONSEFACTORS INFLUENCING DOSE RESPONSE
Poor patient compliancePoor patient compliance Concomitant medicationsConcomitant medications Levels of dietary vitamin KLevels of dietary vitamin K Alcohol Inaccurate lab testingAlcohol Inaccurate lab testing Inaccurate lab testingInaccurate lab testing Hepatic dysfunctionHepatic dysfunction FeverFever
Contraindication for WarfarinContraindication for Warfarin
Hypersensitivity to warfarinHypersensitivity to warfarin Hemorrhagic tendencyHemorrhagic tendency Condition with risk of hemorrhageCondition with risk of hemorrhage Inadequate laboratory techniquesInadequate laboratory techniques Protein C amp S deficiencyProtein C amp S deficiency Vitamin K deficiencyVitamin K deficiency
SIDE EFFECTSSIDE EFFECTS
Hemorrhage Hemorrhage Skin necrosisSkin necrosis Purple toe syndromePurple toe syndrome Microembolization Microembolization TeratogenecityTeratogenecity Agranulocytosis leukopenia Agranulocytosis leukopenia Diarrhoeanausea anorexiaDiarrhoeanausea anorexia
MONITORING OF WARFARIN THERAPYMONITORING OF WARFARIN THERAPY
Prothrombin timeProthrombin time PT ratioPT ratio INR (International Normalized Ratio)INR (International Normalized Ratio)
PROTHROMBIN TIME (PT)PROTHROMBIN TIME (PT)
Time required for blood to coagulate Time required for blood to coagulate is called PT ( normal value ~10sec)is called PT ( normal value ~10sec)
Performed by adding a mixture of Performed by adding a mixture of calcium and thromboplastin to calcium and thromboplastin to citrated plasmacitrated plasma
As a control a normal blood sample is As a control a normal blood sample is tested continuouslytested continuously
PT ratio (PTR) = PT ratio (PTR) = Patientrsquos PTPatientrsquos PT Control PTControl PT
PROBLEMS WITH PTPTRPROBLEMS WITH PTPTR
Thromboplastins are extracts from Thromboplastins are extracts from brain lung or placenta of animalsbrain lung or placenta of animals
Thromboplastins from various Thromboplastins from various manufacturers differ in their manufacturers differ in their sensitivity to prolong PTsensitivity to prolong PT
May result in false control of May result in false control of anticoagulant therapyanticoagulant therapy
INTERNATIONAL NORMALISED RATIO (INR)INTERNATIONAL NORMALISED RATIO (INR)
International Normalized Ratio (INR) International Normalized Ratio (INR) a PT test with a a PT test with a formula based ratio to normalize the often variable source formula based ratio to normalize the often variable source of tissue factor (human rabbit recombinant)of tissue factor (human rabbit recombinant)
INR = [PTINR = [PTptpt] ] ISIISI
[PT[PTRefRef]]
PTPTpt pt ndash prothrombin time of patientndash prothrombin time of patient
PTPTRef Ref ndash prothrombin time of normal pooled samplendash prothrombin time of normal pooled sample
ISI ndash International Sensitivity IndexISI ndash International Sensitivity Index
Warfarin is given orally and titrated to achieve an INR of Warfarin is given orally and titrated to achieve an INR of typically 20 ndash 30typically 20 ndash 30
Heparin versus WarfarinHeparin versus Warfarin
Drug ActionMechan-ism
Moni-toring
Effective
HeparinDirect
Inhibition ofThrombin
ATIIIcofactor
APTTACT
Immediate
WarfarinDecreasesProductionof factors
Vitamin K PTDelay
3-5 days
INR
Recanalization or Antegrade Recanalization or Antegrade Reperfusion StrategiesReperfusion Strategies
Recanalization strategies focus on removing Recanalization strategies focus on removing andor dissolving the occlusive thrombus to re-andor dissolving the occlusive thrombus to re-establish antegrade flow Strategies may be establish antegrade flow Strategies may be classified into 7 different categories on the classified into 7 different categories on the basis of their primary mechanism of action basis of their primary mechanism of action 1) 1) IV andor intraarterial thrombolysis (IAT) IV andor intraarterial thrombolysis (IAT) 2) endovascular thrombectomy2) endovascular thrombectomy3) endovascular thromboaspiration 3) endovascular thromboaspiration 4) endovascular mechanical thrombus disruption or 4) endovascular mechanical thrombus disruption or
thromborrhexisthromborrhexis5) 5) transcranial or endovascular augmented transcranial or endovascular augmented
fibrinolysis fibrinolysis 6) endovascular thrombus entrapment and 6) endovascular thrombus entrapment and 7) temporary endovascular bypass7) temporary endovascular bypass
IAT in Acute Ischemic StrokeIAT in Acute Ischemic Stroke
IAT advantages over IV thrombolysisIAT advantages over IV thrombolysis Coaxial microcatheter techniques the occluded intracranial Coaxial microcatheter techniques the occluded intracranial
vessel is directly accessible and the fibrinolytic agent can be vessel is directly accessible and the fibrinolytic agent can be infused directly into the thrombusinfused directly into the thrombus
This permits a smaller dose of fibrinolytic agent to reach a This permits a smaller dose of fibrinolytic agent to reach a higher local concentration than that reached by systemic higher local concentration than that reached by systemic infusioninfusion
Allows more complete recanalization with lower total doses of Allows more complete recanalization with lower total doses of thrombolytic thrombolytic
With the smaller dose complications from systemic fibrinolytic With the smaller dose complications from systemic fibrinolytic effects including intracranial hemorrhage (ICH) can effects including intracranial hemorrhage (ICH) can theoretically be reduced theoretically be reduced
Treatment window for endovascular techniques can be Treatment window for endovascular techniques can be extended beyond the typical IV window of 3 hours extended beyond the typical IV window of 3 hours
IA techniques have led to higher recanalization rates than IV IA techniques have led to higher recanalization rates than IV thrombolysisthrombolysis
Major disadvantagesMajor disadvantages Relative complexity of the procedure the level Relative complexity of the procedure the level
of required technical expertise and its of required technical expertise and its relatively low availability relatively low availability
Delays in initiating treatmentDelays in initiating treatment InvasiveInvasive
ThrombolyticsThrombolytics
Plasminogen activators
Fibrinolytics
1 Plasminogen Activators 1 Plasminogen Activators drugs act by converting the inactive proenzyme drugs act by converting the inactive proenzyme plasminogen into the active enzyme plasmin Plasmin plasminogen into the active enzyme plasmin Plasmin digests fibrinogen fibrin monomers and cross-linked digests fibrinogen fibrin monomers and cross-linked fibrin (as found in a thrombus) into fibrin degradation fibrin (as found in a thrombus) into fibrin degradation productsproducts
First-Generation Agents First-Generation Agents StreptokinaseStreptokinase a protein derived from group C a protein derived from group C
szlig-hemolytic streptococci has a half-life of 16ndashszlig-hemolytic streptococci has a half-life of 16ndash90 minutes and low fibrin specificity This drug 90 minutes and low fibrin specificity This drug proved to have a very narrow therapeutic proved to have a very narrow therapeutic window and significant rates of ICH and window and significant rates of ICH and systemic hemorrhage18systemic hemorrhage18
UrokinaseUrokinase is a serine protease with a plasma is a serine protease with a plasma half life of 14 minutes and low fibrin specificity half life of 14 minutes and low fibrin specificity
The urokinase dose used in cerebral IAT has The urokinase dose used in cerebral IAT has ranged from 002 to 2 X106unitsranged from 002 to 2 X106units
Second-Generation Agents Second-Generation Agents Alteplase (rtPA) Alteplase (rtPA)
is a serine is a serine protease with a plasma half-life of 35 protease with a plasma half-life of 35 minutes and a high degree of fibrin affinity and minutes and a high degree of fibrin affinity and specificity specificity
Dose used in cerebral IAT has ranged between 20 Dose used in cerebral IAT has ranged between 20 and 60 mgand 60 mg
Disadvantages of alteplase include its relatively short Disadvantages of alteplase include its relatively short halflife and limited penetration into the clot matrix halflife and limited penetration into the clot matrix because of strong binding with surface fibrin which because of strong binding with surface fibrin which could delay recanalization and increase the risk of could delay recanalization and increase the risk of recurrent occlusion recurrent occlusion
Prourokinase (r-prourokinase) Prourokinase (r-prourokinase) is the proenzyme precursor of urokinase is the proenzyme precursor of urokinase T12 of 7 minutes and high fibrin specificity T12 of 7 minutes and high fibrin specificity
Third-Generation AgentsThird-Generation Agents
ReteplaseReteplase is a structurally modified is a structurally modified form of alteplase form of alteplase
with a longer half-life (15ndash18 minutes) In with a longer half-life (15ndash18 minutes) In addition it does not bind as highly to fibrin addition it does not bind as highly to fibrin unbound reteplase can thus theoretically better unbound reteplase can thus theoretically better penetrate the clot and potentially penetrate the clot and potentially improve in improve in vivo fibrinolytic activity vivo fibrinolytic activity
TenecteplaseTenecteplase is another modified form of rtPA with a longer is another modified form of rtPA with a longer
half-life (17 minutes)half-life (17 minutes) greater fibrin specificity and greater greater fibrin specificity and greater
resistance to plasminogen activator inhibitor-1 resistance to plasminogen activator inhibitor-1 IV tenecteplase in acute ischemic stroke IV tenecteplase in acute ischemic stroke
suggest that the drug is safe and promisingsuggest that the drug is safe and promising
Newer plasminogen activatorNewer plasminogen activator
DesmoteplaseDesmoteplase is a genetically engineered is a genetically engineered version of the clot-dissolving factor version of the clot-dissolving factor
found in the saliva found in the saliva of the vampire bat Desmodus rotundusof the vampire bat Desmodus rotundus moremore potent and more selective for fibrin-bound potent and more selective for fibrin-bound
plasminogen than any other known plasminogen plasminogen than any other known plasminogen activatoractivator
Unlike tissue plasminogen activator (tPA) desmoteplase Unlike tissue plasminogen activator (tPA) desmoteplase is not activated by fibrinogen or -amyloid proteins is not activated by fibrinogen or -amyloid proteins factors that may exacerbate the risk for ICH factors that may exacerbate the risk for ICH
The effect of IV administration of desmoteplase 3ndash9 The effect of IV administration of desmoteplase 3ndash9 hours after symptom onset in patients with stroke who hours after symptom onset in patients with stroke who present with mismatch on MR imaging or CT perfusion present with mismatch on MR imaging or CT perfusion
3 DefibrinogenatingFibrinogenolytic 3 DefibrinogenatingFibrinogenolytic Agents Agents
AncrodAncrod(Viprinex)(Viprinex) is is the purified fraction of the Malayan pit viper venomthe purified fraction of the Malayan pit viper venom It acts by directly cleaving and inactivating fibrinogen It acts by directly cleaving and inactivating fibrinogen
and thus indirectly promoting anticoagulation and thus indirectly promoting anticoagulation The reduction in the blood levels of fibrinogen also The reduction in the blood levels of fibrinogen also
leads to a reduced blood viscosity which may improve leads to a reduced blood viscosity which may improve blood flow to the affected areas of the brain blood flow to the affected areas of the brain
In the Stroke Treatment with Ancrod Trial 500 In the Stroke Treatment with Ancrod Trial 500 patients with stroke presenting within 3 hours of patients with stroke presenting within 3 hours of symptom onset were randomized to receive ancrod (symptom onset were randomized to receive ancrod (n n 248) or a placebo (n 252) Good outcome (Barthel 248) or a placebo (n 252) Good outcome (Barthel Index 95ndash100 at 3 months) was achieved in 4221 Index 95ndash100 at 3 months) was achieved in 4221 and 344 of the patients respectively and 344 of the patients respectively
2 Direct Fibrinolytics2 Direct Fibrinolytics
Microplasmin (Microplasmin (ThromboGenics Heverlee Belgium)ThromboGenics Heverlee Belgium) is a truncated form of plasmin that is more resistant to the effects is a truncated form of plasmin that is more resistant to the effects
of antiplasmin of antiplasmin microplasmin can be used upto 4ndash12 hours after stroke onset microplasmin can be used upto 4ndash12 hours after stroke onset There was no evidence of increased bleeding risk with There was no evidence of increased bleeding risk with
microplasminmicroplasmin
Alfimeprase (Nuvelo San Carlos Calif)Alfimeprase (Nuvelo San Carlos Calif) is a recombinant truncated form of fibrolase a fibrinolytic zinc metalloproteinase is a recombinant truncated form of fibrolase a fibrinolytic zinc metalloproteinase
isolated from the venom of the southern copperhead snake isolated from the venom of the southern copperhead snake It degrades fibrin directly and achieves thrombolysis independent It degrades fibrin directly and achieves thrombolysis independent
of plasmin formationof plasmin formation its thrombolytic activity appears to be localized to the site of its thrombolytic activity appears to be localized to the site of
delivery These properties should theoretically result in faster delivery These properties should theoretically result in faster recanalization and lower hemorrhagic conversion riskrecanalization and lower hemorrhagic conversion risk
Anti-fibrinolyticsAnti-fibrinolytics
to limit fibrinolytic activityto limit fibrinolytic activity -aminocaproic acid (EACA) -aminocaproic acid (EACA) competitively inhibitscompetitively inhibits plasminogen and plasminogen activators from plasminogen and plasminogen activators from
binding to fibrinbinding to fibrin
alpha2-antiplasminalpha2-antiplasmin a serine protease inhibitor that a serine protease inhibitor that neutralizes any free circulating plasminneutralizes any free circulating plasmin
Plasminogen activator inhibitor-1Plasminogen activator inhibitor-1 a serine protease a serine protease inhibitor that inhibits tissue-type plasminogen inhibitor that inhibits tissue-type plasminogen activatoractivator
Glycoprotein (GP) IIbIIIa antagonistsGlycoprotein (GP) IIbIIIa antagonists
such as ReoPro (abciximab) Integrilin such as ReoPro (abciximab) Integrilin (eptifibatide) or Aggrastat (tirofiban) in (eptifibatide) or Aggrastat (tirofiban) in ischemic stroke remains investigational ischemic stroke remains investigational Deshmukh et al38 reported 21 patients with Deshmukh et al38 reported 21 patients with large-vessel occlusion refractory to IAT with large-vessel occlusion refractory to IAT with rtPA who were treated with IV andor IA rtPA who were treated with IV andor IA abciximab eptifibatide or tirofiban abciximab eptifibatide or tirofiban
IA Mechanical Approaches in Acute Ischemic Stroke IA Mechanical Approaches in Acute Ischemic Stroke Mechanical strategies have several advantagesMechanical strategies have several advantages First they lessen and may even preclude the use of chemical First they lessen and may even preclude the use of chemical
thrombolytics in this manner very likely reducing the risk of ICHthrombolytics in this manner very likely reducing the risk of ICH Second by avoiding the use of chemical thrombolytics it is Second by avoiding the use of chemical thrombolytics it is
possible to extend the treatment window beyond the limit of 6ndash8 possible to extend the treatment window beyond the limit of 6ndash8 hours hours
Third mechanically fragmenting a clot increases the surface area Third mechanically fragmenting a clot increases the surface area accessible to fibrinolytic agents and allows inflow of fresh accessible to fibrinolytic agents and allows inflow of fresh plasminogen which in turn may increase the speed of plasminogen which in turn may increase the speed of thrombolysis thrombolysis
Finally clot-retrieval devices may provide faster recanalization Finally clot-retrieval devices may provide faster recanalization
The disadvantages of the mechanical The disadvantages of the mechanical approaches approaches technical difficulty of navigating mechanical technical difficulty of navigating mechanical
devices into the intracranial circulation excessive devices into the intracranial circulation excessive trauma to the vasculature (potentially leading to trauma to the vasculature (potentially leading to vasospasm vessel dissection perforation or vasospasm vessel dissection perforation or rupture) rupture)
fragmented thrombus causing distal embolization fragmented thrombus causing distal embolization into previously unaffected territories into previously unaffected territories
Nevertheless the advantages of mechanical stroke Nevertheless the advantages of mechanical stroke therapy appear to significantly outweigh its therapy appear to significantly outweigh its disadvantages and risksdisadvantages and risks
Contraindications to Thrombolytic Contraindications to Thrombolytic agents agents
Recent thoracic abdominal or Recent thoracic abdominal or intracranial surgeryintracranial surgery
Recent haemorrhagic CVA Head injury Recent haemorrhagic CVA Head injury or neoplasmor neoplasm
Bleeding ulcerBleeding ulcer Anticipated invasive procedures (arterial Anticipated invasive procedures (arterial
punctures biopsies)punctures biopsies) Concurrent hemostatic dysfunctionConcurrent hemostatic dysfunction
Monitoring of thrombolytic Monitoring of thrombolytic therapytherapy
Thrombin time Measures the availability of functional
fibrinogen Normal thrombin time is 10-14 sec Prolonged when fibrinogen level is below
75-100 mgdl
Half Life of ThrombolyticsHalf Life of ThrombolyticsAgent Administration Half Life
Streptokinase IA 60-80min
Urokinase IAIV 9-12min
rTPA IAIV 6min
Abciximab(Reopro) IAIV 12hour
Aspirin POIV 15-20min
Heparin IVSC 60min
Coumadin PO 15-25 days
Anti Platelet DrugsAnti Platelet DrugsDrug Drug Mechanism Mechanism UsesUsesAspirinAspirin Permanently inhibits Permanently inhibits
COX-1 and COX-2COX-1 and COX-2CADCAD
Stroke-TIAsStroke-TIAs
NSAIDsNSAIDs Reversibly inhibits Reversibly inhibits COX-1COX-1
LimitedLimited
DipyridamoleDipyridamole Inhibits PDE increases Inhibits PDE increases cAMPcAMP
TIAsTIAs
ThenopyridinesThenopyridines
(Ticlopidine(Ticlopidine
ClopidrgrelClopidrgrel))
Inhibits ADP Inhibits ADP
PlatAg PlatAg
TIAsStrokeTIAsStroke
CAD PVDCAD PVD
Abciximab (ReoPro)Abciximab (ReoPro)
Eptifibatide (Integrilin)Eptifibatide (Integrilin)
TirofibanTirofiban
GP IIBIIIA InhibitorsGP IIBIIIA Inhibitors
Stroke- TIAs Stroke- TIAs
MonitoringMonitoring
Bleeding timeBleeding time
Optical aggregometryOptical aggregometry
Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay
Bleeding timeBleeding time
Requires a skin incision (usually made on the ear lobe or Requires a skin incision (usually made on the ear lobe or forearm offorearm of
a depth that results in disruption of capillary loops and a depth that results in disruption of capillary loops and small vessels)small vessels)
AdvantagesAdvantages Universally availableUniversally available Relatively simple techniquesRelatively simple techniques Can be performed bedsideCan be performed bedside
DisadvantagesDisadvantages Insensitive inaccurate non-specific techniqueInsensitive inaccurate non-specific technique
Poorly reproducible (as depends on multiple variables)Poorly reproducible (as depends on multiple variables)
Optical aggregometryOptical aggregometry
Gold standard assay for platelet functionGold standard assay for platelet function Agonist induced aggregation is measuredAgonist induced aggregation is measured Different agonist are available for different Different agonist are available for different
agentsagents However require unique expertise and are not However require unique expertise and are not
universally availableuniversally available Aspirin measured with ADP or AA(gt70 Aspirin measured with ADP or AA(gt70
aggregation so resistance)aggregation so resistance) Clopidogrel( ADP gt 90 aggregation means Clopidogrel( ADP gt 90 aggregation means
resistance) resistance)
Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay
Can be performed bed sideCan be performed bed side Different assay devices with different Different assay devices with different
agonist are used for each of different agonist are used for each of different antiplatelet agents antiplatelet agents
For Aspirin AA is used (result is reported as aspirin For Aspirin AA is used (result is reported as aspirin reaction units [ARU] ARUgt 550 indicates non-reaction units [ARU] ARUgt 550 indicates non-responsiveness)responsiveness)
Verify IIbIIIa assay device uses TRAP as agonist for Verify IIbIIIa assay device uses TRAP as agonist for Abciximab and TirofibanAbciximab and Tirofiban
Practical Applications Practical Applications related to specific related to specific
Neurovascular Neurovascular interventionsinterventions
Acute ischemic StrokeAcute ischemic Stroke When an artery occludes neurons are affected When an artery occludes neurons are affected
differently depending upon the amount of residual blood differently depending upon the amount of residual blood flowflow
Normal cerebral blood flow is greater than 50 mL100 Normal cerebral blood flow is greater than 50 mL100 mgminmgmin
Once blood flow decreases to less than 20 mL100 Once blood flow decreases to less than 20 mL100 mgmin infarction occursmgmin infarction occurs
If blood flow decreases to less than 10 mL100 mgmin If blood flow decreases to less than 10 mL100 mgmin irreversible neuronal death occurs rapidly irreversible neuronal death occurs rapidly
Blood flow between 11 and 20 mL100 mgmin is thought Blood flow between 11 and 20 mL100 mgmin is thought to represent the ischemic penumbra an area where the to represent the ischemic penumbra an area where the cells are functionally silent because of ischemia but are cells are functionally silent because of ischemia but are still able to recover if blood flow is restored still able to recover if blood flow is restored
Many acute stroke therapies are targeted toward Many acute stroke therapies are targeted toward restoring flow or function to the ischemic penumbrarestoring flow or function to the ischemic penumbra
Therapeutic window in Therapeutic window in management of acute Ischemic management of acute Ischemic
StrokeStrokeThe early diagnosis of ischemic stroke is critical to the The early diagnosis of ischemic stroke is critical to the
with only a narrow therapeutic window in the first few with only a narrow therapeutic window in the first few hours following stroke ictushours following stroke ictus
Diagnosis in the first 3 hours postictus provides the Diagnosis in the first 3 hours postictus provides the opportunity for intravenous or intraarterial thrombolysis opportunity for intravenous or intraarterial thrombolysis and intra-arterial clot mechanical treatment which and intra-arterial clot mechanical treatment which improve the outcome improve the outcome
Diagnosis in the time period between 3 and 6 hours Diagnosis in the time period between 3 and 6 hours provides an opportunity for intra-arterial thrombolysis provides an opportunity for intra-arterial thrombolysis and mechanical treatment and mechanical treatment
Involvement of the posterior circulation especially the Involvement of the posterior circulation especially the basilar artery is treated by some regardless of time of basilar artery is treated by some regardless of time of onset or up until 12 to 24 hours in some practices This is onset or up until 12 to 24 hours in some practices This is related to the potentially high mortality and morbidity related to the potentially high mortality and morbidity associated with basilar artery thrombosisassociated with basilar artery thrombosis
Infarct evaluation on angiographyInfarct evaluation on angiography(CT angiography and catheter (CT angiography and catheter
angiography)angiography)CTA is an excellent first-line examination for CTA is an excellent first-line examination for
evaluation of the head and neck arteries evaluation of the head and neck arteries In comparison with catheter angiography In comparison with catheter angiography
what it gives up in resolution and dynamic what it gives up in resolution and dynamic properties it makes up for with rapid properties it makes up for with rapid acquisition of a 3-D dataset and the potential acquisition of a 3-D dataset and the potential for assessment of whole-brain perfusion and for assessment of whole-brain perfusion and better parenchymal evaluationbetter parenchymal evaluation
Moreover CTA illustrates not only arterial Moreover CTA illustrates not only arterial stenosis or occlusion but also the vessel wall stenosis or occlusion but also the vessel wall This factor is most important for evaluation of This factor is most important for evaluation of intramural dissection and thrombosed intramural dissection and thrombosed aneurysms which may both complicate aneurysms which may both complicate evaluation of stroke patientsevaluation of stroke patients
Early angiographic signs of strokes Early angiographic signs of strokes both CTA both CTA and DSA and DSA
Vessel occlusion or cutoff related to Vessel occlusion or cutoff related to thromboembolithromboemboli
aneurysms aneurysms arterial dissection arterial dissection Meniscus or flattened shape to clot Meniscus or flattened shape to clot
(recent) versus reverse meniscus (older)(recent) versus reverse meniscus (older) tram track (nonocclusive or recanalized tram track (nonocclusive or recanalized
clot) clot) delayed (antegrade) flow (manifest as delayed (antegrade) flow (manifest as
decreased whole-brain perfusion on CTA)decreased whole-brain perfusion on CTA) retrograde collateral flowretrograde collateral flow
Non-occlusive left MCA thrombus on 3-D imaging performed from CTA source data and was confirmed at catheter angiography
Therapy to be started within a 6-hr Therapy to be started within a 6-hr time to treatment (TTT) window time to treatment (TTT) window (while in case of IV thrombolysis (while in case of IV thrombolysis therapy to be started with in 3hrs)therapy to be started with in 3hrs)
Exclusion criteria Exclusion criteria Rapidly improving neurologic deficit or Rapidly improving neurologic deficit or Sustained blood pressure of gt180100 Sustained blood pressure of gt180100 Hemorrhage is detected on CTHemorrhage is detected on CT Infarct involving gt more than 13 rd Infarct involving gt more than 13 rd
territory of MCAterritory of MCA MRADWI-Perfusion mismatchlt 20MRADWI-Perfusion mismatchlt 20 Definite hypodensity on CTDefinite hypodensity on CT
Intra-arterial Thrombolysis
Fibrinolytics + AntiplateletsFibrinolytics + Antiplatelets
PlasminogenPlasminogen activators through fibrinolysis exposes activators through fibrinolysis exposes free thrombin and paradoxically stimulatesfree thrombin and paradoxically stimulates platelet platelet aggregation which leads to formation of aaggregation which leads to formation of a platelet platelet thrombus (white clot) thrombus (white clot)
This new thrombus is relatively resistant to This new thrombus is relatively resistant to fibrinolyticsfibrinolytics
So new regimen in case of acute stroke isSo new regimen in case of acute stroke is fibrinolytics + antiplatelet drugsfibrinolytics + antiplatelet drugs
rtPA + IIbIIIa inhibitors( tirofiban rtPA + IIbIIIa inhibitors( tirofiban abciximab) orabciximab) or
Urokinase + IIbIIIa Urokinase + IIbIIIa inhibitors( tirofiban abciximab)inhibitors( tirofiban abciximab)
Intra-arterial Thrombolysis Tirofiban (04 microgkgmin bolus for 3 min followed by Tirofiban (04 microgkgmin bolus for 3 min followed by
0125 ugkgmin)0125 ugkgmin)
++
Heparin (2000ndash3000 IU bolus followed by Heparin (2000ndash3000 IU bolus followed by 1000 IUhour infusion 1000 IUhour infusion
with ACT maintained bw 200-300) throughout the with ACT maintained bw 200-300) throughout the interventional procedure and for 24ndash48 hours thereafter when interventional procedure and for 24ndash48 hours thereafter when there is neither intraprocedural bleeding nor suspicion of there is neither intraprocedural bleeding nor suspicion of increased risk of bleeding increased risk of bleeding
Maximum dose of Urokinase Maximum dose of Urokinase Anterior circulation stroke - 500000 IU (mean 400000 Anterior circulation stroke - 500000 IU (mean 400000
IU range 300000ndash500000 IU)IU range 300000ndash500000 IU) Posterior circulation stroke -1000000 IU (mean 837000 Posterior circulation stroke -1000000 IU (mean 837000
IU range 300000ndash1000000 IU)IU range 300000ndash1000000 IU)American Journal of NeuroradiologyAmerican Journal of Neuroradiology 262595-2601 2005262595-2601 2005
Intravenous ThrombolysisIntravenous Thrombolysis
The first method to restore cerebral The first method to restore cerebral perfusion is clot lysis with the goal perfusion is clot lysis with the goal of re-establishing blood flow to the of re-establishing blood flow to the affected tissue affected tissue
IV thrombolysis rt-PA is the only IV thrombolysis rt-PA is the only FDA- approved treatment for AIS FDA- approved treatment for AIS
Fibrinolysis is enhanced powerfully Fibrinolysis is enhanced powerfully by rt-PAby rt-PA
Intravenous rTPA Intravenous rTPA administration administration protocolprotocol
Total dose of rt-PA 09 mgkg (maximum dose Total dose of rt-PA 09 mgkg (maximum dose 90 mg)90 mg)
Give 10 as initial IV bolusGive 10 as initial IV bolus Infuse remainder over 1 hourInfuse remainder over 1 hour Admit patient to an ICU or stroke unit for Admit patient to an ICU or stroke unit for
monitoringmonitoring Neurologic assessments every 15 minutes Neurologic assessments every 15 minutes
during infusion then every 30 minutes for next during infusion then every 30 minutes for next 6 hours then every hour until 24hours after 6 hours then every hour until 24hours after treatmenttreatment
Favorable Outcome vs Treatment Time Favorable Outcome vs Treatment Time with IV rTPAwith IV rTPA
Protocol limit = 3 hrs
Benefit ~ 45 hrs
Thromboembolism During coilingThromboembolism During coiling Most feared and frequent complication Most feared and frequent complication Reported incidence - Approx 7 Reported incidence - Approx 7 SourcesSources of Thromboembolism are of Thromboembolism are
- Clots at the aneurysmal neck during or immediately- Clots at the aneurysmal neck during or immediately after after embolization embolization
- Thrombus forming on catheters during- Thrombus forming on catheters during proceduresprocedures
- Stenosis of an adjacent artery dt coil mass- Stenosis of an adjacent artery dt coil mass or herniationor herniation
- Migration of intraaneurysmal- Migration of intraaneurysmal thrombus during coil thrombus during coil placement placement
- Slow flow dt vasospasm - Slow flow dt vasospasm
- Rare and unlikely causes are hypercoagulable- Rare and unlikely causes are hypercoagulable state such state such as antiphospholipid antibody syndrome or due to HITas antiphospholipid antibody syndrome or due to HIT
Occur more often with wide-necked aneurysms (dt Occur more often with wide-necked aneurysms (dt increased exposed surface area of thrombogenic coil increased exposed surface area of thrombogenic coil material)material)
Current regimen of endovascular Current regimen of endovascular managementmanagement
The The glycoprotein IIbIIIa antagonist tirofiban glycoprotein IIbIIIa antagonist tirofiban (04 (04 microgkgmin bolus for 30 minutes followed by infusion of microgkgmin bolus for 30 minutes followed by infusion of 0125 ugkgmin until the thrombus dissolved) 0125 ugkgmin until the thrombus dissolved)
Intraarterial thrombolysis with Intraarterial thrombolysis with urokinase or r- TPA urokinase or r- TPA increase of intravenous (IV) heparin (measured by increase of intravenous (IV) heparin (measured by
ACT) ACT) Intravenous aspirin Intravenous aspirin
Coil-related platelet aggregation (white clot) is Coil-related platelet aggregation (white clot) is unlikely to respond to fibrinolytics but has a high risk unlikely to respond to fibrinolytics but has a high risk of hemorrhage (In ISAT) all 5 patients who had of hemorrhage (In ISAT) all 5 patients who had received thrombolytic therapy with tPA to treat a received thrombolytic therapy with tPA to treat a thromboembolic complication after endovascular thromboembolic complication after endovascular treatment rebleed and all of these patients died)treatment rebleed and all of these patients died)
IntracranialIntracranial Stenting Stenting Metallic foreign body such as stent will accumulate Metallic foreign body such as stent will accumulate
thrombus in the absence of platelet inhibitionthrombus in the absence of platelet inhibition Antiplatelet drugs are important to prevent peri or Antiplatelet drugs are important to prevent peri or
post-interventional thromboembolic eventspost-interventional thromboembolic events Optimal treatment regimens has not been determined Optimal treatment regimens has not been determined
but usually but usually Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-
procedureprocedureOrOr
Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on
morning of proceduremorning of procedure
If need to use stent is not pre-planned thanIf need to use stent is not pre-planned than
Abciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkgAbciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkg IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)
Glycoprotein IIbIIIa inhibitor are not used routinely during elective Glycoprotein IIbIIIa inhibitor are not used routinely during elective stenting procedure dt increased risk of ICH stenting procedure dt increased risk of ICH
Carotid StentingCarotid Stenting
Pre-procedurePre-procedure
Double Antiplatelet therapy is routinely given Double Antiplatelet therapy is routinely given beginning at least 3beginning at least 3
days before the proceduredays before the procedure
Aspirin 325mgd+Clopidogrel 75mgdAspirin 325mgd+Clopidogrel 75mgd During procedureDuring procedure
Heparin is given with target clotting time of 250-Heparin is given with target clotting time of 250-300sec300sec
Post-procedure Post-procedure
Aspirin 325mg is continued indefinitely and Aspirin 325mg is continued indefinitely and
Clopidogrel 75mgd for at least 6 weeks Clopidogrel 75mgd for at least 6 weeks
Inclusion criteria for Local ThrombolysisInclusion criteria for Local Thrombolysis a)a) Patients in severe clinical grade on admission Patients in severe clinical grade on admission
with evidence of dural venous sinus with evidence of dural venous sinus thrombosis and restrictive venous outflow on thrombosis and restrictive venous outflow on cerebral angiogramcerebral angiogram
b)b) Patients in clinical grade 3 worsening on Patients in clinical grade 3 worsening on heparin therapy Restriction to venous heparin therapy Restriction to venous outflow was defined as an increase in brain outflow was defined as an increase in brain circulation time gt 12 s delay in the drainage circulation time gt 12 s delay in the drainage of cortical veins with cortical veins hanging of cortical veins with cortical veins hanging in spacein space
Treatment Options for Venous Thrombosis
CT Grading for Venous ThrombosisCT Grading for Venous Thrombosis Grade I no parenchymal change Grade I no parenchymal change
(hyperdense (hyperdense sinuses cortical veins empty sinuses cortical veins empty delta sign)delta sign)
Grade II non hemorrhagic venous infarct Grade II non hemorrhagic venous infarct without mass effect without mass effect
Grade III non-hemorrhagic infarct with Grade III non-hemorrhagic infarct with mass effectmass effect
Grade IV hemorrhagic venous infarct (max Grade IV hemorrhagic venous infarct (max diameter lt 3 cm) with no mass effectdiameter lt 3 cm) with no mass effect
Grade V hemorrhagic venous infarct (max Grade V hemorrhagic venous infarct (max diameter gt 3 cm) with mass effect diameter gt 3 cm) with mass effect
Local ThrombolysisLocal Thrombolysis
Femoral Jugular access was secured and a guiding Femoral Jugular access was secured and a guiding catheter was placed in the jugular bulb catheter was placed in the jugular bulb Mechanical Mechanical clot maceration clot maceration was done with the guidewire was done with the guidewire following which a microcatheter (was navigated and following which a microcatheter (was navigated and placed in the thrombosed segment of sinus confirmed placed in the thrombosed segment of sinus confirmed on a selective venogram on a selective venogram
Urokinase infusion Bolus dose of 2-6 lacs followed Urokinase infusion Bolus dose of 2-6 lacs followed by 60000 to 100000 units per hour along with by 60000 to 100000 units per hour along with periodic check venogram Along with maintenance periodic check venogram Along with maintenance systemic infusion of Heparinsystemic infusion of Heparin Other agents such as Other agents such as streptokinase altepase or rTPAstreptokinase altepase or rTPA can be also used can be also used
After thrombolysis patient should subjected to oral After thrombolysis patient should subjected to oral anticoagulation for six monthsanticoagulation for six months
Low-molecular-weight Low-molecular-weight heparinheparin
PharmacologyPharmacologyLMWH as its name suggests is a glycosaminoglycan that is approximatelyLMWH as its name suggests is a glycosaminoglycan that is approximately
one third the molecular weight of UFH It is derived from UFH through one third the molecular weight of UFH It is derived from UFH through variousvarious
depolymerization processes LMWH binds to antithrombin which in turn depolymerization processes LMWH binds to antithrombin which in turn
Neutralizes actors Xa and IIa Because LMWH lacks many of the longer Neutralizes actors Xa and IIa Because LMWH lacks many of the longer chains chains
required for binding to thrombin it has less ability to neutralize thrombin required for binding to thrombin it has less ability to neutralize thrombin
relativeto its ability to neutralize factor Xa LMWH also has less relativeto its ability to neutralize factor Xa LMWH also has less nonspecific nonspecific
binding to other proteins There is greater bioavailability with more binding to other proteins There is greater bioavailability with more predictable predictable
pharmacokinetics that eliminates the need for monitoring The smaller pharmacokinetics that eliminates the need for monitoring The smaller size also size also
allows for enhanced subcutaneous absorption when compared with UFHallows for enhanced subcutaneous absorption when compared with UFH
Three LMWH preparations are Three LMWH preparations are currently approved for use in the currently approved for use in the United States (1) enoxaparin (2) United States (1) enoxaparin (2) dalteparin and (3) tinzaparin dalteparin and (3) tinzaparin
They are all administered They are all administered subcutaneously at intervals of either subcutaneously at intervals of either once or twice daily for both once or twice daily for both prophylaxis and treatment dosesprophylaxis and treatment doses
Few Experiences of Few Experiences of ThrombolysisThrombolysis
Vickey 25 Yrs male patient presented Vickey 25 Yrs male patient presented with 12with 12thth day HO severe headache with day HO severe headache with right sided hemiplegiaright sided hemiplegia
MRI shows thrombosis of the superior MRI shows thrombosis of the superior sagittal left transverse left sigmoid sagittal left transverse left sigmoid sinuses and cortical veins in the fronto-sinuses and cortical veins in the fronto-parietal regions with eo haemorrhagic parietal regions with eo haemorrhagic infarct in the left cerebral hemisphere infarct in the left cerebral hemisphere with mass effect( Grade ndashV)with mass effect( Grade ndashV)
Sashi Srivastava 64 yrs FSashi Srivastava 64 yrs F In a follow up case of MRD with infra-renal In a follow up case of MRD with infra-renal
aortic abdominal and bilateral renal artery aortic abdominal and bilateral renal artery thrombosis renal angiogram shows filling thrombosis renal angiogram shows filling defects in the right Renal artery defects in the right Renal artery
Initially Renal angioplasty was done Initially Renal angioplasty was done Following angioplasty few thrombi are seem Following angioplasty few thrombi are seem to extends into the segmental branches and to extends into the segmental branches and causing blockage So Thrombolysis was causing blockage So Thrombolysis was plane to dissolve the run-out thrombi with plane to dissolve the run-out thrombi with urokinase urokinase
Rakesh 34yrsMRakesh 34yrsM Left SFA pseudoaneurysm with Left SFA pseudoaneurysm with
Covered stent placementCovered stent placement Pre operative antiplatelets with post Pre operative antiplatelets with post
procedure heparin Tirofiban procedure heparin Tirofiban followed by aspirin and clopidogrel followed by aspirin and clopidogrel were usedwere used
IAT may be a treatment option for selected patients IAT may be a treatment option for selected patients Possible selection criteria include Possible selection criteria include
presentation between 3 and 6 hours from symptom onsetpresentation between 3 and 6 hours from symptom onset major cerebral artery occlusion major cerebral artery occlusion severe neurologic deficits severe neurologic deficits high risk of systemic hemorrhage with IV rt-PA (eg recent high risk of systemic hemorrhage with IV rt-PA (eg recent
surgery) surgery) The MERCI (Mechanical Embolus Removal in Cerebral The MERCI (Mechanical Embolus Removal in Cerebral
Ischemia) retrievalIschemia) retrieval system system
Has been FDA-approved for recanalizing acutely occluded Has been FDA-approved for recanalizing acutely occluded cerebral arteries cerebral arteries
In the Multi-MERCI study patients who did not improve In the Multi-MERCI study patients who did not improve immediately after IV rt-PA underwent mechanical immediately after IV rt-PA underwent mechanical embolectomy within 8 hours of symptom onset embolectomy within 8 hours of symptom onset
Partial or complete recanalization occurred in 74 of Partial or complete recanalization occurred in 74 of patientspatients
with a symptomatic intracerebral hemorrhage (sICH) rate of with a symptomatic intracerebral hemorrhage (sICH) rate of 67 67
Mechanical embolectomy with the MERCI retriever may be a Mechanical embolectomy with the MERCI retriever may be a feasible and safe option for patients after IV rt-PAfeasible and safe option for patients after IV rt-PA
Penumbra stroke systemPenumbra stroke system This device combines two methods of clot This device combines two methods of clot
extraction aspiration and mechanical extraction aspiration and mechanical extraction extraction
First the clot is aspirated then a thrombus First the clot is aspirated then a thrombus removal ring can be used if necessary to removal ring can be used if necessary to remove remaining clot remove remaining clot
successful recanalizing 82successful recanalizing 82 Bridging therapyBridging therapy
06 mgkg IV rt-PA followed by IAT with IA rt-06 mgkg IV rt-PA followed by IAT with IA rt-PA (up to 20 mg)PA (up to 20 mg)
achieved a higher recanalization rateachieved a higher recanalization rate
Criteria for thrombolysis with rTPACriteria for thrombolysis with rTPA
Inclusion criteriaInclusion criteria Clinical signs and symptoms consistent with ischemic Clinical signs and symptoms consistent with ischemic
strokestroke Patient last seen normal within 3 hoursPatient last seen normal within 3 hours Measurable neurologic deficitMeasurable neurologic deficit
Exclusion criteriaExclusion criteria Any hemorrhage on neuroimaging (CT or MRI)Any hemorrhage on neuroimaging (CT or MRI) Symptoms suggestive of subarachnoid hemorrhageSymptoms suggestive of subarachnoid hemorrhage Seizure at stroke onset that is thought to contribute to Seizure at stroke onset that is thought to contribute to
neurologic deficitneurologic deficit Hypodensity greater than one third cerebral hemisphere Hypodensity greater than one third cerebral hemisphere
on CTon CT SBP greater than 185 mm Hg or DBP greater than 110 SBP greater than 185 mm Hg or DBP greater than 110
mm Hgmm Hg International normalized ratio (INR) greater than 17International normalized ratio (INR) greater than 17
Ischemic Stroke Ischemic Stroke Treatment ndash 2006Treatment ndash 2006
IV tissue plasminogen activator (tPA)IV tissue plasminogen activator (tPA) ndash ndash Only FDA-approved acute stroke drugOnly FDA-approved acute stroke drug ndash ndash 3 hour treatment window3 hour treatment window
MERCI - Concentric clot retrieval MERCI - Concentric clot retrieval devicedevice ndash ndash Rescue therapy - approved 2004Rescue therapy - approved 2004 ndash ndash Device approval (not outcomes-based)Device approval (not outcomes-based)
Off label approachesOff label approaches ndash ndash IV tPA after 3 hoursIV tPA after 3 hours ndash ndash IV-IA tPA sequential strategiesIV-IA tPA sequential strategies ndash ndash IA tPA clot angioplasty fragmentationIA tPA clot angioplasty fragmentation ndash ndash Ultrasound-assisted tPA lysisUltrasound-assisted tPA lysis
rt-PA Trials NINDSrt-PA Trials NINDS
Acute stroke - 624 patientsAcute stroke - 624 patients Treat within 3 hrsTreat within 3 hrs Intravenous 09 mgkg rt-PA vs placeboIntravenous 09 mgkg rt-PA vs placebo Hemorrhage 64 tPA 06 placeboHemorrhage 64 tPA 06 placebo Neurologic recovery better with tPA 30 Neurologic recovery better with tPA 30
more like to have minimal or no disabilitymore like to have minimal or no disability
First proven approved treatment for First proven approved treatment for strokestroke
Limitations of tPALimitations of tPA Only 4 of acute strokes receive tPAOnly 4 of acute strokes receive tPA (Kleindorfer et al Stroke 2004 35 e27-e29)(Kleindorfer et al Stroke 2004 35 e27-e29)
Only 22 of patients present within 3 hoursOnly 22 of patients present within 3 hours1048707 1048707 51 of these ineligible due to51 of these ineligible due to
bull bull Mild severityMild severity bull bull Medical or surgical historyMedical or surgical history bull bull Blood testsBlood tests
Sustained recanalization only 13Sustained recanalization only 13 (Alexandrov et al NEJM 2004 351 2170-8)(Alexandrov et al NEJM 2004 351 2170-8)
Concern for hemorrhageConcern for hemorrhage tPA potentiates apoptotic injury tPA potentiates apoptotic injury (Liu et al Nature Med 2004 101379-83)(Liu et al Nature Med 2004 101379-83)
PROACT II IA Lysis TrialPROACT II IA Lysis Trial Baseline 24 hours 8 days
Baseline 60 minutes 120 minutes
9mg IAProurokinase
Desmoteplase Trials DEDAS Desmoteplase Trials DEDAS DIASDIAS
Trial OverviewTrial Overview Double blind randomized placebo Double blind randomized placebo
controlled trialscontrolled trials IV delivery 3-9 hour time windowIV delivery 3-9 hour time window Plasminogen activator ndash from Plasminogen activator ndash from vampire bat vampire bat
salivasaliva Selection based on PWI-DWI MismatchSelection based on PWI-DWI Mismatch
MRI InclusionMRI Inclusion PWI defect at least 2 cm AND ~20 larger PWI defect at least 2 cm AND ~20 larger
than DWIthan DWI PWI should be obvious even visible on PWI should be obvious even visible on
raw imagesraw imagesMRI ExclusionMRI Exclusion
DWI gt 13 MCADWI gt 13 MCA MRA ICA occlusionMRA ICA occlusion
Desmoteplase ndash DIAS Desmoteplase ndash DIAS ResultsResults
Mechanical Thrombolysis Mechanical Thrombolysis devicesdevices
mechanical thrombolysis potentially extends the treatment mechanical thrombolysis potentially extends the treatment window because they act promptly at the site of the thrombuswindow because they act promptly at the site of the thrombus
The devices can retrieve large clots that pharmaceutical agents The devices can retrieve large clots that pharmaceutical agents may not successfully lysemay not successfully lyse
Patients treated with IV tPA may be considered for treatment of Patients treated with IV tPA may be considered for treatment of residual clot with some of these devicesresidual clot with some of these devices
suction-creating saline jets suction-creating saline jets laser energy ultrasound laser energy ultrasound a corkscrew apparatus to treat strokesa corkscrew apparatus to treat strokes The AngioJet systemThe AngioJet system uses saline jets that are directed back into the catheter to uses saline jets that are directed back into the catheter to
create a low-pressure zone around the catheter tip inducing create a low-pressure zone around the catheter tip inducing suction suction
The clot is pulled into the exhaust lumen and removed from the The clot is pulled into the exhaust lumen and removed from the vessel Although US Food and Drug Administration (FDA) has vessel Although US Food and Drug Administration (FDA) has approved this device for use in arteriovenous dialysis grafts and approved this device for use in arteriovenous dialysis grafts and fistulae and for the treatment of coronary arteries saphenous fistulae and for the treatment of coronary arteries saphenous vein grafts and peripheral vessels clinical trials for the vein grafts and peripheral vessels clinical trials for the treatment of acute stroke are no longer in progress treatment of acute stroke are no longer in progress
Most devices are used in cerebral vessels that 2-5 mm
The Latis laser device The Latis laser device used laser energy to ablate clots used laser energy to ablate clots Arteries 2-5 mm in diameter could be Arteries 2-5 mm in diameter could be
treated including the ICA M1 or M2 treated including the ICA M1 or M2 branch of the MCA A1 branch of the branch of the MCA A1 branch of the anterior cerebral artery (ACA) basilar anterior cerebral artery (ACA) basilar artery posterior cerebral artery (PCA) artery posterior cerebral artery (PCA) and vertebral and vertebral
Patients could receive treatment as late Patients could receive treatment as late as 8 hours after symptom onset in the as 8 hours after symptom onset in the anterior circulation and within 24 hours in anterior circulation and within 24 hours in the posterior circulation the posterior circulation
Endovascular Photo Acoustic Endovascular Photo Acoustic Recanalization (EPAR) Recanalization (EPAR)
A laser power source generated energy for the A laser power source generated energy for the systemsystem
The energy was delivered by means of The energy was delivered by means of fiberoptics to the tip of the catheter at the fiberoptics to the tip of the catheter at the treatment sitetreatment site
Absorption of laser light by darkly pigmented Absorption of laser light by darkly pigmented materials (ie the clot) occurred inside the 1-mm materials (ie the clot) occurred inside the 1-mm catheter tipcatheter tip
the system was designed to minimize scattering the system was designed to minimize scattering of laser light of laser light
Absorption converted photo energy to acoustic Absorption converted photo energy to acoustic energy which then emulsified the clot inside the energy which then emulsified the clot inside the catheter tip catheter tip
EKOS ultrasound( the EKOS ultrasound( the Ultrasound Thrombolytic Ultrasound Thrombolytic
Infusion Catheter) Infusion Catheter) combines the use of a distal ultrasound transducer with combines the use of a distal ultrasound transducer with
infusion of a thrombolytic agent through the infusion of a thrombolytic agent through the microcathetermicrocatheter
Ultrasound changes the structure of the clot to Ultrasound changes the structure of the clot to temporarily increase its permeability while providing an temporarily increase its permeability while providing an acoustic pressure gradient to move the drug into the clot acoustic pressure gradient to move the drug into the clot to speed its dissolution to speed its dissolution
The EKOS catheter is placed in the proximal portion of the The EKOS catheter is placed in the proximal portion of the clot clot
After a 2-mg bolus of tPA was injected through the After a 2-mg bolus of tPA was injected through the catheter catheter
the patient received a continuous infusion of IA tPA 03 the patient received a continuous infusion of IA tPA 03 mgmin to a maximum of 20 mg and simultaneous mgmin to a maximum of 20 mg and simultaneous ultrasound transmission for as long as 60 minutes ultrasound transmission for as long as 60 minutes
One patient was treated with a total of 4 units of One patient was treated with a total of 4 units of recombinant reteplase (Retavase) hand-injected over 60 recombinant reteplase (Retavase) hand-injected over 60 minutes minutes
Penumbra system Penumbra system The Penumbra system (Penumbra Inc) provides a dual The Penumbra system (Penumbra Inc) provides a dual
approach to clot extraction using aspiration followed by approach to clot extraction using aspiration followed by clot retrieval with a ring device if needed clot retrieval with a ring device if needed
Mechanical Embolus Removal in Cerebral Ischemia Mechanical Embolus Removal in Cerebral Ischemia (MERCI)(MERCI)
a corkscrew-like apparatus to remove blood clots from a corkscrew-like apparatus to remove blood clots from the brain in patients experiencing an ischemic stroke the brain in patients experiencing an ischemic stroke
The corkscrew itself resides in the catheter tip which The corkscrew itself resides in the catheter tip which shields it from the wall of the vessel until it is ready to be shields it from the wall of the vessel until it is ready to be burrowed into the clot Once lodged in the clot the device burrowed into the clot Once lodged in the clot the device and clot are withdrawn from the vessel and clot are withdrawn from the vessel
Snarelike devicesSnarelike devices Snares such as the Neuronet snare (Guidant Snares such as the Neuronet snare (Guidant
Endovascular Santa Clara CA) have been developed Endovascular Santa Clara CA) have been developed specifically for use in the treatment of strokes specifically for use in the treatment of strokes
These devices are simple in design and do not require the These devices are simple in design and do not require the clot to be amenable to emulsification clot to be amenable to emulsification
X-Sizer deviceX-Sizer device a device with small moving blades at the a device with small moving blades at the
catheter tip catheter tip This device the X-Sizer device (EndiCor Medical This device the X-Sizer device (EndiCor Medical
San Clemente CA) can be used to excise the San Clemente CA) can be used to excise the thrombus and aspirate it thrombus and aspirate it
The device was being evaluated in randomized The device was being evaluated in randomized studies of coronary vessels and in a registry of studies of coronary vessels and in a registry of patients with acute myocardial infarctionpatients with acute myocardial infarction
Although the manufacturer had modified the Although the manufacturer had modified the device for use in cerebral vessels a safety and device for use in cerebral vessels a safety and feasibility study was indefinitely suspended after feasibility study was indefinitely suspended after only 1 patient was treated with the device in only 1 patient was treated with the device in Europe Europe
Suction thrombectomySuction thrombectomy This method of mechanical thrombolysis is one of the This method of mechanical thrombolysis is one of the
simplestsimplest In this readily available technique suction is applied with In this readily available technique suction is applied with
a syringe to remove thrombus in the ICA a syringe to remove thrombus in the ICA It requires no other devicesIt requires no other devices A catheter with a large inner diameter (Brite Tip Cordis A catheter with a large inner diameter (Brite Tip Cordis
Corporation Miami FL) was placed in the symptomatic Corporation Miami FL) was placed in the symptomatic vessel and navigated over a guidewire into the thrombusvessel and navigated over a guidewire into the thrombus
A 60-mL syringe was used to aspirate the thrombus A 60-mL syringe was used to aspirate the thrombus Each patient required angioplasty and stenting of carotid Each patient required angioplasty and stenting of carotid
bifurcation stenosis and received daily aspirin and bifurcation stenosis and received daily aspirin and ticlopidine after the procedure No complications ticlopidine after the procedure No complications occurred occurred
Summary Acute Stroke Summary Acute Stroke ImagingImaging
PhysiologyPhysiology importance collaterals importance collaterals
ndash ndashGrowing role for perfusion Growing role for perfusion assessmentassessment
tPAtPA guidelines amp limitations guidelines amp limitations Signs on CT amp MRSigns on CT amp MR follow physiology follow physiology Stroke trialsStroke trials PWI-DWI mismatch PWI-DWI mismatch
ndash ndashTreat based on physiology not timeTreat based on physiology not time ProtocolsProtocols should be fast and should be fast and
comprehensivecomprehensive
ACT or aPTTACT or aPTT
Determine when to pull the femoral sheath Determine when to pull the femoral sheath Premature sheath pull can lead to bleedingPremature sheath pull can lead to bleeding Delayed removal can increase time in ICUDelayed removal can increase time in ICU Target set Target set at each siteat each site
ACT targets range from 150 ndash 220 ACT targets range from 150 ndash 220 secondsseconds
aPTT targets range from 40 ndash 70 seconds aPTT targets range from 40 ndash 70 seconds
During neuroangiography-During neuroangiography- Recommended therapeutic range of heparin in Recommended therapeutic range of heparin in
plasma is 02-08 uml ( corresponding to aPTT plasma is 02-08 uml ( corresponding to aPTT ACT values 15-25 times the baseline values)ACT values 15-25 times the baseline values)
Dose In diagnostic angiography bolus dose of Dose In diagnostic angiography bolus dose of 2500 iu is used followed by 1000 iu hour2500 iu is used followed by 1000 iu hour
Bolus dose is Bolus dose is 60 ukg to maintain the therapeutic 60 ukg to maintain the therapeutic range range If procedure continues for more than 75 If procedure continues for more than 75 minutes additional dose is required ( half of the minutes additional dose is required ( half of the initial dose for another 75 minutes) initial dose for another 75 minutes)
(AJNR 199415 51-54)
Mechanisms of HIT( Mechanisms of HIT( Heparin Heparin induced Thrombocytopeniainduced Thrombocytopenia))
Type 1Type 1 Fall in platelet count occurs within the first two Fall in platelet count occurs within the first two
days after heparin initiation often returns to days after heparin initiation often returns to normal with continued heparin administration normal with continued heparin administration and is of no clinical consequence and is of no clinical consequence
The mechanism of the thrombocytopenia is non-The mechanism of the thrombocytopenia is non-immune and appears to be due to a direct effect of immune and appears to be due to a direct effect of heparin on platelet activationheparin on platelet activation
Type 2Type 2 Approximately 03 to 3 percent of patients Approximately 03 to 3 percent of patients
receiving heparin develop an immune receiving heparin develop an immune thrombocytopenia mediated by antibodies to a thrombocytopenia mediated by antibodies to a heparin-platelet factor 4 complex heparin-platelet factor 4 complex
(AJNR 28155-158 2007)
Treatment of heparin-induced Treatment of heparin-induced thrombocytopeniathrombocytopenia
When HIT is diagnosed it is important to When HIT is diagnosed it is important to stop heparin mainly in type 2 and to avoid stop heparin mainly in type 2 and to avoid the use of LMWH the use of LMWH
Because of the increased risk of thrombosis Because of the increased risk of thrombosis however continuation of an anticoagulant however continuation of an anticoagulant must be considered must be considered
The drugs currently approved for the The drugs currently approved for the treatment of HIT in the United States are treatment of HIT in the United States are direct thrombin inhibitors argatroban and direct thrombin inhibitors argatroban and lepirudinlepirudin
WARFARIN MECHANISM OF ACTIONWARFARIN MECHANISM OF ACTION
Inactive factors II VII IX and X
Proteins S and C
Active factors II VII IX and X
Proteins S and C
Vitamin K epoxide
Vitamin K reduced
WA
RF
AR
IN
Prevents the reduction of vitamin K which is essential for Prevents the reduction of vitamin K which is essential for activation of certain factorsactivation of certain factors
Has no effect on previously formed thrombusHas no effect on previously formed thrombus
Antagonist is Vit KAntagonist is Vit K
OPTIMIZING WARFARIN THERAPYOPTIMIZING WARFARIN THERAPY
Use of large loading dose may lead to hemorrhage and Use of large loading dose may lead to hemorrhage and other complicationsother complications
Initial dose 2-5 mg once dailyInitial dose 2-5 mg once daily Maintenance dose 2-10 mg once dailyMaintenance dose 2-10 mg once daily If Immediate anticoagulation is requiredIf Immediate anticoagulation is required Heparin IS Heparin IS
started along with loading dose of warfarin 10 mg started along with loading dose of warfarin 10 mg Heparin is usually discontinued after 4-5 days Heparin is usually discontinued after 4-5 days Before Before discontinuing INR should be in therapeutic range for 2 discontinuing INR should be in therapeutic range for 2 consecutive daysconsecutive days
Daily monitoring of INR until INR is in therapeutic Daily monitoring of INR until INR is in therapeutic range then 3 times weekly for 1-2 weeks then less often range then 3 times weekly for 1-2 weeks then less often (every 4 to 6 weeks)(every 4 to 6 weeks)
OPTIMAL THERAPEUTIC RANGEOPTIMAL THERAPEUTIC RANGE
IndicationIndication INRINR
Prophylaxis of venous Prophylaxis of venous thromboembolismthromboembolism
20-3020-30
Treatment of venous Treatment of venous thromboembolismthromboembolism
20-3020-30
Atrial fibrillationAtrial fibrillation 20-3020-30
Mitral valve stenosisMitral valve stenosis 20-3020-30
Heart valve replacementHeart valve replacement
Bioprosthetic valveBioprosthetic valve
Mechanical valveMechanical valve
20-3020-30
25-3525-35
Myocardial infarctionMyocardial infarction 20-3020-30
25-35 25-35 (high risk patients)(high risk patients)
FACTORS INFLUENCING DOSE RESPONSEFACTORS INFLUENCING DOSE RESPONSE
Poor patient compliancePoor patient compliance Concomitant medicationsConcomitant medications Levels of dietary vitamin KLevels of dietary vitamin K Alcohol Inaccurate lab testingAlcohol Inaccurate lab testing Inaccurate lab testingInaccurate lab testing Hepatic dysfunctionHepatic dysfunction FeverFever
Contraindication for WarfarinContraindication for Warfarin
Hypersensitivity to warfarinHypersensitivity to warfarin Hemorrhagic tendencyHemorrhagic tendency Condition with risk of hemorrhageCondition with risk of hemorrhage Inadequate laboratory techniquesInadequate laboratory techniques Protein C amp S deficiencyProtein C amp S deficiency Vitamin K deficiencyVitamin K deficiency
SIDE EFFECTSSIDE EFFECTS
Hemorrhage Hemorrhage Skin necrosisSkin necrosis Purple toe syndromePurple toe syndrome Microembolization Microembolization TeratogenecityTeratogenecity Agranulocytosis leukopenia Agranulocytosis leukopenia Diarrhoeanausea anorexiaDiarrhoeanausea anorexia
MONITORING OF WARFARIN THERAPYMONITORING OF WARFARIN THERAPY
Prothrombin timeProthrombin time PT ratioPT ratio INR (International Normalized Ratio)INR (International Normalized Ratio)
PROTHROMBIN TIME (PT)PROTHROMBIN TIME (PT)
Time required for blood to coagulate Time required for blood to coagulate is called PT ( normal value ~10sec)is called PT ( normal value ~10sec)
Performed by adding a mixture of Performed by adding a mixture of calcium and thromboplastin to calcium and thromboplastin to citrated plasmacitrated plasma
As a control a normal blood sample is As a control a normal blood sample is tested continuouslytested continuously
PT ratio (PTR) = PT ratio (PTR) = Patientrsquos PTPatientrsquos PT Control PTControl PT
PROBLEMS WITH PTPTRPROBLEMS WITH PTPTR
Thromboplastins are extracts from Thromboplastins are extracts from brain lung or placenta of animalsbrain lung or placenta of animals
Thromboplastins from various Thromboplastins from various manufacturers differ in their manufacturers differ in their sensitivity to prolong PTsensitivity to prolong PT
May result in false control of May result in false control of anticoagulant therapyanticoagulant therapy
INTERNATIONAL NORMALISED RATIO (INR)INTERNATIONAL NORMALISED RATIO (INR)
International Normalized Ratio (INR) International Normalized Ratio (INR) a PT test with a a PT test with a formula based ratio to normalize the often variable source formula based ratio to normalize the often variable source of tissue factor (human rabbit recombinant)of tissue factor (human rabbit recombinant)
INR = [PTINR = [PTptpt] ] ISIISI
[PT[PTRefRef]]
PTPTpt pt ndash prothrombin time of patientndash prothrombin time of patient
PTPTRef Ref ndash prothrombin time of normal pooled samplendash prothrombin time of normal pooled sample
ISI ndash International Sensitivity IndexISI ndash International Sensitivity Index
Warfarin is given orally and titrated to achieve an INR of Warfarin is given orally and titrated to achieve an INR of typically 20 ndash 30typically 20 ndash 30
Heparin versus WarfarinHeparin versus Warfarin
Drug ActionMechan-ism
Moni-toring
Effective
HeparinDirect
Inhibition ofThrombin
ATIIIcofactor
APTTACT
Immediate
WarfarinDecreasesProductionof factors
Vitamin K PTDelay
3-5 days
INR
Recanalization or Antegrade Recanalization or Antegrade Reperfusion StrategiesReperfusion Strategies
Recanalization strategies focus on removing Recanalization strategies focus on removing andor dissolving the occlusive thrombus to re-andor dissolving the occlusive thrombus to re-establish antegrade flow Strategies may be establish antegrade flow Strategies may be classified into 7 different categories on the classified into 7 different categories on the basis of their primary mechanism of action basis of their primary mechanism of action 1) 1) IV andor intraarterial thrombolysis (IAT) IV andor intraarterial thrombolysis (IAT) 2) endovascular thrombectomy2) endovascular thrombectomy3) endovascular thromboaspiration 3) endovascular thromboaspiration 4) endovascular mechanical thrombus disruption or 4) endovascular mechanical thrombus disruption or
thromborrhexisthromborrhexis5) 5) transcranial or endovascular augmented transcranial or endovascular augmented
fibrinolysis fibrinolysis 6) endovascular thrombus entrapment and 6) endovascular thrombus entrapment and 7) temporary endovascular bypass7) temporary endovascular bypass
IAT in Acute Ischemic StrokeIAT in Acute Ischemic Stroke
IAT advantages over IV thrombolysisIAT advantages over IV thrombolysis Coaxial microcatheter techniques the occluded intracranial Coaxial microcatheter techniques the occluded intracranial
vessel is directly accessible and the fibrinolytic agent can be vessel is directly accessible and the fibrinolytic agent can be infused directly into the thrombusinfused directly into the thrombus
This permits a smaller dose of fibrinolytic agent to reach a This permits a smaller dose of fibrinolytic agent to reach a higher local concentration than that reached by systemic higher local concentration than that reached by systemic infusioninfusion
Allows more complete recanalization with lower total doses of Allows more complete recanalization with lower total doses of thrombolytic thrombolytic
With the smaller dose complications from systemic fibrinolytic With the smaller dose complications from systemic fibrinolytic effects including intracranial hemorrhage (ICH) can effects including intracranial hemorrhage (ICH) can theoretically be reduced theoretically be reduced
Treatment window for endovascular techniques can be Treatment window for endovascular techniques can be extended beyond the typical IV window of 3 hours extended beyond the typical IV window of 3 hours
IA techniques have led to higher recanalization rates than IV IA techniques have led to higher recanalization rates than IV thrombolysisthrombolysis
Major disadvantagesMajor disadvantages Relative complexity of the procedure the level Relative complexity of the procedure the level
of required technical expertise and its of required technical expertise and its relatively low availability relatively low availability
Delays in initiating treatmentDelays in initiating treatment InvasiveInvasive
ThrombolyticsThrombolytics
Plasminogen activators
Fibrinolytics
1 Plasminogen Activators 1 Plasminogen Activators drugs act by converting the inactive proenzyme drugs act by converting the inactive proenzyme plasminogen into the active enzyme plasmin Plasmin plasminogen into the active enzyme plasmin Plasmin digests fibrinogen fibrin monomers and cross-linked digests fibrinogen fibrin monomers and cross-linked fibrin (as found in a thrombus) into fibrin degradation fibrin (as found in a thrombus) into fibrin degradation productsproducts
First-Generation Agents First-Generation Agents StreptokinaseStreptokinase a protein derived from group C a protein derived from group C
szlig-hemolytic streptococci has a half-life of 16ndashszlig-hemolytic streptococci has a half-life of 16ndash90 minutes and low fibrin specificity This drug 90 minutes and low fibrin specificity This drug proved to have a very narrow therapeutic proved to have a very narrow therapeutic window and significant rates of ICH and window and significant rates of ICH and systemic hemorrhage18systemic hemorrhage18
UrokinaseUrokinase is a serine protease with a plasma is a serine protease with a plasma half life of 14 minutes and low fibrin specificity half life of 14 minutes and low fibrin specificity
The urokinase dose used in cerebral IAT has The urokinase dose used in cerebral IAT has ranged from 002 to 2 X106unitsranged from 002 to 2 X106units
Second-Generation Agents Second-Generation Agents Alteplase (rtPA) Alteplase (rtPA)
is a serine is a serine protease with a plasma half-life of 35 protease with a plasma half-life of 35 minutes and a high degree of fibrin affinity and minutes and a high degree of fibrin affinity and specificity specificity
Dose used in cerebral IAT has ranged between 20 Dose used in cerebral IAT has ranged between 20 and 60 mgand 60 mg
Disadvantages of alteplase include its relatively short Disadvantages of alteplase include its relatively short halflife and limited penetration into the clot matrix halflife and limited penetration into the clot matrix because of strong binding with surface fibrin which because of strong binding with surface fibrin which could delay recanalization and increase the risk of could delay recanalization and increase the risk of recurrent occlusion recurrent occlusion
Prourokinase (r-prourokinase) Prourokinase (r-prourokinase) is the proenzyme precursor of urokinase is the proenzyme precursor of urokinase T12 of 7 minutes and high fibrin specificity T12 of 7 minutes and high fibrin specificity
Third-Generation AgentsThird-Generation Agents
ReteplaseReteplase is a structurally modified is a structurally modified form of alteplase form of alteplase
with a longer half-life (15ndash18 minutes) In with a longer half-life (15ndash18 minutes) In addition it does not bind as highly to fibrin addition it does not bind as highly to fibrin unbound reteplase can thus theoretically better unbound reteplase can thus theoretically better penetrate the clot and potentially penetrate the clot and potentially improve in improve in vivo fibrinolytic activity vivo fibrinolytic activity
TenecteplaseTenecteplase is another modified form of rtPA with a longer is another modified form of rtPA with a longer
half-life (17 minutes)half-life (17 minutes) greater fibrin specificity and greater greater fibrin specificity and greater
resistance to plasminogen activator inhibitor-1 resistance to plasminogen activator inhibitor-1 IV tenecteplase in acute ischemic stroke IV tenecteplase in acute ischemic stroke
suggest that the drug is safe and promisingsuggest that the drug is safe and promising
Newer plasminogen activatorNewer plasminogen activator
DesmoteplaseDesmoteplase is a genetically engineered is a genetically engineered version of the clot-dissolving factor version of the clot-dissolving factor
found in the saliva found in the saliva of the vampire bat Desmodus rotundusof the vampire bat Desmodus rotundus moremore potent and more selective for fibrin-bound potent and more selective for fibrin-bound
plasminogen than any other known plasminogen plasminogen than any other known plasminogen activatoractivator
Unlike tissue plasminogen activator (tPA) desmoteplase Unlike tissue plasminogen activator (tPA) desmoteplase is not activated by fibrinogen or -amyloid proteins is not activated by fibrinogen or -amyloid proteins factors that may exacerbate the risk for ICH factors that may exacerbate the risk for ICH
The effect of IV administration of desmoteplase 3ndash9 The effect of IV administration of desmoteplase 3ndash9 hours after symptom onset in patients with stroke who hours after symptom onset in patients with stroke who present with mismatch on MR imaging or CT perfusion present with mismatch on MR imaging or CT perfusion
3 DefibrinogenatingFibrinogenolytic 3 DefibrinogenatingFibrinogenolytic Agents Agents
AncrodAncrod(Viprinex)(Viprinex) is is the purified fraction of the Malayan pit viper venomthe purified fraction of the Malayan pit viper venom It acts by directly cleaving and inactivating fibrinogen It acts by directly cleaving and inactivating fibrinogen
and thus indirectly promoting anticoagulation and thus indirectly promoting anticoagulation The reduction in the blood levels of fibrinogen also The reduction in the blood levels of fibrinogen also
leads to a reduced blood viscosity which may improve leads to a reduced blood viscosity which may improve blood flow to the affected areas of the brain blood flow to the affected areas of the brain
In the Stroke Treatment with Ancrod Trial 500 In the Stroke Treatment with Ancrod Trial 500 patients with stroke presenting within 3 hours of patients with stroke presenting within 3 hours of symptom onset were randomized to receive ancrod (symptom onset were randomized to receive ancrod (n n 248) or a placebo (n 252) Good outcome (Barthel 248) or a placebo (n 252) Good outcome (Barthel Index 95ndash100 at 3 months) was achieved in 4221 Index 95ndash100 at 3 months) was achieved in 4221 and 344 of the patients respectively and 344 of the patients respectively
2 Direct Fibrinolytics2 Direct Fibrinolytics
Microplasmin (Microplasmin (ThromboGenics Heverlee Belgium)ThromboGenics Heverlee Belgium) is a truncated form of plasmin that is more resistant to the effects is a truncated form of plasmin that is more resistant to the effects
of antiplasmin of antiplasmin microplasmin can be used upto 4ndash12 hours after stroke onset microplasmin can be used upto 4ndash12 hours after stroke onset There was no evidence of increased bleeding risk with There was no evidence of increased bleeding risk with
microplasminmicroplasmin
Alfimeprase (Nuvelo San Carlos Calif)Alfimeprase (Nuvelo San Carlos Calif) is a recombinant truncated form of fibrolase a fibrinolytic zinc metalloproteinase is a recombinant truncated form of fibrolase a fibrinolytic zinc metalloproteinase
isolated from the venom of the southern copperhead snake isolated from the venom of the southern copperhead snake It degrades fibrin directly and achieves thrombolysis independent It degrades fibrin directly and achieves thrombolysis independent
of plasmin formationof plasmin formation its thrombolytic activity appears to be localized to the site of its thrombolytic activity appears to be localized to the site of
delivery These properties should theoretically result in faster delivery These properties should theoretically result in faster recanalization and lower hemorrhagic conversion riskrecanalization and lower hemorrhagic conversion risk
Anti-fibrinolyticsAnti-fibrinolytics
to limit fibrinolytic activityto limit fibrinolytic activity -aminocaproic acid (EACA) -aminocaproic acid (EACA) competitively inhibitscompetitively inhibits plasminogen and plasminogen activators from plasminogen and plasminogen activators from
binding to fibrinbinding to fibrin
alpha2-antiplasminalpha2-antiplasmin a serine protease inhibitor that a serine protease inhibitor that neutralizes any free circulating plasminneutralizes any free circulating plasmin
Plasminogen activator inhibitor-1Plasminogen activator inhibitor-1 a serine protease a serine protease inhibitor that inhibits tissue-type plasminogen inhibitor that inhibits tissue-type plasminogen activatoractivator
Glycoprotein (GP) IIbIIIa antagonistsGlycoprotein (GP) IIbIIIa antagonists
such as ReoPro (abciximab) Integrilin such as ReoPro (abciximab) Integrilin (eptifibatide) or Aggrastat (tirofiban) in (eptifibatide) or Aggrastat (tirofiban) in ischemic stroke remains investigational ischemic stroke remains investigational Deshmukh et al38 reported 21 patients with Deshmukh et al38 reported 21 patients with large-vessel occlusion refractory to IAT with large-vessel occlusion refractory to IAT with rtPA who were treated with IV andor IA rtPA who were treated with IV andor IA abciximab eptifibatide or tirofiban abciximab eptifibatide or tirofiban
IA Mechanical Approaches in Acute Ischemic Stroke IA Mechanical Approaches in Acute Ischemic Stroke Mechanical strategies have several advantagesMechanical strategies have several advantages First they lessen and may even preclude the use of chemical First they lessen and may even preclude the use of chemical
thrombolytics in this manner very likely reducing the risk of ICHthrombolytics in this manner very likely reducing the risk of ICH Second by avoiding the use of chemical thrombolytics it is Second by avoiding the use of chemical thrombolytics it is
possible to extend the treatment window beyond the limit of 6ndash8 possible to extend the treatment window beyond the limit of 6ndash8 hours hours
Third mechanically fragmenting a clot increases the surface area Third mechanically fragmenting a clot increases the surface area accessible to fibrinolytic agents and allows inflow of fresh accessible to fibrinolytic agents and allows inflow of fresh plasminogen which in turn may increase the speed of plasminogen which in turn may increase the speed of thrombolysis thrombolysis
Finally clot-retrieval devices may provide faster recanalization Finally clot-retrieval devices may provide faster recanalization
The disadvantages of the mechanical The disadvantages of the mechanical approaches approaches technical difficulty of navigating mechanical technical difficulty of navigating mechanical
devices into the intracranial circulation excessive devices into the intracranial circulation excessive trauma to the vasculature (potentially leading to trauma to the vasculature (potentially leading to vasospasm vessel dissection perforation or vasospasm vessel dissection perforation or rupture) rupture)
fragmented thrombus causing distal embolization fragmented thrombus causing distal embolization into previously unaffected territories into previously unaffected territories
Nevertheless the advantages of mechanical stroke Nevertheless the advantages of mechanical stroke therapy appear to significantly outweigh its therapy appear to significantly outweigh its disadvantages and risksdisadvantages and risks
Contraindications to Thrombolytic Contraindications to Thrombolytic agents agents
Recent thoracic abdominal or Recent thoracic abdominal or intracranial surgeryintracranial surgery
Recent haemorrhagic CVA Head injury Recent haemorrhagic CVA Head injury or neoplasmor neoplasm
Bleeding ulcerBleeding ulcer Anticipated invasive procedures (arterial Anticipated invasive procedures (arterial
punctures biopsies)punctures biopsies) Concurrent hemostatic dysfunctionConcurrent hemostatic dysfunction
Monitoring of thrombolytic Monitoring of thrombolytic therapytherapy
Thrombin time Measures the availability of functional
fibrinogen Normal thrombin time is 10-14 sec Prolonged when fibrinogen level is below
75-100 mgdl
Half Life of ThrombolyticsHalf Life of ThrombolyticsAgent Administration Half Life
Streptokinase IA 60-80min
Urokinase IAIV 9-12min
rTPA IAIV 6min
Abciximab(Reopro) IAIV 12hour
Aspirin POIV 15-20min
Heparin IVSC 60min
Coumadin PO 15-25 days
Anti Platelet DrugsAnti Platelet DrugsDrug Drug Mechanism Mechanism UsesUsesAspirinAspirin Permanently inhibits Permanently inhibits
COX-1 and COX-2COX-1 and COX-2CADCAD
Stroke-TIAsStroke-TIAs
NSAIDsNSAIDs Reversibly inhibits Reversibly inhibits COX-1COX-1
LimitedLimited
DipyridamoleDipyridamole Inhibits PDE increases Inhibits PDE increases cAMPcAMP
TIAsTIAs
ThenopyridinesThenopyridines
(Ticlopidine(Ticlopidine
ClopidrgrelClopidrgrel))
Inhibits ADP Inhibits ADP
PlatAg PlatAg
TIAsStrokeTIAsStroke
CAD PVDCAD PVD
Abciximab (ReoPro)Abciximab (ReoPro)
Eptifibatide (Integrilin)Eptifibatide (Integrilin)
TirofibanTirofiban
GP IIBIIIA InhibitorsGP IIBIIIA Inhibitors
Stroke- TIAs Stroke- TIAs
MonitoringMonitoring
Bleeding timeBleeding time
Optical aggregometryOptical aggregometry
Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay
Bleeding timeBleeding time
Requires a skin incision (usually made on the ear lobe or Requires a skin incision (usually made on the ear lobe or forearm offorearm of
a depth that results in disruption of capillary loops and a depth that results in disruption of capillary loops and small vessels)small vessels)
AdvantagesAdvantages Universally availableUniversally available Relatively simple techniquesRelatively simple techniques Can be performed bedsideCan be performed bedside
DisadvantagesDisadvantages Insensitive inaccurate non-specific techniqueInsensitive inaccurate non-specific technique
Poorly reproducible (as depends on multiple variables)Poorly reproducible (as depends on multiple variables)
Optical aggregometryOptical aggregometry
Gold standard assay for platelet functionGold standard assay for platelet function Agonist induced aggregation is measuredAgonist induced aggregation is measured Different agonist are available for different Different agonist are available for different
agentsagents However require unique expertise and are not However require unique expertise and are not
universally availableuniversally available Aspirin measured with ADP or AA(gt70 Aspirin measured with ADP or AA(gt70
aggregation so resistance)aggregation so resistance) Clopidogrel( ADP gt 90 aggregation means Clopidogrel( ADP gt 90 aggregation means
resistance) resistance)
Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay
Can be performed bed sideCan be performed bed side Different assay devices with different Different assay devices with different
agonist are used for each of different agonist are used for each of different antiplatelet agents antiplatelet agents
For Aspirin AA is used (result is reported as aspirin For Aspirin AA is used (result is reported as aspirin reaction units [ARU] ARUgt 550 indicates non-reaction units [ARU] ARUgt 550 indicates non-responsiveness)responsiveness)
Verify IIbIIIa assay device uses TRAP as agonist for Verify IIbIIIa assay device uses TRAP as agonist for Abciximab and TirofibanAbciximab and Tirofiban
Practical Applications Practical Applications related to specific related to specific
Neurovascular Neurovascular interventionsinterventions
Acute ischemic StrokeAcute ischemic Stroke When an artery occludes neurons are affected When an artery occludes neurons are affected
differently depending upon the amount of residual blood differently depending upon the amount of residual blood flowflow
Normal cerebral blood flow is greater than 50 mL100 Normal cerebral blood flow is greater than 50 mL100 mgminmgmin
Once blood flow decreases to less than 20 mL100 Once blood flow decreases to less than 20 mL100 mgmin infarction occursmgmin infarction occurs
If blood flow decreases to less than 10 mL100 mgmin If blood flow decreases to less than 10 mL100 mgmin irreversible neuronal death occurs rapidly irreversible neuronal death occurs rapidly
Blood flow between 11 and 20 mL100 mgmin is thought Blood flow between 11 and 20 mL100 mgmin is thought to represent the ischemic penumbra an area where the to represent the ischemic penumbra an area where the cells are functionally silent because of ischemia but are cells are functionally silent because of ischemia but are still able to recover if blood flow is restored still able to recover if blood flow is restored
Many acute stroke therapies are targeted toward Many acute stroke therapies are targeted toward restoring flow or function to the ischemic penumbrarestoring flow or function to the ischemic penumbra
Therapeutic window in Therapeutic window in management of acute Ischemic management of acute Ischemic
StrokeStrokeThe early diagnosis of ischemic stroke is critical to the The early diagnosis of ischemic stroke is critical to the
with only a narrow therapeutic window in the first few with only a narrow therapeutic window in the first few hours following stroke ictushours following stroke ictus
Diagnosis in the first 3 hours postictus provides the Diagnosis in the first 3 hours postictus provides the opportunity for intravenous or intraarterial thrombolysis opportunity for intravenous or intraarterial thrombolysis and intra-arterial clot mechanical treatment which and intra-arterial clot mechanical treatment which improve the outcome improve the outcome
Diagnosis in the time period between 3 and 6 hours Diagnosis in the time period between 3 and 6 hours provides an opportunity for intra-arterial thrombolysis provides an opportunity for intra-arterial thrombolysis and mechanical treatment and mechanical treatment
Involvement of the posterior circulation especially the Involvement of the posterior circulation especially the basilar artery is treated by some regardless of time of basilar artery is treated by some regardless of time of onset or up until 12 to 24 hours in some practices This is onset or up until 12 to 24 hours in some practices This is related to the potentially high mortality and morbidity related to the potentially high mortality and morbidity associated with basilar artery thrombosisassociated with basilar artery thrombosis
Infarct evaluation on angiographyInfarct evaluation on angiography(CT angiography and catheter (CT angiography and catheter
angiography)angiography)CTA is an excellent first-line examination for CTA is an excellent first-line examination for
evaluation of the head and neck arteries evaluation of the head and neck arteries In comparison with catheter angiography In comparison with catheter angiography
what it gives up in resolution and dynamic what it gives up in resolution and dynamic properties it makes up for with rapid properties it makes up for with rapid acquisition of a 3-D dataset and the potential acquisition of a 3-D dataset and the potential for assessment of whole-brain perfusion and for assessment of whole-brain perfusion and better parenchymal evaluationbetter parenchymal evaluation
Moreover CTA illustrates not only arterial Moreover CTA illustrates not only arterial stenosis or occlusion but also the vessel wall stenosis or occlusion but also the vessel wall This factor is most important for evaluation of This factor is most important for evaluation of intramural dissection and thrombosed intramural dissection and thrombosed aneurysms which may both complicate aneurysms which may both complicate evaluation of stroke patientsevaluation of stroke patients
Early angiographic signs of strokes Early angiographic signs of strokes both CTA both CTA and DSA and DSA
Vessel occlusion or cutoff related to Vessel occlusion or cutoff related to thromboembolithromboemboli
aneurysms aneurysms arterial dissection arterial dissection Meniscus or flattened shape to clot Meniscus or flattened shape to clot
(recent) versus reverse meniscus (older)(recent) versus reverse meniscus (older) tram track (nonocclusive or recanalized tram track (nonocclusive or recanalized
clot) clot) delayed (antegrade) flow (manifest as delayed (antegrade) flow (manifest as
decreased whole-brain perfusion on CTA)decreased whole-brain perfusion on CTA) retrograde collateral flowretrograde collateral flow
Non-occlusive left MCA thrombus on 3-D imaging performed from CTA source data and was confirmed at catheter angiography
Therapy to be started within a 6-hr Therapy to be started within a 6-hr time to treatment (TTT) window time to treatment (TTT) window (while in case of IV thrombolysis (while in case of IV thrombolysis therapy to be started with in 3hrs)therapy to be started with in 3hrs)
Exclusion criteria Exclusion criteria Rapidly improving neurologic deficit or Rapidly improving neurologic deficit or Sustained blood pressure of gt180100 Sustained blood pressure of gt180100 Hemorrhage is detected on CTHemorrhage is detected on CT Infarct involving gt more than 13 rd Infarct involving gt more than 13 rd
territory of MCAterritory of MCA MRADWI-Perfusion mismatchlt 20MRADWI-Perfusion mismatchlt 20 Definite hypodensity on CTDefinite hypodensity on CT
Intra-arterial Thrombolysis
Fibrinolytics + AntiplateletsFibrinolytics + Antiplatelets
PlasminogenPlasminogen activators through fibrinolysis exposes activators through fibrinolysis exposes free thrombin and paradoxically stimulatesfree thrombin and paradoxically stimulates platelet platelet aggregation which leads to formation of aaggregation which leads to formation of a platelet platelet thrombus (white clot) thrombus (white clot)
This new thrombus is relatively resistant to This new thrombus is relatively resistant to fibrinolyticsfibrinolytics
So new regimen in case of acute stroke isSo new regimen in case of acute stroke is fibrinolytics + antiplatelet drugsfibrinolytics + antiplatelet drugs
rtPA + IIbIIIa inhibitors( tirofiban rtPA + IIbIIIa inhibitors( tirofiban abciximab) orabciximab) or
Urokinase + IIbIIIa Urokinase + IIbIIIa inhibitors( tirofiban abciximab)inhibitors( tirofiban abciximab)
Intra-arterial Thrombolysis Tirofiban (04 microgkgmin bolus for 3 min followed by Tirofiban (04 microgkgmin bolus for 3 min followed by
0125 ugkgmin)0125 ugkgmin)
++
Heparin (2000ndash3000 IU bolus followed by Heparin (2000ndash3000 IU bolus followed by 1000 IUhour infusion 1000 IUhour infusion
with ACT maintained bw 200-300) throughout the with ACT maintained bw 200-300) throughout the interventional procedure and for 24ndash48 hours thereafter when interventional procedure and for 24ndash48 hours thereafter when there is neither intraprocedural bleeding nor suspicion of there is neither intraprocedural bleeding nor suspicion of increased risk of bleeding increased risk of bleeding
Maximum dose of Urokinase Maximum dose of Urokinase Anterior circulation stroke - 500000 IU (mean 400000 Anterior circulation stroke - 500000 IU (mean 400000
IU range 300000ndash500000 IU)IU range 300000ndash500000 IU) Posterior circulation stroke -1000000 IU (mean 837000 Posterior circulation stroke -1000000 IU (mean 837000
IU range 300000ndash1000000 IU)IU range 300000ndash1000000 IU)American Journal of NeuroradiologyAmerican Journal of Neuroradiology 262595-2601 2005262595-2601 2005
Intravenous ThrombolysisIntravenous Thrombolysis
The first method to restore cerebral The first method to restore cerebral perfusion is clot lysis with the goal perfusion is clot lysis with the goal of re-establishing blood flow to the of re-establishing blood flow to the affected tissue affected tissue
IV thrombolysis rt-PA is the only IV thrombolysis rt-PA is the only FDA- approved treatment for AIS FDA- approved treatment for AIS
Fibrinolysis is enhanced powerfully Fibrinolysis is enhanced powerfully by rt-PAby rt-PA
Intravenous rTPA Intravenous rTPA administration administration protocolprotocol
Total dose of rt-PA 09 mgkg (maximum dose Total dose of rt-PA 09 mgkg (maximum dose 90 mg)90 mg)
Give 10 as initial IV bolusGive 10 as initial IV bolus Infuse remainder over 1 hourInfuse remainder over 1 hour Admit patient to an ICU or stroke unit for Admit patient to an ICU or stroke unit for
monitoringmonitoring Neurologic assessments every 15 minutes Neurologic assessments every 15 minutes
during infusion then every 30 minutes for next during infusion then every 30 minutes for next 6 hours then every hour until 24hours after 6 hours then every hour until 24hours after treatmenttreatment
Favorable Outcome vs Treatment Time Favorable Outcome vs Treatment Time with IV rTPAwith IV rTPA
Protocol limit = 3 hrs
Benefit ~ 45 hrs
Thromboembolism During coilingThromboembolism During coiling Most feared and frequent complication Most feared and frequent complication Reported incidence - Approx 7 Reported incidence - Approx 7 SourcesSources of Thromboembolism are of Thromboembolism are
- Clots at the aneurysmal neck during or immediately- Clots at the aneurysmal neck during or immediately after after embolization embolization
- Thrombus forming on catheters during- Thrombus forming on catheters during proceduresprocedures
- Stenosis of an adjacent artery dt coil mass- Stenosis of an adjacent artery dt coil mass or herniationor herniation
- Migration of intraaneurysmal- Migration of intraaneurysmal thrombus during coil thrombus during coil placement placement
- Slow flow dt vasospasm - Slow flow dt vasospasm
- Rare and unlikely causes are hypercoagulable- Rare and unlikely causes are hypercoagulable state such state such as antiphospholipid antibody syndrome or due to HITas antiphospholipid antibody syndrome or due to HIT
Occur more often with wide-necked aneurysms (dt Occur more often with wide-necked aneurysms (dt increased exposed surface area of thrombogenic coil increased exposed surface area of thrombogenic coil material)material)
Current regimen of endovascular Current regimen of endovascular managementmanagement
The The glycoprotein IIbIIIa antagonist tirofiban glycoprotein IIbIIIa antagonist tirofiban (04 (04 microgkgmin bolus for 30 minutes followed by infusion of microgkgmin bolus for 30 minutes followed by infusion of 0125 ugkgmin until the thrombus dissolved) 0125 ugkgmin until the thrombus dissolved)
Intraarterial thrombolysis with Intraarterial thrombolysis with urokinase or r- TPA urokinase or r- TPA increase of intravenous (IV) heparin (measured by increase of intravenous (IV) heparin (measured by
ACT) ACT) Intravenous aspirin Intravenous aspirin
Coil-related platelet aggregation (white clot) is Coil-related platelet aggregation (white clot) is unlikely to respond to fibrinolytics but has a high risk unlikely to respond to fibrinolytics but has a high risk of hemorrhage (In ISAT) all 5 patients who had of hemorrhage (In ISAT) all 5 patients who had received thrombolytic therapy with tPA to treat a received thrombolytic therapy with tPA to treat a thromboembolic complication after endovascular thromboembolic complication after endovascular treatment rebleed and all of these patients died)treatment rebleed and all of these patients died)
IntracranialIntracranial Stenting Stenting Metallic foreign body such as stent will accumulate Metallic foreign body such as stent will accumulate
thrombus in the absence of platelet inhibitionthrombus in the absence of platelet inhibition Antiplatelet drugs are important to prevent peri or Antiplatelet drugs are important to prevent peri or
post-interventional thromboembolic eventspost-interventional thromboembolic events Optimal treatment regimens has not been determined Optimal treatment regimens has not been determined
but usually but usually Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-
procedureprocedureOrOr
Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on
morning of proceduremorning of procedure
If need to use stent is not pre-planned thanIf need to use stent is not pre-planned than
Abciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkgAbciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkg IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)
Glycoprotein IIbIIIa inhibitor are not used routinely during elective Glycoprotein IIbIIIa inhibitor are not used routinely during elective stenting procedure dt increased risk of ICH stenting procedure dt increased risk of ICH
Carotid StentingCarotid Stenting
Pre-procedurePre-procedure
Double Antiplatelet therapy is routinely given Double Antiplatelet therapy is routinely given beginning at least 3beginning at least 3
days before the proceduredays before the procedure
Aspirin 325mgd+Clopidogrel 75mgdAspirin 325mgd+Clopidogrel 75mgd During procedureDuring procedure
Heparin is given with target clotting time of 250-Heparin is given with target clotting time of 250-300sec300sec
Post-procedure Post-procedure
Aspirin 325mg is continued indefinitely and Aspirin 325mg is continued indefinitely and
Clopidogrel 75mgd for at least 6 weeks Clopidogrel 75mgd for at least 6 weeks
Inclusion criteria for Local ThrombolysisInclusion criteria for Local Thrombolysis a)a) Patients in severe clinical grade on admission Patients in severe clinical grade on admission
with evidence of dural venous sinus with evidence of dural venous sinus thrombosis and restrictive venous outflow on thrombosis and restrictive venous outflow on cerebral angiogramcerebral angiogram
b)b) Patients in clinical grade 3 worsening on Patients in clinical grade 3 worsening on heparin therapy Restriction to venous heparin therapy Restriction to venous outflow was defined as an increase in brain outflow was defined as an increase in brain circulation time gt 12 s delay in the drainage circulation time gt 12 s delay in the drainage of cortical veins with cortical veins hanging of cortical veins with cortical veins hanging in spacein space
Treatment Options for Venous Thrombosis
CT Grading for Venous ThrombosisCT Grading for Venous Thrombosis Grade I no parenchymal change Grade I no parenchymal change
(hyperdense (hyperdense sinuses cortical veins empty sinuses cortical veins empty delta sign)delta sign)
Grade II non hemorrhagic venous infarct Grade II non hemorrhagic venous infarct without mass effect without mass effect
Grade III non-hemorrhagic infarct with Grade III non-hemorrhagic infarct with mass effectmass effect
Grade IV hemorrhagic venous infarct (max Grade IV hemorrhagic venous infarct (max diameter lt 3 cm) with no mass effectdiameter lt 3 cm) with no mass effect
Grade V hemorrhagic venous infarct (max Grade V hemorrhagic venous infarct (max diameter gt 3 cm) with mass effect diameter gt 3 cm) with mass effect
Local ThrombolysisLocal Thrombolysis
Femoral Jugular access was secured and a guiding Femoral Jugular access was secured and a guiding catheter was placed in the jugular bulb catheter was placed in the jugular bulb Mechanical Mechanical clot maceration clot maceration was done with the guidewire was done with the guidewire following which a microcatheter (was navigated and following which a microcatheter (was navigated and placed in the thrombosed segment of sinus confirmed placed in the thrombosed segment of sinus confirmed on a selective venogram on a selective venogram
Urokinase infusion Bolus dose of 2-6 lacs followed Urokinase infusion Bolus dose of 2-6 lacs followed by 60000 to 100000 units per hour along with by 60000 to 100000 units per hour along with periodic check venogram Along with maintenance periodic check venogram Along with maintenance systemic infusion of Heparinsystemic infusion of Heparin Other agents such as Other agents such as streptokinase altepase or rTPAstreptokinase altepase or rTPA can be also used can be also used
After thrombolysis patient should subjected to oral After thrombolysis patient should subjected to oral anticoagulation for six monthsanticoagulation for six months
Low-molecular-weight Low-molecular-weight heparinheparin
PharmacologyPharmacologyLMWH as its name suggests is a glycosaminoglycan that is approximatelyLMWH as its name suggests is a glycosaminoglycan that is approximately
one third the molecular weight of UFH It is derived from UFH through one third the molecular weight of UFH It is derived from UFH through variousvarious
depolymerization processes LMWH binds to antithrombin which in turn depolymerization processes LMWH binds to antithrombin which in turn
Neutralizes actors Xa and IIa Because LMWH lacks many of the longer Neutralizes actors Xa and IIa Because LMWH lacks many of the longer chains chains
required for binding to thrombin it has less ability to neutralize thrombin required for binding to thrombin it has less ability to neutralize thrombin
relativeto its ability to neutralize factor Xa LMWH also has less relativeto its ability to neutralize factor Xa LMWH also has less nonspecific nonspecific
binding to other proteins There is greater bioavailability with more binding to other proteins There is greater bioavailability with more predictable predictable
pharmacokinetics that eliminates the need for monitoring The smaller pharmacokinetics that eliminates the need for monitoring The smaller size also size also
allows for enhanced subcutaneous absorption when compared with UFHallows for enhanced subcutaneous absorption when compared with UFH
Three LMWH preparations are Three LMWH preparations are currently approved for use in the currently approved for use in the United States (1) enoxaparin (2) United States (1) enoxaparin (2) dalteparin and (3) tinzaparin dalteparin and (3) tinzaparin
They are all administered They are all administered subcutaneously at intervals of either subcutaneously at intervals of either once or twice daily for both once or twice daily for both prophylaxis and treatment dosesprophylaxis and treatment doses
Few Experiences of Few Experiences of ThrombolysisThrombolysis
Vickey 25 Yrs male patient presented Vickey 25 Yrs male patient presented with 12with 12thth day HO severe headache with day HO severe headache with right sided hemiplegiaright sided hemiplegia
MRI shows thrombosis of the superior MRI shows thrombosis of the superior sagittal left transverse left sigmoid sagittal left transverse left sigmoid sinuses and cortical veins in the fronto-sinuses and cortical veins in the fronto-parietal regions with eo haemorrhagic parietal regions with eo haemorrhagic infarct in the left cerebral hemisphere infarct in the left cerebral hemisphere with mass effect( Grade ndashV)with mass effect( Grade ndashV)
Sashi Srivastava 64 yrs FSashi Srivastava 64 yrs F In a follow up case of MRD with infra-renal In a follow up case of MRD with infra-renal
aortic abdominal and bilateral renal artery aortic abdominal and bilateral renal artery thrombosis renal angiogram shows filling thrombosis renal angiogram shows filling defects in the right Renal artery defects in the right Renal artery
Initially Renal angioplasty was done Initially Renal angioplasty was done Following angioplasty few thrombi are seem Following angioplasty few thrombi are seem to extends into the segmental branches and to extends into the segmental branches and causing blockage So Thrombolysis was causing blockage So Thrombolysis was plane to dissolve the run-out thrombi with plane to dissolve the run-out thrombi with urokinase urokinase
Rakesh 34yrsMRakesh 34yrsM Left SFA pseudoaneurysm with Left SFA pseudoaneurysm with
Covered stent placementCovered stent placement Pre operative antiplatelets with post Pre operative antiplatelets with post
procedure heparin Tirofiban procedure heparin Tirofiban followed by aspirin and clopidogrel followed by aspirin and clopidogrel were usedwere used
IAT may be a treatment option for selected patients IAT may be a treatment option for selected patients Possible selection criteria include Possible selection criteria include
presentation between 3 and 6 hours from symptom onsetpresentation between 3 and 6 hours from symptom onset major cerebral artery occlusion major cerebral artery occlusion severe neurologic deficits severe neurologic deficits high risk of systemic hemorrhage with IV rt-PA (eg recent high risk of systemic hemorrhage with IV rt-PA (eg recent
surgery) surgery) The MERCI (Mechanical Embolus Removal in Cerebral The MERCI (Mechanical Embolus Removal in Cerebral
Ischemia) retrievalIschemia) retrieval system system
Has been FDA-approved for recanalizing acutely occluded Has been FDA-approved for recanalizing acutely occluded cerebral arteries cerebral arteries
In the Multi-MERCI study patients who did not improve In the Multi-MERCI study patients who did not improve immediately after IV rt-PA underwent mechanical immediately after IV rt-PA underwent mechanical embolectomy within 8 hours of symptom onset embolectomy within 8 hours of symptom onset
Partial or complete recanalization occurred in 74 of Partial or complete recanalization occurred in 74 of patientspatients
with a symptomatic intracerebral hemorrhage (sICH) rate of with a symptomatic intracerebral hemorrhage (sICH) rate of 67 67
Mechanical embolectomy with the MERCI retriever may be a Mechanical embolectomy with the MERCI retriever may be a feasible and safe option for patients after IV rt-PAfeasible and safe option for patients after IV rt-PA
Penumbra stroke systemPenumbra stroke system This device combines two methods of clot This device combines two methods of clot
extraction aspiration and mechanical extraction aspiration and mechanical extraction extraction
First the clot is aspirated then a thrombus First the clot is aspirated then a thrombus removal ring can be used if necessary to removal ring can be used if necessary to remove remaining clot remove remaining clot
successful recanalizing 82successful recanalizing 82 Bridging therapyBridging therapy
06 mgkg IV rt-PA followed by IAT with IA rt-06 mgkg IV rt-PA followed by IAT with IA rt-PA (up to 20 mg)PA (up to 20 mg)
achieved a higher recanalization rateachieved a higher recanalization rate
Criteria for thrombolysis with rTPACriteria for thrombolysis with rTPA
Inclusion criteriaInclusion criteria Clinical signs and symptoms consistent with ischemic Clinical signs and symptoms consistent with ischemic
strokestroke Patient last seen normal within 3 hoursPatient last seen normal within 3 hours Measurable neurologic deficitMeasurable neurologic deficit
Exclusion criteriaExclusion criteria Any hemorrhage on neuroimaging (CT or MRI)Any hemorrhage on neuroimaging (CT or MRI) Symptoms suggestive of subarachnoid hemorrhageSymptoms suggestive of subarachnoid hemorrhage Seizure at stroke onset that is thought to contribute to Seizure at stroke onset that is thought to contribute to
neurologic deficitneurologic deficit Hypodensity greater than one third cerebral hemisphere Hypodensity greater than one third cerebral hemisphere
on CTon CT SBP greater than 185 mm Hg or DBP greater than 110 SBP greater than 185 mm Hg or DBP greater than 110
mm Hgmm Hg International normalized ratio (INR) greater than 17International normalized ratio (INR) greater than 17
Ischemic Stroke Ischemic Stroke Treatment ndash 2006Treatment ndash 2006
IV tissue plasminogen activator (tPA)IV tissue plasminogen activator (tPA) ndash ndash Only FDA-approved acute stroke drugOnly FDA-approved acute stroke drug ndash ndash 3 hour treatment window3 hour treatment window
MERCI - Concentric clot retrieval MERCI - Concentric clot retrieval devicedevice ndash ndash Rescue therapy - approved 2004Rescue therapy - approved 2004 ndash ndash Device approval (not outcomes-based)Device approval (not outcomes-based)
Off label approachesOff label approaches ndash ndash IV tPA after 3 hoursIV tPA after 3 hours ndash ndash IV-IA tPA sequential strategiesIV-IA tPA sequential strategies ndash ndash IA tPA clot angioplasty fragmentationIA tPA clot angioplasty fragmentation ndash ndash Ultrasound-assisted tPA lysisUltrasound-assisted tPA lysis
rt-PA Trials NINDSrt-PA Trials NINDS
Acute stroke - 624 patientsAcute stroke - 624 patients Treat within 3 hrsTreat within 3 hrs Intravenous 09 mgkg rt-PA vs placeboIntravenous 09 mgkg rt-PA vs placebo Hemorrhage 64 tPA 06 placeboHemorrhage 64 tPA 06 placebo Neurologic recovery better with tPA 30 Neurologic recovery better with tPA 30
more like to have minimal or no disabilitymore like to have minimal or no disability
First proven approved treatment for First proven approved treatment for strokestroke
Limitations of tPALimitations of tPA Only 4 of acute strokes receive tPAOnly 4 of acute strokes receive tPA (Kleindorfer et al Stroke 2004 35 e27-e29)(Kleindorfer et al Stroke 2004 35 e27-e29)
Only 22 of patients present within 3 hoursOnly 22 of patients present within 3 hours1048707 1048707 51 of these ineligible due to51 of these ineligible due to
bull bull Mild severityMild severity bull bull Medical or surgical historyMedical or surgical history bull bull Blood testsBlood tests
Sustained recanalization only 13Sustained recanalization only 13 (Alexandrov et al NEJM 2004 351 2170-8)(Alexandrov et al NEJM 2004 351 2170-8)
Concern for hemorrhageConcern for hemorrhage tPA potentiates apoptotic injury tPA potentiates apoptotic injury (Liu et al Nature Med 2004 101379-83)(Liu et al Nature Med 2004 101379-83)
PROACT II IA Lysis TrialPROACT II IA Lysis Trial Baseline 24 hours 8 days
Baseline 60 minutes 120 minutes
9mg IAProurokinase
Desmoteplase Trials DEDAS Desmoteplase Trials DEDAS DIASDIAS
Trial OverviewTrial Overview Double blind randomized placebo Double blind randomized placebo
controlled trialscontrolled trials IV delivery 3-9 hour time windowIV delivery 3-9 hour time window Plasminogen activator ndash from Plasminogen activator ndash from vampire bat vampire bat
salivasaliva Selection based on PWI-DWI MismatchSelection based on PWI-DWI Mismatch
MRI InclusionMRI Inclusion PWI defect at least 2 cm AND ~20 larger PWI defect at least 2 cm AND ~20 larger
than DWIthan DWI PWI should be obvious even visible on PWI should be obvious even visible on
raw imagesraw imagesMRI ExclusionMRI Exclusion
DWI gt 13 MCADWI gt 13 MCA MRA ICA occlusionMRA ICA occlusion
Desmoteplase ndash DIAS Desmoteplase ndash DIAS ResultsResults
Mechanical Thrombolysis Mechanical Thrombolysis devicesdevices
mechanical thrombolysis potentially extends the treatment mechanical thrombolysis potentially extends the treatment window because they act promptly at the site of the thrombuswindow because they act promptly at the site of the thrombus
The devices can retrieve large clots that pharmaceutical agents The devices can retrieve large clots that pharmaceutical agents may not successfully lysemay not successfully lyse
Patients treated with IV tPA may be considered for treatment of Patients treated with IV tPA may be considered for treatment of residual clot with some of these devicesresidual clot with some of these devices
suction-creating saline jets suction-creating saline jets laser energy ultrasound laser energy ultrasound a corkscrew apparatus to treat strokesa corkscrew apparatus to treat strokes The AngioJet systemThe AngioJet system uses saline jets that are directed back into the catheter to uses saline jets that are directed back into the catheter to
create a low-pressure zone around the catheter tip inducing create a low-pressure zone around the catheter tip inducing suction suction
The clot is pulled into the exhaust lumen and removed from the The clot is pulled into the exhaust lumen and removed from the vessel Although US Food and Drug Administration (FDA) has vessel Although US Food and Drug Administration (FDA) has approved this device for use in arteriovenous dialysis grafts and approved this device for use in arteriovenous dialysis grafts and fistulae and for the treatment of coronary arteries saphenous fistulae and for the treatment of coronary arteries saphenous vein grafts and peripheral vessels clinical trials for the vein grafts and peripheral vessels clinical trials for the treatment of acute stroke are no longer in progress treatment of acute stroke are no longer in progress
Most devices are used in cerebral vessels that 2-5 mm
The Latis laser device The Latis laser device used laser energy to ablate clots used laser energy to ablate clots Arteries 2-5 mm in diameter could be Arteries 2-5 mm in diameter could be
treated including the ICA M1 or M2 treated including the ICA M1 or M2 branch of the MCA A1 branch of the branch of the MCA A1 branch of the anterior cerebral artery (ACA) basilar anterior cerebral artery (ACA) basilar artery posterior cerebral artery (PCA) artery posterior cerebral artery (PCA) and vertebral and vertebral
Patients could receive treatment as late Patients could receive treatment as late as 8 hours after symptom onset in the as 8 hours after symptom onset in the anterior circulation and within 24 hours in anterior circulation and within 24 hours in the posterior circulation the posterior circulation
Endovascular Photo Acoustic Endovascular Photo Acoustic Recanalization (EPAR) Recanalization (EPAR)
A laser power source generated energy for the A laser power source generated energy for the systemsystem
The energy was delivered by means of The energy was delivered by means of fiberoptics to the tip of the catheter at the fiberoptics to the tip of the catheter at the treatment sitetreatment site
Absorption of laser light by darkly pigmented Absorption of laser light by darkly pigmented materials (ie the clot) occurred inside the 1-mm materials (ie the clot) occurred inside the 1-mm catheter tipcatheter tip
the system was designed to minimize scattering the system was designed to minimize scattering of laser light of laser light
Absorption converted photo energy to acoustic Absorption converted photo energy to acoustic energy which then emulsified the clot inside the energy which then emulsified the clot inside the catheter tip catheter tip
EKOS ultrasound( the EKOS ultrasound( the Ultrasound Thrombolytic Ultrasound Thrombolytic
Infusion Catheter) Infusion Catheter) combines the use of a distal ultrasound transducer with combines the use of a distal ultrasound transducer with
infusion of a thrombolytic agent through the infusion of a thrombolytic agent through the microcathetermicrocatheter
Ultrasound changes the structure of the clot to Ultrasound changes the structure of the clot to temporarily increase its permeability while providing an temporarily increase its permeability while providing an acoustic pressure gradient to move the drug into the clot acoustic pressure gradient to move the drug into the clot to speed its dissolution to speed its dissolution
The EKOS catheter is placed in the proximal portion of the The EKOS catheter is placed in the proximal portion of the clot clot
After a 2-mg bolus of tPA was injected through the After a 2-mg bolus of tPA was injected through the catheter catheter
the patient received a continuous infusion of IA tPA 03 the patient received a continuous infusion of IA tPA 03 mgmin to a maximum of 20 mg and simultaneous mgmin to a maximum of 20 mg and simultaneous ultrasound transmission for as long as 60 minutes ultrasound transmission for as long as 60 minutes
One patient was treated with a total of 4 units of One patient was treated with a total of 4 units of recombinant reteplase (Retavase) hand-injected over 60 recombinant reteplase (Retavase) hand-injected over 60 minutes minutes
Penumbra system Penumbra system The Penumbra system (Penumbra Inc) provides a dual The Penumbra system (Penumbra Inc) provides a dual
approach to clot extraction using aspiration followed by approach to clot extraction using aspiration followed by clot retrieval with a ring device if needed clot retrieval with a ring device if needed
Mechanical Embolus Removal in Cerebral Ischemia Mechanical Embolus Removal in Cerebral Ischemia (MERCI)(MERCI)
a corkscrew-like apparatus to remove blood clots from a corkscrew-like apparatus to remove blood clots from the brain in patients experiencing an ischemic stroke the brain in patients experiencing an ischemic stroke
The corkscrew itself resides in the catheter tip which The corkscrew itself resides in the catheter tip which shields it from the wall of the vessel until it is ready to be shields it from the wall of the vessel until it is ready to be burrowed into the clot Once lodged in the clot the device burrowed into the clot Once lodged in the clot the device and clot are withdrawn from the vessel and clot are withdrawn from the vessel
Snarelike devicesSnarelike devices Snares such as the Neuronet snare (Guidant Snares such as the Neuronet snare (Guidant
Endovascular Santa Clara CA) have been developed Endovascular Santa Clara CA) have been developed specifically for use in the treatment of strokes specifically for use in the treatment of strokes
These devices are simple in design and do not require the These devices are simple in design and do not require the clot to be amenable to emulsification clot to be amenable to emulsification
X-Sizer deviceX-Sizer device a device with small moving blades at the a device with small moving blades at the
catheter tip catheter tip This device the X-Sizer device (EndiCor Medical This device the X-Sizer device (EndiCor Medical
San Clemente CA) can be used to excise the San Clemente CA) can be used to excise the thrombus and aspirate it thrombus and aspirate it
The device was being evaluated in randomized The device was being evaluated in randomized studies of coronary vessels and in a registry of studies of coronary vessels and in a registry of patients with acute myocardial infarctionpatients with acute myocardial infarction
Although the manufacturer had modified the Although the manufacturer had modified the device for use in cerebral vessels a safety and device for use in cerebral vessels a safety and feasibility study was indefinitely suspended after feasibility study was indefinitely suspended after only 1 patient was treated with the device in only 1 patient was treated with the device in Europe Europe
Suction thrombectomySuction thrombectomy This method of mechanical thrombolysis is one of the This method of mechanical thrombolysis is one of the
simplestsimplest In this readily available technique suction is applied with In this readily available technique suction is applied with
a syringe to remove thrombus in the ICA a syringe to remove thrombus in the ICA It requires no other devicesIt requires no other devices A catheter with a large inner diameter (Brite Tip Cordis A catheter with a large inner diameter (Brite Tip Cordis
Corporation Miami FL) was placed in the symptomatic Corporation Miami FL) was placed in the symptomatic vessel and navigated over a guidewire into the thrombusvessel and navigated over a guidewire into the thrombus
A 60-mL syringe was used to aspirate the thrombus A 60-mL syringe was used to aspirate the thrombus Each patient required angioplasty and stenting of carotid Each patient required angioplasty and stenting of carotid
bifurcation stenosis and received daily aspirin and bifurcation stenosis and received daily aspirin and ticlopidine after the procedure No complications ticlopidine after the procedure No complications occurred occurred
Summary Acute Stroke Summary Acute Stroke ImagingImaging
PhysiologyPhysiology importance collaterals importance collaterals
ndash ndashGrowing role for perfusion Growing role for perfusion assessmentassessment
tPAtPA guidelines amp limitations guidelines amp limitations Signs on CT amp MRSigns on CT amp MR follow physiology follow physiology Stroke trialsStroke trials PWI-DWI mismatch PWI-DWI mismatch
ndash ndashTreat based on physiology not timeTreat based on physiology not time ProtocolsProtocols should be fast and should be fast and
comprehensivecomprehensive
During neuroangiography-During neuroangiography- Recommended therapeutic range of heparin in Recommended therapeutic range of heparin in
plasma is 02-08 uml ( corresponding to aPTT plasma is 02-08 uml ( corresponding to aPTT ACT values 15-25 times the baseline values)ACT values 15-25 times the baseline values)
Dose In diagnostic angiography bolus dose of Dose In diagnostic angiography bolus dose of 2500 iu is used followed by 1000 iu hour2500 iu is used followed by 1000 iu hour
Bolus dose is Bolus dose is 60 ukg to maintain the therapeutic 60 ukg to maintain the therapeutic range range If procedure continues for more than 75 If procedure continues for more than 75 minutes additional dose is required ( half of the minutes additional dose is required ( half of the initial dose for another 75 minutes) initial dose for another 75 minutes)
(AJNR 199415 51-54)
Mechanisms of HIT( Mechanisms of HIT( Heparin Heparin induced Thrombocytopeniainduced Thrombocytopenia))
Type 1Type 1 Fall in platelet count occurs within the first two Fall in platelet count occurs within the first two
days after heparin initiation often returns to days after heparin initiation often returns to normal with continued heparin administration normal with continued heparin administration and is of no clinical consequence and is of no clinical consequence
The mechanism of the thrombocytopenia is non-The mechanism of the thrombocytopenia is non-immune and appears to be due to a direct effect of immune and appears to be due to a direct effect of heparin on platelet activationheparin on platelet activation
Type 2Type 2 Approximately 03 to 3 percent of patients Approximately 03 to 3 percent of patients
receiving heparin develop an immune receiving heparin develop an immune thrombocytopenia mediated by antibodies to a thrombocytopenia mediated by antibodies to a heparin-platelet factor 4 complex heparin-platelet factor 4 complex
(AJNR 28155-158 2007)
Treatment of heparin-induced Treatment of heparin-induced thrombocytopeniathrombocytopenia
When HIT is diagnosed it is important to When HIT is diagnosed it is important to stop heparin mainly in type 2 and to avoid stop heparin mainly in type 2 and to avoid the use of LMWH the use of LMWH
Because of the increased risk of thrombosis Because of the increased risk of thrombosis however continuation of an anticoagulant however continuation of an anticoagulant must be considered must be considered
The drugs currently approved for the The drugs currently approved for the treatment of HIT in the United States are treatment of HIT in the United States are direct thrombin inhibitors argatroban and direct thrombin inhibitors argatroban and lepirudinlepirudin
WARFARIN MECHANISM OF ACTIONWARFARIN MECHANISM OF ACTION
Inactive factors II VII IX and X
Proteins S and C
Active factors II VII IX and X
Proteins S and C
Vitamin K epoxide
Vitamin K reduced
WA
RF
AR
IN
Prevents the reduction of vitamin K which is essential for Prevents the reduction of vitamin K which is essential for activation of certain factorsactivation of certain factors
Has no effect on previously formed thrombusHas no effect on previously formed thrombus
Antagonist is Vit KAntagonist is Vit K
OPTIMIZING WARFARIN THERAPYOPTIMIZING WARFARIN THERAPY
Use of large loading dose may lead to hemorrhage and Use of large loading dose may lead to hemorrhage and other complicationsother complications
Initial dose 2-5 mg once dailyInitial dose 2-5 mg once daily Maintenance dose 2-10 mg once dailyMaintenance dose 2-10 mg once daily If Immediate anticoagulation is requiredIf Immediate anticoagulation is required Heparin IS Heparin IS
started along with loading dose of warfarin 10 mg started along with loading dose of warfarin 10 mg Heparin is usually discontinued after 4-5 days Heparin is usually discontinued after 4-5 days Before Before discontinuing INR should be in therapeutic range for 2 discontinuing INR should be in therapeutic range for 2 consecutive daysconsecutive days
Daily monitoring of INR until INR is in therapeutic Daily monitoring of INR until INR is in therapeutic range then 3 times weekly for 1-2 weeks then less often range then 3 times weekly for 1-2 weeks then less often (every 4 to 6 weeks)(every 4 to 6 weeks)
OPTIMAL THERAPEUTIC RANGEOPTIMAL THERAPEUTIC RANGE
IndicationIndication INRINR
Prophylaxis of venous Prophylaxis of venous thromboembolismthromboembolism
20-3020-30
Treatment of venous Treatment of venous thromboembolismthromboembolism
20-3020-30
Atrial fibrillationAtrial fibrillation 20-3020-30
Mitral valve stenosisMitral valve stenosis 20-3020-30
Heart valve replacementHeart valve replacement
Bioprosthetic valveBioprosthetic valve
Mechanical valveMechanical valve
20-3020-30
25-3525-35
Myocardial infarctionMyocardial infarction 20-3020-30
25-35 25-35 (high risk patients)(high risk patients)
FACTORS INFLUENCING DOSE RESPONSEFACTORS INFLUENCING DOSE RESPONSE
Poor patient compliancePoor patient compliance Concomitant medicationsConcomitant medications Levels of dietary vitamin KLevels of dietary vitamin K Alcohol Inaccurate lab testingAlcohol Inaccurate lab testing Inaccurate lab testingInaccurate lab testing Hepatic dysfunctionHepatic dysfunction FeverFever
Contraindication for WarfarinContraindication for Warfarin
Hypersensitivity to warfarinHypersensitivity to warfarin Hemorrhagic tendencyHemorrhagic tendency Condition with risk of hemorrhageCondition with risk of hemorrhage Inadequate laboratory techniquesInadequate laboratory techniques Protein C amp S deficiencyProtein C amp S deficiency Vitamin K deficiencyVitamin K deficiency
SIDE EFFECTSSIDE EFFECTS
Hemorrhage Hemorrhage Skin necrosisSkin necrosis Purple toe syndromePurple toe syndrome Microembolization Microembolization TeratogenecityTeratogenecity Agranulocytosis leukopenia Agranulocytosis leukopenia Diarrhoeanausea anorexiaDiarrhoeanausea anorexia
MONITORING OF WARFARIN THERAPYMONITORING OF WARFARIN THERAPY
Prothrombin timeProthrombin time PT ratioPT ratio INR (International Normalized Ratio)INR (International Normalized Ratio)
PROTHROMBIN TIME (PT)PROTHROMBIN TIME (PT)
Time required for blood to coagulate Time required for blood to coagulate is called PT ( normal value ~10sec)is called PT ( normal value ~10sec)
Performed by adding a mixture of Performed by adding a mixture of calcium and thromboplastin to calcium and thromboplastin to citrated plasmacitrated plasma
As a control a normal blood sample is As a control a normal blood sample is tested continuouslytested continuously
PT ratio (PTR) = PT ratio (PTR) = Patientrsquos PTPatientrsquos PT Control PTControl PT
PROBLEMS WITH PTPTRPROBLEMS WITH PTPTR
Thromboplastins are extracts from Thromboplastins are extracts from brain lung or placenta of animalsbrain lung or placenta of animals
Thromboplastins from various Thromboplastins from various manufacturers differ in their manufacturers differ in their sensitivity to prolong PTsensitivity to prolong PT
May result in false control of May result in false control of anticoagulant therapyanticoagulant therapy
INTERNATIONAL NORMALISED RATIO (INR)INTERNATIONAL NORMALISED RATIO (INR)
International Normalized Ratio (INR) International Normalized Ratio (INR) a PT test with a a PT test with a formula based ratio to normalize the often variable source formula based ratio to normalize the often variable source of tissue factor (human rabbit recombinant)of tissue factor (human rabbit recombinant)
INR = [PTINR = [PTptpt] ] ISIISI
[PT[PTRefRef]]
PTPTpt pt ndash prothrombin time of patientndash prothrombin time of patient
PTPTRef Ref ndash prothrombin time of normal pooled samplendash prothrombin time of normal pooled sample
ISI ndash International Sensitivity IndexISI ndash International Sensitivity Index
Warfarin is given orally and titrated to achieve an INR of Warfarin is given orally and titrated to achieve an INR of typically 20 ndash 30typically 20 ndash 30
Heparin versus WarfarinHeparin versus Warfarin
Drug ActionMechan-ism
Moni-toring
Effective
HeparinDirect
Inhibition ofThrombin
ATIIIcofactor
APTTACT
Immediate
WarfarinDecreasesProductionof factors
Vitamin K PTDelay
3-5 days
INR
Recanalization or Antegrade Recanalization or Antegrade Reperfusion StrategiesReperfusion Strategies
Recanalization strategies focus on removing Recanalization strategies focus on removing andor dissolving the occlusive thrombus to re-andor dissolving the occlusive thrombus to re-establish antegrade flow Strategies may be establish antegrade flow Strategies may be classified into 7 different categories on the classified into 7 different categories on the basis of their primary mechanism of action basis of their primary mechanism of action 1) 1) IV andor intraarterial thrombolysis (IAT) IV andor intraarterial thrombolysis (IAT) 2) endovascular thrombectomy2) endovascular thrombectomy3) endovascular thromboaspiration 3) endovascular thromboaspiration 4) endovascular mechanical thrombus disruption or 4) endovascular mechanical thrombus disruption or
thromborrhexisthromborrhexis5) 5) transcranial or endovascular augmented transcranial or endovascular augmented
fibrinolysis fibrinolysis 6) endovascular thrombus entrapment and 6) endovascular thrombus entrapment and 7) temporary endovascular bypass7) temporary endovascular bypass
IAT in Acute Ischemic StrokeIAT in Acute Ischemic Stroke
IAT advantages over IV thrombolysisIAT advantages over IV thrombolysis Coaxial microcatheter techniques the occluded intracranial Coaxial microcatheter techniques the occluded intracranial
vessel is directly accessible and the fibrinolytic agent can be vessel is directly accessible and the fibrinolytic agent can be infused directly into the thrombusinfused directly into the thrombus
This permits a smaller dose of fibrinolytic agent to reach a This permits a smaller dose of fibrinolytic agent to reach a higher local concentration than that reached by systemic higher local concentration than that reached by systemic infusioninfusion
Allows more complete recanalization with lower total doses of Allows more complete recanalization with lower total doses of thrombolytic thrombolytic
With the smaller dose complications from systemic fibrinolytic With the smaller dose complications from systemic fibrinolytic effects including intracranial hemorrhage (ICH) can effects including intracranial hemorrhage (ICH) can theoretically be reduced theoretically be reduced
Treatment window for endovascular techniques can be Treatment window for endovascular techniques can be extended beyond the typical IV window of 3 hours extended beyond the typical IV window of 3 hours
IA techniques have led to higher recanalization rates than IV IA techniques have led to higher recanalization rates than IV thrombolysisthrombolysis
Major disadvantagesMajor disadvantages Relative complexity of the procedure the level Relative complexity of the procedure the level
of required technical expertise and its of required technical expertise and its relatively low availability relatively low availability
Delays in initiating treatmentDelays in initiating treatment InvasiveInvasive
ThrombolyticsThrombolytics
Plasminogen activators
Fibrinolytics
1 Plasminogen Activators 1 Plasminogen Activators drugs act by converting the inactive proenzyme drugs act by converting the inactive proenzyme plasminogen into the active enzyme plasmin Plasmin plasminogen into the active enzyme plasmin Plasmin digests fibrinogen fibrin monomers and cross-linked digests fibrinogen fibrin monomers and cross-linked fibrin (as found in a thrombus) into fibrin degradation fibrin (as found in a thrombus) into fibrin degradation productsproducts
First-Generation Agents First-Generation Agents StreptokinaseStreptokinase a protein derived from group C a protein derived from group C
szlig-hemolytic streptococci has a half-life of 16ndashszlig-hemolytic streptococci has a half-life of 16ndash90 minutes and low fibrin specificity This drug 90 minutes and low fibrin specificity This drug proved to have a very narrow therapeutic proved to have a very narrow therapeutic window and significant rates of ICH and window and significant rates of ICH and systemic hemorrhage18systemic hemorrhage18
UrokinaseUrokinase is a serine protease with a plasma is a serine protease with a plasma half life of 14 minutes and low fibrin specificity half life of 14 minutes and low fibrin specificity
The urokinase dose used in cerebral IAT has The urokinase dose used in cerebral IAT has ranged from 002 to 2 X106unitsranged from 002 to 2 X106units
Second-Generation Agents Second-Generation Agents Alteplase (rtPA) Alteplase (rtPA)
is a serine is a serine protease with a plasma half-life of 35 protease with a plasma half-life of 35 minutes and a high degree of fibrin affinity and minutes and a high degree of fibrin affinity and specificity specificity
Dose used in cerebral IAT has ranged between 20 Dose used in cerebral IAT has ranged between 20 and 60 mgand 60 mg
Disadvantages of alteplase include its relatively short Disadvantages of alteplase include its relatively short halflife and limited penetration into the clot matrix halflife and limited penetration into the clot matrix because of strong binding with surface fibrin which because of strong binding with surface fibrin which could delay recanalization and increase the risk of could delay recanalization and increase the risk of recurrent occlusion recurrent occlusion
Prourokinase (r-prourokinase) Prourokinase (r-prourokinase) is the proenzyme precursor of urokinase is the proenzyme precursor of urokinase T12 of 7 minutes and high fibrin specificity T12 of 7 minutes and high fibrin specificity
Third-Generation AgentsThird-Generation Agents
ReteplaseReteplase is a structurally modified is a structurally modified form of alteplase form of alteplase
with a longer half-life (15ndash18 minutes) In with a longer half-life (15ndash18 minutes) In addition it does not bind as highly to fibrin addition it does not bind as highly to fibrin unbound reteplase can thus theoretically better unbound reteplase can thus theoretically better penetrate the clot and potentially penetrate the clot and potentially improve in improve in vivo fibrinolytic activity vivo fibrinolytic activity
TenecteplaseTenecteplase is another modified form of rtPA with a longer is another modified form of rtPA with a longer
half-life (17 minutes)half-life (17 minutes) greater fibrin specificity and greater greater fibrin specificity and greater
resistance to plasminogen activator inhibitor-1 resistance to plasminogen activator inhibitor-1 IV tenecteplase in acute ischemic stroke IV tenecteplase in acute ischemic stroke
suggest that the drug is safe and promisingsuggest that the drug is safe and promising
Newer plasminogen activatorNewer plasminogen activator
DesmoteplaseDesmoteplase is a genetically engineered is a genetically engineered version of the clot-dissolving factor version of the clot-dissolving factor
found in the saliva found in the saliva of the vampire bat Desmodus rotundusof the vampire bat Desmodus rotundus moremore potent and more selective for fibrin-bound potent and more selective for fibrin-bound
plasminogen than any other known plasminogen plasminogen than any other known plasminogen activatoractivator
Unlike tissue plasminogen activator (tPA) desmoteplase Unlike tissue plasminogen activator (tPA) desmoteplase is not activated by fibrinogen or -amyloid proteins is not activated by fibrinogen or -amyloid proteins factors that may exacerbate the risk for ICH factors that may exacerbate the risk for ICH
The effect of IV administration of desmoteplase 3ndash9 The effect of IV administration of desmoteplase 3ndash9 hours after symptom onset in patients with stroke who hours after symptom onset in patients with stroke who present with mismatch on MR imaging or CT perfusion present with mismatch on MR imaging or CT perfusion
3 DefibrinogenatingFibrinogenolytic 3 DefibrinogenatingFibrinogenolytic Agents Agents
AncrodAncrod(Viprinex)(Viprinex) is is the purified fraction of the Malayan pit viper venomthe purified fraction of the Malayan pit viper venom It acts by directly cleaving and inactivating fibrinogen It acts by directly cleaving and inactivating fibrinogen
and thus indirectly promoting anticoagulation and thus indirectly promoting anticoagulation The reduction in the blood levels of fibrinogen also The reduction in the blood levels of fibrinogen also
leads to a reduced blood viscosity which may improve leads to a reduced blood viscosity which may improve blood flow to the affected areas of the brain blood flow to the affected areas of the brain
In the Stroke Treatment with Ancrod Trial 500 In the Stroke Treatment with Ancrod Trial 500 patients with stroke presenting within 3 hours of patients with stroke presenting within 3 hours of symptom onset were randomized to receive ancrod (symptom onset were randomized to receive ancrod (n n 248) or a placebo (n 252) Good outcome (Barthel 248) or a placebo (n 252) Good outcome (Barthel Index 95ndash100 at 3 months) was achieved in 4221 Index 95ndash100 at 3 months) was achieved in 4221 and 344 of the patients respectively and 344 of the patients respectively
2 Direct Fibrinolytics2 Direct Fibrinolytics
Microplasmin (Microplasmin (ThromboGenics Heverlee Belgium)ThromboGenics Heverlee Belgium) is a truncated form of plasmin that is more resistant to the effects is a truncated form of plasmin that is more resistant to the effects
of antiplasmin of antiplasmin microplasmin can be used upto 4ndash12 hours after stroke onset microplasmin can be used upto 4ndash12 hours after stroke onset There was no evidence of increased bleeding risk with There was no evidence of increased bleeding risk with
microplasminmicroplasmin
Alfimeprase (Nuvelo San Carlos Calif)Alfimeprase (Nuvelo San Carlos Calif) is a recombinant truncated form of fibrolase a fibrinolytic zinc metalloproteinase is a recombinant truncated form of fibrolase a fibrinolytic zinc metalloproteinase
isolated from the venom of the southern copperhead snake isolated from the venom of the southern copperhead snake It degrades fibrin directly and achieves thrombolysis independent It degrades fibrin directly and achieves thrombolysis independent
of plasmin formationof plasmin formation its thrombolytic activity appears to be localized to the site of its thrombolytic activity appears to be localized to the site of
delivery These properties should theoretically result in faster delivery These properties should theoretically result in faster recanalization and lower hemorrhagic conversion riskrecanalization and lower hemorrhagic conversion risk
Anti-fibrinolyticsAnti-fibrinolytics
to limit fibrinolytic activityto limit fibrinolytic activity -aminocaproic acid (EACA) -aminocaproic acid (EACA) competitively inhibitscompetitively inhibits plasminogen and plasminogen activators from plasminogen and plasminogen activators from
binding to fibrinbinding to fibrin
alpha2-antiplasminalpha2-antiplasmin a serine protease inhibitor that a serine protease inhibitor that neutralizes any free circulating plasminneutralizes any free circulating plasmin
Plasminogen activator inhibitor-1Plasminogen activator inhibitor-1 a serine protease a serine protease inhibitor that inhibits tissue-type plasminogen inhibitor that inhibits tissue-type plasminogen activatoractivator
Glycoprotein (GP) IIbIIIa antagonistsGlycoprotein (GP) IIbIIIa antagonists
such as ReoPro (abciximab) Integrilin such as ReoPro (abciximab) Integrilin (eptifibatide) or Aggrastat (tirofiban) in (eptifibatide) or Aggrastat (tirofiban) in ischemic stroke remains investigational ischemic stroke remains investigational Deshmukh et al38 reported 21 patients with Deshmukh et al38 reported 21 patients with large-vessel occlusion refractory to IAT with large-vessel occlusion refractory to IAT with rtPA who were treated with IV andor IA rtPA who were treated with IV andor IA abciximab eptifibatide or tirofiban abciximab eptifibatide or tirofiban
IA Mechanical Approaches in Acute Ischemic Stroke IA Mechanical Approaches in Acute Ischemic Stroke Mechanical strategies have several advantagesMechanical strategies have several advantages First they lessen and may even preclude the use of chemical First they lessen and may even preclude the use of chemical
thrombolytics in this manner very likely reducing the risk of ICHthrombolytics in this manner very likely reducing the risk of ICH Second by avoiding the use of chemical thrombolytics it is Second by avoiding the use of chemical thrombolytics it is
possible to extend the treatment window beyond the limit of 6ndash8 possible to extend the treatment window beyond the limit of 6ndash8 hours hours
Third mechanically fragmenting a clot increases the surface area Third mechanically fragmenting a clot increases the surface area accessible to fibrinolytic agents and allows inflow of fresh accessible to fibrinolytic agents and allows inflow of fresh plasminogen which in turn may increase the speed of plasminogen which in turn may increase the speed of thrombolysis thrombolysis
Finally clot-retrieval devices may provide faster recanalization Finally clot-retrieval devices may provide faster recanalization
The disadvantages of the mechanical The disadvantages of the mechanical approaches approaches technical difficulty of navigating mechanical technical difficulty of navigating mechanical
devices into the intracranial circulation excessive devices into the intracranial circulation excessive trauma to the vasculature (potentially leading to trauma to the vasculature (potentially leading to vasospasm vessel dissection perforation or vasospasm vessel dissection perforation or rupture) rupture)
fragmented thrombus causing distal embolization fragmented thrombus causing distal embolization into previously unaffected territories into previously unaffected territories
Nevertheless the advantages of mechanical stroke Nevertheless the advantages of mechanical stroke therapy appear to significantly outweigh its therapy appear to significantly outweigh its disadvantages and risksdisadvantages and risks
Contraindications to Thrombolytic Contraindications to Thrombolytic agents agents
Recent thoracic abdominal or Recent thoracic abdominal or intracranial surgeryintracranial surgery
Recent haemorrhagic CVA Head injury Recent haemorrhagic CVA Head injury or neoplasmor neoplasm
Bleeding ulcerBleeding ulcer Anticipated invasive procedures (arterial Anticipated invasive procedures (arterial
punctures biopsies)punctures biopsies) Concurrent hemostatic dysfunctionConcurrent hemostatic dysfunction
Monitoring of thrombolytic Monitoring of thrombolytic therapytherapy
Thrombin time Measures the availability of functional
fibrinogen Normal thrombin time is 10-14 sec Prolonged when fibrinogen level is below
75-100 mgdl
Half Life of ThrombolyticsHalf Life of ThrombolyticsAgent Administration Half Life
Streptokinase IA 60-80min
Urokinase IAIV 9-12min
rTPA IAIV 6min
Abciximab(Reopro) IAIV 12hour
Aspirin POIV 15-20min
Heparin IVSC 60min
Coumadin PO 15-25 days
Anti Platelet DrugsAnti Platelet DrugsDrug Drug Mechanism Mechanism UsesUsesAspirinAspirin Permanently inhibits Permanently inhibits
COX-1 and COX-2COX-1 and COX-2CADCAD
Stroke-TIAsStroke-TIAs
NSAIDsNSAIDs Reversibly inhibits Reversibly inhibits COX-1COX-1
LimitedLimited
DipyridamoleDipyridamole Inhibits PDE increases Inhibits PDE increases cAMPcAMP
TIAsTIAs
ThenopyridinesThenopyridines
(Ticlopidine(Ticlopidine
ClopidrgrelClopidrgrel))
Inhibits ADP Inhibits ADP
PlatAg PlatAg
TIAsStrokeTIAsStroke
CAD PVDCAD PVD
Abciximab (ReoPro)Abciximab (ReoPro)
Eptifibatide (Integrilin)Eptifibatide (Integrilin)
TirofibanTirofiban
GP IIBIIIA InhibitorsGP IIBIIIA Inhibitors
Stroke- TIAs Stroke- TIAs
MonitoringMonitoring
Bleeding timeBleeding time
Optical aggregometryOptical aggregometry
Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay
Bleeding timeBleeding time
Requires a skin incision (usually made on the ear lobe or Requires a skin incision (usually made on the ear lobe or forearm offorearm of
a depth that results in disruption of capillary loops and a depth that results in disruption of capillary loops and small vessels)small vessels)
AdvantagesAdvantages Universally availableUniversally available Relatively simple techniquesRelatively simple techniques Can be performed bedsideCan be performed bedside
DisadvantagesDisadvantages Insensitive inaccurate non-specific techniqueInsensitive inaccurate non-specific technique
Poorly reproducible (as depends on multiple variables)Poorly reproducible (as depends on multiple variables)
Optical aggregometryOptical aggregometry
Gold standard assay for platelet functionGold standard assay for platelet function Agonist induced aggregation is measuredAgonist induced aggregation is measured Different agonist are available for different Different agonist are available for different
agentsagents However require unique expertise and are not However require unique expertise and are not
universally availableuniversally available Aspirin measured with ADP or AA(gt70 Aspirin measured with ADP or AA(gt70
aggregation so resistance)aggregation so resistance) Clopidogrel( ADP gt 90 aggregation means Clopidogrel( ADP gt 90 aggregation means
resistance) resistance)
Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay
Can be performed bed sideCan be performed bed side Different assay devices with different Different assay devices with different
agonist are used for each of different agonist are used for each of different antiplatelet agents antiplatelet agents
For Aspirin AA is used (result is reported as aspirin For Aspirin AA is used (result is reported as aspirin reaction units [ARU] ARUgt 550 indicates non-reaction units [ARU] ARUgt 550 indicates non-responsiveness)responsiveness)
Verify IIbIIIa assay device uses TRAP as agonist for Verify IIbIIIa assay device uses TRAP as agonist for Abciximab and TirofibanAbciximab and Tirofiban
Practical Applications Practical Applications related to specific related to specific
Neurovascular Neurovascular interventionsinterventions
Acute ischemic StrokeAcute ischemic Stroke When an artery occludes neurons are affected When an artery occludes neurons are affected
differently depending upon the amount of residual blood differently depending upon the amount of residual blood flowflow
Normal cerebral blood flow is greater than 50 mL100 Normal cerebral blood flow is greater than 50 mL100 mgminmgmin
Once blood flow decreases to less than 20 mL100 Once blood flow decreases to less than 20 mL100 mgmin infarction occursmgmin infarction occurs
If blood flow decreases to less than 10 mL100 mgmin If blood flow decreases to less than 10 mL100 mgmin irreversible neuronal death occurs rapidly irreversible neuronal death occurs rapidly
Blood flow between 11 and 20 mL100 mgmin is thought Blood flow between 11 and 20 mL100 mgmin is thought to represent the ischemic penumbra an area where the to represent the ischemic penumbra an area where the cells are functionally silent because of ischemia but are cells are functionally silent because of ischemia but are still able to recover if blood flow is restored still able to recover if blood flow is restored
Many acute stroke therapies are targeted toward Many acute stroke therapies are targeted toward restoring flow or function to the ischemic penumbrarestoring flow or function to the ischemic penumbra
Therapeutic window in Therapeutic window in management of acute Ischemic management of acute Ischemic
StrokeStrokeThe early diagnosis of ischemic stroke is critical to the The early diagnosis of ischemic stroke is critical to the
with only a narrow therapeutic window in the first few with only a narrow therapeutic window in the first few hours following stroke ictushours following stroke ictus
Diagnosis in the first 3 hours postictus provides the Diagnosis in the first 3 hours postictus provides the opportunity for intravenous or intraarterial thrombolysis opportunity for intravenous or intraarterial thrombolysis and intra-arterial clot mechanical treatment which and intra-arterial clot mechanical treatment which improve the outcome improve the outcome
Diagnosis in the time period between 3 and 6 hours Diagnosis in the time period between 3 and 6 hours provides an opportunity for intra-arterial thrombolysis provides an opportunity for intra-arterial thrombolysis and mechanical treatment and mechanical treatment
Involvement of the posterior circulation especially the Involvement of the posterior circulation especially the basilar artery is treated by some regardless of time of basilar artery is treated by some regardless of time of onset or up until 12 to 24 hours in some practices This is onset or up until 12 to 24 hours in some practices This is related to the potentially high mortality and morbidity related to the potentially high mortality and morbidity associated with basilar artery thrombosisassociated with basilar artery thrombosis
Infarct evaluation on angiographyInfarct evaluation on angiography(CT angiography and catheter (CT angiography and catheter
angiography)angiography)CTA is an excellent first-line examination for CTA is an excellent first-line examination for
evaluation of the head and neck arteries evaluation of the head and neck arteries In comparison with catheter angiography In comparison with catheter angiography
what it gives up in resolution and dynamic what it gives up in resolution and dynamic properties it makes up for with rapid properties it makes up for with rapid acquisition of a 3-D dataset and the potential acquisition of a 3-D dataset and the potential for assessment of whole-brain perfusion and for assessment of whole-brain perfusion and better parenchymal evaluationbetter parenchymal evaluation
Moreover CTA illustrates not only arterial Moreover CTA illustrates not only arterial stenosis or occlusion but also the vessel wall stenosis or occlusion but also the vessel wall This factor is most important for evaluation of This factor is most important for evaluation of intramural dissection and thrombosed intramural dissection and thrombosed aneurysms which may both complicate aneurysms which may both complicate evaluation of stroke patientsevaluation of stroke patients
Early angiographic signs of strokes Early angiographic signs of strokes both CTA both CTA and DSA and DSA
Vessel occlusion or cutoff related to Vessel occlusion or cutoff related to thromboembolithromboemboli
aneurysms aneurysms arterial dissection arterial dissection Meniscus or flattened shape to clot Meniscus or flattened shape to clot
(recent) versus reverse meniscus (older)(recent) versus reverse meniscus (older) tram track (nonocclusive or recanalized tram track (nonocclusive or recanalized
clot) clot) delayed (antegrade) flow (manifest as delayed (antegrade) flow (manifest as
decreased whole-brain perfusion on CTA)decreased whole-brain perfusion on CTA) retrograde collateral flowretrograde collateral flow
Non-occlusive left MCA thrombus on 3-D imaging performed from CTA source data and was confirmed at catheter angiography
Therapy to be started within a 6-hr Therapy to be started within a 6-hr time to treatment (TTT) window time to treatment (TTT) window (while in case of IV thrombolysis (while in case of IV thrombolysis therapy to be started with in 3hrs)therapy to be started with in 3hrs)
Exclusion criteria Exclusion criteria Rapidly improving neurologic deficit or Rapidly improving neurologic deficit or Sustained blood pressure of gt180100 Sustained blood pressure of gt180100 Hemorrhage is detected on CTHemorrhage is detected on CT Infarct involving gt more than 13 rd Infarct involving gt more than 13 rd
territory of MCAterritory of MCA MRADWI-Perfusion mismatchlt 20MRADWI-Perfusion mismatchlt 20 Definite hypodensity on CTDefinite hypodensity on CT
Intra-arterial Thrombolysis
Fibrinolytics + AntiplateletsFibrinolytics + Antiplatelets
PlasminogenPlasminogen activators through fibrinolysis exposes activators through fibrinolysis exposes free thrombin and paradoxically stimulatesfree thrombin and paradoxically stimulates platelet platelet aggregation which leads to formation of aaggregation which leads to formation of a platelet platelet thrombus (white clot) thrombus (white clot)
This new thrombus is relatively resistant to This new thrombus is relatively resistant to fibrinolyticsfibrinolytics
So new regimen in case of acute stroke isSo new regimen in case of acute stroke is fibrinolytics + antiplatelet drugsfibrinolytics + antiplatelet drugs
rtPA + IIbIIIa inhibitors( tirofiban rtPA + IIbIIIa inhibitors( tirofiban abciximab) orabciximab) or
Urokinase + IIbIIIa Urokinase + IIbIIIa inhibitors( tirofiban abciximab)inhibitors( tirofiban abciximab)
Intra-arterial Thrombolysis Tirofiban (04 microgkgmin bolus for 3 min followed by Tirofiban (04 microgkgmin bolus for 3 min followed by
0125 ugkgmin)0125 ugkgmin)
++
Heparin (2000ndash3000 IU bolus followed by Heparin (2000ndash3000 IU bolus followed by 1000 IUhour infusion 1000 IUhour infusion
with ACT maintained bw 200-300) throughout the with ACT maintained bw 200-300) throughout the interventional procedure and for 24ndash48 hours thereafter when interventional procedure and for 24ndash48 hours thereafter when there is neither intraprocedural bleeding nor suspicion of there is neither intraprocedural bleeding nor suspicion of increased risk of bleeding increased risk of bleeding
Maximum dose of Urokinase Maximum dose of Urokinase Anterior circulation stroke - 500000 IU (mean 400000 Anterior circulation stroke - 500000 IU (mean 400000
IU range 300000ndash500000 IU)IU range 300000ndash500000 IU) Posterior circulation stroke -1000000 IU (mean 837000 Posterior circulation stroke -1000000 IU (mean 837000
IU range 300000ndash1000000 IU)IU range 300000ndash1000000 IU)American Journal of NeuroradiologyAmerican Journal of Neuroradiology 262595-2601 2005262595-2601 2005
Intravenous ThrombolysisIntravenous Thrombolysis
The first method to restore cerebral The first method to restore cerebral perfusion is clot lysis with the goal perfusion is clot lysis with the goal of re-establishing blood flow to the of re-establishing blood flow to the affected tissue affected tissue
IV thrombolysis rt-PA is the only IV thrombolysis rt-PA is the only FDA- approved treatment for AIS FDA- approved treatment for AIS
Fibrinolysis is enhanced powerfully Fibrinolysis is enhanced powerfully by rt-PAby rt-PA
Intravenous rTPA Intravenous rTPA administration administration protocolprotocol
Total dose of rt-PA 09 mgkg (maximum dose Total dose of rt-PA 09 mgkg (maximum dose 90 mg)90 mg)
Give 10 as initial IV bolusGive 10 as initial IV bolus Infuse remainder over 1 hourInfuse remainder over 1 hour Admit patient to an ICU or stroke unit for Admit patient to an ICU or stroke unit for
monitoringmonitoring Neurologic assessments every 15 minutes Neurologic assessments every 15 minutes
during infusion then every 30 minutes for next during infusion then every 30 minutes for next 6 hours then every hour until 24hours after 6 hours then every hour until 24hours after treatmenttreatment
Favorable Outcome vs Treatment Time Favorable Outcome vs Treatment Time with IV rTPAwith IV rTPA
Protocol limit = 3 hrs
Benefit ~ 45 hrs
Thromboembolism During coilingThromboembolism During coiling Most feared and frequent complication Most feared and frequent complication Reported incidence - Approx 7 Reported incidence - Approx 7 SourcesSources of Thromboembolism are of Thromboembolism are
- Clots at the aneurysmal neck during or immediately- Clots at the aneurysmal neck during or immediately after after embolization embolization
- Thrombus forming on catheters during- Thrombus forming on catheters during proceduresprocedures
- Stenosis of an adjacent artery dt coil mass- Stenosis of an adjacent artery dt coil mass or herniationor herniation
- Migration of intraaneurysmal- Migration of intraaneurysmal thrombus during coil thrombus during coil placement placement
- Slow flow dt vasospasm - Slow flow dt vasospasm
- Rare and unlikely causes are hypercoagulable- Rare and unlikely causes are hypercoagulable state such state such as antiphospholipid antibody syndrome or due to HITas antiphospholipid antibody syndrome or due to HIT
Occur more often with wide-necked aneurysms (dt Occur more often with wide-necked aneurysms (dt increased exposed surface area of thrombogenic coil increased exposed surface area of thrombogenic coil material)material)
Current regimen of endovascular Current regimen of endovascular managementmanagement
The The glycoprotein IIbIIIa antagonist tirofiban glycoprotein IIbIIIa antagonist tirofiban (04 (04 microgkgmin bolus for 30 minutes followed by infusion of microgkgmin bolus for 30 minutes followed by infusion of 0125 ugkgmin until the thrombus dissolved) 0125 ugkgmin until the thrombus dissolved)
Intraarterial thrombolysis with Intraarterial thrombolysis with urokinase or r- TPA urokinase or r- TPA increase of intravenous (IV) heparin (measured by increase of intravenous (IV) heparin (measured by
ACT) ACT) Intravenous aspirin Intravenous aspirin
Coil-related platelet aggregation (white clot) is Coil-related platelet aggregation (white clot) is unlikely to respond to fibrinolytics but has a high risk unlikely to respond to fibrinolytics but has a high risk of hemorrhage (In ISAT) all 5 patients who had of hemorrhage (In ISAT) all 5 patients who had received thrombolytic therapy with tPA to treat a received thrombolytic therapy with tPA to treat a thromboembolic complication after endovascular thromboembolic complication after endovascular treatment rebleed and all of these patients died)treatment rebleed and all of these patients died)
IntracranialIntracranial Stenting Stenting Metallic foreign body such as stent will accumulate Metallic foreign body such as stent will accumulate
thrombus in the absence of platelet inhibitionthrombus in the absence of platelet inhibition Antiplatelet drugs are important to prevent peri or Antiplatelet drugs are important to prevent peri or
post-interventional thromboembolic eventspost-interventional thromboembolic events Optimal treatment regimens has not been determined Optimal treatment regimens has not been determined
but usually but usually Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-
procedureprocedureOrOr
Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on
morning of proceduremorning of procedure
If need to use stent is not pre-planned thanIf need to use stent is not pre-planned than
Abciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkgAbciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkg IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)
Glycoprotein IIbIIIa inhibitor are not used routinely during elective Glycoprotein IIbIIIa inhibitor are not used routinely during elective stenting procedure dt increased risk of ICH stenting procedure dt increased risk of ICH
Carotid StentingCarotid Stenting
Pre-procedurePre-procedure
Double Antiplatelet therapy is routinely given Double Antiplatelet therapy is routinely given beginning at least 3beginning at least 3
days before the proceduredays before the procedure
Aspirin 325mgd+Clopidogrel 75mgdAspirin 325mgd+Clopidogrel 75mgd During procedureDuring procedure
Heparin is given with target clotting time of 250-Heparin is given with target clotting time of 250-300sec300sec
Post-procedure Post-procedure
Aspirin 325mg is continued indefinitely and Aspirin 325mg is continued indefinitely and
Clopidogrel 75mgd for at least 6 weeks Clopidogrel 75mgd for at least 6 weeks
Inclusion criteria for Local ThrombolysisInclusion criteria for Local Thrombolysis a)a) Patients in severe clinical grade on admission Patients in severe clinical grade on admission
with evidence of dural venous sinus with evidence of dural venous sinus thrombosis and restrictive venous outflow on thrombosis and restrictive venous outflow on cerebral angiogramcerebral angiogram
b)b) Patients in clinical grade 3 worsening on Patients in clinical grade 3 worsening on heparin therapy Restriction to venous heparin therapy Restriction to venous outflow was defined as an increase in brain outflow was defined as an increase in brain circulation time gt 12 s delay in the drainage circulation time gt 12 s delay in the drainage of cortical veins with cortical veins hanging of cortical veins with cortical veins hanging in spacein space
Treatment Options for Venous Thrombosis
CT Grading for Venous ThrombosisCT Grading for Venous Thrombosis Grade I no parenchymal change Grade I no parenchymal change
(hyperdense (hyperdense sinuses cortical veins empty sinuses cortical veins empty delta sign)delta sign)
Grade II non hemorrhagic venous infarct Grade II non hemorrhagic venous infarct without mass effect without mass effect
Grade III non-hemorrhagic infarct with Grade III non-hemorrhagic infarct with mass effectmass effect
Grade IV hemorrhagic venous infarct (max Grade IV hemorrhagic venous infarct (max diameter lt 3 cm) with no mass effectdiameter lt 3 cm) with no mass effect
Grade V hemorrhagic venous infarct (max Grade V hemorrhagic venous infarct (max diameter gt 3 cm) with mass effect diameter gt 3 cm) with mass effect
Local ThrombolysisLocal Thrombolysis
Femoral Jugular access was secured and a guiding Femoral Jugular access was secured and a guiding catheter was placed in the jugular bulb catheter was placed in the jugular bulb Mechanical Mechanical clot maceration clot maceration was done with the guidewire was done with the guidewire following which a microcatheter (was navigated and following which a microcatheter (was navigated and placed in the thrombosed segment of sinus confirmed placed in the thrombosed segment of sinus confirmed on a selective venogram on a selective venogram
Urokinase infusion Bolus dose of 2-6 lacs followed Urokinase infusion Bolus dose of 2-6 lacs followed by 60000 to 100000 units per hour along with by 60000 to 100000 units per hour along with periodic check venogram Along with maintenance periodic check venogram Along with maintenance systemic infusion of Heparinsystemic infusion of Heparin Other agents such as Other agents such as streptokinase altepase or rTPAstreptokinase altepase or rTPA can be also used can be also used
After thrombolysis patient should subjected to oral After thrombolysis patient should subjected to oral anticoagulation for six monthsanticoagulation for six months
Low-molecular-weight Low-molecular-weight heparinheparin
PharmacologyPharmacologyLMWH as its name suggests is a glycosaminoglycan that is approximatelyLMWH as its name suggests is a glycosaminoglycan that is approximately
one third the molecular weight of UFH It is derived from UFH through one third the molecular weight of UFH It is derived from UFH through variousvarious
depolymerization processes LMWH binds to antithrombin which in turn depolymerization processes LMWH binds to antithrombin which in turn
Neutralizes actors Xa and IIa Because LMWH lacks many of the longer Neutralizes actors Xa and IIa Because LMWH lacks many of the longer chains chains
required for binding to thrombin it has less ability to neutralize thrombin required for binding to thrombin it has less ability to neutralize thrombin
relativeto its ability to neutralize factor Xa LMWH also has less relativeto its ability to neutralize factor Xa LMWH also has less nonspecific nonspecific
binding to other proteins There is greater bioavailability with more binding to other proteins There is greater bioavailability with more predictable predictable
pharmacokinetics that eliminates the need for monitoring The smaller pharmacokinetics that eliminates the need for monitoring The smaller size also size also
allows for enhanced subcutaneous absorption when compared with UFHallows for enhanced subcutaneous absorption when compared with UFH
Three LMWH preparations are Three LMWH preparations are currently approved for use in the currently approved for use in the United States (1) enoxaparin (2) United States (1) enoxaparin (2) dalteparin and (3) tinzaparin dalteparin and (3) tinzaparin
They are all administered They are all administered subcutaneously at intervals of either subcutaneously at intervals of either once or twice daily for both once or twice daily for both prophylaxis and treatment dosesprophylaxis and treatment doses
Few Experiences of Few Experiences of ThrombolysisThrombolysis
Vickey 25 Yrs male patient presented Vickey 25 Yrs male patient presented with 12with 12thth day HO severe headache with day HO severe headache with right sided hemiplegiaright sided hemiplegia
MRI shows thrombosis of the superior MRI shows thrombosis of the superior sagittal left transverse left sigmoid sagittal left transverse left sigmoid sinuses and cortical veins in the fronto-sinuses and cortical veins in the fronto-parietal regions with eo haemorrhagic parietal regions with eo haemorrhagic infarct in the left cerebral hemisphere infarct in the left cerebral hemisphere with mass effect( Grade ndashV)with mass effect( Grade ndashV)
Sashi Srivastava 64 yrs FSashi Srivastava 64 yrs F In a follow up case of MRD with infra-renal In a follow up case of MRD with infra-renal
aortic abdominal and bilateral renal artery aortic abdominal and bilateral renal artery thrombosis renal angiogram shows filling thrombosis renal angiogram shows filling defects in the right Renal artery defects in the right Renal artery
Initially Renal angioplasty was done Initially Renal angioplasty was done Following angioplasty few thrombi are seem Following angioplasty few thrombi are seem to extends into the segmental branches and to extends into the segmental branches and causing blockage So Thrombolysis was causing blockage So Thrombolysis was plane to dissolve the run-out thrombi with plane to dissolve the run-out thrombi with urokinase urokinase
Rakesh 34yrsMRakesh 34yrsM Left SFA pseudoaneurysm with Left SFA pseudoaneurysm with
Covered stent placementCovered stent placement Pre operative antiplatelets with post Pre operative antiplatelets with post
procedure heparin Tirofiban procedure heparin Tirofiban followed by aspirin and clopidogrel followed by aspirin and clopidogrel were usedwere used
IAT may be a treatment option for selected patients IAT may be a treatment option for selected patients Possible selection criteria include Possible selection criteria include
presentation between 3 and 6 hours from symptom onsetpresentation between 3 and 6 hours from symptom onset major cerebral artery occlusion major cerebral artery occlusion severe neurologic deficits severe neurologic deficits high risk of systemic hemorrhage with IV rt-PA (eg recent high risk of systemic hemorrhage with IV rt-PA (eg recent
surgery) surgery) The MERCI (Mechanical Embolus Removal in Cerebral The MERCI (Mechanical Embolus Removal in Cerebral
Ischemia) retrievalIschemia) retrieval system system
Has been FDA-approved for recanalizing acutely occluded Has been FDA-approved for recanalizing acutely occluded cerebral arteries cerebral arteries
In the Multi-MERCI study patients who did not improve In the Multi-MERCI study patients who did not improve immediately after IV rt-PA underwent mechanical immediately after IV rt-PA underwent mechanical embolectomy within 8 hours of symptom onset embolectomy within 8 hours of symptom onset
Partial or complete recanalization occurred in 74 of Partial or complete recanalization occurred in 74 of patientspatients
with a symptomatic intracerebral hemorrhage (sICH) rate of with a symptomatic intracerebral hemorrhage (sICH) rate of 67 67
Mechanical embolectomy with the MERCI retriever may be a Mechanical embolectomy with the MERCI retriever may be a feasible and safe option for patients after IV rt-PAfeasible and safe option for patients after IV rt-PA
Penumbra stroke systemPenumbra stroke system This device combines two methods of clot This device combines two methods of clot
extraction aspiration and mechanical extraction aspiration and mechanical extraction extraction
First the clot is aspirated then a thrombus First the clot is aspirated then a thrombus removal ring can be used if necessary to removal ring can be used if necessary to remove remaining clot remove remaining clot
successful recanalizing 82successful recanalizing 82 Bridging therapyBridging therapy
06 mgkg IV rt-PA followed by IAT with IA rt-06 mgkg IV rt-PA followed by IAT with IA rt-PA (up to 20 mg)PA (up to 20 mg)
achieved a higher recanalization rateachieved a higher recanalization rate
Criteria for thrombolysis with rTPACriteria for thrombolysis with rTPA
Inclusion criteriaInclusion criteria Clinical signs and symptoms consistent with ischemic Clinical signs and symptoms consistent with ischemic
strokestroke Patient last seen normal within 3 hoursPatient last seen normal within 3 hours Measurable neurologic deficitMeasurable neurologic deficit
Exclusion criteriaExclusion criteria Any hemorrhage on neuroimaging (CT or MRI)Any hemorrhage on neuroimaging (CT or MRI) Symptoms suggestive of subarachnoid hemorrhageSymptoms suggestive of subarachnoid hemorrhage Seizure at stroke onset that is thought to contribute to Seizure at stroke onset that is thought to contribute to
neurologic deficitneurologic deficit Hypodensity greater than one third cerebral hemisphere Hypodensity greater than one third cerebral hemisphere
on CTon CT SBP greater than 185 mm Hg or DBP greater than 110 SBP greater than 185 mm Hg or DBP greater than 110
mm Hgmm Hg International normalized ratio (INR) greater than 17International normalized ratio (INR) greater than 17
Ischemic Stroke Ischemic Stroke Treatment ndash 2006Treatment ndash 2006
IV tissue plasminogen activator (tPA)IV tissue plasminogen activator (tPA) ndash ndash Only FDA-approved acute stroke drugOnly FDA-approved acute stroke drug ndash ndash 3 hour treatment window3 hour treatment window
MERCI - Concentric clot retrieval MERCI - Concentric clot retrieval devicedevice ndash ndash Rescue therapy - approved 2004Rescue therapy - approved 2004 ndash ndash Device approval (not outcomes-based)Device approval (not outcomes-based)
Off label approachesOff label approaches ndash ndash IV tPA after 3 hoursIV tPA after 3 hours ndash ndash IV-IA tPA sequential strategiesIV-IA tPA sequential strategies ndash ndash IA tPA clot angioplasty fragmentationIA tPA clot angioplasty fragmentation ndash ndash Ultrasound-assisted tPA lysisUltrasound-assisted tPA lysis
rt-PA Trials NINDSrt-PA Trials NINDS
Acute stroke - 624 patientsAcute stroke - 624 patients Treat within 3 hrsTreat within 3 hrs Intravenous 09 mgkg rt-PA vs placeboIntravenous 09 mgkg rt-PA vs placebo Hemorrhage 64 tPA 06 placeboHemorrhage 64 tPA 06 placebo Neurologic recovery better with tPA 30 Neurologic recovery better with tPA 30
more like to have minimal or no disabilitymore like to have minimal or no disability
First proven approved treatment for First proven approved treatment for strokestroke
Limitations of tPALimitations of tPA Only 4 of acute strokes receive tPAOnly 4 of acute strokes receive tPA (Kleindorfer et al Stroke 2004 35 e27-e29)(Kleindorfer et al Stroke 2004 35 e27-e29)
Only 22 of patients present within 3 hoursOnly 22 of patients present within 3 hours1048707 1048707 51 of these ineligible due to51 of these ineligible due to
bull bull Mild severityMild severity bull bull Medical or surgical historyMedical or surgical history bull bull Blood testsBlood tests
Sustained recanalization only 13Sustained recanalization only 13 (Alexandrov et al NEJM 2004 351 2170-8)(Alexandrov et al NEJM 2004 351 2170-8)
Concern for hemorrhageConcern for hemorrhage tPA potentiates apoptotic injury tPA potentiates apoptotic injury (Liu et al Nature Med 2004 101379-83)(Liu et al Nature Med 2004 101379-83)
PROACT II IA Lysis TrialPROACT II IA Lysis Trial Baseline 24 hours 8 days
Baseline 60 minutes 120 minutes
9mg IAProurokinase
Desmoteplase Trials DEDAS Desmoteplase Trials DEDAS DIASDIAS
Trial OverviewTrial Overview Double blind randomized placebo Double blind randomized placebo
controlled trialscontrolled trials IV delivery 3-9 hour time windowIV delivery 3-9 hour time window Plasminogen activator ndash from Plasminogen activator ndash from vampire bat vampire bat
salivasaliva Selection based on PWI-DWI MismatchSelection based on PWI-DWI Mismatch
MRI InclusionMRI Inclusion PWI defect at least 2 cm AND ~20 larger PWI defect at least 2 cm AND ~20 larger
than DWIthan DWI PWI should be obvious even visible on PWI should be obvious even visible on
raw imagesraw imagesMRI ExclusionMRI Exclusion
DWI gt 13 MCADWI gt 13 MCA MRA ICA occlusionMRA ICA occlusion
Desmoteplase ndash DIAS Desmoteplase ndash DIAS ResultsResults
Mechanical Thrombolysis Mechanical Thrombolysis devicesdevices
mechanical thrombolysis potentially extends the treatment mechanical thrombolysis potentially extends the treatment window because they act promptly at the site of the thrombuswindow because they act promptly at the site of the thrombus
The devices can retrieve large clots that pharmaceutical agents The devices can retrieve large clots that pharmaceutical agents may not successfully lysemay not successfully lyse
Patients treated with IV tPA may be considered for treatment of Patients treated with IV tPA may be considered for treatment of residual clot with some of these devicesresidual clot with some of these devices
suction-creating saline jets suction-creating saline jets laser energy ultrasound laser energy ultrasound a corkscrew apparatus to treat strokesa corkscrew apparatus to treat strokes The AngioJet systemThe AngioJet system uses saline jets that are directed back into the catheter to uses saline jets that are directed back into the catheter to
create a low-pressure zone around the catheter tip inducing create a low-pressure zone around the catheter tip inducing suction suction
The clot is pulled into the exhaust lumen and removed from the The clot is pulled into the exhaust lumen and removed from the vessel Although US Food and Drug Administration (FDA) has vessel Although US Food and Drug Administration (FDA) has approved this device for use in arteriovenous dialysis grafts and approved this device for use in arteriovenous dialysis grafts and fistulae and for the treatment of coronary arteries saphenous fistulae and for the treatment of coronary arteries saphenous vein grafts and peripheral vessels clinical trials for the vein grafts and peripheral vessels clinical trials for the treatment of acute stroke are no longer in progress treatment of acute stroke are no longer in progress
Most devices are used in cerebral vessels that 2-5 mm
The Latis laser device The Latis laser device used laser energy to ablate clots used laser energy to ablate clots Arteries 2-5 mm in diameter could be Arteries 2-5 mm in diameter could be
treated including the ICA M1 or M2 treated including the ICA M1 or M2 branch of the MCA A1 branch of the branch of the MCA A1 branch of the anterior cerebral artery (ACA) basilar anterior cerebral artery (ACA) basilar artery posterior cerebral artery (PCA) artery posterior cerebral artery (PCA) and vertebral and vertebral
Patients could receive treatment as late Patients could receive treatment as late as 8 hours after symptom onset in the as 8 hours after symptom onset in the anterior circulation and within 24 hours in anterior circulation and within 24 hours in the posterior circulation the posterior circulation
Endovascular Photo Acoustic Endovascular Photo Acoustic Recanalization (EPAR) Recanalization (EPAR)
A laser power source generated energy for the A laser power source generated energy for the systemsystem
The energy was delivered by means of The energy was delivered by means of fiberoptics to the tip of the catheter at the fiberoptics to the tip of the catheter at the treatment sitetreatment site
Absorption of laser light by darkly pigmented Absorption of laser light by darkly pigmented materials (ie the clot) occurred inside the 1-mm materials (ie the clot) occurred inside the 1-mm catheter tipcatheter tip
the system was designed to minimize scattering the system was designed to minimize scattering of laser light of laser light
Absorption converted photo energy to acoustic Absorption converted photo energy to acoustic energy which then emulsified the clot inside the energy which then emulsified the clot inside the catheter tip catheter tip
EKOS ultrasound( the EKOS ultrasound( the Ultrasound Thrombolytic Ultrasound Thrombolytic
Infusion Catheter) Infusion Catheter) combines the use of a distal ultrasound transducer with combines the use of a distal ultrasound transducer with
infusion of a thrombolytic agent through the infusion of a thrombolytic agent through the microcathetermicrocatheter
Ultrasound changes the structure of the clot to Ultrasound changes the structure of the clot to temporarily increase its permeability while providing an temporarily increase its permeability while providing an acoustic pressure gradient to move the drug into the clot acoustic pressure gradient to move the drug into the clot to speed its dissolution to speed its dissolution
The EKOS catheter is placed in the proximal portion of the The EKOS catheter is placed in the proximal portion of the clot clot
After a 2-mg bolus of tPA was injected through the After a 2-mg bolus of tPA was injected through the catheter catheter
the patient received a continuous infusion of IA tPA 03 the patient received a continuous infusion of IA tPA 03 mgmin to a maximum of 20 mg and simultaneous mgmin to a maximum of 20 mg and simultaneous ultrasound transmission for as long as 60 minutes ultrasound transmission for as long as 60 minutes
One patient was treated with a total of 4 units of One patient was treated with a total of 4 units of recombinant reteplase (Retavase) hand-injected over 60 recombinant reteplase (Retavase) hand-injected over 60 minutes minutes
Penumbra system Penumbra system The Penumbra system (Penumbra Inc) provides a dual The Penumbra system (Penumbra Inc) provides a dual
approach to clot extraction using aspiration followed by approach to clot extraction using aspiration followed by clot retrieval with a ring device if needed clot retrieval with a ring device if needed
Mechanical Embolus Removal in Cerebral Ischemia Mechanical Embolus Removal in Cerebral Ischemia (MERCI)(MERCI)
a corkscrew-like apparatus to remove blood clots from a corkscrew-like apparatus to remove blood clots from the brain in patients experiencing an ischemic stroke the brain in patients experiencing an ischemic stroke
The corkscrew itself resides in the catheter tip which The corkscrew itself resides in the catheter tip which shields it from the wall of the vessel until it is ready to be shields it from the wall of the vessel until it is ready to be burrowed into the clot Once lodged in the clot the device burrowed into the clot Once lodged in the clot the device and clot are withdrawn from the vessel and clot are withdrawn from the vessel
Snarelike devicesSnarelike devices Snares such as the Neuronet snare (Guidant Snares such as the Neuronet snare (Guidant
Endovascular Santa Clara CA) have been developed Endovascular Santa Clara CA) have been developed specifically for use in the treatment of strokes specifically for use in the treatment of strokes
These devices are simple in design and do not require the These devices are simple in design and do not require the clot to be amenable to emulsification clot to be amenable to emulsification
X-Sizer deviceX-Sizer device a device with small moving blades at the a device with small moving blades at the
catheter tip catheter tip This device the X-Sizer device (EndiCor Medical This device the X-Sizer device (EndiCor Medical
San Clemente CA) can be used to excise the San Clemente CA) can be used to excise the thrombus and aspirate it thrombus and aspirate it
The device was being evaluated in randomized The device was being evaluated in randomized studies of coronary vessels and in a registry of studies of coronary vessels and in a registry of patients with acute myocardial infarctionpatients with acute myocardial infarction
Although the manufacturer had modified the Although the manufacturer had modified the device for use in cerebral vessels a safety and device for use in cerebral vessels a safety and feasibility study was indefinitely suspended after feasibility study was indefinitely suspended after only 1 patient was treated with the device in only 1 patient was treated with the device in Europe Europe
Suction thrombectomySuction thrombectomy This method of mechanical thrombolysis is one of the This method of mechanical thrombolysis is one of the
simplestsimplest In this readily available technique suction is applied with In this readily available technique suction is applied with
a syringe to remove thrombus in the ICA a syringe to remove thrombus in the ICA It requires no other devicesIt requires no other devices A catheter with a large inner diameter (Brite Tip Cordis A catheter with a large inner diameter (Brite Tip Cordis
Corporation Miami FL) was placed in the symptomatic Corporation Miami FL) was placed in the symptomatic vessel and navigated over a guidewire into the thrombusvessel and navigated over a guidewire into the thrombus
A 60-mL syringe was used to aspirate the thrombus A 60-mL syringe was used to aspirate the thrombus Each patient required angioplasty and stenting of carotid Each patient required angioplasty and stenting of carotid
bifurcation stenosis and received daily aspirin and bifurcation stenosis and received daily aspirin and ticlopidine after the procedure No complications ticlopidine after the procedure No complications occurred occurred
Summary Acute Stroke Summary Acute Stroke ImagingImaging
PhysiologyPhysiology importance collaterals importance collaterals
ndash ndashGrowing role for perfusion Growing role for perfusion assessmentassessment
tPAtPA guidelines amp limitations guidelines amp limitations Signs on CT amp MRSigns on CT amp MR follow physiology follow physiology Stroke trialsStroke trials PWI-DWI mismatch PWI-DWI mismatch
ndash ndashTreat based on physiology not timeTreat based on physiology not time ProtocolsProtocols should be fast and should be fast and
comprehensivecomprehensive
Mechanisms of HIT( Mechanisms of HIT( Heparin Heparin induced Thrombocytopeniainduced Thrombocytopenia))
Type 1Type 1 Fall in platelet count occurs within the first two Fall in platelet count occurs within the first two
days after heparin initiation often returns to days after heparin initiation often returns to normal with continued heparin administration normal with continued heparin administration and is of no clinical consequence and is of no clinical consequence
The mechanism of the thrombocytopenia is non-The mechanism of the thrombocytopenia is non-immune and appears to be due to a direct effect of immune and appears to be due to a direct effect of heparin on platelet activationheparin on platelet activation
Type 2Type 2 Approximately 03 to 3 percent of patients Approximately 03 to 3 percent of patients
receiving heparin develop an immune receiving heparin develop an immune thrombocytopenia mediated by antibodies to a thrombocytopenia mediated by antibodies to a heparin-platelet factor 4 complex heparin-platelet factor 4 complex
(AJNR 28155-158 2007)
Treatment of heparin-induced Treatment of heparin-induced thrombocytopeniathrombocytopenia
When HIT is diagnosed it is important to When HIT is diagnosed it is important to stop heparin mainly in type 2 and to avoid stop heparin mainly in type 2 and to avoid the use of LMWH the use of LMWH
Because of the increased risk of thrombosis Because of the increased risk of thrombosis however continuation of an anticoagulant however continuation of an anticoagulant must be considered must be considered
The drugs currently approved for the The drugs currently approved for the treatment of HIT in the United States are treatment of HIT in the United States are direct thrombin inhibitors argatroban and direct thrombin inhibitors argatroban and lepirudinlepirudin
WARFARIN MECHANISM OF ACTIONWARFARIN MECHANISM OF ACTION
Inactive factors II VII IX and X
Proteins S and C
Active factors II VII IX and X
Proteins S and C
Vitamin K epoxide
Vitamin K reduced
WA
RF
AR
IN
Prevents the reduction of vitamin K which is essential for Prevents the reduction of vitamin K which is essential for activation of certain factorsactivation of certain factors
Has no effect on previously formed thrombusHas no effect on previously formed thrombus
Antagonist is Vit KAntagonist is Vit K
OPTIMIZING WARFARIN THERAPYOPTIMIZING WARFARIN THERAPY
Use of large loading dose may lead to hemorrhage and Use of large loading dose may lead to hemorrhage and other complicationsother complications
Initial dose 2-5 mg once dailyInitial dose 2-5 mg once daily Maintenance dose 2-10 mg once dailyMaintenance dose 2-10 mg once daily If Immediate anticoagulation is requiredIf Immediate anticoagulation is required Heparin IS Heparin IS
started along with loading dose of warfarin 10 mg started along with loading dose of warfarin 10 mg Heparin is usually discontinued after 4-5 days Heparin is usually discontinued after 4-5 days Before Before discontinuing INR should be in therapeutic range for 2 discontinuing INR should be in therapeutic range for 2 consecutive daysconsecutive days
Daily monitoring of INR until INR is in therapeutic Daily monitoring of INR until INR is in therapeutic range then 3 times weekly for 1-2 weeks then less often range then 3 times weekly for 1-2 weeks then less often (every 4 to 6 weeks)(every 4 to 6 weeks)
OPTIMAL THERAPEUTIC RANGEOPTIMAL THERAPEUTIC RANGE
IndicationIndication INRINR
Prophylaxis of venous Prophylaxis of venous thromboembolismthromboembolism
20-3020-30
Treatment of venous Treatment of venous thromboembolismthromboembolism
20-3020-30
Atrial fibrillationAtrial fibrillation 20-3020-30
Mitral valve stenosisMitral valve stenosis 20-3020-30
Heart valve replacementHeart valve replacement
Bioprosthetic valveBioprosthetic valve
Mechanical valveMechanical valve
20-3020-30
25-3525-35
Myocardial infarctionMyocardial infarction 20-3020-30
25-35 25-35 (high risk patients)(high risk patients)
FACTORS INFLUENCING DOSE RESPONSEFACTORS INFLUENCING DOSE RESPONSE
Poor patient compliancePoor patient compliance Concomitant medicationsConcomitant medications Levels of dietary vitamin KLevels of dietary vitamin K Alcohol Inaccurate lab testingAlcohol Inaccurate lab testing Inaccurate lab testingInaccurate lab testing Hepatic dysfunctionHepatic dysfunction FeverFever
Contraindication for WarfarinContraindication for Warfarin
Hypersensitivity to warfarinHypersensitivity to warfarin Hemorrhagic tendencyHemorrhagic tendency Condition with risk of hemorrhageCondition with risk of hemorrhage Inadequate laboratory techniquesInadequate laboratory techniques Protein C amp S deficiencyProtein C amp S deficiency Vitamin K deficiencyVitamin K deficiency
SIDE EFFECTSSIDE EFFECTS
Hemorrhage Hemorrhage Skin necrosisSkin necrosis Purple toe syndromePurple toe syndrome Microembolization Microembolization TeratogenecityTeratogenecity Agranulocytosis leukopenia Agranulocytosis leukopenia Diarrhoeanausea anorexiaDiarrhoeanausea anorexia
MONITORING OF WARFARIN THERAPYMONITORING OF WARFARIN THERAPY
Prothrombin timeProthrombin time PT ratioPT ratio INR (International Normalized Ratio)INR (International Normalized Ratio)
PROTHROMBIN TIME (PT)PROTHROMBIN TIME (PT)
Time required for blood to coagulate Time required for blood to coagulate is called PT ( normal value ~10sec)is called PT ( normal value ~10sec)
Performed by adding a mixture of Performed by adding a mixture of calcium and thromboplastin to calcium and thromboplastin to citrated plasmacitrated plasma
As a control a normal blood sample is As a control a normal blood sample is tested continuouslytested continuously
PT ratio (PTR) = PT ratio (PTR) = Patientrsquos PTPatientrsquos PT Control PTControl PT
PROBLEMS WITH PTPTRPROBLEMS WITH PTPTR
Thromboplastins are extracts from Thromboplastins are extracts from brain lung or placenta of animalsbrain lung or placenta of animals
Thromboplastins from various Thromboplastins from various manufacturers differ in their manufacturers differ in their sensitivity to prolong PTsensitivity to prolong PT
May result in false control of May result in false control of anticoagulant therapyanticoagulant therapy
INTERNATIONAL NORMALISED RATIO (INR)INTERNATIONAL NORMALISED RATIO (INR)
International Normalized Ratio (INR) International Normalized Ratio (INR) a PT test with a a PT test with a formula based ratio to normalize the often variable source formula based ratio to normalize the often variable source of tissue factor (human rabbit recombinant)of tissue factor (human rabbit recombinant)
INR = [PTINR = [PTptpt] ] ISIISI
[PT[PTRefRef]]
PTPTpt pt ndash prothrombin time of patientndash prothrombin time of patient
PTPTRef Ref ndash prothrombin time of normal pooled samplendash prothrombin time of normal pooled sample
ISI ndash International Sensitivity IndexISI ndash International Sensitivity Index
Warfarin is given orally and titrated to achieve an INR of Warfarin is given orally and titrated to achieve an INR of typically 20 ndash 30typically 20 ndash 30
Heparin versus WarfarinHeparin versus Warfarin
Drug ActionMechan-ism
Moni-toring
Effective
HeparinDirect
Inhibition ofThrombin
ATIIIcofactor
APTTACT
Immediate
WarfarinDecreasesProductionof factors
Vitamin K PTDelay
3-5 days
INR
Recanalization or Antegrade Recanalization or Antegrade Reperfusion StrategiesReperfusion Strategies
Recanalization strategies focus on removing Recanalization strategies focus on removing andor dissolving the occlusive thrombus to re-andor dissolving the occlusive thrombus to re-establish antegrade flow Strategies may be establish antegrade flow Strategies may be classified into 7 different categories on the classified into 7 different categories on the basis of their primary mechanism of action basis of their primary mechanism of action 1) 1) IV andor intraarterial thrombolysis (IAT) IV andor intraarterial thrombolysis (IAT) 2) endovascular thrombectomy2) endovascular thrombectomy3) endovascular thromboaspiration 3) endovascular thromboaspiration 4) endovascular mechanical thrombus disruption or 4) endovascular mechanical thrombus disruption or
thromborrhexisthromborrhexis5) 5) transcranial or endovascular augmented transcranial or endovascular augmented
fibrinolysis fibrinolysis 6) endovascular thrombus entrapment and 6) endovascular thrombus entrapment and 7) temporary endovascular bypass7) temporary endovascular bypass
IAT in Acute Ischemic StrokeIAT in Acute Ischemic Stroke
IAT advantages over IV thrombolysisIAT advantages over IV thrombolysis Coaxial microcatheter techniques the occluded intracranial Coaxial microcatheter techniques the occluded intracranial
vessel is directly accessible and the fibrinolytic agent can be vessel is directly accessible and the fibrinolytic agent can be infused directly into the thrombusinfused directly into the thrombus
This permits a smaller dose of fibrinolytic agent to reach a This permits a smaller dose of fibrinolytic agent to reach a higher local concentration than that reached by systemic higher local concentration than that reached by systemic infusioninfusion
Allows more complete recanalization with lower total doses of Allows more complete recanalization with lower total doses of thrombolytic thrombolytic
With the smaller dose complications from systemic fibrinolytic With the smaller dose complications from systemic fibrinolytic effects including intracranial hemorrhage (ICH) can effects including intracranial hemorrhage (ICH) can theoretically be reduced theoretically be reduced
Treatment window for endovascular techniques can be Treatment window for endovascular techniques can be extended beyond the typical IV window of 3 hours extended beyond the typical IV window of 3 hours
IA techniques have led to higher recanalization rates than IV IA techniques have led to higher recanalization rates than IV thrombolysisthrombolysis
Major disadvantagesMajor disadvantages Relative complexity of the procedure the level Relative complexity of the procedure the level
of required technical expertise and its of required technical expertise and its relatively low availability relatively low availability
Delays in initiating treatmentDelays in initiating treatment InvasiveInvasive
ThrombolyticsThrombolytics
Plasminogen activators
Fibrinolytics
1 Plasminogen Activators 1 Plasminogen Activators drugs act by converting the inactive proenzyme drugs act by converting the inactive proenzyme plasminogen into the active enzyme plasmin Plasmin plasminogen into the active enzyme plasmin Plasmin digests fibrinogen fibrin monomers and cross-linked digests fibrinogen fibrin monomers and cross-linked fibrin (as found in a thrombus) into fibrin degradation fibrin (as found in a thrombus) into fibrin degradation productsproducts
First-Generation Agents First-Generation Agents StreptokinaseStreptokinase a protein derived from group C a protein derived from group C
szlig-hemolytic streptococci has a half-life of 16ndashszlig-hemolytic streptococci has a half-life of 16ndash90 minutes and low fibrin specificity This drug 90 minutes and low fibrin specificity This drug proved to have a very narrow therapeutic proved to have a very narrow therapeutic window and significant rates of ICH and window and significant rates of ICH and systemic hemorrhage18systemic hemorrhage18
UrokinaseUrokinase is a serine protease with a plasma is a serine protease with a plasma half life of 14 minutes and low fibrin specificity half life of 14 minutes and low fibrin specificity
The urokinase dose used in cerebral IAT has The urokinase dose used in cerebral IAT has ranged from 002 to 2 X106unitsranged from 002 to 2 X106units
Second-Generation Agents Second-Generation Agents Alteplase (rtPA) Alteplase (rtPA)
is a serine is a serine protease with a plasma half-life of 35 protease with a plasma half-life of 35 minutes and a high degree of fibrin affinity and minutes and a high degree of fibrin affinity and specificity specificity
Dose used in cerebral IAT has ranged between 20 Dose used in cerebral IAT has ranged between 20 and 60 mgand 60 mg
Disadvantages of alteplase include its relatively short Disadvantages of alteplase include its relatively short halflife and limited penetration into the clot matrix halflife and limited penetration into the clot matrix because of strong binding with surface fibrin which because of strong binding with surface fibrin which could delay recanalization and increase the risk of could delay recanalization and increase the risk of recurrent occlusion recurrent occlusion
Prourokinase (r-prourokinase) Prourokinase (r-prourokinase) is the proenzyme precursor of urokinase is the proenzyme precursor of urokinase T12 of 7 minutes and high fibrin specificity T12 of 7 minutes and high fibrin specificity
Third-Generation AgentsThird-Generation Agents
ReteplaseReteplase is a structurally modified is a structurally modified form of alteplase form of alteplase
with a longer half-life (15ndash18 minutes) In with a longer half-life (15ndash18 minutes) In addition it does not bind as highly to fibrin addition it does not bind as highly to fibrin unbound reteplase can thus theoretically better unbound reteplase can thus theoretically better penetrate the clot and potentially penetrate the clot and potentially improve in improve in vivo fibrinolytic activity vivo fibrinolytic activity
TenecteplaseTenecteplase is another modified form of rtPA with a longer is another modified form of rtPA with a longer
half-life (17 minutes)half-life (17 minutes) greater fibrin specificity and greater greater fibrin specificity and greater
resistance to plasminogen activator inhibitor-1 resistance to plasminogen activator inhibitor-1 IV tenecteplase in acute ischemic stroke IV tenecteplase in acute ischemic stroke
suggest that the drug is safe and promisingsuggest that the drug is safe and promising
Newer plasminogen activatorNewer plasminogen activator
DesmoteplaseDesmoteplase is a genetically engineered is a genetically engineered version of the clot-dissolving factor version of the clot-dissolving factor
found in the saliva found in the saliva of the vampire bat Desmodus rotundusof the vampire bat Desmodus rotundus moremore potent and more selective for fibrin-bound potent and more selective for fibrin-bound
plasminogen than any other known plasminogen plasminogen than any other known plasminogen activatoractivator
Unlike tissue plasminogen activator (tPA) desmoteplase Unlike tissue plasminogen activator (tPA) desmoteplase is not activated by fibrinogen or -amyloid proteins is not activated by fibrinogen or -amyloid proteins factors that may exacerbate the risk for ICH factors that may exacerbate the risk for ICH
The effect of IV administration of desmoteplase 3ndash9 The effect of IV administration of desmoteplase 3ndash9 hours after symptom onset in patients with stroke who hours after symptom onset in patients with stroke who present with mismatch on MR imaging or CT perfusion present with mismatch on MR imaging or CT perfusion
3 DefibrinogenatingFibrinogenolytic 3 DefibrinogenatingFibrinogenolytic Agents Agents
AncrodAncrod(Viprinex)(Viprinex) is is the purified fraction of the Malayan pit viper venomthe purified fraction of the Malayan pit viper venom It acts by directly cleaving and inactivating fibrinogen It acts by directly cleaving and inactivating fibrinogen
and thus indirectly promoting anticoagulation and thus indirectly promoting anticoagulation The reduction in the blood levels of fibrinogen also The reduction in the blood levels of fibrinogen also
leads to a reduced blood viscosity which may improve leads to a reduced blood viscosity which may improve blood flow to the affected areas of the brain blood flow to the affected areas of the brain
In the Stroke Treatment with Ancrod Trial 500 In the Stroke Treatment with Ancrod Trial 500 patients with stroke presenting within 3 hours of patients with stroke presenting within 3 hours of symptom onset were randomized to receive ancrod (symptom onset were randomized to receive ancrod (n n 248) or a placebo (n 252) Good outcome (Barthel 248) or a placebo (n 252) Good outcome (Barthel Index 95ndash100 at 3 months) was achieved in 4221 Index 95ndash100 at 3 months) was achieved in 4221 and 344 of the patients respectively and 344 of the patients respectively
2 Direct Fibrinolytics2 Direct Fibrinolytics
Microplasmin (Microplasmin (ThromboGenics Heverlee Belgium)ThromboGenics Heverlee Belgium) is a truncated form of plasmin that is more resistant to the effects is a truncated form of plasmin that is more resistant to the effects
of antiplasmin of antiplasmin microplasmin can be used upto 4ndash12 hours after stroke onset microplasmin can be used upto 4ndash12 hours after stroke onset There was no evidence of increased bleeding risk with There was no evidence of increased bleeding risk with
microplasminmicroplasmin
Alfimeprase (Nuvelo San Carlos Calif)Alfimeprase (Nuvelo San Carlos Calif) is a recombinant truncated form of fibrolase a fibrinolytic zinc metalloproteinase is a recombinant truncated form of fibrolase a fibrinolytic zinc metalloproteinase
isolated from the venom of the southern copperhead snake isolated from the venom of the southern copperhead snake It degrades fibrin directly and achieves thrombolysis independent It degrades fibrin directly and achieves thrombolysis independent
of plasmin formationof plasmin formation its thrombolytic activity appears to be localized to the site of its thrombolytic activity appears to be localized to the site of
delivery These properties should theoretically result in faster delivery These properties should theoretically result in faster recanalization and lower hemorrhagic conversion riskrecanalization and lower hemorrhagic conversion risk
Anti-fibrinolyticsAnti-fibrinolytics
to limit fibrinolytic activityto limit fibrinolytic activity -aminocaproic acid (EACA) -aminocaproic acid (EACA) competitively inhibitscompetitively inhibits plasminogen and plasminogen activators from plasminogen and plasminogen activators from
binding to fibrinbinding to fibrin
alpha2-antiplasminalpha2-antiplasmin a serine protease inhibitor that a serine protease inhibitor that neutralizes any free circulating plasminneutralizes any free circulating plasmin
Plasminogen activator inhibitor-1Plasminogen activator inhibitor-1 a serine protease a serine protease inhibitor that inhibits tissue-type plasminogen inhibitor that inhibits tissue-type plasminogen activatoractivator
Glycoprotein (GP) IIbIIIa antagonistsGlycoprotein (GP) IIbIIIa antagonists
such as ReoPro (abciximab) Integrilin such as ReoPro (abciximab) Integrilin (eptifibatide) or Aggrastat (tirofiban) in (eptifibatide) or Aggrastat (tirofiban) in ischemic stroke remains investigational ischemic stroke remains investigational Deshmukh et al38 reported 21 patients with Deshmukh et al38 reported 21 patients with large-vessel occlusion refractory to IAT with large-vessel occlusion refractory to IAT with rtPA who were treated with IV andor IA rtPA who were treated with IV andor IA abciximab eptifibatide or tirofiban abciximab eptifibatide or tirofiban
IA Mechanical Approaches in Acute Ischemic Stroke IA Mechanical Approaches in Acute Ischemic Stroke Mechanical strategies have several advantagesMechanical strategies have several advantages First they lessen and may even preclude the use of chemical First they lessen and may even preclude the use of chemical
thrombolytics in this manner very likely reducing the risk of ICHthrombolytics in this manner very likely reducing the risk of ICH Second by avoiding the use of chemical thrombolytics it is Second by avoiding the use of chemical thrombolytics it is
possible to extend the treatment window beyond the limit of 6ndash8 possible to extend the treatment window beyond the limit of 6ndash8 hours hours
Third mechanically fragmenting a clot increases the surface area Third mechanically fragmenting a clot increases the surface area accessible to fibrinolytic agents and allows inflow of fresh accessible to fibrinolytic agents and allows inflow of fresh plasminogen which in turn may increase the speed of plasminogen which in turn may increase the speed of thrombolysis thrombolysis
Finally clot-retrieval devices may provide faster recanalization Finally clot-retrieval devices may provide faster recanalization
The disadvantages of the mechanical The disadvantages of the mechanical approaches approaches technical difficulty of navigating mechanical technical difficulty of navigating mechanical
devices into the intracranial circulation excessive devices into the intracranial circulation excessive trauma to the vasculature (potentially leading to trauma to the vasculature (potentially leading to vasospasm vessel dissection perforation or vasospasm vessel dissection perforation or rupture) rupture)
fragmented thrombus causing distal embolization fragmented thrombus causing distal embolization into previously unaffected territories into previously unaffected territories
Nevertheless the advantages of mechanical stroke Nevertheless the advantages of mechanical stroke therapy appear to significantly outweigh its therapy appear to significantly outweigh its disadvantages and risksdisadvantages and risks
Contraindications to Thrombolytic Contraindications to Thrombolytic agents agents
Recent thoracic abdominal or Recent thoracic abdominal or intracranial surgeryintracranial surgery
Recent haemorrhagic CVA Head injury Recent haemorrhagic CVA Head injury or neoplasmor neoplasm
Bleeding ulcerBleeding ulcer Anticipated invasive procedures (arterial Anticipated invasive procedures (arterial
punctures biopsies)punctures biopsies) Concurrent hemostatic dysfunctionConcurrent hemostatic dysfunction
Monitoring of thrombolytic Monitoring of thrombolytic therapytherapy
Thrombin time Measures the availability of functional
fibrinogen Normal thrombin time is 10-14 sec Prolonged when fibrinogen level is below
75-100 mgdl
Half Life of ThrombolyticsHalf Life of ThrombolyticsAgent Administration Half Life
Streptokinase IA 60-80min
Urokinase IAIV 9-12min
rTPA IAIV 6min
Abciximab(Reopro) IAIV 12hour
Aspirin POIV 15-20min
Heparin IVSC 60min
Coumadin PO 15-25 days
Anti Platelet DrugsAnti Platelet DrugsDrug Drug Mechanism Mechanism UsesUsesAspirinAspirin Permanently inhibits Permanently inhibits
COX-1 and COX-2COX-1 and COX-2CADCAD
Stroke-TIAsStroke-TIAs
NSAIDsNSAIDs Reversibly inhibits Reversibly inhibits COX-1COX-1
LimitedLimited
DipyridamoleDipyridamole Inhibits PDE increases Inhibits PDE increases cAMPcAMP
TIAsTIAs
ThenopyridinesThenopyridines
(Ticlopidine(Ticlopidine
ClopidrgrelClopidrgrel))
Inhibits ADP Inhibits ADP
PlatAg PlatAg
TIAsStrokeTIAsStroke
CAD PVDCAD PVD
Abciximab (ReoPro)Abciximab (ReoPro)
Eptifibatide (Integrilin)Eptifibatide (Integrilin)
TirofibanTirofiban
GP IIBIIIA InhibitorsGP IIBIIIA Inhibitors
Stroke- TIAs Stroke- TIAs
MonitoringMonitoring
Bleeding timeBleeding time
Optical aggregometryOptical aggregometry
Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay
Bleeding timeBleeding time
Requires a skin incision (usually made on the ear lobe or Requires a skin incision (usually made on the ear lobe or forearm offorearm of
a depth that results in disruption of capillary loops and a depth that results in disruption of capillary loops and small vessels)small vessels)
AdvantagesAdvantages Universally availableUniversally available Relatively simple techniquesRelatively simple techniques Can be performed bedsideCan be performed bedside
DisadvantagesDisadvantages Insensitive inaccurate non-specific techniqueInsensitive inaccurate non-specific technique
Poorly reproducible (as depends on multiple variables)Poorly reproducible (as depends on multiple variables)
Optical aggregometryOptical aggregometry
Gold standard assay for platelet functionGold standard assay for platelet function Agonist induced aggregation is measuredAgonist induced aggregation is measured Different agonist are available for different Different agonist are available for different
agentsagents However require unique expertise and are not However require unique expertise and are not
universally availableuniversally available Aspirin measured with ADP or AA(gt70 Aspirin measured with ADP or AA(gt70
aggregation so resistance)aggregation so resistance) Clopidogrel( ADP gt 90 aggregation means Clopidogrel( ADP gt 90 aggregation means
resistance) resistance)
Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay
Can be performed bed sideCan be performed bed side Different assay devices with different Different assay devices with different
agonist are used for each of different agonist are used for each of different antiplatelet agents antiplatelet agents
For Aspirin AA is used (result is reported as aspirin For Aspirin AA is used (result is reported as aspirin reaction units [ARU] ARUgt 550 indicates non-reaction units [ARU] ARUgt 550 indicates non-responsiveness)responsiveness)
Verify IIbIIIa assay device uses TRAP as agonist for Verify IIbIIIa assay device uses TRAP as agonist for Abciximab and TirofibanAbciximab and Tirofiban
Practical Applications Practical Applications related to specific related to specific
Neurovascular Neurovascular interventionsinterventions
Acute ischemic StrokeAcute ischemic Stroke When an artery occludes neurons are affected When an artery occludes neurons are affected
differently depending upon the amount of residual blood differently depending upon the amount of residual blood flowflow
Normal cerebral blood flow is greater than 50 mL100 Normal cerebral blood flow is greater than 50 mL100 mgminmgmin
Once blood flow decreases to less than 20 mL100 Once blood flow decreases to less than 20 mL100 mgmin infarction occursmgmin infarction occurs
If blood flow decreases to less than 10 mL100 mgmin If blood flow decreases to less than 10 mL100 mgmin irreversible neuronal death occurs rapidly irreversible neuronal death occurs rapidly
Blood flow between 11 and 20 mL100 mgmin is thought Blood flow between 11 and 20 mL100 mgmin is thought to represent the ischemic penumbra an area where the to represent the ischemic penumbra an area where the cells are functionally silent because of ischemia but are cells are functionally silent because of ischemia but are still able to recover if blood flow is restored still able to recover if blood flow is restored
Many acute stroke therapies are targeted toward Many acute stroke therapies are targeted toward restoring flow or function to the ischemic penumbrarestoring flow or function to the ischemic penumbra
Therapeutic window in Therapeutic window in management of acute Ischemic management of acute Ischemic
StrokeStrokeThe early diagnosis of ischemic stroke is critical to the The early diagnosis of ischemic stroke is critical to the
with only a narrow therapeutic window in the first few with only a narrow therapeutic window in the first few hours following stroke ictushours following stroke ictus
Diagnosis in the first 3 hours postictus provides the Diagnosis in the first 3 hours postictus provides the opportunity for intravenous or intraarterial thrombolysis opportunity for intravenous or intraarterial thrombolysis and intra-arterial clot mechanical treatment which and intra-arterial clot mechanical treatment which improve the outcome improve the outcome
Diagnosis in the time period between 3 and 6 hours Diagnosis in the time period between 3 and 6 hours provides an opportunity for intra-arterial thrombolysis provides an opportunity for intra-arterial thrombolysis and mechanical treatment and mechanical treatment
Involvement of the posterior circulation especially the Involvement of the posterior circulation especially the basilar artery is treated by some regardless of time of basilar artery is treated by some regardless of time of onset or up until 12 to 24 hours in some practices This is onset or up until 12 to 24 hours in some practices This is related to the potentially high mortality and morbidity related to the potentially high mortality and morbidity associated with basilar artery thrombosisassociated with basilar artery thrombosis
Infarct evaluation on angiographyInfarct evaluation on angiography(CT angiography and catheter (CT angiography and catheter
angiography)angiography)CTA is an excellent first-line examination for CTA is an excellent first-line examination for
evaluation of the head and neck arteries evaluation of the head and neck arteries In comparison with catheter angiography In comparison with catheter angiography
what it gives up in resolution and dynamic what it gives up in resolution and dynamic properties it makes up for with rapid properties it makes up for with rapid acquisition of a 3-D dataset and the potential acquisition of a 3-D dataset and the potential for assessment of whole-brain perfusion and for assessment of whole-brain perfusion and better parenchymal evaluationbetter parenchymal evaluation
Moreover CTA illustrates not only arterial Moreover CTA illustrates not only arterial stenosis or occlusion but also the vessel wall stenosis or occlusion but also the vessel wall This factor is most important for evaluation of This factor is most important for evaluation of intramural dissection and thrombosed intramural dissection and thrombosed aneurysms which may both complicate aneurysms which may both complicate evaluation of stroke patientsevaluation of stroke patients
Early angiographic signs of strokes Early angiographic signs of strokes both CTA both CTA and DSA and DSA
Vessel occlusion or cutoff related to Vessel occlusion or cutoff related to thromboembolithromboemboli
aneurysms aneurysms arterial dissection arterial dissection Meniscus or flattened shape to clot Meniscus or flattened shape to clot
(recent) versus reverse meniscus (older)(recent) versus reverse meniscus (older) tram track (nonocclusive or recanalized tram track (nonocclusive or recanalized
clot) clot) delayed (antegrade) flow (manifest as delayed (antegrade) flow (manifest as
decreased whole-brain perfusion on CTA)decreased whole-brain perfusion on CTA) retrograde collateral flowretrograde collateral flow
Non-occlusive left MCA thrombus on 3-D imaging performed from CTA source data and was confirmed at catheter angiography
Therapy to be started within a 6-hr Therapy to be started within a 6-hr time to treatment (TTT) window time to treatment (TTT) window (while in case of IV thrombolysis (while in case of IV thrombolysis therapy to be started with in 3hrs)therapy to be started with in 3hrs)
Exclusion criteria Exclusion criteria Rapidly improving neurologic deficit or Rapidly improving neurologic deficit or Sustained blood pressure of gt180100 Sustained blood pressure of gt180100 Hemorrhage is detected on CTHemorrhage is detected on CT Infarct involving gt more than 13 rd Infarct involving gt more than 13 rd
territory of MCAterritory of MCA MRADWI-Perfusion mismatchlt 20MRADWI-Perfusion mismatchlt 20 Definite hypodensity on CTDefinite hypodensity on CT
Intra-arterial Thrombolysis
Fibrinolytics + AntiplateletsFibrinolytics + Antiplatelets
PlasminogenPlasminogen activators through fibrinolysis exposes activators through fibrinolysis exposes free thrombin and paradoxically stimulatesfree thrombin and paradoxically stimulates platelet platelet aggregation which leads to formation of aaggregation which leads to formation of a platelet platelet thrombus (white clot) thrombus (white clot)
This new thrombus is relatively resistant to This new thrombus is relatively resistant to fibrinolyticsfibrinolytics
So new regimen in case of acute stroke isSo new regimen in case of acute stroke is fibrinolytics + antiplatelet drugsfibrinolytics + antiplatelet drugs
rtPA + IIbIIIa inhibitors( tirofiban rtPA + IIbIIIa inhibitors( tirofiban abciximab) orabciximab) or
Urokinase + IIbIIIa Urokinase + IIbIIIa inhibitors( tirofiban abciximab)inhibitors( tirofiban abciximab)
Intra-arterial Thrombolysis Tirofiban (04 microgkgmin bolus for 3 min followed by Tirofiban (04 microgkgmin bolus for 3 min followed by
0125 ugkgmin)0125 ugkgmin)
++
Heparin (2000ndash3000 IU bolus followed by Heparin (2000ndash3000 IU bolus followed by 1000 IUhour infusion 1000 IUhour infusion
with ACT maintained bw 200-300) throughout the with ACT maintained bw 200-300) throughout the interventional procedure and for 24ndash48 hours thereafter when interventional procedure and for 24ndash48 hours thereafter when there is neither intraprocedural bleeding nor suspicion of there is neither intraprocedural bleeding nor suspicion of increased risk of bleeding increased risk of bleeding
Maximum dose of Urokinase Maximum dose of Urokinase Anterior circulation stroke - 500000 IU (mean 400000 Anterior circulation stroke - 500000 IU (mean 400000
IU range 300000ndash500000 IU)IU range 300000ndash500000 IU) Posterior circulation stroke -1000000 IU (mean 837000 Posterior circulation stroke -1000000 IU (mean 837000
IU range 300000ndash1000000 IU)IU range 300000ndash1000000 IU)American Journal of NeuroradiologyAmerican Journal of Neuroradiology 262595-2601 2005262595-2601 2005
Intravenous ThrombolysisIntravenous Thrombolysis
The first method to restore cerebral The first method to restore cerebral perfusion is clot lysis with the goal perfusion is clot lysis with the goal of re-establishing blood flow to the of re-establishing blood flow to the affected tissue affected tissue
IV thrombolysis rt-PA is the only IV thrombolysis rt-PA is the only FDA- approved treatment for AIS FDA- approved treatment for AIS
Fibrinolysis is enhanced powerfully Fibrinolysis is enhanced powerfully by rt-PAby rt-PA
Intravenous rTPA Intravenous rTPA administration administration protocolprotocol
Total dose of rt-PA 09 mgkg (maximum dose Total dose of rt-PA 09 mgkg (maximum dose 90 mg)90 mg)
Give 10 as initial IV bolusGive 10 as initial IV bolus Infuse remainder over 1 hourInfuse remainder over 1 hour Admit patient to an ICU or stroke unit for Admit patient to an ICU or stroke unit for
monitoringmonitoring Neurologic assessments every 15 minutes Neurologic assessments every 15 minutes
during infusion then every 30 minutes for next during infusion then every 30 minutes for next 6 hours then every hour until 24hours after 6 hours then every hour until 24hours after treatmenttreatment
Favorable Outcome vs Treatment Time Favorable Outcome vs Treatment Time with IV rTPAwith IV rTPA
Protocol limit = 3 hrs
Benefit ~ 45 hrs
Thromboembolism During coilingThromboembolism During coiling Most feared and frequent complication Most feared and frequent complication Reported incidence - Approx 7 Reported incidence - Approx 7 SourcesSources of Thromboembolism are of Thromboembolism are
- Clots at the aneurysmal neck during or immediately- Clots at the aneurysmal neck during or immediately after after embolization embolization
- Thrombus forming on catheters during- Thrombus forming on catheters during proceduresprocedures
- Stenosis of an adjacent artery dt coil mass- Stenosis of an adjacent artery dt coil mass or herniationor herniation
- Migration of intraaneurysmal- Migration of intraaneurysmal thrombus during coil thrombus during coil placement placement
- Slow flow dt vasospasm - Slow flow dt vasospasm
- Rare and unlikely causes are hypercoagulable- Rare and unlikely causes are hypercoagulable state such state such as antiphospholipid antibody syndrome or due to HITas antiphospholipid antibody syndrome or due to HIT
Occur more often with wide-necked aneurysms (dt Occur more often with wide-necked aneurysms (dt increased exposed surface area of thrombogenic coil increased exposed surface area of thrombogenic coil material)material)
Current regimen of endovascular Current regimen of endovascular managementmanagement
The The glycoprotein IIbIIIa antagonist tirofiban glycoprotein IIbIIIa antagonist tirofiban (04 (04 microgkgmin bolus for 30 minutes followed by infusion of microgkgmin bolus for 30 minutes followed by infusion of 0125 ugkgmin until the thrombus dissolved) 0125 ugkgmin until the thrombus dissolved)
Intraarterial thrombolysis with Intraarterial thrombolysis with urokinase or r- TPA urokinase or r- TPA increase of intravenous (IV) heparin (measured by increase of intravenous (IV) heparin (measured by
ACT) ACT) Intravenous aspirin Intravenous aspirin
Coil-related platelet aggregation (white clot) is Coil-related platelet aggregation (white clot) is unlikely to respond to fibrinolytics but has a high risk unlikely to respond to fibrinolytics but has a high risk of hemorrhage (In ISAT) all 5 patients who had of hemorrhage (In ISAT) all 5 patients who had received thrombolytic therapy with tPA to treat a received thrombolytic therapy with tPA to treat a thromboembolic complication after endovascular thromboembolic complication after endovascular treatment rebleed and all of these patients died)treatment rebleed and all of these patients died)
IntracranialIntracranial Stenting Stenting Metallic foreign body such as stent will accumulate Metallic foreign body such as stent will accumulate
thrombus in the absence of platelet inhibitionthrombus in the absence of platelet inhibition Antiplatelet drugs are important to prevent peri or Antiplatelet drugs are important to prevent peri or
post-interventional thromboembolic eventspost-interventional thromboembolic events Optimal treatment regimens has not been determined Optimal treatment regimens has not been determined
but usually but usually Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-
procedureprocedureOrOr
Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on
morning of proceduremorning of procedure
If need to use stent is not pre-planned thanIf need to use stent is not pre-planned than
Abciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkgAbciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkg IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)
Glycoprotein IIbIIIa inhibitor are not used routinely during elective Glycoprotein IIbIIIa inhibitor are not used routinely during elective stenting procedure dt increased risk of ICH stenting procedure dt increased risk of ICH
Carotid StentingCarotid Stenting
Pre-procedurePre-procedure
Double Antiplatelet therapy is routinely given Double Antiplatelet therapy is routinely given beginning at least 3beginning at least 3
days before the proceduredays before the procedure
Aspirin 325mgd+Clopidogrel 75mgdAspirin 325mgd+Clopidogrel 75mgd During procedureDuring procedure
Heparin is given with target clotting time of 250-Heparin is given with target clotting time of 250-300sec300sec
Post-procedure Post-procedure
Aspirin 325mg is continued indefinitely and Aspirin 325mg is continued indefinitely and
Clopidogrel 75mgd for at least 6 weeks Clopidogrel 75mgd for at least 6 weeks
Inclusion criteria for Local ThrombolysisInclusion criteria for Local Thrombolysis a)a) Patients in severe clinical grade on admission Patients in severe clinical grade on admission
with evidence of dural venous sinus with evidence of dural venous sinus thrombosis and restrictive venous outflow on thrombosis and restrictive venous outflow on cerebral angiogramcerebral angiogram
b)b) Patients in clinical grade 3 worsening on Patients in clinical grade 3 worsening on heparin therapy Restriction to venous heparin therapy Restriction to venous outflow was defined as an increase in brain outflow was defined as an increase in brain circulation time gt 12 s delay in the drainage circulation time gt 12 s delay in the drainage of cortical veins with cortical veins hanging of cortical veins with cortical veins hanging in spacein space
Treatment Options for Venous Thrombosis
CT Grading for Venous ThrombosisCT Grading for Venous Thrombosis Grade I no parenchymal change Grade I no parenchymal change
(hyperdense (hyperdense sinuses cortical veins empty sinuses cortical veins empty delta sign)delta sign)
Grade II non hemorrhagic venous infarct Grade II non hemorrhagic venous infarct without mass effect without mass effect
Grade III non-hemorrhagic infarct with Grade III non-hemorrhagic infarct with mass effectmass effect
Grade IV hemorrhagic venous infarct (max Grade IV hemorrhagic venous infarct (max diameter lt 3 cm) with no mass effectdiameter lt 3 cm) with no mass effect
Grade V hemorrhagic venous infarct (max Grade V hemorrhagic venous infarct (max diameter gt 3 cm) with mass effect diameter gt 3 cm) with mass effect
Local ThrombolysisLocal Thrombolysis
Femoral Jugular access was secured and a guiding Femoral Jugular access was secured and a guiding catheter was placed in the jugular bulb catheter was placed in the jugular bulb Mechanical Mechanical clot maceration clot maceration was done with the guidewire was done with the guidewire following which a microcatheter (was navigated and following which a microcatheter (was navigated and placed in the thrombosed segment of sinus confirmed placed in the thrombosed segment of sinus confirmed on a selective venogram on a selective venogram
Urokinase infusion Bolus dose of 2-6 lacs followed Urokinase infusion Bolus dose of 2-6 lacs followed by 60000 to 100000 units per hour along with by 60000 to 100000 units per hour along with periodic check venogram Along with maintenance periodic check venogram Along with maintenance systemic infusion of Heparinsystemic infusion of Heparin Other agents such as Other agents such as streptokinase altepase or rTPAstreptokinase altepase or rTPA can be also used can be also used
After thrombolysis patient should subjected to oral After thrombolysis patient should subjected to oral anticoagulation for six monthsanticoagulation for six months
Low-molecular-weight Low-molecular-weight heparinheparin
PharmacologyPharmacologyLMWH as its name suggests is a glycosaminoglycan that is approximatelyLMWH as its name suggests is a glycosaminoglycan that is approximately
one third the molecular weight of UFH It is derived from UFH through one third the molecular weight of UFH It is derived from UFH through variousvarious
depolymerization processes LMWH binds to antithrombin which in turn depolymerization processes LMWH binds to antithrombin which in turn
Neutralizes actors Xa and IIa Because LMWH lacks many of the longer Neutralizes actors Xa and IIa Because LMWH lacks many of the longer chains chains
required for binding to thrombin it has less ability to neutralize thrombin required for binding to thrombin it has less ability to neutralize thrombin
relativeto its ability to neutralize factor Xa LMWH also has less relativeto its ability to neutralize factor Xa LMWH also has less nonspecific nonspecific
binding to other proteins There is greater bioavailability with more binding to other proteins There is greater bioavailability with more predictable predictable
pharmacokinetics that eliminates the need for monitoring The smaller pharmacokinetics that eliminates the need for monitoring The smaller size also size also
allows for enhanced subcutaneous absorption when compared with UFHallows for enhanced subcutaneous absorption when compared with UFH
Three LMWH preparations are Three LMWH preparations are currently approved for use in the currently approved for use in the United States (1) enoxaparin (2) United States (1) enoxaparin (2) dalteparin and (3) tinzaparin dalteparin and (3) tinzaparin
They are all administered They are all administered subcutaneously at intervals of either subcutaneously at intervals of either once or twice daily for both once or twice daily for both prophylaxis and treatment dosesprophylaxis and treatment doses
Few Experiences of Few Experiences of ThrombolysisThrombolysis
Vickey 25 Yrs male patient presented Vickey 25 Yrs male patient presented with 12with 12thth day HO severe headache with day HO severe headache with right sided hemiplegiaright sided hemiplegia
MRI shows thrombosis of the superior MRI shows thrombosis of the superior sagittal left transverse left sigmoid sagittal left transverse left sigmoid sinuses and cortical veins in the fronto-sinuses and cortical veins in the fronto-parietal regions with eo haemorrhagic parietal regions with eo haemorrhagic infarct in the left cerebral hemisphere infarct in the left cerebral hemisphere with mass effect( Grade ndashV)with mass effect( Grade ndashV)
Sashi Srivastava 64 yrs FSashi Srivastava 64 yrs F In a follow up case of MRD with infra-renal In a follow up case of MRD with infra-renal
aortic abdominal and bilateral renal artery aortic abdominal and bilateral renal artery thrombosis renal angiogram shows filling thrombosis renal angiogram shows filling defects in the right Renal artery defects in the right Renal artery
Initially Renal angioplasty was done Initially Renal angioplasty was done Following angioplasty few thrombi are seem Following angioplasty few thrombi are seem to extends into the segmental branches and to extends into the segmental branches and causing blockage So Thrombolysis was causing blockage So Thrombolysis was plane to dissolve the run-out thrombi with plane to dissolve the run-out thrombi with urokinase urokinase
Rakesh 34yrsMRakesh 34yrsM Left SFA pseudoaneurysm with Left SFA pseudoaneurysm with
Covered stent placementCovered stent placement Pre operative antiplatelets with post Pre operative antiplatelets with post
procedure heparin Tirofiban procedure heparin Tirofiban followed by aspirin and clopidogrel followed by aspirin and clopidogrel were usedwere used
IAT may be a treatment option for selected patients IAT may be a treatment option for selected patients Possible selection criteria include Possible selection criteria include
presentation between 3 and 6 hours from symptom onsetpresentation between 3 and 6 hours from symptom onset major cerebral artery occlusion major cerebral artery occlusion severe neurologic deficits severe neurologic deficits high risk of systemic hemorrhage with IV rt-PA (eg recent high risk of systemic hemorrhage with IV rt-PA (eg recent
surgery) surgery) The MERCI (Mechanical Embolus Removal in Cerebral The MERCI (Mechanical Embolus Removal in Cerebral
Ischemia) retrievalIschemia) retrieval system system
Has been FDA-approved for recanalizing acutely occluded Has been FDA-approved for recanalizing acutely occluded cerebral arteries cerebral arteries
In the Multi-MERCI study patients who did not improve In the Multi-MERCI study patients who did not improve immediately after IV rt-PA underwent mechanical immediately after IV rt-PA underwent mechanical embolectomy within 8 hours of symptom onset embolectomy within 8 hours of symptom onset
Partial or complete recanalization occurred in 74 of Partial or complete recanalization occurred in 74 of patientspatients
with a symptomatic intracerebral hemorrhage (sICH) rate of with a symptomatic intracerebral hemorrhage (sICH) rate of 67 67
Mechanical embolectomy with the MERCI retriever may be a Mechanical embolectomy with the MERCI retriever may be a feasible and safe option for patients after IV rt-PAfeasible and safe option for patients after IV rt-PA
Penumbra stroke systemPenumbra stroke system This device combines two methods of clot This device combines two methods of clot
extraction aspiration and mechanical extraction aspiration and mechanical extraction extraction
First the clot is aspirated then a thrombus First the clot is aspirated then a thrombus removal ring can be used if necessary to removal ring can be used if necessary to remove remaining clot remove remaining clot
successful recanalizing 82successful recanalizing 82 Bridging therapyBridging therapy
06 mgkg IV rt-PA followed by IAT with IA rt-06 mgkg IV rt-PA followed by IAT with IA rt-PA (up to 20 mg)PA (up to 20 mg)
achieved a higher recanalization rateachieved a higher recanalization rate
Criteria for thrombolysis with rTPACriteria for thrombolysis with rTPA
Inclusion criteriaInclusion criteria Clinical signs and symptoms consistent with ischemic Clinical signs and symptoms consistent with ischemic
strokestroke Patient last seen normal within 3 hoursPatient last seen normal within 3 hours Measurable neurologic deficitMeasurable neurologic deficit
Exclusion criteriaExclusion criteria Any hemorrhage on neuroimaging (CT or MRI)Any hemorrhage on neuroimaging (CT or MRI) Symptoms suggestive of subarachnoid hemorrhageSymptoms suggestive of subarachnoid hemorrhage Seizure at stroke onset that is thought to contribute to Seizure at stroke onset that is thought to contribute to
neurologic deficitneurologic deficit Hypodensity greater than one third cerebral hemisphere Hypodensity greater than one third cerebral hemisphere
on CTon CT SBP greater than 185 mm Hg or DBP greater than 110 SBP greater than 185 mm Hg or DBP greater than 110
mm Hgmm Hg International normalized ratio (INR) greater than 17International normalized ratio (INR) greater than 17
Ischemic Stroke Ischemic Stroke Treatment ndash 2006Treatment ndash 2006
IV tissue plasminogen activator (tPA)IV tissue plasminogen activator (tPA) ndash ndash Only FDA-approved acute stroke drugOnly FDA-approved acute stroke drug ndash ndash 3 hour treatment window3 hour treatment window
MERCI - Concentric clot retrieval MERCI - Concentric clot retrieval devicedevice ndash ndash Rescue therapy - approved 2004Rescue therapy - approved 2004 ndash ndash Device approval (not outcomes-based)Device approval (not outcomes-based)
Off label approachesOff label approaches ndash ndash IV tPA after 3 hoursIV tPA after 3 hours ndash ndash IV-IA tPA sequential strategiesIV-IA tPA sequential strategies ndash ndash IA tPA clot angioplasty fragmentationIA tPA clot angioplasty fragmentation ndash ndash Ultrasound-assisted tPA lysisUltrasound-assisted tPA lysis
rt-PA Trials NINDSrt-PA Trials NINDS
Acute stroke - 624 patientsAcute stroke - 624 patients Treat within 3 hrsTreat within 3 hrs Intravenous 09 mgkg rt-PA vs placeboIntravenous 09 mgkg rt-PA vs placebo Hemorrhage 64 tPA 06 placeboHemorrhage 64 tPA 06 placebo Neurologic recovery better with tPA 30 Neurologic recovery better with tPA 30
more like to have minimal or no disabilitymore like to have minimal or no disability
First proven approved treatment for First proven approved treatment for strokestroke
Limitations of tPALimitations of tPA Only 4 of acute strokes receive tPAOnly 4 of acute strokes receive tPA (Kleindorfer et al Stroke 2004 35 e27-e29)(Kleindorfer et al Stroke 2004 35 e27-e29)
Only 22 of patients present within 3 hoursOnly 22 of patients present within 3 hours1048707 1048707 51 of these ineligible due to51 of these ineligible due to
bull bull Mild severityMild severity bull bull Medical or surgical historyMedical or surgical history bull bull Blood testsBlood tests
Sustained recanalization only 13Sustained recanalization only 13 (Alexandrov et al NEJM 2004 351 2170-8)(Alexandrov et al NEJM 2004 351 2170-8)
Concern for hemorrhageConcern for hemorrhage tPA potentiates apoptotic injury tPA potentiates apoptotic injury (Liu et al Nature Med 2004 101379-83)(Liu et al Nature Med 2004 101379-83)
PROACT II IA Lysis TrialPROACT II IA Lysis Trial Baseline 24 hours 8 days
Baseline 60 minutes 120 minutes
9mg IAProurokinase
Desmoteplase Trials DEDAS Desmoteplase Trials DEDAS DIASDIAS
Trial OverviewTrial Overview Double blind randomized placebo Double blind randomized placebo
controlled trialscontrolled trials IV delivery 3-9 hour time windowIV delivery 3-9 hour time window Plasminogen activator ndash from Plasminogen activator ndash from vampire bat vampire bat
salivasaliva Selection based on PWI-DWI MismatchSelection based on PWI-DWI Mismatch
MRI InclusionMRI Inclusion PWI defect at least 2 cm AND ~20 larger PWI defect at least 2 cm AND ~20 larger
than DWIthan DWI PWI should be obvious even visible on PWI should be obvious even visible on
raw imagesraw imagesMRI ExclusionMRI Exclusion
DWI gt 13 MCADWI gt 13 MCA MRA ICA occlusionMRA ICA occlusion
Desmoteplase ndash DIAS Desmoteplase ndash DIAS ResultsResults
Mechanical Thrombolysis Mechanical Thrombolysis devicesdevices
mechanical thrombolysis potentially extends the treatment mechanical thrombolysis potentially extends the treatment window because they act promptly at the site of the thrombuswindow because they act promptly at the site of the thrombus
The devices can retrieve large clots that pharmaceutical agents The devices can retrieve large clots that pharmaceutical agents may not successfully lysemay not successfully lyse
Patients treated with IV tPA may be considered for treatment of Patients treated with IV tPA may be considered for treatment of residual clot with some of these devicesresidual clot with some of these devices
suction-creating saline jets suction-creating saline jets laser energy ultrasound laser energy ultrasound a corkscrew apparatus to treat strokesa corkscrew apparatus to treat strokes The AngioJet systemThe AngioJet system uses saline jets that are directed back into the catheter to uses saline jets that are directed back into the catheter to
create a low-pressure zone around the catheter tip inducing create a low-pressure zone around the catheter tip inducing suction suction
The clot is pulled into the exhaust lumen and removed from the The clot is pulled into the exhaust lumen and removed from the vessel Although US Food and Drug Administration (FDA) has vessel Although US Food and Drug Administration (FDA) has approved this device for use in arteriovenous dialysis grafts and approved this device for use in arteriovenous dialysis grafts and fistulae and for the treatment of coronary arteries saphenous fistulae and for the treatment of coronary arteries saphenous vein grafts and peripheral vessels clinical trials for the vein grafts and peripheral vessels clinical trials for the treatment of acute stroke are no longer in progress treatment of acute stroke are no longer in progress
Most devices are used in cerebral vessels that 2-5 mm
The Latis laser device The Latis laser device used laser energy to ablate clots used laser energy to ablate clots Arteries 2-5 mm in diameter could be Arteries 2-5 mm in diameter could be
treated including the ICA M1 or M2 treated including the ICA M1 or M2 branch of the MCA A1 branch of the branch of the MCA A1 branch of the anterior cerebral artery (ACA) basilar anterior cerebral artery (ACA) basilar artery posterior cerebral artery (PCA) artery posterior cerebral artery (PCA) and vertebral and vertebral
Patients could receive treatment as late Patients could receive treatment as late as 8 hours after symptom onset in the as 8 hours after symptom onset in the anterior circulation and within 24 hours in anterior circulation and within 24 hours in the posterior circulation the posterior circulation
Endovascular Photo Acoustic Endovascular Photo Acoustic Recanalization (EPAR) Recanalization (EPAR)
A laser power source generated energy for the A laser power source generated energy for the systemsystem
The energy was delivered by means of The energy was delivered by means of fiberoptics to the tip of the catheter at the fiberoptics to the tip of the catheter at the treatment sitetreatment site
Absorption of laser light by darkly pigmented Absorption of laser light by darkly pigmented materials (ie the clot) occurred inside the 1-mm materials (ie the clot) occurred inside the 1-mm catheter tipcatheter tip
the system was designed to minimize scattering the system was designed to minimize scattering of laser light of laser light
Absorption converted photo energy to acoustic Absorption converted photo energy to acoustic energy which then emulsified the clot inside the energy which then emulsified the clot inside the catheter tip catheter tip
EKOS ultrasound( the EKOS ultrasound( the Ultrasound Thrombolytic Ultrasound Thrombolytic
Infusion Catheter) Infusion Catheter) combines the use of a distal ultrasound transducer with combines the use of a distal ultrasound transducer with
infusion of a thrombolytic agent through the infusion of a thrombolytic agent through the microcathetermicrocatheter
Ultrasound changes the structure of the clot to Ultrasound changes the structure of the clot to temporarily increase its permeability while providing an temporarily increase its permeability while providing an acoustic pressure gradient to move the drug into the clot acoustic pressure gradient to move the drug into the clot to speed its dissolution to speed its dissolution
The EKOS catheter is placed in the proximal portion of the The EKOS catheter is placed in the proximal portion of the clot clot
After a 2-mg bolus of tPA was injected through the After a 2-mg bolus of tPA was injected through the catheter catheter
the patient received a continuous infusion of IA tPA 03 the patient received a continuous infusion of IA tPA 03 mgmin to a maximum of 20 mg and simultaneous mgmin to a maximum of 20 mg and simultaneous ultrasound transmission for as long as 60 minutes ultrasound transmission for as long as 60 minutes
One patient was treated with a total of 4 units of One patient was treated with a total of 4 units of recombinant reteplase (Retavase) hand-injected over 60 recombinant reteplase (Retavase) hand-injected over 60 minutes minutes
Penumbra system Penumbra system The Penumbra system (Penumbra Inc) provides a dual The Penumbra system (Penumbra Inc) provides a dual
approach to clot extraction using aspiration followed by approach to clot extraction using aspiration followed by clot retrieval with a ring device if needed clot retrieval with a ring device if needed
Mechanical Embolus Removal in Cerebral Ischemia Mechanical Embolus Removal in Cerebral Ischemia (MERCI)(MERCI)
a corkscrew-like apparatus to remove blood clots from a corkscrew-like apparatus to remove blood clots from the brain in patients experiencing an ischemic stroke the brain in patients experiencing an ischemic stroke
The corkscrew itself resides in the catheter tip which The corkscrew itself resides in the catheter tip which shields it from the wall of the vessel until it is ready to be shields it from the wall of the vessel until it is ready to be burrowed into the clot Once lodged in the clot the device burrowed into the clot Once lodged in the clot the device and clot are withdrawn from the vessel and clot are withdrawn from the vessel
Snarelike devicesSnarelike devices Snares such as the Neuronet snare (Guidant Snares such as the Neuronet snare (Guidant
Endovascular Santa Clara CA) have been developed Endovascular Santa Clara CA) have been developed specifically for use in the treatment of strokes specifically for use in the treatment of strokes
These devices are simple in design and do not require the These devices are simple in design and do not require the clot to be amenable to emulsification clot to be amenable to emulsification
X-Sizer deviceX-Sizer device a device with small moving blades at the a device with small moving blades at the
catheter tip catheter tip This device the X-Sizer device (EndiCor Medical This device the X-Sizer device (EndiCor Medical
San Clemente CA) can be used to excise the San Clemente CA) can be used to excise the thrombus and aspirate it thrombus and aspirate it
The device was being evaluated in randomized The device was being evaluated in randomized studies of coronary vessels and in a registry of studies of coronary vessels and in a registry of patients with acute myocardial infarctionpatients with acute myocardial infarction
Although the manufacturer had modified the Although the manufacturer had modified the device for use in cerebral vessels a safety and device for use in cerebral vessels a safety and feasibility study was indefinitely suspended after feasibility study was indefinitely suspended after only 1 patient was treated with the device in only 1 patient was treated with the device in Europe Europe
Suction thrombectomySuction thrombectomy This method of mechanical thrombolysis is one of the This method of mechanical thrombolysis is one of the
simplestsimplest In this readily available technique suction is applied with In this readily available technique suction is applied with
a syringe to remove thrombus in the ICA a syringe to remove thrombus in the ICA It requires no other devicesIt requires no other devices A catheter with a large inner diameter (Brite Tip Cordis A catheter with a large inner diameter (Brite Tip Cordis
Corporation Miami FL) was placed in the symptomatic Corporation Miami FL) was placed in the symptomatic vessel and navigated over a guidewire into the thrombusvessel and navigated over a guidewire into the thrombus
A 60-mL syringe was used to aspirate the thrombus A 60-mL syringe was used to aspirate the thrombus Each patient required angioplasty and stenting of carotid Each patient required angioplasty and stenting of carotid
bifurcation stenosis and received daily aspirin and bifurcation stenosis and received daily aspirin and ticlopidine after the procedure No complications ticlopidine after the procedure No complications occurred occurred
Summary Acute Stroke Summary Acute Stroke ImagingImaging
PhysiologyPhysiology importance collaterals importance collaterals
ndash ndashGrowing role for perfusion Growing role for perfusion assessmentassessment
tPAtPA guidelines amp limitations guidelines amp limitations Signs on CT amp MRSigns on CT amp MR follow physiology follow physiology Stroke trialsStroke trials PWI-DWI mismatch PWI-DWI mismatch
ndash ndashTreat based on physiology not timeTreat based on physiology not time ProtocolsProtocols should be fast and should be fast and
comprehensivecomprehensive
(AJNR 28155-158 2007)
Treatment of heparin-induced Treatment of heparin-induced thrombocytopeniathrombocytopenia
When HIT is diagnosed it is important to When HIT is diagnosed it is important to stop heparin mainly in type 2 and to avoid stop heparin mainly in type 2 and to avoid the use of LMWH the use of LMWH
Because of the increased risk of thrombosis Because of the increased risk of thrombosis however continuation of an anticoagulant however continuation of an anticoagulant must be considered must be considered
The drugs currently approved for the The drugs currently approved for the treatment of HIT in the United States are treatment of HIT in the United States are direct thrombin inhibitors argatroban and direct thrombin inhibitors argatroban and lepirudinlepirudin
WARFARIN MECHANISM OF ACTIONWARFARIN MECHANISM OF ACTION
Inactive factors II VII IX and X
Proteins S and C
Active factors II VII IX and X
Proteins S and C
Vitamin K epoxide
Vitamin K reduced
WA
RF
AR
IN
Prevents the reduction of vitamin K which is essential for Prevents the reduction of vitamin K which is essential for activation of certain factorsactivation of certain factors
Has no effect on previously formed thrombusHas no effect on previously formed thrombus
Antagonist is Vit KAntagonist is Vit K
OPTIMIZING WARFARIN THERAPYOPTIMIZING WARFARIN THERAPY
Use of large loading dose may lead to hemorrhage and Use of large loading dose may lead to hemorrhage and other complicationsother complications
Initial dose 2-5 mg once dailyInitial dose 2-5 mg once daily Maintenance dose 2-10 mg once dailyMaintenance dose 2-10 mg once daily If Immediate anticoagulation is requiredIf Immediate anticoagulation is required Heparin IS Heparin IS
started along with loading dose of warfarin 10 mg started along with loading dose of warfarin 10 mg Heparin is usually discontinued after 4-5 days Heparin is usually discontinued after 4-5 days Before Before discontinuing INR should be in therapeutic range for 2 discontinuing INR should be in therapeutic range for 2 consecutive daysconsecutive days
Daily monitoring of INR until INR is in therapeutic Daily monitoring of INR until INR is in therapeutic range then 3 times weekly for 1-2 weeks then less often range then 3 times weekly for 1-2 weeks then less often (every 4 to 6 weeks)(every 4 to 6 weeks)
OPTIMAL THERAPEUTIC RANGEOPTIMAL THERAPEUTIC RANGE
IndicationIndication INRINR
Prophylaxis of venous Prophylaxis of venous thromboembolismthromboembolism
20-3020-30
Treatment of venous Treatment of venous thromboembolismthromboembolism
20-3020-30
Atrial fibrillationAtrial fibrillation 20-3020-30
Mitral valve stenosisMitral valve stenosis 20-3020-30
Heart valve replacementHeart valve replacement
Bioprosthetic valveBioprosthetic valve
Mechanical valveMechanical valve
20-3020-30
25-3525-35
Myocardial infarctionMyocardial infarction 20-3020-30
25-35 25-35 (high risk patients)(high risk patients)
FACTORS INFLUENCING DOSE RESPONSEFACTORS INFLUENCING DOSE RESPONSE
Poor patient compliancePoor patient compliance Concomitant medicationsConcomitant medications Levels of dietary vitamin KLevels of dietary vitamin K Alcohol Inaccurate lab testingAlcohol Inaccurate lab testing Inaccurate lab testingInaccurate lab testing Hepatic dysfunctionHepatic dysfunction FeverFever
Contraindication for WarfarinContraindication for Warfarin
Hypersensitivity to warfarinHypersensitivity to warfarin Hemorrhagic tendencyHemorrhagic tendency Condition with risk of hemorrhageCondition with risk of hemorrhage Inadequate laboratory techniquesInadequate laboratory techniques Protein C amp S deficiencyProtein C amp S deficiency Vitamin K deficiencyVitamin K deficiency
SIDE EFFECTSSIDE EFFECTS
Hemorrhage Hemorrhage Skin necrosisSkin necrosis Purple toe syndromePurple toe syndrome Microembolization Microembolization TeratogenecityTeratogenecity Agranulocytosis leukopenia Agranulocytosis leukopenia Diarrhoeanausea anorexiaDiarrhoeanausea anorexia
MONITORING OF WARFARIN THERAPYMONITORING OF WARFARIN THERAPY
Prothrombin timeProthrombin time PT ratioPT ratio INR (International Normalized Ratio)INR (International Normalized Ratio)
PROTHROMBIN TIME (PT)PROTHROMBIN TIME (PT)
Time required for blood to coagulate Time required for blood to coagulate is called PT ( normal value ~10sec)is called PT ( normal value ~10sec)
Performed by adding a mixture of Performed by adding a mixture of calcium and thromboplastin to calcium and thromboplastin to citrated plasmacitrated plasma
As a control a normal blood sample is As a control a normal blood sample is tested continuouslytested continuously
PT ratio (PTR) = PT ratio (PTR) = Patientrsquos PTPatientrsquos PT Control PTControl PT
PROBLEMS WITH PTPTRPROBLEMS WITH PTPTR
Thromboplastins are extracts from Thromboplastins are extracts from brain lung or placenta of animalsbrain lung or placenta of animals
Thromboplastins from various Thromboplastins from various manufacturers differ in their manufacturers differ in their sensitivity to prolong PTsensitivity to prolong PT
May result in false control of May result in false control of anticoagulant therapyanticoagulant therapy
INTERNATIONAL NORMALISED RATIO (INR)INTERNATIONAL NORMALISED RATIO (INR)
International Normalized Ratio (INR) International Normalized Ratio (INR) a PT test with a a PT test with a formula based ratio to normalize the often variable source formula based ratio to normalize the often variable source of tissue factor (human rabbit recombinant)of tissue factor (human rabbit recombinant)
INR = [PTINR = [PTptpt] ] ISIISI
[PT[PTRefRef]]
PTPTpt pt ndash prothrombin time of patientndash prothrombin time of patient
PTPTRef Ref ndash prothrombin time of normal pooled samplendash prothrombin time of normal pooled sample
ISI ndash International Sensitivity IndexISI ndash International Sensitivity Index
Warfarin is given orally and titrated to achieve an INR of Warfarin is given orally and titrated to achieve an INR of typically 20 ndash 30typically 20 ndash 30
Heparin versus WarfarinHeparin versus Warfarin
Drug ActionMechan-ism
Moni-toring
Effective
HeparinDirect
Inhibition ofThrombin
ATIIIcofactor
APTTACT
Immediate
WarfarinDecreasesProductionof factors
Vitamin K PTDelay
3-5 days
INR
Recanalization or Antegrade Recanalization or Antegrade Reperfusion StrategiesReperfusion Strategies
Recanalization strategies focus on removing Recanalization strategies focus on removing andor dissolving the occlusive thrombus to re-andor dissolving the occlusive thrombus to re-establish antegrade flow Strategies may be establish antegrade flow Strategies may be classified into 7 different categories on the classified into 7 different categories on the basis of their primary mechanism of action basis of their primary mechanism of action 1) 1) IV andor intraarterial thrombolysis (IAT) IV andor intraarterial thrombolysis (IAT) 2) endovascular thrombectomy2) endovascular thrombectomy3) endovascular thromboaspiration 3) endovascular thromboaspiration 4) endovascular mechanical thrombus disruption or 4) endovascular mechanical thrombus disruption or
thromborrhexisthromborrhexis5) 5) transcranial or endovascular augmented transcranial or endovascular augmented
fibrinolysis fibrinolysis 6) endovascular thrombus entrapment and 6) endovascular thrombus entrapment and 7) temporary endovascular bypass7) temporary endovascular bypass
IAT in Acute Ischemic StrokeIAT in Acute Ischemic Stroke
IAT advantages over IV thrombolysisIAT advantages over IV thrombolysis Coaxial microcatheter techniques the occluded intracranial Coaxial microcatheter techniques the occluded intracranial
vessel is directly accessible and the fibrinolytic agent can be vessel is directly accessible and the fibrinolytic agent can be infused directly into the thrombusinfused directly into the thrombus
This permits a smaller dose of fibrinolytic agent to reach a This permits a smaller dose of fibrinolytic agent to reach a higher local concentration than that reached by systemic higher local concentration than that reached by systemic infusioninfusion
Allows more complete recanalization with lower total doses of Allows more complete recanalization with lower total doses of thrombolytic thrombolytic
With the smaller dose complications from systemic fibrinolytic With the smaller dose complications from systemic fibrinolytic effects including intracranial hemorrhage (ICH) can effects including intracranial hemorrhage (ICH) can theoretically be reduced theoretically be reduced
Treatment window for endovascular techniques can be Treatment window for endovascular techniques can be extended beyond the typical IV window of 3 hours extended beyond the typical IV window of 3 hours
IA techniques have led to higher recanalization rates than IV IA techniques have led to higher recanalization rates than IV thrombolysisthrombolysis
Major disadvantagesMajor disadvantages Relative complexity of the procedure the level Relative complexity of the procedure the level
of required technical expertise and its of required technical expertise and its relatively low availability relatively low availability
Delays in initiating treatmentDelays in initiating treatment InvasiveInvasive
ThrombolyticsThrombolytics
Plasminogen activators
Fibrinolytics
1 Plasminogen Activators 1 Plasminogen Activators drugs act by converting the inactive proenzyme drugs act by converting the inactive proenzyme plasminogen into the active enzyme plasmin Plasmin plasminogen into the active enzyme plasmin Plasmin digests fibrinogen fibrin monomers and cross-linked digests fibrinogen fibrin monomers and cross-linked fibrin (as found in a thrombus) into fibrin degradation fibrin (as found in a thrombus) into fibrin degradation productsproducts
First-Generation Agents First-Generation Agents StreptokinaseStreptokinase a protein derived from group C a protein derived from group C
szlig-hemolytic streptococci has a half-life of 16ndashszlig-hemolytic streptococci has a half-life of 16ndash90 minutes and low fibrin specificity This drug 90 minutes and low fibrin specificity This drug proved to have a very narrow therapeutic proved to have a very narrow therapeutic window and significant rates of ICH and window and significant rates of ICH and systemic hemorrhage18systemic hemorrhage18
UrokinaseUrokinase is a serine protease with a plasma is a serine protease with a plasma half life of 14 minutes and low fibrin specificity half life of 14 minutes and low fibrin specificity
The urokinase dose used in cerebral IAT has The urokinase dose used in cerebral IAT has ranged from 002 to 2 X106unitsranged from 002 to 2 X106units
Second-Generation Agents Second-Generation Agents Alteplase (rtPA) Alteplase (rtPA)
is a serine is a serine protease with a plasma half-life of 35 protease with a plasma half-life of 35 minutes and a high degree of fibrin affinity and minutes and a high degree of fibrin affinity and specificity specificity
Dose used in cerebral IAT has ranged between 20 Dose used in cerebral IAT has ranged between 20 and 60 mgand 60 mg
Disadvantages of alteplase include its relatively short Disadvantages of alteplase include its relatively short halflife and limited penetration into the clot matrix halflife and limited penetration into the clot matrix because of strong binding with surface fibrin which because of strong binding with surface fibrin which could delay recanalization and increase the risk of could delay recanalization and increase the risk of recurrent occlusion recurrent occlusion
Prourokinase (r-prourokinase) Prourokinase (r-prourokinase) is the proenzyme precursor of urokinase is the proenzyme precursor of urokinase T12 of 7 minutes and high fibrin specificity T12 of 7 minutes and high fibrin specificity
Third-Generation AgentsThird-Generation Agents
ReteplaseReteplase is a structurally modified is a structurally modified form of alteplase form of alteplase
with a longer half-life (15ndash18 minutes) In with a longer half-life (15ndash18 minutes) In addition it does not bind as highly to fibrin addition it does not bind as highly to fibrin unbound reteplase can thus theoretically better unbound reteplase can thus theoretically better penetrate the clot and potentially penetrate the clot and potentially improve in improve in vivo fibrinolytic activity vivo fibrinolytic activity
TenecteplaseTenecteplase is another modified form of rtPA with a longer is another modified form of rtPA with a longer
half-life (17 minutes)half-life (17 minutes) greater fibrin specificity and greater greater fibrin specificity and greater
resistance to plasminogen activator inhibitor-1 resistance to plasminogen activator inhibitor-1 IV tenecteplase in acute ischemic stroke IV tenecteplase in acute ischemic stroke
suggest that the drug is safe and promisingsuggest that the drug is safe and promising
Newer plasminogen activatorNewer plasminogen activator
DesmoteplaseDesmoteplase is a genetically engineered is a genetically engineered version of the clot-dissolving factor version of the clot-dissolving factor
found in the saliva found in the saliva of the vampire bat Desmodus rotundusof the vampire bat Desmodus rotundus moremore potent and more selective for fibrin-bound potent and more selective for fibrin-bound
plasminogen than any other known plasminogen plasminogen than any other known plasminogen activatoractivator
Unlike tissue plasminogen activator (tPA) desmoteplase Unlike tissue plasminogen activator (tPA) desmoteplase is not activated by fibrinogen or -amyloid proteins is not activated by fibrinogen or -amyloid proteins factors that may exacerbate the risk for ICH factors that may exacerbate the risk for ICH
The effect of IV administration of desmoteplase 3ndash9 The effect of IV administration of desmoteplase 3ndash9 hours after symptom onset in patients with stroke who hours after symptom onset in patients with stroke who present with mismatch on MR imaging or CT perfusion present with mismatch on MR imaging or CT perfusion
3 DefibrinogenatingFibrinogenolytic 3 DefibrinogenatingFibrinogenolytic Agents Agents
AncrodAncrod(Viprinex)(Viprinex) is is the purified fraction of the Malayan pit viper venomthe purified fraction of the Malayan pit viper venom It acts by directly cleaving and inactivating fibrinogen It acts by directly cleaving and inactivating fibrinogen
and thus indirectly promoting anticoagulation and thus indirectly promoting anticoagulation The reduction in the blood levels of fibrinogen also The reduction in the blood levels of fibrinogen also
leads to a reduced blood viscosity which may improve leads to a reduced blood viscosity which may improve blood flow to the affected areas of the brain blood flow to the affected areas of the brain
In the Stroke Treatment with Ancrod Trial 500 In the Stroke Treatment with Ancrod Trial 500 patients with stroke presenting within 3 hours of patients with stroke presenting within 3 hours of symptom onset were randomized to receive ancrod (symptom onset were randomized to receive ancrod (n n 248) or a placebo (n 252) Good outcome (Barthel 248) or a placebo (n 252) Good outcome (Barthel Index 95ndash100 at 3 months) was achieved in 4221 Index 95ndash100 at 3 months) was achieved in 4221 and 344 of the patients respectively and 344 of the patients respectively
2 Direct Fibrinolytics2 Direct Fibrinolytics
Microplasmin (Microplasmin (ThromboGenics Heverlee Belgium)ThromboGenics Heverlee Belgium) is a truncated form of plasmin that is more resistant to the effects is a truncated form of plasmin that is more resistant to the effects
of antiplasmin of antiplasmin microplasmin can be used upto 4ndash12 hours after stroke onset microplasmin can be used upto 4ndash12 hours after stroke onset There was no evidence of increased bleeding risk with There was no evidence of increased bleeding risk with
microplasminmicroplasmin
Alfimeprase (Nuvelo San Carlos Calif)Alfimeprase (Nuvelo San Carlos Calif) is a recombinant truncated form of fibrolase a fibrinolytic zinc metalloproteinase is a recombinant truncated form of fibrolase a fibrinolytic zinc metalloproteinase
isolated from the venom of the southern copperhead snake isolated from the venom of the southern copperhead snake It degrades fibrin directly and achieves thrombolysis independent It degrades fibrin directly and achieves thrombolysis independent
of plasmin formationof plasmin formation its thrombolytic activity appears to be localized to the site of its thrombolytic activity appears to be localized to the site of
delivery These properties should theoretically result in faster delivery These properties should theoretically result in faster recanalization and lower hemorrhagic conversion riskrecanalization and lower hemorrhagic conversion risk
Anti-fibrinolyticsAnti-fibrinolytics
to limit fibrinolytic activityto limit fibrinolytic activity -aminocaproic acid (EACA) -aminocaproic acid (EACA) competitively inhibitscompetitively inhibits plasminogen and plasminogen activators from plasminogen and plasminogen activators from
binding to fibrinbinding to fibrin
alpha2-antiplasminalpha2-antiplasmin a serine protease inhibitor that a serine protease inhibitor that neutralizes any free circulating plasminneutralizes any free circulating plasmin
Plasminogen activator inhibitor-1Plasminogen activator inhibitor-1 a serine protease a serine protease inhibitor that inhibits tissue-type plasminogen inhibitor that inhibits tissue-type plasminogen activatoractivator
Glycoprotein (GP) IIbIIIa antagonistsGlycoprotein (GP) IIbIIIa antagonists
such as ReoPro (abciximab) Integrilin such as ReoPro (abciximab) Integrilin (eptifibatide) or Aggrastat (tirofiban) in (eptifibatide) or Aggrastat (tirofiban) in ischemic stroke remains investigational ischemic stroke remains investigational Deshmukh et al38 reported 21 patients with Deshmukh et al38 reported 21 patients with large-vessel occlusion refractory to IAT with large-vessel occlusion refractory to IAT with rtPA who were treated with IV andor IA rtPA who were treated with IV andor IA abciximab eptifibatide or tirofiban abciximab eptifibatide or tirofiban
IA Mechanical Approaches in Acute Ischemic Stroke IA Mechanical Approaches in Acute Ischemic Stroke Mechanical strategies have several advantagesMechanical strategies have several advantages First they lessen and may even preclude the use of chemical First they lessen and may even preclude the use of chemical
thrombolytics in this manner very likely reducing the risk of ICHthrombolytics in this manner very likely reducing the risk of ICH Second by avoiding the use of chemical thrombolytics it is Second by avoiding the use of chemical thrombolytics it is
possible to extend the treatment window beyond the limit of 6ndash8 possible to extend the treatment window beyond the limit of 6ndash8 hours hours
Third mechanically fragmenting a clot increases the surface area Third mechanically fragmenting a clot increases the surface area accessible to fibrinolytic agents and allows inflow of fresh accessible to fibrinolytic agents and allows inflow of fresh plasminogen which in turn may increase the speed of plasminogen which in turn may increase the speed of thrombolysis thrombolysis
Finally clot-retrieval devices may provide faster recanalization Finally clot-retrieval devices may provide faster recanalization
The disadvantages of the mechanical The disadvantages of the mechanical approaches approaches technical difficulty of navigating mechanical technical difficulty of navigating mechanical
devices into the intracranial circulation excessive devices into the intracranial circulation excessive trauma to the vasculature (potentially leading to trauma to the vasculature (potentially leading to vasospasm vessel dissection perforation or vasospasm vessel dissection perforation or rupture) rupture)
fragmented thrombus causing distal embolization fragmented thrombus causing distal embolization into previously unaffected territories into previously unaffected territories
Nevertheless the advantages of mechanical stroke Nevertheless the advantages of mechanical stroke therapy appear to significantly outweigh its therapy appear to significantly outweigh its disadvantages and risksdisadvantages and risks
Contraindications to Thrombolytic Contraindications to Thrombolytic agents agents
Recent thoracic abdominal or Recent thoracic abdominal or intracranial surgeryintracranial surgery
Recent haemorrhagic CVA Head injury Recent haemorrhagic CVA Head injury or neoplasmor neoplasm
Bleeding ulcerBleeding ulcer Anticipated invasive procedures (arterial Anticipated invasive procedures (arterial
punctures biopsies)punctures biopsies) Concurrent hemostatic dysfunctionConcurrent hemostatic dysfunction
Monitoring of thrombolytic Monitoring of thrombolytic therapytherapy
Thrombin time Measures the availability of functional
fibrinogen Normal thrombin time is 10-14 sec Prolonged when fibrinogen level is below
75-100 mgdl
Half Life of ThrombolyticsHalf Life of ThrombolyticsAgent Administration Half Life
Streptokinase IA 60-80min
Urokinase IAIV 9-12min
rTPA IAIV 6min
Abciximab(Reopro) IAIV 12hour
Aspirin POIV 15-20min
Heparin IVSC 60min
Coumadin PO 15-25 days
Anti Platelet DrugsAnti Platelet DrugsDrug Drug Mechanism Mechanism UsesUsesAspirinAspirin Permanently inhibits Permanently inhibits
COX-1 and COX-2COX-1 and COX-2CADCAD
Stroke-TIAsStroke-TIAs
NSAIDsNSAIDs Reversibly inhibits Reversibly inhibits COX-1COX-1
LimitedLimited
DipyridamoleDipyridamole Inhibits PDE increases Inhibits PDE increases cAMPcAMP
TIAsTIAs
ThenopyridinesThenopyridines
(Ticlopidine(Ticlopidine
ClopidrgrelClopidrgrel))
Inhibits ADP Inhibits ADP
PlatAg PlatAg
TIAsStrokeTIAsStroke
CAD PVDCAD PVD
Abciximab (ReoPro)Abciximab (ReoPro)
Eptifibatide (Integrilin)Eptifibatide (Integrilin)
TirofibanTirofiban
GP IIBIIIA InhibitorsGP IIBIIIA Inhibitors
Stroke- TIAs Stroke- TIAs
MonitoringMonitoring
Bleeding timeBleeding time
Optical aggregometryOptical aggregometry
Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay
Bleeding timeBleeding time
Requires a skin incision (usually made on the ear lobe or Requires a skin incision (usually made on the ear lobe or forearm offorearm of
a depth that results in disruption of capillary loops and a depth that results in disruption of capillary loops and small vessels)small vessels)
AdvantagesAdvantages Universally availableUniversally available Relatively simple techniquesRelatively simple techniques Can be performed bedsideCan be performed bedside
DisadvantagesDisadvantages Insensitive inaccurate non-specific techniqueInsensitive inaccurate non-specific technique
Poorly reproducible (as depends on multiple variables)Poorly reproducible (as depends on multiple variables)
Optical aggregometryOptical aggregometry
Gold standard assay for platelet functionGold standard assay for platelet function Agonist induced aggregation is measuredAgonist induced aggregation is measured Different agonist are available for different Different agonist are available for different
agentsagents However require unique expertise and are not However require unique expertise and are not
universally availableuniversally available Aspirin measured with ADP or AA(gt70 Aspirin measured with ADP or AA(gt70
aggregation so resistance)aggregation so resistance) Clopidogrel( ADP gt 90 aggregation means Clopidogrel( ADP gt 90 aggregation means
resistance) resistance)
Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay
Can be performed bed sideCan be performed bed side Different assay devices with different Different assay devices with different
agonist are used for each of different agonist are used for each of different antiplatelet agents antiplatelet agents
For Aspirin AA is used (result is reported as aspirin For Aspirin AA is used (result is reported as aspirin reaction units [ARU] ARUgt 550 indicates non-reaction units [ARU] ARUgt 550 indicates non-responsiveness)responsiveness)
Verify IIbIIIa assay device uses TRAP as agonist for Verify IIbIIIa assay device uses TRAP as agonist for Abciximab and TirofibanAbciximab and Tirofiban
Practical Applications Practical Applications related to specific related to specific
Neurovascular Neurovascular interventionsinterventions
Acute ischemic StrokeAcute ischemic Stroke When an artery occludes neurons are affected When an artery occludes neurons are affected
differently depending upon the amount of residual blood differently depending upon the amount of residual blood flowflow
Normal cerebral blood flow is greater than 50 mL100 Normal cerebral blood flow is greater than 50 mL100 mgminmgmin
Once blood flow decreases to less than 20 mL100 Once blood flow decreases to less than 20 mL100 mgmin infarction occursmgmin infarction occurs
If blood flow decreases to less than 10 mL100 mgmin If blood flow decreases to less than 10 mL100 mgmin irreversible neuronal death occurs rapidly irreversible neuronal death occurs rapidly
Blood flow between 11 and 20 mL100 mgmin is thought Blood flow between 11 and 20 mL100 mgmin is thought to represent the ischemic penumbra an area where the to represent the ischemic penumbra an area where the cells are functionally silent because of ischemia but are cells are functionally silent because of ischemia but are still able to recover if blood flow is restored still able to recover if blood flow is restored
Many acute stroke therapies are targeted toward Many acute stroke therapies are targeted toward restoring flow or function to the ischemic penumbrarestoring flow or function to the ischemic penumbra
Therapeutic window in Therapeutic window in management of acute Ischemic management of acute Ischemic
StrokeStrokeThe early diagnosis of ischemic stroke is critical to the The early diagnosis of ischemic stroke is critical to the
with only a narrow therapeutic window in the first few with only a narrow therapeutic window in the first few hours following stroke ictushours following stroke ictus
Diagnosis in the first 3 hours postictus provides the Diagnosis in the first 3 hours postictus provides the opportunity for intravenous or intraarterial thrombolysis opportunity for intravenous or intraarterial thrombolysis and intra-arterial clot mechanical treatment which and intra-arterial clot mechanical treatment which improve the outcome improve the outcome
Diagnosis in the time period between 3 and 6 hours Diagnosis in the time period between 3 and 6 hours provides an opportunity for intra-arterial thrombolysis provides an opportunity for intra-arterial thrombolysis and mechanical treatment and mechanical treatment
Involvement of the posterior circulation especially the Involvement of the posterior circulation especially the basilar artery is treated by some regardless of time of basilar artery is treated by some regardless of time of onset or up until 12 to 24 hours in some practices This is onset or up until 12 to 24 hours in some practices This is related to the potentially high mortality and morbidity related to the potentially high mortality and morbidity associated with basilar artery thrombosisassociated with basilar artery thrombosis
Infarct evaluation on angiographyInfarct evaluation on angiography(CT angiography and catheter (CT angiography and catheter
angiography)angiography)CTA is an excellent first-line examination for CTA is an excellent first-line examination for
evaluation of the head and neck arteries evaluation of the head and neck arteries In comparison with catheter angiography In comparison with catheter angiography
what it gives up in resolution and dynamic what it gives up in resolution and dynamic properties it makes up for with rapid properties it makes up for with rapid acquisition of a 3-D dataset and the potential acquisition of a 3-D dataset and the potential for assessment of whole-brain perfusion and for assessment of whole-brain perfusion and better parenchymal evaluationbetter parenchymal evaluation
Moreover CTA illustrates not only arterial Moreover CTA illustrates not only arterial stenosis or occlusion but also the vessel wall stenosis or occlusion but also the vessel wall This factor is most important for evaluation of This factor is most important for evaluation of intramural dissection and thrombosed intramural dissection and thrombosed aneurysms which may both complicate aneurysms which may both complicate evaluation of stroke patientsevaluation of stroke patients
Early angiographic signs of strokes Early angiographic signs of strokes both CTA both CTA and DSA and DSA
Vessel occlusion or cutoff related to Vessel occlusion or cutoff related to thromboembolithromboemboli
aneurysms aneurysms arterial dissection arterial dissection Meniscus or flattened shape to clot Meniscus or flattened shape to clot
(recent) versus reverse meniscus (older)(recent) versus reverse meniscus (older) tram track (nonocclusive or recanalized tram track (nonocclusive or recanalized
clot) clot) delayed (antegrade) flow (manifest as delayed (antegrade) flow (manifest as
decreased whole-brain perfusion on CTA)decreased whole-brain perfusion on CTA) retrograde collateral flowretrograde collateral flow
Non-occlusive left MCA thrombus on 3-D imaging performed from CTA source data and was confirmed at catheter angiography
Therapy to be started within a 6-hr Therapy to be started within a 6-hr time to treatment (TTT) window time to treatment (TTT) window (while in case of IV thrombolysis (while in case of IV thrombolysis therapy to be started with in 3hrs)therapy to be started with in 3hrs)
Exclusion criteria Exclusion criteria Rapidly improving neurologic deficit or Rapidly improving neurologic deficit or Sustained blood pressure of gt180100 Sustained blood pressure of gt180100 Hemorrhage is detected on CTHemorrhage is detected on CT Infarct involving gt more than 13 rd Infarct involving gt more than 13 rd
territory of MCAterritory of MCA MRADWI-Perfusion mismatchlt 20MRADWI-Perfusion mismatchlt 20 Definite hypodensity on CTDefinite hypodensity on CT
Intra-arterial Thrombolysis
Fibrinolytics + AntiplateletsFibrinolytics + Antiplatelets
PlasminogenPlasminogen activators through fibrinolysis exposes activators through fibrinolysis exposes free thrombin and paradoxically stimulatesfree thrombin and paradoxically stimulates platelet platelet aggregation which leads to formation of aaggregation which leads to formation of a platelet platelet thrombus (white clot) thrombus (white clot)
This new thrombus is relatively resistant to This new thrombus is relatively resistant to fibrinolyticsfibrinolytics
So new regimen in case of acute stroke isSo new regimen in case of acute stroke is fibrinolytics + antiplatelet drugsfibrinolytics + antiplatelet drugs
rtPA + IIbIIIa inhibitors( tirofiban rtPA + IIbIIIa inhibitors( tirofiban abciximab) orabciximab) or
Urokinase + IIbIIIa Urokinase + IIbIIIa inhibitors( tirofiban abciximab)inhibitors( tirofiban abciximab)
Intra-arterial Thrombolysis Tirofiban (04 microgkgmin bolus for 3 min followed by Tirofiban (04 microgkgmin bolus for 3 min followed by
0125 ugkgmin)0125 ugkgmin)
++
Heparin (2000ndash3000 IU bolus followed by Heparin (2000ndash3000 IU bolus followed by 1000 IUhour infusion 1000 IUhour infusion
with ACT maintained bw 200-300) throughout the with ACT maintained bw 200-300) throughout the interventional procedure and for 24ndash48 hours thereafter when interventional procedure and for 24ndash48 hours thereafter when there is neither intraprocedural bleeding nor suspicion of there is neither intraprocedural bleeding nor suspicion of increased risk of bleeding increased risk of bleeding
Maximum dose of Urokinase Maximum dose of Urokinase Anterior circulation stroke - 500000 IU (mean 400000 Anterior circulation stroke - 500000 IU (mean 400000
IU range 300000ndash500000 IU)IU range 300000ndash500000 IU) Posterior circulation stroke -1000000 IU (mean 837000 Posterior circulation stroke -1000000 IU (mean 837000
IU range 300000ndash1000000 IU)IU range 300000ndash1000000 IU)American Journal of NeuroradiologyAmerican Journal of Neuroradiology 262595-2601 2005262595-2601 2005
Intravenous ThrombolysisIntravenous Thrombolysis
The first method to restore cerebral The first method to restore cerebral perfusion is clot lysis with the goal perfusion is clot lysis with the goal of re-establishing blood flow to the of re-establishing blood flow to the affected tissue affected tissue
IV thrombolysis rt-PA is the only IV thrombolysis rt-PA is the only FDA- approved treatment for AIS FDA- approved treatment for AIS
Fibrinolysis is enhanced powerfully Fibrinolysis is enhanced powerfully by rt-PAby rt-PA
Intravenous rTPA Intravenous rTPA administration administration protocolprotocol
Total dose of rt-PA 09 mgkg (maximum dose Total dose of rt-PA 09 mgkg (maximum dose 90 mg)90 mg)
Give 10 as initial IV bolusGive 10 as initial IV bolus Infuse remainder over 1 hourInfuse remainder over 1 hour Admit patient to an ICU or stroke unit for Admit patient to an ICU or stroke unit for
monitoringmonitoring Neurologic assessments every 15 minutes Neurologic assessments every 15 minutes
during infusion then every 30 minutes for next during infusion then every 30 minutes for next 6 hours then every hour until 24hours after 6 hours then every hour until 24hours after treatmenttreatment
Favorable Outcome vs Treatment Time Favorable Outcome vs Treatment Time with IV rTPAwith IV rTPA
Protocol limit = 3 hrs
Benefit ~ 45 hrs
Thromboembolism During coilingThromboembolism During coiling Most feared and frequent complication Most feared and frequent complication Reported incidence - Approx 7 Reported incidence - Approx 7 SourcesSources of Thromboembolism are of Thromboembolism are
- Clots at the aneurysmal neck during or immediately- Clots at the aneurysmal neck during or immediately after after embolization embolization
- Thrombus forming on catheters during- Thrombus forming on catheters during proceduresprocedures
- Stenosis of an adjacent artery dt coil mass- Stenosis of an adjacent artery dt coil mass or herniationor herniation
- Migration of intraaneurysmal- Migration of intraaneurysmal thrombus during coil thrombus during coil placement placement
- Slow flow dt vasospasm - Slow flow dt vasospasm
- Rare and unlikely causes are hypercoagulable- Rare and unlikely causes are hypercoagulable state such state such as antiphospholipid antibody syndrome or due to HITas antiphospholipid antibody syndrome or due to HIT
Occur more often with wide-necked aneurysms (dt Occur more often with wide-necked aneurysms (dt increased exposed surface area of thrombogenic coil increased exposed surface area of thrombogenic coil material)material)
Current regimen of endovascular Current regimen of endovascular managementmanagement
The The glycoprotein IIbIIIa antagonist tirofiban glycoprotein IIbIIIa antagonist tirofiban (04 (04 microgkgmin bolus for 30 minutes followed by infusion of microgkgmin bolus for 30 minutes followed by infusion of 0125 ugkgmin until the thrombus dissolved) 0125 ugkgmin until the thrombus dissolved)
Intraarterial thrombolysis with Intraarterial thrombolysis with urokinase or r- TPA urokinase or r- TPA increase of intravenous (IV) heparin (measured by increase of intravenous (IV) heparin (measured by
ACT) ACT) Intravenous aspirin Intravenous aspirin
Coil-related platelet aggregation (white clot) is Coil-related platelet aggregation (white clot) is unlikely to respond to fibrinolytics but has a high risk unlikely to respond to fibrinolytics but has a high risk of hemorrhage (In ISAT) all 5 patients who had of hemorrhage (In ISAT) all 5 patients who had received thrombolytic therapy with tPA to treat a received thrombolytic therapy with tPA to treat a thromboembolic complication after endovascular thromboembolic complication after endovascular treatment rebleed and all of these patients died)treatment rebleed and all of these patients died)
IntracranialIntracranial Stenting Stenting Metallic foreign body such as stent will accumulate Metallic foreign body such as stent will accumulate
thrombus in the absence of platelet inhibitionthrombus in the absence of platelet inhibition Antiplatelet drugs are important to prevent peri or Antiplatelet drugs are important to prevent peri or
post-interventional thromboembolic eventspost-interventional thromboembolic events Optimal treatment regimens has not been determined Optimal treatment regimens has not been determined
but usually but usually Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-
procedureprocedureOrOr
Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on
morning of proceduremorning of procedure
If need to use stent is not pre-planned thanIf need to use stent is not pre-planned than
Abciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkgAbciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkg IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)
Glycoprotein IIbIIIa inhibitor are not used routinely during elective Glycoprotein IIbIIIa inhibitor are not used routinely during elective stenting procedure dt increased risk of ICH stenting procedure dt increased risk of ICH
Carotid StentingCarotid Stenting
Pre-procedurePre-procedure
Double Antiplatelet therapy is routinely given Double Antiplatelet therapy is routinely given beginning at least 3beginning at least 3
days before the proceduredays before the procedure
Aspirin 325mgd+Clopidogrel 75mgdAspirin 325mgd+Clopidogrel 75mgd During procedureDuring procedure
Heparin is given with target clotting time of 250-Heparin is given with target clotting time of 250-300sec300sec
Post-procedure Post-procedure
Aspirin 325mg is continued indefinitely and Aspirin 325mg is continued indefinitely and
Clopidogrel 75mgd for at least 6 weeks Clopidogrel 75mgd for at least 6 weeks
Inclusion criteria for Local ThrombolysisInclusion criteria for Local Thrombolysis a)a) Patients in severe clinical grade on admission Patients in severe clinical grade on admission
with evidence of dural venous sinus with evidence of dural venous sinus thrombosis and restrictive venous outflow on thrombosis and restrictive venous outflow on cerebral angiogramcerebral angiogram
b)b) Patients in clinical grade 3 worsening on Patients in clinical grade 3 worsening on heparin therapy Restriction to venous heparin therapy Restriction to venous outflow was defined as an increase in brain outflow was defined as an increase in brain circulation time gt 12 s delay in the drainage circulation time gt 12 s delay in the drainage of cortical veins with cortical veins hanging of cortical veins with cortical veins hanging in spacein space
Treatment Options for Venous Thrombosis
CT Grading for Venous ThrombosisCT Grading for Venous Thrombosis Grade I no parenchymal change Grade I no parenchymal change
(hyperdense (hyperdense sinuses cortical veins empty sinuses cortical veins empty delta sign)delta sign)
Grade II non hemorrhagic venous infarct Grade II non hemorrhagic venous infarct without mass effect without mass effect
Grade III non-hemorrhagic infarct with Grade III non-hemorrhagic infarct with mass effectmass effect
Grade IV hemorrhagic venous infarct (max Grade IV hemorrhagic venous infarct (max diameter lt 3 cm) with no mass effectdiameter lt 3 cm) with no mass effect
Grade V hemorrhagic venous infarct (max Grade V hemorrhagic venous infarct (max diameter gt 3 cm) with mass effect diameter gt 3 cm) with mass effect
Local ThrombolysisLocal Thrombolysis
Femoral Jugular access was secured and a guiding Femoral Jugular access was secured and a guiding catheter was placed in the jugular bulb catheter was placed in the jugular bulb Mechanical Mechanical clot maceration clot maceration was done with the guidewire was done with the guidewire following which a microcatheter (was navigated and following which a microcatheter (was navigated and placed in the thrombosed segment of sinus confirmed placed in the thrombosed segment of sinus confirmed on a selective venogram on a selective venogram
Urokinase infusion Bolus dose of 2-6 lacs followed Urokinase infusion Bolus dose of 2-6 lacs followed by 60000 to 100000 units per hour along with by 60000 to 100000 units per hour along with periodic check venogram Along with maintenance periodic check venogram Along with maintenance systemic infusion of Heparinsystemic infusion of Heparin Other agents such as Other agents such as streptokinase altepase or rTPAstreptokinase altepase or rTPA can be also used can be also used
After thrombolysis patient should subjected to oral After thrombolysis patient should subjected to oral anticoagulation for six monthsanticoagulation for six months
Low-molecular-weight Low-molecular-weight heparinheparin
PharmacologyPharmacologyLMWH as its name suggests is a glycosaminoglycan that is approximatelyLMWH as its name suggests is a glycosaminoglycan that is approximately
one third the molecular weight of UFH It is derived from UFH through one third the molecular weight of UFH It is derived from UFH through variousvarious
depolymerization processes LMWH binds to antithrombin which in turn depolymerization processes LMWH binds to antithrombin which in turn
Neutralizes actors Xa and IIa Because LMWH lacks many of the longer Neutralizes actors Xa and IIa Because LMWH lacks many of the longer chains chains
required for binding to thrombin it has less ability to neutralize thrombin required for binding to thrombin it has less ability to neutralize thrombin
relativeto its ability to neutralize factor Xa LMWH also has less relativeto its ability to neutralize factor Xa LMWH also has less nonspecific nonspecific
binding to other proteins There is greater bioavailability with more binding to other proteins There is greater bioavailability with more predictable predictable
pharmacokinetics that eliminates the need for monitoring The smaller pharmacokinetics that eliminates the need for monitoring The smaller size also size also
allows for enhanced subcutaneous absorption when compared with UFHallows for enhanced subcutaneous absorption when compared with UFH
Three LMWH preparations are Three LMWH preparations are currently approved for use in the currently approved for use in the United States (1) enoxaparin (2) United States (1) enoxaparin (2) dalteparin and (3) tinzaparin dalteparin and (3) tinzaparin
They are all administered They are all administered subcutaneously at intervals of either subcutaneously at intervals of either once or twice daily for both once or twice daily for both prophylaxis and treatment dosesprophylaxis and treatment doses
Few Experiences of Few Experiences of ThrombolysisThrombolysis
Vickey 25 Yrs male patient presented Vickey 25 Yrs male patient presented with 12with 12thth day HO severe headache with day HO severe headache with right sided hemiplegiaright sided hemiplegia
MRI shows thrombosis of the superior MRI shows thrombosis of the superior sagittal left transverse left sigmoid sagittal left transverse left sigmoid sinuses and cortical veins in the fronto-sinuses and cortical veins in the fronto-parietal regions with eo haemorrhagic parietal regions with eo haemorrhagic infarct in the left cerebral hemisphere infarct in the left cerebral hemisphere with mass effect( Grade ndashV)with mass effect( Grade ndashV)
Sashi Srivastava 64 yrs FSashi Srivastava 64 yrs F In a follow up case of MRD with infra-renal In a follow up case of MRD with infra-renal
aortic abdominal and bilateral renal artery aortic abdominal and bilateral renal artery thrombosis renal angiogram shows filling thrombosis renal angiogram shows filling defects in the right Renal artery defects in the right Renal artery
Initially Renal angioplasty was done Initially Renal angioplasty was done Following angioplasty few thrombi are seem Following angioplasty few thrombi are seem to extends into the segmental branches and to extends into the segmental branches and causing blockage So Thrombolysis was causing blockage So Thrombolysis was plane to dissolve the run-out thrombi with plane to dissolve the run-out thrombi with urokinase urokinase
Rakesh 34yrsMRakesh 34yrsM Left SFA pseudoaneurysm with Left SFA pseudoaneurysm with
Covered stent placementCovered stent placement Pre operative antiplatelets with post Pre operative antiplatelets with post
procedure heparin Tirofiban procedure heparin Tirofiban followed by aspirin and clopidogrel followed by aspirin and clopidogrel were usedwere used
IAT may be a treatment option for selected patients IAT may be a treatment option for selected patients Possible selection criteria include Possible selection criteria include
presentation between 3 and 6 hours from symptom onsetpresentation between 3 and 6 hours from symptom onset major cerebral artery occlusion major cerebral artery occlusion severe neurologic deficits severe neurologic deficits high risk of systemic hemorrhage with IV rt-PA (eg recent high risk of systemic hemorrhage with IV rt-PA (eg recent
surgery) surgery) The MERCI (Mechanical Embolus Removal in Cerebral The MERCI (Mechanical Embolus Removal in Cerebral
Ischemia) retrievalIschemia) retrieval system system
Has been FDA-approved for recanalizing acutely occluded Has been FDA-approved for recanalizing acutely occluded cerebral arteries cerebral arteries
In the Multi-MERCI study patients who did not improve In the Multi-MERCI study patients who did not improve immediately after IV rt-PA underwent mechanical immediately after IV rt-PA underwent mechanical embolectomy within 8 hours of symptom onset embolectomy within 8 hours of symptom onset
Partial or complete recanalization occurred in 74 of Partial or complete recanalization occurred in 74 of patientspatients
with a symptomatic intracerebral hemorrhage (sICH) rate of with a symptomatic intracerebral hemorrhage (sICH) rate of 67 67
Mechanical embolectomy with the MERCI retriever may be a Mechanical embolectomy with the MERCI retriever may be a feasible and safe option for patients after IV rt-PAfeasible and safe option for patients after IV rt-PA
Penumbra stroke systemPenumbra stroke system This device combines two methods of clot This device combines two methods of clot
extraction aspiration and mechanical extraction aspiration and mechanical extraction extraction
First the clot is aspirated then a thrombus First the clot is aspirated then a thrombus removal ring can be used if necessary to removal ring can be used if necessary to remove remaining clot remove remaining clot
successful recanalizing 82successful recanalizing 82 Bridging therapyBridging therapy
06 mgkg IV rt-PA followed by IAT with IA rt-06 mgkg IV rt-PA followed by IAT with IA rt-PA (up to 20 mg)PA (up to 20 mg)
achieved a higher recanalization rateachieved a higher recanalization rate
Criteria for thrombolysis with rTPACriteria for thrombolysis with rTPA
Inclusion criteriaInclusion criteria Clinical signs and symptoms consistent with ischemic Clinical signs and symptoms consistent with ischemic
strokestroke Patient last seen normal within 3 hoursPatient last seen normal within 3 hours Measurable neurologic deficitMeasurable neurologic deficit
Exclusion criteriaExclusion criteria Any hemorrhage on neuroimaging (CT or MRI)Any hemorrhage on neuroimaging (CT or MRI) Symptoms suggestive of subarachnoid hemorrhageSymptoms suggestive of subarachnoid hemorrhage Seizure at stroke onset that is thought to contribute to Seizure at stroke onset that is thought to contribute to
neurologic deficitneurologic deficit Hypodensity greater than one third cerebral hemisphere Hypodensity greater than one third cerebral hemisphere
on CTon CT SBP greater than 185 mm Hg or DBP greater than 110 SBP greater than 185 mm Hg or DBP greater than 110
mm Hgmm Hg International normalized ratio (INR) greater than 17International normalized ratio (INR) greater than 17
Ischemic Stroke Ischemic Stroke Treatment ndash 2006Treatment ndash 2006
IV tissue plasminogen activator (tPA)IV tissue plasminogen activator (tPA) ndash ndash Only FDA-approved acute stroke drugOnly FDA-approved acute stroke drug ndash ndash 3 hour treatment window3 hour treatment window
MERCI - Concentric clot retrieval MERCI - Concentric clot retrieval devicedevice ndash ndash Rescue therapy - approved 2004Rescue therapy - approved 2004 ndash ndash Device approval (not outcomes-based)Device approval (not outcomes-based)
Off label approachesOff label approaches ndash ndash IV tPA after 3 hoursIV tPA after 3 hours ndash ndash IV-IA tPA sequential strategiesIV-IA tPA sequential strategies ndash ndash IA tPA clot angioplasty fragmentationIA tPA clot angioplasty fragmentation ndash ndash Ultrasound-assisted tPA lysisUltrasound-assisted tPA lysis
rt-PA Trials NINDSrt-PA Trials NINDS
Acute stroke - 624 patientsAcute stroke - 624 patients Treat within 3 hrsTreat within 3 hrs Intravenous 09 mgkg rt-PA vs placeboIntravenous 09 mgkg rt-PA vs placebo Hemorrhage 64 tPA 06 placeboHemorrhage 64 tPA 06 placebo Neurologic recovery better with tPA 30 Neurologic recovery better with tPA 30
more like to have minimal or no disabilitymore like to have minimal or no disability
First proven approved treatment for First proven approved treatment for strokestroke
Limitations of tPALimitations of tPA Only 4 of acute strokes receive tPAOnly 4 of acute strokes receive tPA (Kleindorfer et al Stroke 2004 35 e27-e29)(Kleindorfer et al Stroke 2004 35 e27-e29)
Only 22 of patients present within 3 hoursOnly 22 of patients present within 3 hours1048707 1048707 51 of these ineligible due to51 of these ineligible due to
bull bull Mild severityMild severity bull bull Medical or surgical historyMedical or surgical history bull bull Blood testsBlood tests
Sustained recanalization only 13Sustained recanalization only 13 (Alexandrov et al NEJM 2004 351 2170-8)(Alexandrov et al NEJM 2004 351 2170-8)
Concern for hemorrhageConcern for hemorrhage tPA potentiates apoptotic injury tPA potentiates apoptotic injury (Liu et al Nature Med 2004 101379-83)(Liu et al Nature Med 2004 101379-83)
PROACT II IA Lysis TrialPROACT II IA Lysis Trial Baseline 24 hours 8 days
Baseline 60 minutes 120 minutes
9mg IAProurokinase
Desmoteplase Trials DEDAS Desmoteplase Trials DEDAS DIASDIAS
Trial OverviewTrial Overview Double blind randomized placebo Double blind randomized placebo
controlled trialscontrolled trials IV delivery 3-9 hour time windowIV delivery 3-9 hour time window Plasminogen activator ndash from Plasminogen activator ndash from vampire bat vampire bat
salivasaliva Selection based on PWI-DWI MismatchSelection based on PWI-DWI Mismatch
MRI InclusionMRI Inclusion PWI defect at least 2 cm AND ~20 larger PWI defect at least 2 cm AND ~20 larger
than DWIthan DWI PWI should be obvious even visible on PWI should be obvious even visible on
raw imagesraw imagesMRI ExclusionMRI Exclusion
DWI gt 13 MCADWI gt 13 MCA MRA ICA occlusionMRA ICA occlusion
Desmoteplase ndash DIAS Desmoteplase ndash DIAS ResultsResults
Mechanical Thrombolysis Mechanical Thrombolysis devicesdevices
mechanical thrombolysis potentially extends the treatment mechanical thrombolysis potentially extends the treatment window because they act promptly at the site of the thrombuswindow because they act promptly at the site of the thrombus
The devices can retrieve large clots that pharmaceutical agents The devices can retrieve large clots that pharmaceutical agents may not successfully lysemay not successfully lyse
Patients treated with IV tPA may be considered for treatment of Patients treated with IV tPA may be considered for treatment of residual clot with some of these devicesresidual clot with some of these devices
suction-creating saline jets suction-creating saline jets laser energy ultrasound laser energy ultrasound a corkscrew apparatus to treat strokesa corkscrew apparatus to treat strokes The AngioJet systemThe AngioJet system uses saline jets that are directed back into the catheter to uses saline jets that are directed back into the catheter to
create a low-pressure zone around the catheter tip inducing create a low-pressure zone around the catheter tip inducing suction suction
The clot is pulled into the exhaust lumen and removed from the The clot is pulled into the exhaust lumen and removed from the vessel Although US Food and Drug Administration (FDA) has vessel Although US Food and Drug Administration (FDA) has approved this device for use in arteriovenous dialysis grafts and approved this device for use in arteriovenous dialysis grafts and fistulae and for the treatment of coronary arteries saphenous fistulae and for the treatment of coronary arteries saphenous vein grafts and peripheral vessels clinical trials for the vein grafts and peripheral vessels clinical trials for the treatment of acute stroke are no longer in progress treatment of acute stroke are no longer in progress
Most devices are used in cerebral vessels that 2-5 mm
The Latis laser device The Latis laser device used laser energy to ablate clots used laser energy to ablate clots Arteries 2-5 mm in diameter could be Arteries 2-5 mm in diameter could be
treated including the ICA M1 or M2 treated including the ICA M1 or M2 branch of the MCA A1 branch of the branch of the MCA A1 branch of the anterior cerebral artery (ACA) basilar anterior cerebral artery (ACA) basilar artery posterior cerebral artery (PCA) artery posterior cerebral artery (PCA) and vertebral and vertebral
Patients could receive treatment as late Patients could receive treatment as late as 8 hours after symptom onset in the as 8 hours after symptom onset in the anterior circulation and within 24 hours in anterior circulation and within 24 hours in the posterior circulation the posterior circulation
Endovascular Photo Acoustic Endovascular Photo Acoustic Recanalization (EPAR) Recanalization (EPAR)
A laser power source generated energy for the A laser power source generated energy for the systemsystem
The energy was delivered by means of The energy was delivered by means of fiberoptics to the tip of the catheter at the fiberoptics to the tip of the catheter at the treatment sitetreatment site
Absorption of laser light by darkly pigmented Absorption of laser light by darkly pigmented materials (ie the clot) occurred inside the 1-mm materials (ie the clot) occurred inside the 1-mm catheter tipcatheter tip
the system was designed to minimize scattering the system was designed to minimize scattering of laser light of laser light
Absorption converted photo energy to acoustic Absorption converted photo energy to acoustic energy which then emulsified the clot inside the energy which then emulsified the clot inside the catheter tip catheter tip
EKOS ultrasound( the EKOS ultrasound( the Ultrasound Thrombolytic Ultrasound Thrombolytic
Infusion Catheter) Infusion Catheter) combines the use of a distal ultrasound transducer with combines the use of a distal ultrasound transducer with
infusion of a thrombolytic agent through the infusion of a thrombolytic agent through the microcathetermicrocatheter
Ultrasound changes the structure of the clot to Ultrasound changes the structure of the clot to temporarily increase its permeability while providing an temporarily increase its permeability while providing an acoustic pressure gradient to move the drug into the clot acoustic pressure gradient to move the drug into the clot to speed its dissolution to speed its dissolution
The EKOS catheter is placed in the proximal portion of the The EKOS catheter is placed in the proximal portion of the clot clot
After a 2-mg bolus of tPA was injected through the After a 2-mg bolus of tPA was injected through the catheter catheter
the patient received a continuous infusion of IA tPA 03 the patient received a continuous infusion of IA tPA 03 mgmin to a maximum of 20 mg and simultaneous mgmin to a maximum of 20 mg and simultaneous ultrasound transmission for as long as 60 minutes ultrasound transmission for as long as 60 minutes
One patient was treated with a total of 4 units of One patient was treated with a total of 4 units of recombinant reteplase (Retavase) hand-injected over 60 recombinant reteplase (Retavase) hand-injected over 60 minutes minutes
Penumbra system Penumbra system The Penumbra system (Penumbra Inc) provides a dual The Penumbra system (Penumbra Inc) provides a dual
approach to clot extraction using aspiration followed by approach to clot extraction using aspiration followed by clot retrieval with a ring device if needed clot retrieval with a ring device if needed
Mechanical Embolus Removal in Cerebral Ischemia Mechanical Embolus Removal in Cerebral Ischemia (MERCI)(MERCI)
a corkscrew-like apparatus to remove blood clots from a corkscrew-like apparatus to remove blood clots from the brain in patients experiencing an ischemic stroke the brain in patients experiencing an ischemic stroke
The corkscrew itself resides in the catheter tip which The corkscrew itself resides in the catheter tip which shields it from the wall of the vessel until it is ready to be shields it from the wall of the vessel until it is ready to be burrowed into the clot Once lodged in the clot the device burrowed into the clot Once lodged in the clot the device and clot are withdrawn from the vessel and clot are withdrawn from the vessel
Snarelike devicesSnarelike devices Snares such as the Neuronet snare (Guidant Snares such as the Neuronet snare (Guidant
Endovascular Santa Clara CA) have been developed Endovascular Santa Clara CA) have been developed specifically for use in the treatment of strokes specifically for use in the treatment of strokes
These devices are simple in design and do not require the These devices are simple in design and do not require the clot to be amenable to emulsification clot to be amenable to emulsification
X-Sizer deviceX-Sizer device a device with small moving blades at the a device with small moving blades at the
catheter tip catheter tip This device the X-Sizer device (EndiCor Medical This device the X-Sizer device (EndiCor Medical
San Clemente CA) can be used to excise the San Clemente CA) can be used to excise the thrombus and aspirate it thrombus and aspirate it
The device was being evaluated in randomized The device was being evaluated in randomized studies of coronary vessels and in a registry of studies of coronary vessels and in a registry of patients with acute myocardial infarctionpatients with acute myocardial infarction
Although the manufacturer had modified the Although the manufacturer had modified the device for use in cerebral vessels a safety and device for use in cerebral vessels a safety and feasibility study was indefinitely suspended after feasibility study was indefinitely suspended after only 1 patient was treated with the device in only 1 patient was treated with the device in Europe Europe
Suction thrombectomySuction thrombectomy This method of mechanical thrombolysis is one of the This method of mechanical thrombolysis is one of the
simplestsimplest In this readily available technique suction is applied with In this readily available technique suction is applied with
a syringe to remove thrombus in the ICA a syringe to remove thrombus in the ICA It requires no other devicesIt requires no other devices A catheter with a large inner diameter (Brite Tip Cordis A catheter with a large inner diameter (Brite Tip Cordis
Corporation Miami FL) was placed in the symptomatic Corporation Miami FL) was placed in the symptomatic vessel and navigated over a guidewire into the thrombusvessel and navigated over a guidewire into the thrombus
A 60-mL syringe was used to aspirate the thrombus A 60-mL syringe was used to aspirate the thrombus Each patient required angioplasty and stenting of carotid Each patient required angioplasty and stenting of carotid
bifurcation stenosis and received daily aspirin and bifurcation stenosis and received daily aspirin and ticlopidine after the procedure No complications ticlopidine after the procedure No complications occurred occurred
Summary Acute Stroke Summary Acute Stroke ImagingImaging
PhysiologyPhysiology importance collaterals importance collaterals
ndash ndashGrowing role for perfusion Growing role for perfusion assessmentassessment
tPAtPA guidelines amp limitations guidelines amp limitations Signs on CT amp MRSigns on CT amp MR follow physiology follow physiology Stroke trialsStroke trials PWI-DWI mismatch PWI-DWI mismatch
ndash ndashTreat based on physiology not timeTreat based on physiology not time ProtocolsProtocols should be fast and should be fast and
comprehensivecomprehensive
Treatment of heparin-induced Treatment of heparin-induced thrombocytopeniathrombocytopenia
When HIT is diagnosed it is important to When HIT is diagnosed it is important to stop heparin mainly in type 2 and to avoid stop heparin mainly in type 2 and to avoid the use of LMWH the use of LMWH
Because of the increased risk of thrombosis Because of the increased risk of thrombosis however continuation of an anticoagulant however continuation of an anticoagulant must be considered must be considered
The drugs currently approved for the The drugs currently approved for the treatment of HIT in the United States are treatment of HIT in the United States are direct thrombin inhibitors argatroban and direct thrombin inhibitors argatroban and lepirudinlepirudin
WARFARIN MECHANISM OF ACTIONWARFARIN MECHANISM OF ACTION
Inactive factors II VII IX and X
Proteins S and C
Active factors II VII IX and X
Proteins S and C
Vitamin K epoxide
Vitamin K reduced
WA
RF
AR
IN
Prevents the reduction of vitamin K which is essential for Prevents the reduction of vitamin K which is essential for activation of certain factorsactivation of certain factors
Has no effect on previously formed thrombusHas no effect on previously formed thrombus
Antagonist is Vit KAntagonist is Vit K
OPTIMIZING WARFARIN THERAPYOPTIMIZING WARFARIN THERAPY
Use of large loading dose may lead to hemorrhage and Use of large loading dose may lead to hemorrhage and other complicationsother complications
Initial dose 2-5 mg once dailyInitial dose 2-5 mg once daily Maintenance dose 2-10 mg once dailyMaintenance dose 2-10 mg once daily If Immediate anticoagulation is requiredIf Immediate anticoagulation is required Heparin IS Heparin IS
started along with loading dose of warfarin 10 mg started along with loading dose of warfarin 10 mg Heparin is usually discontinued after 4-5 days Heparin is usually discontinued after 4-5 days Before Before discontinuing INR should be in therapeutic range for 2 discontinuing INR should be in therapeutic range for 2 consecutive daysconsecutive days
Daily monitoring of INR until INR is in therapeutic Daily monitoring of INR until INR is in therapeutic range then 3 times weekly for 1-2 weeks then less often range then 3 times weekly for 1-2 weeks then less often (every 4 to 6 weeks)(every 4 to 6 weeks)
OPTIMAL THERAPEUTIC RANGEOPTIMAL THERAPEUTIC RANGE
IndicationIndication INRINR
Prophylaxis of venous Prophylaxis of venous thromboembolismthromboembolism
20-3020-30
Treatment of venous Treatment of venous thromboembolismthromboembolism
20-3020-30
Atrial fibrillationAtrial fibrillation 20-3020-30
Mitral valve stenosisMitral valve stenosis 20-3020-30
Heart valve replacementHeart valve replacement
Bioprosthetic valveBioprosthetic valve
Mechanical valveMechanical valve
20-3020-30
25-3525-35
Myocardial infarctionMyocardial infarction 20-3020-30
25-35 25-35 (high risk patients)(high risk patients)
FACTORS INFLUENCING DOSE RESPONSEFACTORS INFLUENCING DOSE RESPONSE
Poor patient compliancePoor patient compliance Concomitant medicationsConcomitant medications Levels of dietary vitamin KLevels of dietary vitamin K Alcohol Inaccurate lab testingAlcohol Inaccurate lab testing Inaccurate lab testingInaccurate lab testing Hepatic dysfunctionHepatic dysfunction FeverFever
Contraindication for WarfarinContraindication for Warfarin
Hypersensitivity to warfarinHypersensitivity to warfarin Hemorrhagic tendencyHemorrhagic tendency Condition with risk of hemorrhageCondition with risk of hemorrhage Inadequate laboratory techniquesInadequate laboratory techniques Protein C amp S deficiencyProtein C amp S deficiency Vitamin K deficiencyVitamin K deficiency
SIDE EFFECTSSIDE EFFECTS
Hemorrhage Hemorrhage Skin necrosisSkin necrosis Purple toe syndromePurple toe syndrome Microembolization Microembolization TeratogenecityTeratogenecity Agranulocytosis leukopenia Agranulocytosis leukopenia Diarrhoeanausea anorexiaDiarrhoeanausea anorexia
MONITORING OF WARFARIN THERAPYMONITORING OF WARFARIN THERAPY
Prothrombin timeProthrombin time PT ratioPT ratio INR (International Normalized Ratio)INR (International Normalized Ratio)
PROTHROMBIN TIME (PT)PROTHROMBIN TIME (PT)
Time required for blood to coagulate Time required for blood to coagulate is called PT ( normal value ~10sec)is called PT ( normal value ~10sec)
Performed by adding a mixture of Performed by adding a mixture of calcium and thromboplastin to calcium and thromboplastin to citrated plasmacitrated plasma
As a control a normal blood sample is As a control a normal blood sample is tested continuouslytested continuously
PT ratio (PTR) = PT ratio (PTR) = Patientrsquos PTPatientrsquos PT Control PTControl PT
PROBLEMS WITH PTPTRPROBLEMS WITH PTPTR
Thromboplastins are extracts from Thromboplastins are extracts from brain lung or placenta of animalsbrain lung or placenta of animals
Thromboplastins from various Thromboplastins from various manufacturers differ in their manufacturers differ in their sensitivity to prolong PTsensitivity to prolong PT
May result in false control of May result in false control of anticoagulant therapyanticoagulant therapy
INTERNATIONAL NORMALISED RATIO (INR)INTERNATIONAL NORMALISED RATIO (INR)
International Normalized Ratio (INR) International Normalized Ratio (INR) a PT test with a a PT test with a formula based ratio to normalize the often variable source formula based ratio to normalize the often variable source of tissue factor (human rabbit recombinant)of tissue factor (human rabbit recombinant)
INR = [PTINR = [PTptpt] ] ISIISI
[PT[PTRefRef]]
PTPTpt pt ndash prothrombin time of patientndash prothrombin time of patient
PTPTRef Ref ndash prothrombin time of normal pooled samplendash prothrombin time of normal pooled sample
ISI ndash International Sensitivity IndexISI ndash International Sensitivity Index
Warfarin is given orally and titrated to achieve an INR of Warfarin is given orally and titrated to achieve an INR of typically 20 ndash 30typically 20 ndash 30
Heparin versus WarfarinHeparin versus Warfarin
Drug ActionMechan-ism
Moni-toring
Effective
HeparinDirect
Inhibition ofThrombin
ATIIIcofactor
APTTACT
Immediate
WarfarinDecreasesProductionof factors
Vitamin K PTDelay
3-5 days
INR
Recanalization or Antegrade Recanalization or Antegrade Reperfusion StrategiesReperfusion Strategies
Recanalization strategies focus on removing Recanalization strategies focus on removing andor dissolving the occlusive thrombus to re-andor dissolving the occlusive thrombus to re-establish antegrade flow Strategies may be establish antegrade flow Strategies may be classified into 7 different categories on the classified into 7 different categories on the basis of their primary mechanism of action basis of their primary mechanism of action 1) 1) IV andor intraarterial thrombolysis (IAT) IV andor intraarterial thrombolysis (IAT) 2) endovascular thrombectomy2) endovascular thrombectomy3) endovascular thromboaspiration 3) endovascular thromboaspiration 4) endovascular mechanical thrombus disruption or 4) endovascular mechanical thrombus disruption or
thromborrhexisthromborrhexis5) 5) transcranial or endovascular augmented transcranial or endovascular augmented
fibrinolysis fibrinolysis 6) endovascular thrombus entrapment and 6) endovascular thrombus entrapment and 7) temporary endovascular bypass7) temporary endovascular bypass
IAT in Acute Ischemic StrokeIAT in Acute Ischemic Stroke
IAT advantages over IV thrombolysisIAT advantages over IV thrombolysis Coaxial microcatheter techniques the occluded intracranial Coaxial microcatheter techniques the occluded intracranial
vessel is directly accessible and the fibrinolytic agent can be vessel is directly accessible and the fibrinolytic agent can be infused directly into the thrombusinfused directly into the thrombus
This permits a smaller dose of fibrinolytic agent to reach a This permits a smaller dose of fibrinolytic agent to reach a higher local concentration than that reached by systemic higher local concentration than that reached by systemic infusioninfusion
Allows more complete recanalization with lower total doses of Allows more complete recanalization with lower total doses of thrombolytic thrombolytic
With the smaller dose complications from systemic fibrinolytic With the smaller dose complications from systemic fibrinolytic effects including intracranial hemorrhage (ICH) can effects including intracranial hemorrhage (ICH) can theoretically be reduced theoretically be reduced
Treatment window for endovascular techniques can be Treatment window for endovascular techniques can be extended beyond the typical IV window of 3 hours extended beyond the typical IV window of 3 hours
IA techniques have led to higher recanalization rates than IV IA techniques have led to higher recanalization rates than IV thrombolysisthrombolysis
Major disadvantagesMajor disadvantages Relative complexity of the procedure the level Relative complexity of the procedure the level
of required technical expertise and its of required technical expertise and its relatively low availability relatively low availability
Delays in initiating treatmentDelays in initiating treatment InvasiveInvasive
ThrombolyticsThrombolytics
Plasminogen activators
Fibrinolytics
1 Plasminogen Activators 1 Plasminogen Activators drugs act by converting the inactive proenzyme drugs act by converting the inactive proenzyme plasminogen into the active enzyme plasmin Plasmin plasminogen into the active enzyme plasmin Plasmin digests fibrinogen fibrin monomers and cross-linked digests fibrinogen fibrin monomers and cross-linked fibrin (as found in a thrombus) into fibrin degradation fibrin (as found in a thrombus) into fibrin degradation productsproducts
First-Generation Agents First-Generation Agents StreptokinaseStreptokinase a protein derived from group C a protein derived from group C
szlig-hemolytic streptococci has a half-life of 16ndashszlig-hemolytic streptococci has a half-life of 16ndash90 minutes and low fibrin specificity This drug 90 minutes and low fibrin specificity This drug proved to have a very narrow therapeutic proved to have a very narrow therapeutic window and significant rates of ICH and window and significant rates of ICH and systemic hemorrhage18systemic hemorrhage18
UrokinaseUrokinase is a serine protease with a plasma is a serine protease with a plasma half life of 14 minutes and low fibrin specificity half life of 14 minutes and low fibrin specificity
The urokinase dose used in cerebral IAT has The urokinase dose used in cerebral IAT has ranged from 002 to 2 X106unitsranged from 002 to 2 X106units
Second-Generation Agents Second-Generation Agents Alteplase (rtPA) Alteplase (rtPA)
is a serine is a serine protease with a plasma half-life of 35 protease with a plasma half-life of 35 minutes and a high degree of fibrin affinity and minutes and a high degree of fibrin affinity and specificity specificity
Dose used in cerebral IAT has ranged between 20 Dose used in cerebral IAT has ranged between 20 and 60 mgand 60 mg
Disadvantages of alteplase include its relatively short Disadvantages of alteplase include its relatively short halflife and limited penetration into the clot matrix halflife and limited penetration into the clot matrix because of strong binding with surface fibrin which because of strong binding with surface fibrin which could delay recanalization and increase the risk of could delay recanalization and increase the risk of recurrent occlusion recurrent occlusion
Prourokinase (r-prourokinase) Prourokinase (r-prourokinase) is the proenzyme precursor of urokinase is the proenzyme precursor of urokinase T12 of 7 minutes and high fibrin specificity T12 of 7 minutes and high fibrin specificity
Third-Generation AgentsThird-Generation Agents
ReteplaseReteplase is a structurally modified is a structurally modified form of alteplase form of alteplase
with a longer half-life (15ndash18 minutes) In with a longer half-life (15ndash18 minutes) In addition it does not bind as highly to fibrin addition it does not bind as highly to fibrin unbound reteplase can thus theoretically better unbound reteplase can thus theoretically better penetrate the clot and potentially penetrate the clot and potentially improve in improve in vivo fibrinolytic activity vivo fibrinolytic activity
TenecteplaseTenecteplase is another modified form of rtPA with a longer is another modified form of rtPA with a longer
half-life (17 minutes)half-life (17 minutes) greater fibrin specificity and greater greater fibrin specificity and greater
resistance to plasminogen activator inhibitor-1 resistance to plasminogen activator inhibitor-1 IV tenecteplase in acute ischemic stroke IV tenecteplase in acute ischemic stroke
suggest that the drug is safe and promisingsuggest that the drug is safe and promising
Newer plasminogen activatorNewer plasminogen activator
DesmoteplaseDesmoteplase is a genetically engineered is a genetically engineered version of the clot-dissolving factor version of the clot-dissolving factor
found in the saliva found in the saliva of the vampire bat Desmodus rotundusof the vampire bat Desmodus rotundus moremore potent and more selective for fibrin-bound potent and more selective for fibrin-bound
plasminogen than any other known plasminogen plasminogen than any other known plasminogen activatoractivator
Unlike tissue plasminogen activator (tPA) desmoteplase Unlike tissue plasminogen activator (tPA) desmoteplase is not activated by fibrinogen or -amyloid proteins is not activated by fibrinogen or -amyloid proteins factors that may exacerbate the risk for ICH factors that may exacerbate the risk for ICH
The effect of IV administration of desmoteplase 3ndash9 The effect of IV administration of desmoteplase 3ndash9 hours after symptom onset in patients with stroke who hours after symptom onset in patients with stroke who present with mismatch on MR imaging or CT perfusion present with mismatch on MR imaging or CT perfusion
3 DefibrinogenatingFibrinogenolytic 3 DefibrinogenatingFibrinogenolytic Agents Agents
AncrodAncrod(Viprinex)(Viprinex) is is the purified fraction of the Malayan pit viper venomthe purified fraction of the Malayan pit viper venom It acts by directly cleaving and inactivating fibrinogen It acts by directly cleaving and inactivating fibrinogen
and thus indirectly promoting anticoagulation and thus indirectly promoting anticoagulation The reduction in the blood levels of fibrinogen also The reduction in the blood levels of fibrinogen also
leads to a reduced blood viscosity which may improve leads to a reduced blood viscosity which may improve blood flow to the affected areas of the brain blood flow to the affected areas of the brain
In the Stroke Treatment with Ancrod Trial 500 In the Stroke Treatment with Ancrod Trial 500 patients with stroke presenting within 3 hours of patients with stroke presenting within 3 hours of symptom onset were randomized to receive ancrod (symptom onset were randomized to receive ancrod (n n 248) or a placebo (n 252) Good outcome (Barthel 248) or a placebo (n 252) Good outcome (Barthel Index 95ndash100 at 3 months) was achieved in 4221 Index 95ndash100 at 3 months) was achieved in 4221 and 344 of the patients respectively and 344 of the patients respectively
2 Direct Fibrinolytics2 Direct Fibrinolytics
Microplasmin (Microplasmin (ThromboGenics Heverlee Belgium)ThromboGenics Heverlee Belgium) is a truncated form of plasmin that is more resistant to the effects is a truncated form of plasmin that is more resistant to the effects
of antiplasmin of antiplasmin microplasmin can be used upto 4ndash12 hours after stroke onset microplasmin can be used upto 4ndash12 hours after stroke onset There was no evidence of increased bleeding risk with There was no evidence of increased bleeding risk with
microplasminmicroplasmin
Alfimeprase (Nuvelo San Carlos Calif)Alfimeprase (Nuvelo San Carlos Calif) is a recombinant truncated form of fibrolase a fibrinolytic zinc metalloproteinase is a recombinant truncated form of fibrolase a fibrinolytic zinc metalloproteinase
isolated from the venom of the southern copperhead snake isolated from the venom of the southern copperhead snake It degrades fibrin directly and achieves thrombolysis independent It degrades fibrin directly and achieves thrombolysis independent
of plasmin formationof plasmin formation its thrombolytic activity appears to be localized to the site of its thrombolytic activity appears to be localized to the site of
delivery These properties should theoretically result in faster delivery These properties should theoretically result in faster recanalization and lower hemorrhagic conversion riskrecanalization and lower hemorrhagic conversion risk
Anti-fibrinolyticsAnti-fibrinolytics
to limit fibrinolytic activityto limit fibrinolytic activity -aminocaproic acid (EACA) -aminocaproic acid (EACA) competitively inhibitscompetitively inhibits plasminogen and plasminogen activators from plasminogen and plasminogen activators from
binding to fibrinbinding to fibrin
alpha2-antiplasminalpha2-antiplasmin a serine protease inhibitor that a serine protease inhibitor that neutralizes any free circulating plasminneutralizes any free circulating plasmin
Plasminogen activator inhibitor-1Plasminogen activator inhibitor-1 a serine protease a serine protease inhibitor that inhibits tissue-type plasminogen inhibitor that inhibits tissue-type plasminogen activatoractivator
Glycoprotein (GP) IIbIIIa antagonistsGlycoprotein (GP) IIbIIIa antagonists
such as ReoPro (abciximab) Integrilin such as ReoPro (abciximab) Integrilin (eptifibatide) or Aggrastat (tirofiban) in (eptifibatide) or Aggrastat (tirofiban) in ischemic stroke remains investigational ischemic stroke remains investigational Deshmukh et al38 reported 21 patients with Deshmukh et al38 reported 21 patients with large-vessel occlusion refractory to IAT with large-vessel occlusion refractory to IAT with rtPA who were treated with IV andor IA rtPA who were treated with IV andor IA abciximab eptifibatide or tirofiban abciximab eptifibatide or tirofiban
IA Mechanical Approaches in Acute Ischemic Stroke IA Mechanical Approaches in Acute Ischemic Stroke Mechanical strategies have several advantagesMechanical strategies have several advantages First they lessen and may even preclude the use of chemical First they lessen and may even preclude the use of chemical
thrombolytics in this manner very likely reducing the risk of ICHthrombolytics in this manner very likely reducing the risk of ICH Second by avoiding the use of chemical thrombolytics it is Second by avoiding the use of chemical thrombolytics it is
possible to extend the treatment window beyond the limit of 6ndash8 possible to extend the treatment window beyond the limit of 6ndash8 hours hours
Third mechanically fragmenting a clot increases the surface area Third mechanically fragmenting a clot increases the surface area accessible to fibrinolytic agents and allows inflow of fresh accessible to fibrinolytic agents and allows inflow of fresh plasminogen which in turn may increase the speed of plasminogen which in turn may increase the speed of thrombolysis thrombolysis
Finally clot-retrieval devices may provide faster recanalization Finally clot-retrieval devices may provide faster recanalization
The disadvantages of the mechanical The disadvantages of the mechanical approaches approaches technical difficulty of navigating mechanical technical difficulty of navigating mechanical
devices into the intracranial circulation excessive devices into the intracranial circulation excessive trauma to the vasculature (potentially leading to trauma to the vasculature (potentially leading to vasospasm vessel dissection perforation or vasospasm vessel dissection perforation or rupture) rupture)
fragmented thrombus causing distal embolization fragmented thrombus causing distal embolization into previously unaffected territories into previously unaffected territories
Nevertheless the advantages of mechanical stroke Nevertheless the advantages of mechanical stroke therapy appear to significantly outweigh its therapy appear to significantly outweigh its disadvantages and risksdisadvantages and risks
Contraindications to Thrombolytic Contraindications to Thrombolytic agents agents
Recent thoracic abdominal or Recent thoracic abdominal or intracranial surgeryintracranial surgery
Recent haemorrhagic CVA Head injury Recent haemorrhagic CVA Head injury or neoplasmor neoplasm
Bleeding ulcerBleeding ulcer Anticipated invasive procedures (arterial Anticipated invasive procedures (arterial
punctures biopsies)punctures biopsies) Concurrent hemostatic dysfunctionConcurrent hemostatic dysfunction
Monitoring of thrombolytic Monitoring of thrombolytic therapytherapy
Thrombin time Measures the availability of functional
fibrinogen Normal thrombin time is 10-14 sec Prolonged when fibrinogen level is below
75-100 mgdl
Half Life of ThrombolyticsHalf Life of ThrombolyticsAgent Administration Half Life
Streptokinase IA 60-80min
Urokinase IAIV 9-12min
rTPA IAIV 6min
Abciximab(Reopro) IAIV 12hour
Aspirin POIV 15-20min
Heparin IVSC 60min
Coumadin PO 15-25 days
Anti Platelet DrugsAnti Platelet DrugsDrug Drug Mechanism Mechanism UsesUsesAspirinAspirin Permanently inhibits Permanently inhibits
COX-1 and COX-2COX-1 and COX-2CADCAD
Stroke-TIAsStroke-TIAs
NSAIDsNSAIDs Reversibly inhibits Reversibly inhibits COX-1COX-1
LimitedLimited
DipyridamoleDipyridamole Inhibits PDE increases Inhibits PDE increases cAMPcAMP
TIAsTIAs
ThenopyridinesThenopyridines
(Ticlopidine(Ticlopidine
ClopidrgrelClopidrgrel))
Inhibits ADP Inhibits ADP
PlatAg PlatAg
TIAsStrokeTIAsStroke
CAD PVDCAD PVD
Abciximab (ReoPro)Abciximab (ReoPro)
Eptifibatide (Integrilin)Eptifibatide (Integrilin)
TirofibanTirofiban
GP IIBIIIA InhibitorsGP IIBIIIA Inhibitors
Stroke- TIAs Stroke- TIAs
MonitoringMonitoring
Bleeding timeBleeding time
Optical aggregometryOptical aggregometry
Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay
Bleeding timeBleeding time
Requires a skin incision (usually made on the ear lobe or Requires a skin incision (usually made on the ear lobe or forearm offorearm of
a depth that results in disruption of capillary loops and a depth that results in disruption of capillary loops and small vessels)small vessels)
AdvantagesAdvantages Universally availableUniversally available Relatively simple techniquesRelatively simple techniques Can be performed bedsideCan be performed bedside
DisadvantagesDisadvantages Insensitive inaccurate non-specific techniqueInsensitive inaccurate non-specific technique
Poorly reproducible (as depends on multiple variables)Poorly reproducible (as depends on multiple variables)
Optical aggregometryOptical aggregometry
Gold standard assay for platelet functionGold standard assay for platelet function Agonist induced aggregation is measuredAgonist induced aggregation is measured Different agonist are available for different Different agonist are available for different
agentsagents However require unique expertise and are not However require unique expertise and are not
universally availableuniversally available Aspirin measured with ADP or AA(gt70 Aspirin measured with ADP or AA(gt70
aggregation so resistance)aggregation so resistance) Clopidogrel( ADP gt 90 aggregation means Clopidogrel( ADP gt 90 aggregation means
resistance) resistance)
Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay
Can be performed bed sideCan be performed bed side Different assay devices with different Different assay devices with different
agonist are used for each of different agonist are used for each of different antiplatelet agents antiplatelet agents
For Aspirin AA is used (result is reported as aspirin For Aspirin AA is used (result is reported as aspirin reaction units [ARU] ARUgt 550 indicates non-reaction units [ARU] ARUgt 550 indicates non-responsiveness)responsiveness)
Verify IIbIIIa assay device uses TRAP as agonist for Verify IIbIIIa assay device uses TRAP as agonist for Abciximab and TirofibanAbciximab and Tirofiban
Practical Applications Practical Applications related to specific related to specific
Neurovascular Neurovascular interventionsinterventions
Acute ischemic StrokeAcute ischemic Stroke When an artery occludes neurons are affected When an artery occludes neurons are affected
differently depending upon the amount of residual blood differently depending upon the amount of residual blood flowflow
Normal cerebral blood flow is greater than 50 mL100 Normal cerebral blood flow is greater than 50 mL100 mgminmgmin
Once blood flow decreases to less than 20 mL100 Once blood flow decreases to less than 20 mL100 mgmin infarction occursmgmin infarction occurs
If blood flow decreases to less than 10 mL100 mgmin If blood flow decreases to less than 10 mL100 mgmin irreversible neuronal death occurs rapidly irreversible neuronal death occurs rapidly
Blood flow between 11 and 20 mL100 mgmin is thought Blood flow between 11 and 20 mL100 mgmin is thought to represent the ischemic penumbra an area where the to represent the ischemic penumbra an area where the cells are functionally silent because of ischemia but are cells are functionally silent because of ischemia but are still able to recover if blood flow is restored still able to recover if blood flow is restored
Many acute stroke therapies are targeted toward Many acute stroke therapies are targeted toward restoring flow or function to the ischemic penumbrarestoring flow or function to the ischemic penumbra
Therapeutic window in Therapeutic window in management of acute Ischemic management of acute Ischemic
StrokeStrokeThe early diagnosis of ischemic stroke is critical to the The early diagnosis of ischemic stroke is critical to the
with only a narrow therapeutic window in the first few with only a narrow therapeutic window in the first few hours following stroke ictushours following stroke ictus
Diagnosis in the first 3 hours postictus provides the Diagnosis in the first 3 hours postictus provides the opportunity for intravenous or intraarterial thrombolysis opportunity for intravenous or intraarterial thrombolysis and intra-arterial clot mechanical treatment which and intra-arterial clot mechanical treatment which improve the outcome improve the outcome
Diagnosis in the time period between 3 and 6 hours Diagnosis in the time period between 3 and 6 hours provides an opportunity for intra-arterial thrombolysis provides an opportunity for intra-arterial thrombolysis and mechanical treatment and mechanical treatment
Involvement of the posterior circulation especially the Involvement of the posterior circulation especially the basilar artery is treated by some regardless of time of basilar artery is treated by some regardless of time of onset or up until 12 to 24 hours in some practices This is onset or up until 12 to 24 hours in some practices This is related to the potentially high mortality and morbidity related to the potentially high mortality and morbidity associated with basilar artery thrombosisassociated with basilar artery thrombosis
Infarct evaluation on angiographyInfarct evaluation on angiography(CT angiography and catheter (CT angiography and catheter
angiography)angiography)CTA is an excellent first-line examination for CTA is an excellent first-line examination for
evaluation of the head and neck arteries evaluation of the head and neck arteries In comparison with catheter angiography In comparison with catheter angiography
what it gives up in resolution and dynamic what it gives up in resolution and dynamic properties it makes up for with rapid properties it makes up for with rapid acquisition of a 3-D dataset and the potential acquisition of a 3-D dataset and the potential for assessment of whole-brain perfusion and for assessment of whole-brain perfusion and better parenchymal evaluationbetter parenchymal evaluation
Moreover CTA illustrates not only arterial Moreover CTA illustrates not only arterial stenosis or occlusion but also the vessel wall stenosis or occlusion but also the vessel wall This factor is most important for evaluation of This factor is most important for evaluation of intramural dissection and thrombosed intramural dissection and thrombosed aneurysms which may both complicate aneurysms which may both complicate evaluation of stroke patientsevaluation of stroke patients
Early angiographic signs of strokes Early angiographic signs of strokes both CTA both CTA and DSA and DSA
Vessel occlusion or cutoff related to Vessel occlusion or cutoff related to thromboembolithromboemboli
aneurysms aneurysms arterial dissection arterial dissection Meniscus or flattened shape to clot Meniscus or flattened shape to clot
(recent) versus reverse meniscus (older)(recent) versus reverse meniscus (older) tram track (nonocclusive or recanalized tram track (nonocclusive or recanalized
clot) clot) delayed (antegrade) flow (manifest as delayed (antegrade) flow (manifest as
decreased whole-brain perfusion on CTA)decreased whole-brain perfusion on CTA) retrograde collateral flowretrograde collateral flow
Non-occlusive left MCA thrombus on 3-D imaging performed from CTA source data and was confirmed at catheter angiography
Therapy to be started within a 6-hr Therapy to be started within a 6-hr time to treatment (TTT) window time to treatment (TTT) window (while in case of IV thrombolysis (while in case of IV thrombolysis therapy to be started with in 3hrs)therapy to be started with in 3hrs)
Exclusion criteria Exclusion criteria Rapidly improving neurologic deficit or Rapidly improving neurologic deficit or Sustained blood pressure of gt180100 Sustained blood pressure of gt180100 Hemorrhage is detected on CTHemorrhage is detected on CT Infarct involving gt more than 13 rd Infarct involving gt more than 13 rd
territory of MCAterritory of MCA MRADWI-Perfusion mismatchlt 20MRADWI-Perfusion mismatchlt 20 Definite hypodensity on CTDefinite hypodensity on CT
Intra-arterial Thrombolysis
Fibrinolytics + AntiplateletsFibrinolytics + Antiplatelets
PlasminogenPlasminogen activators through fibrinolysis exposes activators through fibrinolysis exposes free thrombin and paradoxically stimulatesfree thrombin and paradoxically stimulates platelet platelet aggregation which leads to formation of aaggregation which leads to formation of a platelet platelet thrombus (white clot) thrombus (white clot)
This new thrombus is relatively resistant to This new thrombus is relatively resistant to fibrinolyticsfibrinolytics
So new regimen in case of acute stroke isSo new regimen in case of acute stroke is fibrinolytics + antiplatelet drugsfibrinolytics + antiplatelet drugs
rtPA + IIbIIIa inhibitors( tirofiban rtPA + IIbIIIa inhibitors( tirofiban abciximab) orabciximab) or
Urokinase + IIbIIIa Urokinase + IIbIIIa inhibitors( tirofiban abciximab)inhibitors( tirofiban abciximab)
Intra-arterial Thrombolysis Tirofiban (04 microgkgmin bolus for 3 min followed by Tirofiban (04 microgkgmin bolus for 3 min followed by
0125 ugkgmin)0125 ugkgmin)
++
Heparin (2000ndash3000 IU bolus followed by Heparin (2000ndash3000 IU bolus followed by 1000 IUhour infusion 1000 IUhour infusion
with ACT maintained bw 200-300) throughout the with ACT maintained bw 200-300) throughout the interventional procedure and for 24ndash48 hours thereafter when interventional procedure and for 24ndash48 hours thereafter when there is neither intraprocedural bleeding nor suspicion of there is neither intraprocedural bleeding nor suspicion of increased risk of bleeding increased risk of bleeding
Maximum dose of Urokinase Maximum dose of Urokinase Anterior circulation stroke - 500000 IU (mean 400000 Anterior circulation stroke - 500000 IU (mean 400000
IU range 300000ndash500000 IU)IU range 300000ndash500000 IU) Posterior circulation stroke -1000000 IU (mean 837000 Posterior circulation stroke -1000000 IU (mean 837000
IU range 300000ndash1000000 IU)IU range 300000ndash1000000 IU)American Journal of NeuroradiologyAmerican Journal of Neuroradiology 262595-2601 2005262595-2601 2005
Intravenous ThrombolysisIntravenous Thrombolysis
The first method to restore cerebral The first method to restore cerebral perfusion is clot lysis with the goal perfusion is clot lysis with the goal of re-establishing blood flow to the of re-establishing blood flow to the affected tissue affected tissue
IV thrombolysis rt-PA is the only IV thrombolysis rt-PA is the only FDA- approved treatment for AIS FDA- approved treatment for AIS
Fibrinolysis is enhanced powerfully Fibrinolysis is enhanced powerfully by rt-PAby rt-PA
Intravenous rTPA Intravenous rTPA administration administration protocolprotocol
Total dose of rt-PA 09 mgkg (maximum dose Total dose of rt-PA 09 mgkg (maximum dose 90 mg)90 mg)
Give 10 as initial IV bolusGive 10 as initial IV bolus Infuse remainder over 1 hourInfuse remainder over 1 hour Admit patient to an ICU or stroke unit for Admit patient to an ICU or stroke unit for
monitoringmonitoring Neurologic assessments every 15 minutes Neurologic assessments every 15 minutes
during infusion then every 30 minutes for next during infusion then every 30 minutes for next 6 hours then every hour until 24hours after 6 hours then every hour until 24hours after treatmenttreatment
Favorable Outcome vs Treatment Time Favorable Outcome vs Treatment Time with IV rTPAwith IV rTPA
Protocol limit = 3 hrs
Benefit ~ 45 hrs
Thromboembolism During coilingThromboembolism During coiling Most feared and frequent complication Most feared and frequent complication Reported incidence - Approx 7 Reported incidence - Approx 7 SourcesSources of Thromboembolism are of Thromboembolism are
- Clots at the aneurysmal neck during or immediately- Clots at the aneurysmal neck during or immediately after after embolization embolization
- Thrombus forming on catheters during- Thrombus forming on catheters during proceduresprocedures
- Stenosis of an adjacent artery dt coil mass- Stenosis of an adjacent artery dt coil mass or herniationor herniation
- Migration of intraaneurysmal- Migration of intraaneurysmal thrombus during coil thrombus during coil placement placement
- Slow flow dt vasospasm - Slow flow dt vasospasm
- Rare and unlikely causes are hypercoagulable- Rare and unlikely causes are hypercoagulable state such state such as antiphospholipid antibody syndrome or due to HITas antiphospholipid antibody syndrome or due to HIT
Occur more often with wide-necked aneurysms (dt Occur more often with wide-necked aneurysms (dt increased exposed surface area of thrombogenic coil increased exposed surface area of thrombogenic coil material)material)
Current regimen of endovascular Current regimen of endovascular managementmanagement
The The glycoprotein IIbIIIa antagonist tirofiban glycoprotein IIbIIIa antagonist tirofiban (04 (04 microgkgmin bolus for 30 minutes followed by infusion of microgkgmin bolus for 30 minutes followed by infusion of 0125 ugkgmin until the thrombus dissolved) 0125 ugkgmin until the thrombus dissolved)
Intraarterial thrombolysis with Intraarterial thrombolysis with urokinase or r- TPA urokinase or r- TPA increase of intravenous (IV) heparin (measured by increase of intravenous (IV) heparin (measured by
ACT) ACT) Intravenous aspirin Intravenous aspirin
Coil-related platelet aggregation (white clot) is Coil-related platelet aggregation (white clot) is unlikely to respond to fibrinolytics but has a high risk unlikely to respond to fibrinolytics but has a high risk of hemorrhage (In ISAT) all 5 patients who had of hemorrhage (In ISAT) all 5 patients who had received thrombolytic therapy with tPA to treat a received thrombolytic therapy with tPA to treat a thromboembolic complication after endovascular thromboembolic complication after endovascular treatment rebleed and all of these patients died)treatment rebleed and all of these patients died)
IntracranialIntracranial Stenting Stenting Metallic foreign body such as stent will accumulate Metallic foreign body such as stent will accumulate
thrombus in the absence of platelet inhibitionthrombus in the absence of platelet inhibition Antiplatelet drugs are important to prevent peri or Antiplatelet drugs are important to prevent peri or
post-interventional thromboembolic eventspost-interventional thromboembolic events Optimal treatment regimens has not been determined Optimal treatment regimens has not been determined
but usually but usually Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-
procedureprocedureOrOr
Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on
morning of proceduremorning of procedure
If need to use stent is not pre-planned thanIf need to use stent is not pre-planned than
Abciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkgAbciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkg IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)
Glycoprotein IIbIIIa inhibitor are not used routinely during elective Glycoprotein IIbIIIa inhibitor are not used routinely during elective stenting procedure dt increased risk of ICH stenting procedure dt increased risk of ICH
Carotid StentingCarotid Stenting
Pre-procedurePre-procedure
Double Antiplatelet therapy is routinely given Double Antiplatelet therapy is routinely given beginning at least 3beginning at least 3
days before the proceduredays before the procedure
Aspirin 325mgd+Clopidogrel 75mgdAspirin 325mgd+Clopidogrel 75mgd During procedureDuring procedure
Heparin is given with target clotting time of 250-Heparin is given with target clotting time of 250-300sec300sec
Post-procedure Post-procedure
Aspirin 325mg is continued indefinitely and Aspirin 325mg is continued indefinitely and
Clopidogrel 75mgd for at least 6 weeks Clopidogrel 75mgd for at least 6 weeks
Inclusion criteria for Local ThrombolysisInclusion criteria for Local Thrombolysis a)a) Patients in severe clinical grade on admission Patients in severe clinical grade on admission
with evidence of dural venous sinus with evidence of dural venous sinus thrombosis and restrictive venous outflow on thrombosis and restrictive venous outflow on cerebral angiogramcerebral angiogram
b)b) Patients in clinical grade 3 worsening on Patients in clinical grade 3 worsening on heparin therapy Restriction to venous heparin therapy Restriction to venous outflow was defined as an increase in brain outflow was defined as an increase in brain circulation time gt 12 s delay in the drainage circulation time gt 12 s delay in the drainage of cortical veins with cortical veins hanging of cortical veins with cortical veins hanging in spacein space
Treatment Options for Venous Thrombosis
CT Grading for Venous ThrombosisCT Grading for Venous Thrombosis Grade I no parenchymal change Grade I no parenchymal change
(hyperdense (hyperdense sinuses cortical veins empty sinuses cortical veins empty delta sign)delta sign)
Grade II non hemorrhagic venous infarct Grade II non hemorrhagic venous infarct without mass effect without mass effect
Grade III non-hemorrhagic infarct with Grade III non-hemorrhagic infarct with mass effectmass effect
Grade IV hemorrhagic venous infarct (max Grade IV hemorrhagic venous infarct (max diameter lt 3 cm) with no mass effectdiameter lt 3 cm) with no mass effect
Grade V hemorrhagic venous infarct (max Grade V hemorrhagic venous infarct (max diameter gt 3 cm) with mass effect diameter gt 3 cm) with mass effect
Local ThrombolysisLocal Thrombolysis
Femoral Jugular access was secured and a guiding Femoral Jugular access was secured and a guiding catheter was placed in the jugular bulb catheter was placed in the jugular bulb Mechanical Mechanical clot maceration clot maceration was done with the guidewire was done with the guidewire following which a microcatheter (was navigated and following which a microcatheter (was navigated and placed in the thrombosed segment of sinus confirmed placed in the thrombosed segment of sinus confirmed on a selective venogram on a selective venogram
Urokinase infusion Bolus dose of 2-6 lacs followed Urokinase infusion Bolus dose of 2-6 lacs followed by 60000 to 100000 units per hour along with by 60000 to 100000 units per hour along with periodic check venogram Along with maintenance periodic check venogram Along with maintenance systemic infusion of Heparinsystemic infusion of Heparin Other agents such as Other agents such as streptokinase altepase or rTPAstreptokinase altepase or rTPA can be also used can be also used
After thrombolysis patient should subjected to oral After thrombolysis patient should subjected to oral anticoagulation for six monthsanticoagulation for six months
Low-molecular-weight Low-molecular-weight heparinheparin
PharmacologyPharmacologyLMWH as its name suggests is a glycosaminoglycan that is approximatelyLMWH as its name suggests is a glycosaminoglycan that is approximately
one third the molecular weight of UFH It is derived from UFH through one third the molecular weight of UFH It is derived from UFH through variousvarious
depolymerization processes LMWH binds to antithrombin which in turn depolymerization processes LMWH binds to antithrombin which in turn
Neutralizes actors Xa and IIa Because LMWH lacks many of the longer Neutralizes actors Xa and IIa Because LMWH lacks many of the longer chains chains
required for binding to thrombin it has less ability to neutralize thrombin required for binding to thrombin it has less ability to neutralize thrombin
relativeto its ability to neutralize factor Xa LMWH also has less relativeto its ability to neutralize factor Xa LMWH also has less nonspecific nonspecific
binding to other proteins There is greater bioavailability with more binding to other proteins There is greater bioavailability with more predictable predictable
pharmacokinetics that eliminates the need for monitoring The smaller pharmacokinetics that eliminates the need for monitoring The smaller size also size also
allows for enhanced subcutaneous absorption when compared with UFHallows for enhanced subcutaneous absorption when compared with UFH
Three LMWH preparations are Three LMWH preparations are currently approved for use in the currently approved for use in the United States (1) enoxaparin (2) United States (1) enoxaparin (2) dalteparin and (3) tinzaparin dalteparin and (3) tinzaparin
They are all administered They are all administered subcutaneously at intervals of either subcutaneously at intervals of either once or twice daily for both once or twice daily for both prophylaxis and treatment dosesprophylaxis and treatment doses
Few Experiences of Few Experiences of ThrombolysisThrombolysis
Vickey 25 Yrs male patient presented Vickey 25 Yrs male patient presented with 12with 12thth day HO severe headache with day HO severe headache with right sided hemiplegiaright sided hemiplegia
MRI shows thrombosis of the superior MRI shows thrombosis of the superior sagittal left transverse left sigmoid sagittal left transverse left sigmoid sinuses and cortical veins in the fronto-sinuses and cortical veins in the fronto-parietal regions with eo haemorrhagic parietal regions with eo haemorrhagic infarct in the left cerebral hemisphere infarct in the left cerebral hemisphere with mass effect( Grade ndashV)with mass effect( Grade ndashV)
Sashi Srivastava 64 yrs FSashi Srivastava 64 yrs F In a follow up case of MRD with infra-renal In a follow up case of MRD with infra-renal
aortic abdominal and bilateral renal artery aortic abdominal and bilateral renal artery thrombosis renal angiogram shows filling thrombosis renal angiogram shows filling defects in the right Renal artery defects in the right Renal artery
Initially Renal angioplasty was done Initially Renal angioplasty was done Following angioplasty few thrombi are seem Following angioplasty few thrombi are seem to extends into the segmental branches and to extends into the segmental branches and causing blockage So Thrombolysis was causing blockage So Thrombolysis was plane to dissolve the run-out thrombi with plane to dissolve the run-out thrombi with urokinase urokinase
Rakesh 34yrsMRakesh 34yrsM Left SFA pseudoaneurysm with Left SFA pseudoaneurysm with
Covered stent placementCovered stent placement Pre operative antiplatelets with post Pre operative antiplatelets with post
procedure heparin Tirofiban procedure heparin Tirofiban followed by aspirin and clopidogrel followed by aspirin and clopidogrel were usedwere used
IAT may be a treatment option for selected patients IAT may be a treatment option for selected patients Possible selection criteria include Possible selection criteria include
presentation between 3 and 6 hours from symptom onsetpresentation between 3 and 6 hours from symptom onset major cerebral artery occlusion major cerebral artery occlusion severe neurologic deficits severe neurologic deficits high risk of systemic hemorrhage with IV rt-PA (eg recent high risk of systemic hemorrhage with IV rt-PA (eg recent
surgery) surgery) The MERCI (Mechanical Embolus Removal in Cerebral The MERCI (Mechanical Embolus Removal in Cerebral
Ischemia) retrievalIschemia) retrieval system system
Has been FDA-approved for recanalizing acutely occluded Has been FDA-approved for recanalizing acutely occluded cerebral arteries cerebral arteries
In the Multi-MERCI study patients who did not improve In the Multi-MERCI study patients who did not improve immediately after IV rt-PA underwent mechanical immediately after IV rt-PA underwent mechanical embolectomy within 8 hours of symptom onset embolectomy within 8 hours of symptom onset
Partial or complete recanalization occurred in 74 of Partial or complete recanalization occurred in 74 of patientspatients
with a symptomatic intracerebral hemorrhage (sICH) rate of with a symptomatic intracerebral hemorrhage (sICH) rate of 67 67
Mechanical embolectomy with the MERCI retriever may be a Mechanical embolectomy with the MERCI retriever may be a feasible and safe option for patients after IV rt-PAfeasible and safe option for patients after IV rt-PA
Penumbra stroke systemPenumbra stroke system This device combines two methods of clot This device combines two methods of clot
extraction aspiration and mechanical extraction aspiration and mechanical extraction extraction
First the clot is aspirated then a thrombus First the clot is aspirated then a thrombus removal ring can be used if necessary to removal ring can be used if necessary to remove remaining clot remove remaining clot
successful recanalizing 82successful recanalizing 82 Bridging therapyBridging therapy
06 mgkg IV rt-PA followed by IAT with IA rt-06 mgkg IV rt-PA followed by IAT with IA rt-PA (up to 20 mg)PA (up to 20 mg)
achieved a higher recanalization rateachieved a higher recanalization rate
Criteria for thrombolysis with rTPACriteria for thrombolysis with rTPA
Inclusion criteriaInclusion criteria Clinical signs and symptoms consistent with ischemic Clinical signs and symptoms consistent with ischemic
strokestroke Patient last seen normal within 3 hoursPatient last seen normal within 3 hours Measurable neurologic deficitMeasurable neurologic deficit
Exclusion criteriaExclusion criteria Any hemorrhage on neuroimaging (CT or MRI)Any hemorrhage on neuroimaging (CT or MRI) Symptoms suggestive of subarachnoid hemorrhageSymptoms suggestive of subarachnoid hemorrhage Seizure at stroke onset that is thought to contribute to Seizure at stroke onset that is thought to contribute to
neurologic deficitneurologic deficit Hypodensity greater than one third cerebral hemisphere Hypodensity greater than one third cerebral hemisphere
on CTon CT SBP greater than 185 mm Hg or DBP greater than 110 SBP greater than 185 mm Hg or DBP greater than 110
mm Hgmm Hg International normalized ratio (INR) greater than 17International normalized ratio (INR) greater than 17
Ischemic Stroke Ischemic Stroke Treatment ndash 2006Treatment ndash 2006
IV tissue plasminogen activator (tPA)IV tissue plasminogen activator (tPA) ndash ndash Only FDA-approved acute stroke drugOnly FDA-approved acute stroke drug ndash ndash 3 hour treatment window3 hour treatment window
MERCI - Concentric clot retrieval MERCI - Concentric clot retrieval devicedevice ndash ndash Rescue therapy - approved 2004Rescue therapy - approved 2004 ndash ndash Device approval (not outcomes-based)Device approval (not outcomes-based)
Off label approachesOff label approaches ndash ndash IV tPA after 3 hoursIV tPA after 3 hours ndash ndash IV-IA tPA sequential strategiesIV-IA tPA sequential strategies ndash ndash IA tPA clot angioplasty fragmentationIA tPA clot angioplasty fragmentation ndash ndash Ultrasound-assisted tPA lysisUltrasound-assisted tPA lysis
rt-PA Trials NINDSrt-PA Trials NINDS
Acute stroke - 624 patientsAcute stroke - 624 patients Treat within 3 hrsTreat within 3 hrs Intravenous 09 mgkg rt-PA vs placeboIntravenous 09 mgkg rt-PA vs placebo Hemorrhage 64 tPA 06 placeboHemorrhage 64 tPA 06 placebo Neurologic recovery better with tPA 30 Neurologic recovery better with tPA 30
more like to have minimal or no disabilitymore like to have minimal or no disability
First proven approved treatment for First proven approved treatment for strokestroke
Limitations of tPALimitations of tPA Only 4 of acute strokes receive tPAOnly 4 of acute strokes receive tPA (Kleindorfer et al Stroke 2004 35 e27-e29)(Kleindorfer et al Stroke 2004 35 e27-e29)
Only 22 of patients present within 3 hoursOnly 22 of patients present within 3 hours1048707 1048707 51 of these ineligible due to51 of these ineligible due to
bull bull Mild severityMild severity bull bull Medical or surgical historyMedical or surgical history bull bull Blood testsBlood tests
Sustained recanalization only 13Sustained recanalization only 13 (Alexandrov et al NEJM 2004 351 2170-8)(Alexandrov et al NEJM 2004 351 2170-8)
Concern for hemorrhageConcern for hemorrhage tPA potentiates apoptotic injury tPA potentiates apoptotic injury (Liu et al Nature Med 2004 101379-83)(Liu et al Nature Med 2004 101379-83)
PROACT II IA Lysis TrialPROACT II IA Lysis Trial Baseline 24 hours 8 days
Baseline 60 minutes 120 minutes
9mg IAProurokinase
Desmoteplase Trials DEDAS Desmoteplase Trials DEDAS DIASDIAS
Trial OverviewTrial Overview Double blind randomized placebo Double blind randomized placebo
controlled trialscontrolled trials IV delivery 3-9 hour time windowIV delivery 3-9 hour time window Plasminogen activator ndash from Plasminogen activator ndash from vampire bat vampire bat
salivasaliva Selection based on PWI-DWI MismatchSelection based on PWI-DWI Mismatch
MRI InclusionMRI Inclusion PWI defect at least 2 cm AND ~20 larger PWI defect at least 2 cm AND ~20 larger
than DWIthan DWI PWI should be obvious even visible on PWI should be obvious even visible on
raw imagesraw imagesMRI ExclusionMRI Exclusion
DWI gt 13 MCADWI gt 13 MCA MRA ICA occlusionMRA ICA occlusion
Desmoteplase ndash DIAS Desmoteplase ndash DIAS ResultsResults
Mechanical Thrombolysis Mechanical Thrombolysis devicesdevices
mechanical thrombolysis potentially extends the treatment mechanical thrombolysis potentially extends the treatment window because they act promptly at the site of the thrombuswindow because they act promptly at the site of the thrombus
The devices can retrieve large clots that pharmaceutical agents The devices can retrieve large clots that pharmaceutical agents may not successfully lysemay not successfully lyse
Patients treated with IV tPA may be considered for treatment of Patients treated with IV tPA may be considered for treatment of residual clot with some of these devicesresidual clot with some of these devices
suction-creating saline jets suction-creating saline jets laser energy ultrasound laser energy ultrasound a corkscrew apparatus to treat strokesa corkscrew apparatus to treat strokes The AngioJet systemThe AngioJet system uses saline jets that are directed back into the catheter to uses saline jets that are directed back into the catheter to
create a low-pressure zone around the catheter tip inducing create a low-pressure zone around the catheter tip inducing suction suction
The clot is pulled into the exhaust lumen and removed from the The clot is pulled into the exhaust lumen and removed from the vessel Although US Food and Drug Administration (FDA) has vessel Although US Food and Drug Administration (FDA) has approved this device for use in arteriovenous dialysis grafts and approved this device for use in arteriovenous dialysis grafts and fistulae and for the treatment of coronary arteries saphenous fistulae and for the treatment of coronary arteries saphenous vein grafts and peripheral vessels clinical trials for the vein grafts and peripheral vessels clinical trials for the treatment of acute stroke are no longer in progress treatment of acute stroke are no longer in progress
Most devices are used in cerebral vessels that 2-5 mm
The Latis laser device The Latis laser device used laser energy to ablate clots used laser energy to ablate clots Arteries 2-5 mm in diameter could be Arteries 2-5 mm in diameter could be
treated including the ICA M1 or M2 treated including the ICA M1 or M2 branch of the MCA A1 branch of the branch of the MCA A1 branch of the anterior cerebral artery (ACA) basilar anterior cerebral artery (ACA) basilar artery posterior cerebral artery (PCA) artery posterior cerebral artery (PCA) and vertebral and vertebral
Patients could receive treatment as late Patients could receive treatment as late as 8 hours after symptom onset in the as 8 hours after symptom onset in the anterior circulation and within 24 hours in anterior circulation and within 24 hours in the posterior circulation the posterior circulation
Endovascular Photo Acoustic Endovascular Photo Acoustic Recanalization (EPAR) Recanalization (EPAR)
A laser power source generated energy for the A laser power source generated energy for the systemsystem
The energy was delivered by means of The energy was delivered by means of fiberoptics to the tip of the catheter at the fiberoptics to the tip of the catheter at the treatment sitetreatment site
Absorption of laser light by darkly pigmented Absorption of laser light by darkly pigmented materials (ie the clot) occurred inside the 1-mm materials (ie the clot) occurred inside the 1-mm catheter tipcatheter tip
the system was designed to minimize scattering the system was designed to minimize scattering of laser light of laser light
Absorption converted photo energy to acoustic Absorption converted photo energy to acoustic energy which then emulsified the clot inside the energy which then emulsified the clot inside the catheter tip catheter tip
EKOS ultrasound( the EKOS ultrasound( the Ultrasound Thrombolytic Ultrasound Thrombolytic
Infusion Catheter) Infusion Catheter) combines the use of a distal ultrasound transducer with combines the use of a distal ultrasound transducer with
infusion of a thrombolytic agent through the infusion of a thrombolytic agent through the microcathetermicrocatheter
Ultrasound changes the structure of the clot to Ultrasound changes the structure of the clot to temporarily increase its permeability while providing an temporarily increase its permeability while providing an acoustic pressure gradient to move the drug into the clot acoustic pressure gradient to move the drug into the clot to speed its dissolution to speed its dissolution
The EKOS catheter is placed in the proximal portion of the The EKOS catheter is placed in the proximal portion of the clot clot
After a 2-mg bolus of tPA was injected through the After a 2-mg bolus of tPA was injected through the catheter catheter
the patient received a continuous infusion of IA tPA 03 the patient received a continuous infusion of IA tPA 03 mgmin to a maximum of 20 mg and simultaneous mgmin to a maximum of 20 mg and simultaneous ultrasound transmission for as long as 60 minutes ultrasound transmission for as long as 60 minutes
One patient was treated with a total of 4 units of One patient was treated with a total of 4 units of recombinant reteplase (Retavase) hand-injected over 60 recombinant reteplase (Retavase) hand-injected over 60 minutes minutes
Penumbra system Penumbra system The Penumbra system (Penumbra Inc) provides a dual The Penumbra system (Penumbra Inc) provides a dual
approach to clot extraction using aspiration followed by approach to clot extraction using aspiration followed by clot retrieval with a ring device if needed clot retrieval with a ring device if needed
Mechanical Embolus Removal in Cerebral Ischemia Mechanical Embolus Removal in Cerebral Ischemia (MERCI)(MERCI)
a corkscrew-like apparatus to remove blood clots from a corkscrew-like apparatus to remove blood clots from the brain in patients experiencing an ischemic stroke the brain in patients experiencing an ischemic stroke
The corkscrew itself resides in the catheter tip which The corkscrew itself resides in the catheter tip which shields it from the wall of the vessel until it is ready to be shields it from the wall of the vessel until it is ready to be burrowed into the clot Once lodged in the clot the device burrowed into the clot Once lodged in the clot the device and clot are withdrawn from the vessel and clot are withdrawn from the vessel
Snarelike devicesSnarelike devices Snares such as the Neuronet snare (Guidant Snares such as the Neuronet snare (Guidant
Endovascular Santa Clara CA) have been developed Endovascular Santa Clara CA) have been developed specifically for use in the treatment of strokes specifically for use in the treatment of strokes
These devices are simple in design and do not require the These devices are simple in design and do not require the clot to be amenable to emulsification clot to be amenable to emulsification
X-Sizer deviceX-Sizer device a device with small moving blades at the a device with small moving blades at the
catheter tip catheter tip This device the X-Sizer device (EndiCor Medical This device the X-Sizer device (EndiCor Medical
San Clemente CA) can be used to excise the San Clemente CA) can be used to excise the thrombus and aspirate it thrombus and aspirate it
The device was being evaluated in randomized The device was being evaluated in randomized studies of coronary vessels and in a registry of studies of coronary vessels and in a registry of patients with acute myocardial infarctionpatients with acute myocardial infarction
Although the manufacturer had modified the Although the manufacturer had modified the device for use in cerebral vessels a safety and device for use in cerebral vessels a safety and feasibility study was indefinitely suspended after feasibility study was indefinitely suspended after only 1 patient was treated with the device in only 1 patient was treated with the device in Europe Europe
Suction thrombectomySuction thrombectomy This method of mechanical thrombolysis is one of the This method of mechanical thrombolysis is one of the
simplestsimplest In this readily available technique suction is applied with In this readily available technique suction is applied with
a syringe to remove thrombus in the ICA a syringe to remove thrombus in the ICA It requires no other devicesIt requires no other devices A catheter with a large inner diameter (Brite Tip Cordis A catheter with a large inner diameter (Brite Tip Cordis
Corporation Miami FL) was placed in the symptomatic Corporation Miami FL) was placed in the symptomatic vessel and navigated over a guidewire into the thrombusvessel and navigated over a guidewire into the thrombus
A 60-mL syringe was used to aspirate the thrombus A 60-mL syringe was used to aspirate the thrombus Each patient required angioplasty and stenting of carotid Each patient required angioplasty and stenting of carotid
bifurcation stenosis and received daily aspirin and bifurcation stenosis and received daily aspirin and ticlopidine after the procedure No complications ticlopidine after the procedure No complications occurred occurred
Summary Acute Stroke Summary Acute Stroke ImagingImaging
PhysiologyPhysiology importance collaterals importance collaterals
ndash ndashGrowing role for perfusion Growing role for perfusion assessmentassessment
tPAtPA guidelines amp limitations guidelines amp limitations Signs on CT amp MRSigns on CT amp MR follow physiology follow physiology Stroke trialsStroke trials PWI-DWI mismatch PWI-DWI mismatch
ndash ndashTreat based on physiology not timeTreat based on physiology not time ProtocolsProtocols should be fast and should be fast and
comprehensivecomprehensive
WARFARIN MECHANISM OF ACTIONWARFARIN MECHANISM OF ACTION
Inactive factors II VII IX and X
Proteins S and C
Active factors II VII IX and X
Proteins S and C
Vitamin K epoxide
Vitamin K reduced
WA
RF
AR
IN
Prevents the reduction of vitamin K which is essential for Prevents the reduction of vitamin K which is essential for activation of certain factorsactivation of certain factors
Has no effect on previously formed thrombusHas no effect on previously formed thrombus
Antagonist is Vit KAntagonist is Vit K
OPTIMIZING WARFARIN THERAPYOPTIMIZING WARFARIN THERAPY
Use of large loading dose may lead to hemorrhage and Use of large loading dose may lead to hemorrhage and other complicationsother complications
Initial dose 2-5 mg once dailyInitial dose 2-5 mg once daily Maintenance dose 2-10 mg once dailyMaintenance dose 2-10 mg once daily If Immediate anticoagulation is requiredIf Immediate anticoagulation is required Heparin IS Heparin IS
started along with loading dose of warfarin 10 mg started along with loading dose of warfarin 10 mg Heparin is usually discontinued after 4-5 days Heparin is usually discontinued after 4-5 days Before Before discontinuing INR should be in therapeutic range for 2 discontinuing INR should be in therapeutic range for 2 consecutive daysconsecutive days
Daily monitoring of INR until INR is in therapeutic Daily monitoring of INR until INR is in therapeutic range then 3 times weekly for 1-2 weeks then less often range then 3 times weekly for 1-2 weeks then less often (every 4 to 6 weeks)(every 4 to 6 weeks)
OPTIMAL THERAPEUTIC RANGEOPTIMAL THERAPEUTIC RANGE
IndicationIndication INRINR
Prophylaxis of venous Prophylaxis of venous thromboembolismthromboembolism
20-3020-30
Treatment of venous Treatment of venous thromboembolismthromboembolism
20-3020-30
Atrial fibrillationAtrial fibrillation 20-3020-30
Mitral valve stenosisMitral valve stenosis 20-3020-30
Heart valve replacementHeart valve replacement
Bioprosthetic valveBioprosthetic valve
Mechanical valveMechanical valve
20-3020-30
25-3525-35
Myocardial infarctionMyocardial infarction 20-3020-30
25-35 25-35 (high risk patients)(high risk patients)
FACTORS INFLUENCING DOSE RESPONSEFACTORS INFLUENCING DOSE RESPONSE
Poor patient compliancePoor patient compliance Concomitant medicationsConcomitant medications Levels of dietary vitamin KLevels of dietary vitamin K Alcohol Inaccurate lab testingAlcohol Inaccurate lab testing Inaccurate lab testingInaccurate lab testing Hepatic dysfunctionHepatic dysfunction FeverFever
Contraindication for WarfarinContraindication for Warfarin
Hypersensitivity to warfarinHypersensitivity to warfarin Hemorrhagic tendencyHemorrhagic tendency Condition with risk of hemorrhageCondition with risk of hemorrhage Inadequate laboratory techniquesInadequate laboratory techniques Protein C amp S deficiencyProtein C amp S deficiency Vitamin K deficiencyVitamin K deficiency
SIDE EFFECTSSIDE EFFECTS
Hemorrhage Hemorrhage Skin necrosisSkin necrosis Purple toe syndromePurple toe syndrome Microembolization Microembolization TeratogenecityTeratogenecity Agranulocytosis leukopenia Agranulocytosis leukopenia Diarrhoeanausea anorexiaDiarrhoeanausea anorexia
MONITORING OF WARFARIN THERAPYMONITORING OF WARFARIN THERAPY
Prothrombin timeProthrombin time PT ratioPT ratio INR (International Normalized Ratio)INR (International Normalized Ratio)
PROTHROMBIN TIME (PT)PROTHROMBIN TIME (PT)
Time required for blood to coagulate Time required for blood to coagulate is called PT ( normal value ~10sec)is called PT ( normal value ~10sec)
Performed by adding a mixture of Performed by adding a mixture of calcium and thromboplastin to calcium and thromboplastin to citrated plasmacitrated plasma
As a control a normal blood sample is As a control a normal blood sample is tested continuouslytested continuously
PT ratio (PTR) = PT ratio (PTR) = Patientrsquos PTPatientrsquos PT Control PTControl PT
PROBLEMS WITH PTPTRPROBLEMS WITH PTPTR
Thromboplastins are extracts from Thromboplastins are extracts from brain lung or placenta of animalsbrain lung or placenta of animals
Thromboplastins from various Thromboplastins from various manufacturers differ in their manufacturers differ in their sensitivity to prolong PTsensitivity to prolong PT
May result in false control of May result in false control of anticoagulant therapyanticoagulant therapy
INTERNATIONAL NORMALISED RATIO (INR)INTERNATIONAL NORMALISED RATIO (INR)
International Normalized Ratio (INR) International Normalized Ratio (INR) a PT test with a a PT test with a formula based ratio to normalize the often variable source formula based ratio to normalize the often variable source of tissue factor (human rabbit recombinant)of tissue factor (human rabbit recombinant)
INR = [PTINR = [PTptpt] ] ISIISI
[PT[PTRefRef]]
PTPTpt pt ndash prothrombin time of patientndash prothrombin time of patient
PTPTRef Ref ndash prothrombin time of normal pooled samplendash prothrombin time of normal pooled sample
ISI ndash International Sensitivity IndexISI ndash International Sensitivity Index
Warfarin is given orally and titrated to achieve an INR of Warfarin is given orally and titrated to achieve an INR of typically 20 ndash 30typically 20 ndash 30
Heparin versus WarfarinHeparin versus Warfarin
Drug ActionMechan-ism
Moni-toring
Effective
HeparinDirect
Inhibition ofThrombin
ATIIIcofactor
APTTACT
Immediate
WarfarinDecreasesProductionof factors
Vitamin K PTDelay
3-5 days
INR
Recanalization or Antegrade Recanalization or Antegrade Reperfusion StrategiesReperfusion Strategies
Recanalization strategies focus on removing Recanalization strategies focus on removing andor dissolving the occlusive thrombus to re-andor dissolving the occlusive thrombus to re-establish antegrade flow Strategies may be establish antegrade flow Strategies may be classified into 7 different categories on the classified into 7 different categories on the basis of their primary mechanism of action basis of their primary mechanism of action 1) 1) IV andor intraarterial thrombolysis (IAT) IV andor intraarterial thrombolysis (IAT) 2) endovascular thrombectomy2) endovascular thrombectomy3) endovascular thromboaspiration 3) endovascular thromboaspiration 4) endovascular mechanical thrombus disruption or 4) endovascular mechanical thrombus disruption or
thromborrhexisthromborrhexis5) 5) transcranial or endovascular augmented transcranial or endovascular augmented
fibrinolysis fibrinolysis 6) endovascular thrombus entrapment and 6) endovascular thrombus entrapment and 7) temporary endovascular bypass7) temporary endovascular bypass
IAT in Acute Ischemic StrokeIAT in Acute Ischemic Stroke
IAT advantages over IV thrombolysisIAT advantages over IV thrombolysis Coaxial microcatheter techniques the occluded intracranial Coaxial microcatheter techniques the occluded intracranial
vessel is directly accessible and the fibrinolytic agent can be vessel is directly accessible and the fibrinolytic agent can be infused directly into the thrombusinfused directly into the thrombus
This permits a smaller dose of fibrinolytic agent to reach a This permits a smaller dose of fibrinolytic agent to reach a higher local concentration than that reached by systemic higher local concentration than that reached by systemic infusioninfusion
Allows more complete recanalization with lower total doses of Allows more complete recanalization with lower total doses of thrombolytic thrombolytic
With the smaller dose complications from systemic fibrinolytic With the smaller dose complications from systemic fibrinolytic effects including intracranial hemorrhage (ICH) can effects including intracranial hemorrhage (ICH) can theoretically be reduced theoretically be reduced
Treatment window for endovascular techniques can be Treatment window for endovascular techniques can be extended beyond the typical IV window of 3 hours extended beyond the typical IV window of 3 hours
IA techniques have led to higher recanalization rates than IV IA techniques have led to higher recanalization rates than IV thrombolysisthrombolysis
Major disadvantagesMajor disadvantages Relative complexity of the procedure the level Relative complexity of the procedure the level
of required technical expertise and its of required technical expertise and its relatively low availability relatively low availability
Delays in initiating treatmentDelays in initiating treatment InvasiveInvasive
ThrombolyticsThrombolytics
Plasminogen activators
Fibrinolytics
1 Plasminogen Activators 1 Plasminogen Activators drugs act by converting the inactive proenzyme drugs act by converting the inactive proenzyme plasminogen into the active enzyme plasmin Plasmin plasminogen into the active enzyme plasmin Plasmin digests fibrinogen fibrin monomers and cross-linked digests fibrinogen fibrin monomers and cross-linked fibrin (as found in a thrombus) into fibrin degradation fibrin (as found in a thrombus) into fibrin degradation productsproducts
First-Generation Agents First-Generation Agents StreptokinaseStreptokinase a protein derived from group C a protein derived from group C
szlig-hemolytic streptococci has a half-life of 16ndashszlig-hemolytic streptococci has a half-life of 16ndash90 minutes and low fibrin specificity This drug 90 minutes and low fibrin specificity This drug proved to have a very narrow therapeutic proved to have a very narrow therapeutic window and significant rates of ICH and window and significant rates of ICH and systemic hemorrhage18systemic hemorrhage18
UrokinaseUrokinase is a serine protease with a plasma is a serine protease with a plasma half life of 14 minutes and low fibrin specificity half life of 14 minutes and low fibrin specificity
The urokinase dose used in cerebral IAT has The urokinase dose used in cerebral IAT has ranged from 002 to 2 X106unitsranged from 002 to 2 X106units
Second-Generation Agents Second-Generation Agents Alteplase (rtPA) Alteplase (rtPA)
is a serine is a serine protease with a plasma half-life of 35 protease with a plasma half-life of 35 minutes and a high degree of fibrin affinity and minutes and a high degree of fibrin affinity and specificity specificity
Dose used in cerebral IAT has ranged between 20 Dose used in cerebral IAT has ranged between 20 and 60 mgand 60 mg
Disadvantages of alteplase include its relatively short Disadvantages of alteplase include its relatively short halflife and limited penetration into the clot matrix halflife and limited penetration into the clot matrix because of strong binding with surface fibrin which because of strong binding with surface fibrin which could delay recanalization and increase the risk of could delay recanalization and increase the risk of recurrent occlusion recurrent occlusion
Prourokinase (r-prourokinase) Prourokinase (r-prourokinase) is the proenzyme precursor of urokinase is the proenzyme precursor of urokinase T12 of 7 minutes and high fibrin specificity T12 of 7 minutes and high fibrin specificity
Third-Generation AgentsThird-Generation Agents
ReteplaseReteplase is a structurally modified is a structurally modified form of alteplase form of alteplase
with a longer half-life (15ndash18 minutes) In with a longer half-life (15ndash18 minutes) In addition it does not bind as highly to fibrin addition it does not bind as highly to fibrin unbound reteplase can thus theoretically better unbound reteplase can thus theoretically better penetrate the clot and potentially penetrate the clot and potentially improve in improve in vivo fibrinolytic activity vivo fibrinolytic activity
TenecteplaseTenecteplase is another modified form of rtPA with a longer is another modified form of rtPA with a longer
half-life (17 minutes)half-life (17 minutes) greater fibrin specificity and greater greater fibrin specificity and greater
resistance to plasminogen activator inhibitor-1 resistance to plasminogen activator inhibitor-1 IV tenecteplase in acute ischemic stroke IV tenecteplase in acute ischemic stroke
suggest that the drug is safe and promisingsuggest that the drug is safe and promising
Newer plasminogen activatorNewer plasminogen activator
DesmoteplaseDesmoteplase is a genetically engineered is a genetically engineered version of the clot-dissolving factor version of the clot-dissolving factor
found in the saliva found in the saliva of the vampire bat Desmodus rotundusof the vampire bat Desmodus rotundus moremore potent and more selective for fibrin-bound potent and more selective for fibrin-bound
plasminogen than any other known plasminogen plasminogen than any other known plasminogen activatoractivator
Unlike tissue plasminogen activator (tPA) desmoteplase Unlike tissue plasminogen activator (tPA) desmoteplase is not activated by fibrinogen or -amyloid proteins is not activated by fibrinogen or -amyloid proteins factors that may exacerbate the risk for ICH factors that may exacerbate the risk for ICH
The effect of IV administration of desmoteplase 3ndash9 The effect of IV administration of desmoteplase 3ndash9 hours after symptom onset in patients with stroke who hours after symptom onset in patients with stroke who present with mismatch on MR imaging or CT perfusion present with mismatch on MR imaging or CT perfusion
3 DefibrinogenatingFibrinogenolytic 3 DefibrinogenatingFibrinogenolytic Agents Agents
AncrodAncrod(Viprinex)(Viprinex) is is the purified fraction of the Malayan pit viper venomthe purified fraction of the Malayan pit viper venom It acts by directly cleaving and inactivating fibrinogen It acts by directly cleaving and inactivating fibrinogen
and thus indirectly promoting anticoagulation and thus indirectly promoting anticoagulation The reduction in the blood levels of fibrinogen also The reduction in the blood levels of fibrinogen also
leads to a reduced blood viscosity which may improve leads to a reduced blood viscosity which may improve blood flow to the affected areas of the brain blood flow to the affected areas of the brain
In the Stroke Treatment with Ancrod Trial 500 In the Stroke Treatment with Ancrod Trial 500 patients with stroke presenting within 3 hours of patients with stroke presenting within 3 hours of symptom onset were randomized to receive ancrod (symptom onset were randomized to receive ancrod (n n 248) or a placebo (n 252) Good outcome (Barthel 248) or a placebo (n 252) Good outcome (Barthel Index 95ndash100 at 3 months) was achieved in 4221 Index 95ndash100 at 3 months) was achieved in 4221 and 344 of the patients respectively and 344 of the patients respectively
2 Direct Fibrinolytics2 Direct Fibrinolytics
Microplasmin (Microplasmin (ThromboGenics Heverlee Belgium)ThromboGenics Heverlee Belgium) is a truncated form of plasmin that is more resistant to the effects is a truncated form of plasmin that is more resistant to the effects
of antiplasmin of antiplasmin microplasmin can be used upto 4ndash12 hours after stroke onset microplasmin can be used upto 4ndash12 hours after stroke onset There was no evidence of increased bleeding risk with There was no evidence of increased bleeding risk with
microplasminmicroplasmin
Alfimeprase (Nuvelo San Carlos Calif)Alfimeprase (Nuvelo San Carlos Calif) is a recombinant truncated form of fibrolase a fibrinolytic zinc metalloproteinase is a recombinant truncated form of fibrolase a fibrinolytic zinc metalloproteinase
isolated from the venom of the southern copperhead snake isolated from the venom of the southern copperhead snake It degrades fibrin directly and achieves thrombolysis independent It degrades fibrin directly and achieves thrombolysis independent
of plasmin formationof plasmin formation its thrombolytic activity appears to be localized to the site of its thrombolytic activity appears to be localized to the site of
delivery These properties should theoretically result in faster delivery These properties should theoretically result in faster recanalization and lower hemorrhagic conversion riskrecanalization and lower hemorrhagic conversion risk
Anti-fibrinolyticsAnti-fibrinolytics
to limit fibrinolytic activityto limit fibrinolytic activity -aminocaproic acid (EACA) -aminocaproic acid (EACA) competitively inhibitscompetitively inhibits plasminogen and plasminogen activators from plasminogen and plasminogen activators from
binding to fibrinbinding to fibrin
alpha2-antiplasminalpha2-antiplasmin a serine protease inhibitor that a serine protease inhibitor that neutralizes any free circulating plasminneutralizes any free circulating plasmin
Plasminogen activator inhibitor-1Plasminogen activator inhibitor-1 a serine protease a serine protease inhibitor that inhibits tissue-type plasminogen inhibitor that inhibits tissue-type plasminogen activatoractivator
Glycoprotein (GP) IIbIIIa antagonistsGlycoprotein (GP) IIbIIIa antagonists
such as ReoPro (abciximab) Integrilin such as ReoPro (abciximab) Integrilin (eptifibatide) or Aggrastat (tirofiban) in (eptifibatide) or Aggrastat (tirofiban) in ischemic stroke remains investigational ischemic stroke remains investigational Deshmukh et al38 reported 21 patients with Deshmukh et al38 reported 21 patients with large-vessel occlusion refractory to IAT with large-vessel occlusion refractory to IAT with rtPA who were treated with IV andor IA rtPA who were treated with IV andor IA abciximab eptifibatide or tirofiban abciximab eptifibatide or tirofiban
IA Mechanical Approaches in Acute Ischemic Stroke IA Mechanical Approaches in Acute Ischemic Stroke Mechanical strategies have several advantagesMechanical strategies have several advantages First they lessen and may even preclude the use of chemical First they lessen and may even preclude the use of chemical
thrombolytics in this manner very likely reducing the risk of ICHthrombolytics in this manner very likely reducing the risk of ICH Second by avoiding the use of chemical thrombolytics it is Second by avoiding the use of chemical thrombolytics it is
possible to extend the treatment window beyond the limit of 6ndash8 possible to extend the treatment window beyond the limit of 6ndash8 hours hours
Third mechanically fragmenting a clot increases the surface area Third mechanically fragmenting a clot increases the surface area accessible to fibrinolytic agents and allows inflow of fresh accessible to fibrinolytic agents and allows inflow of fresh plasminogen which in turn may increase the speed of plasminogen which in turn may increase the speed of thrombolysis thrombolysis
Finally clot-retrieval devices may provide faster recanalization Finally clot-retrieval devices may provide faster recanalization
The disadvantages of the mechanical The disadvantages of the mechanical approaches approaches technical difficulty of navigating mechanical technical difficulty of navigating mechanical
devices into the intracranial circulation excessive devices into the intracranial circulation excessive trauma to the vasculature (potentially leading to trauma to the vasculature (potentially leading to vasospasm vessel dissection perforation or vasospasm vessel dissection perforation or rupture) rupture)
fragmented thrombus causing distal embolization fragmented thrombus causing distal embolization into previously unaffected territories into previously unaffected territories
Nevertheless the advantages of mechanical stroke Nevertheless the advantages of mechanical stroke therapy appear to significantly outweigh its therapy appear to significantly outweigh its disadvantages and risksdisadvantages and risks
Contraindications to Thrombolytic Contraindications to Thrombolytic agents agents
Recent thoracic abdominal or Recent thoracic abdominal or intracranial surgeryintracranial surgery
Recent haemorrhagic CVA Head injury Recent haemorrhagic CVA Head injury or neoplasmor neoplasm
Bleeding ulcerBleeding ulcer Anticipated invasive procedures (arterial Anticipated invasive procedures (arterial
punctures biopsies)punctures biopsies) Concurrent hemostatic dysfunctionConcurrent hemostatic dysfunction
Monitoring of thrombolytic Monitoring of thrombolytic therapytherapy
Thrombin time Measures the availability of functional
fibrinogen Normal thrombin time is 10-14 sec Prolonged when fibrinogen level is below
75-100 mgdl
Half Life of ThrombolyticsHalf Life of ThrombolyticsAgent Administration Half Life
Streptokinase IA 60-80min
Urokinase IAIV 9-12min
rTPA IAIV 6min
Abciximab(Reopro) IAIV 12hour
Aspirin POIV 15-20min
Heparin IVSC 60min
Coumadin PO 15-25 days
Anti Platelet DrugsAnti Platelet DrugsDrug Drug Mechanism Mechanism UsesUsesAspirinAspirin Permanently inhibits Permanently inhibits
COX-1 and COX-2COX-1 and COX-2CADCAD
Stroke-TIAsStroke-TIAs
NSAIDsNSAIDs Reversibly inhibits Reversibly inhibits COX-1COX-1
LimitedLimited
DipyridamoleDipyridamole Inhibits PDE increases Inhibits PDE increases cAMPcAMP
TIAsTIAs
ThenopyridinesThenopyridines
(Ticlopidine(Ticlopidine
ClopidrgrelClopidrgrel))
Inhibits ADP Inhibits ADP
PlatAg PlatAg
TIAsStrokeTIAsStroke
CAD PVDCAD PVD
Abciximab (ReoPro)Abciximab (ReoPro)
Eptifibatide (Integrilin)Eptifibatide (Integrilin)
TirofibanTirofiban
GP IIBIIIA InhibitorsGP IIBIIIA Inhibitors
Stroke- TIAs Stroke- TIAs
MonitoringMonitoring
Bleeding timeBleeding time
Optical aggregometryOptical aggregometry
Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay
Bleeding timeBleeding time
Requires a skin incision (usually made on the ear lobe or Requires a skin incision (usually made on the ear lobe or forearm offorearm of
a depth that results in disruption of capillary loops and a depth that results in disruption of capillary loops and small vessels)small vessels)
AdvantagesAdvantages Universally availableUniversally available Relatively simple techniquesRelatively simple techniques Can be performed bedsideCan be performed bedside
DisadvantagesDisadvantages Insensitive inaccurate non-specific techniqueInsensitive inaccurate non-specific technique
Poorly reproducible (as depends on multiple variables)Poorly reproducible (as depends on multiple variables)
Optical aggregometryOptical aggregometry
Gold standard assay for platelet functionGold standard assay for platelet function Agonist induced aggregation is measuredAgonist induced aggregation is measured Different agonist are available for different Different agonist are available for different
agentsagents However require unique expertise and are not However require unique expertise and are not
universally availableuniversally available Aspirin measured with ADP or AA(gt70 Aspirin measured with ADP or AA(gt70
aggregation so resistance)aggregation so resistance) Clopidogrel( ADP gt 90 aggregation means Clopidogrel( ADP gt 90 aggregation means
resistance) resistance)
Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay
Can be performed bed sideCan be performed bed side Different assay devices with different Different assay devices with different
agonist are used for each of different agonist are used for each of different antiplatelet agents antiplatelet agents
For Aspirin AA is used (result is reported as aspirin For Aspirin AA is used (result is reported as aspirin reaction units [ARU] ARUgt 550 indicates non-reaction units [ARU] ARUgt 550 indicates non-responsiveness)responsiveness)
Verify IIbIIIa assay device uses TRAP as agonist for Verify IIbIIIa assay device uses TRAP as agonist for Abciximab and TirofibanAbciximab and Tirofiban
Practical Applications Practical Applications related to specific related to specific
Neurovascular Neurovascular interventionsinterventions
Acute ischemic StrokeAcute ischemic Stroke When an artery occludes neurons are affected When an artery occludes neurons are affected
differently depending upon the amount of residual blood differently depending upon the amount of residual blood flowflow
Normal cerebral blood flow is greater than 50 mL100 Normal cerebral blood flow is greater than 50 mL100 mgminmgmin
Once blood flow decreases to less than 20 mL100 Once blood flow decreases to less than 20 mL100 mgmin infarction occursmgmin infarction occurs
If blood flow decreases to less than 10 mL100 mgmin If blood flow decreases to less than 10 mL100 mgmin irreversible neuronal death occurs rapidly irreversible neuronal death occurs rapidly
Blood flow between 11 and 20 mL100 mgmin is thought Blood flow between 11 and 20 mL100 mgmin is thought to represent the ischemic penumbra an area where the to represent the ischemic penumbra an area where the cells are functionally silent because of ischemia but are cells are functionally silent because of ischemia but are still able to recover if blood flow is restored still able to recover if blood flow is restored
Many acute stroke therapies are targeted toward Many acute stroke therapies are targeted toward restoring flow or function to the ischemic penumbrarestoring flow or function to the ischemic penumbra
Therapeutic window in Therapeutic window in management of acute Ischemic management of acute Ischemic
StrokeStrokeThe early diagnosis of ischemic stroke is critical to the The early diagnosis of ischemic stroke is critical to the
with only a narrow therapeutic window in the first few with only a narrow therapeutic window in the first few hours following stroke ictushours following stroke ictus
Diagnosis in the first 3 hours postictus provides the Diagnosis in the first 3 hours postictus provides the opportunity for intravenous or intraarterial thrombolysis opportunity for intravenous or intraarterial thrombolysis and intra-arterial clot mechanical treatment which and intra-arterial clot mechanical treatment which improve the outcome improve the outcome
Diagnosis in the time period between 3 and 6 hours Diagnosis in the time period between 3 and 6 hours provides an opportunity for intra-arterial thrombolysis provides an opportunity for intra-arterial thrombolysis and mechanical treatment and mechanical treatment
Involvement of the posterior circulation especially the Involvement of the posterior circulation especially the basilar artery is treated by some regardless of time of basilar artery is treated by some regardless of time of onset or up until 12 to 24 hours in some practices This is onset or up until 12 to 24 hours in some practices This is related to the potentially high mortality and morbidity related to the potentially high mortality and morbidity associated with basilar artery thrombosisassociated with basilar artery thrombosis
Infarct evaluation on angiographyInfarct evaluation on angiography(CT angiography and catheter (CT angiography and catheter
angiography)angiography)CTA is an excellent first-line examination for CTA is an excellent first-line examination for
evaluation of the head and neck arteries evaluation of the head and neck arteries In comparison with catheter angiography In comparison with catheter angiography
what it gives up in resolution and dynamic what it gives up in resolution and dynamic properties it makes up for with rapid properties it makes up for with rapid acquisition of a 3-D dataset and the potential acquisition of a 3-D dataset and the potential for assessment of whole-brain perfusion and for assessment of whole-brain perfusion and better parenchymal evaluationbetter parenchymal evaluation
Moreover CTA illustrates not only arterial Moreover CTA illustrates not only arterial stenosis or occlusion but also the vessel wall stenosis or occlusion but also the vessel wall This factor is most important for evaluation of This factor is most important for evaluation of intramural dissection and thrombosed intramural dissection and thrombosed aneurysms which may both complicate aneurysms which may both complicate evaluation of stroke patientsevaluation of stroke patients
Early angiographic signs of strokes Early angiographic signs of strokes both CTA both CTA and DSA and DSA
Vessel occlusion or cutoff related to Vessel occlusion or cutoff related to thromboembolithromboemboli
aneurysms aneurysms arterial dissection arterial dissection Meniscus or flattened shape to clot Meniscus or flattened shape to clot
(recent) versus reverse meniscus (older)(recent) versus reverse meniscus (older) tram track (nonocclusive or recanalized tram track (nonocclusive or recanalized
clot) clot) delayed (antegrade) flow (manifest as delayed (antegrade) flow (manifest as
decreased whole-brain perfusion on CTA)decreased whole-brain perfusion on CTA) retrograde collateral flowretrograde collateral flow
Non-occlusive left MCA thrombus on 3-D imaging performed from CTA source data and was confirmed at catheter angiography
Therapy to be started within a 6-hr Therapy to be started within a 6-hr time to treatment (TTT) window time to treatment (TTT) window (while in case of IV thrombolysis (while in case of IV thrombolysis therapy to be started with in 3hrs)therapy to be started with in 3hrs)
Exclusion criteria Exclusion criteria Rapidly improving neurologic deficit or Rapidly improving neurologic deficit or Sustained blood pressure of gt180100 Sustained blood pressure of gt180100 Hemorrhage is detected on CTHemorrhage is detected on CT Infarct involving gt more than 13 rd Infarct involving gt more than 13 rd
territory of MCAterritory of MCA MRADWI-Perfusion mismatchlt 20MRADWI-Perfusion mismatchlt 20 Definite hypodensity on CTDefinite hypodensity on CT
Intra-arterial Thrombolysis
Fibrinolytics + AntiplateletsFibrinolytics + Antiplatelets
PlasminogenPlasminogen activators through fibrinolysis exposes activators through fibrinolysis exposes free thrombin and paradoxically stimulatesfree thrombin and paradoxically stimulates platelet platelet aggregation which leads to formation of aaggregation which leads to formation of a platelet platelet thrombus (white clot) thrombus (white clot)
This new thrombus is relatively resistant to This new thrombus is relatively resistant to fibrinolyticsfibrinolytics
So new regimen in case of acute stroke isSo new regimen in case of acute stroke is fibrinolytics + antiplatelet drugsfibrinolytics + antiplatelet drugs
rtPA + IIbIIIa inhibitors( tirofiban rtPA + IIbIIIa inhibitors( tirofiban abciximab) orabciximab) or
Urokinase + IIbIIIa Urokinase + IIbIIIa inhibitors( tirofiban abciximab)inhibitors( tirofiban abciximab)
Intra-arterial Thrombolysis Tirofiban (04 microgkgmin bolus for 3 min followed by Tirofiban (04 microgkgmin bolus for 3 min followed by
0125 ugkgmin)0125 ugkgmin)
++
Heparin (2000ndash3000 IU bolus followed by Heparin (2000ndash3000 IU bolus followed by 1000 IUhour infusion 1000 IUhour infusion
with ACT maintained bw 200-300) throughout the with ACT maintained bw 200-300) throughout the interventional procedure and for 24ndash48 hours thereafter when interventional procedure and for 24ndash48 hours thereafter when there is neither intraprocedural bleeding nor suspicion of there is neither intraprocedural bleeding nor suspicion of increased risk of bleeding increased risk of bleeding
Maximum dose of Urokinase Maximum dose of Urokinase Anterior circulation stroke - 500000 IU (mean 400000 Anterior circulation stroke - 500000 IU (mean 400000
IU range 300000ndash500000 IU)IU range 300000ndash500000 IU) Posterior circulation stroke -1000000 IU (mean 837000 Posterior circulation stroke -1000000 IU (mean 837000
IU range 300000ndash1000000 IU)IU range 300000ndash1000000 IU)American Journal of NeuroradiologyAmerican Journal of Neuroradiology 262595-2601 2005262595-2601 2005
Intravenous ThrombolysisIntravenous Thrombolysis
The first method to restore cerebral The first method to restore cerebral perfusion is clot lysis with the goal perfusion is clot lysis with the goal of re-establishing blood flow to the of re-establishing blood flow to the affected tissue affected tissue
IV thrombolysis rt-PA is the only IV thrombolysis rt-PA is the only FDA- approved treatment for AIS FDA- approved treatment for AIS
Fibrinolysis is enhanced powerfully Fibrinolysis is enhanced powerfully by rt-PAby rt-PA
Intravenous rTPA Intravenous rTPA administration administration protocolprotocol
Total dose of rt-PA 09 mgkg (maximum dose Total dose of rt-PA 09 mgkg (maximum dose 90 mg)90 mg)
Give 10 as initial IV bolusGive 10 as initial IV bolus Infuse remainder over 1 hourInfuse remainder over 1 hour Admit patient to an ICU or stroke unit for Admit patient to an ICU or stroke unit for
monitoringmonitoring Neurologic assessments every 15 minutes Neurologic assessments every 15 minutes
during infusion then every 30 minutes for next during infusion then every 30 minutes for next 6 hours then every hour until 24hours after 6 hours then every hour until 24hours after treatmenttreatment
Favorable Outcome vs Treatment Time Favorable Outcome vs Treatment Time with IV rTPAwith IV rTPA
Protocol limit = 3 hrs
Benefit ~ 45 hrs
Thromboembolism During coilingThromboembolism During coiling Most feared and frequent complication Most feared and frequent complication Reported incidence - Approx 7 Reported incidence - Approx 7 SourcesSources of Thromboembolism are of Thromboembolism are
- Clots at the aneurysmal neck during or immediately- Clots at the aneurysmal neck during or immediately after after embolization embolization
- Thrombus forming on catheters during- Thrombus forming on catheters during proceduresprocedures
- Stenosis of an adjacent artery dt coil mass- Stenosis of an adjacent artery dt coil mass or herniationor herniation
- Migration of intraaneurysmal- Migration of intraaneurysmal thrombus during coil thrombus during coil placement placement
- Slow flow dt vasospasm - Slow flow dt vasospasm
- Rare and unlikely causes are hypercoagulable- Rare and unlikely causes are hypercoagulable state such state such as antiphospholipid antibody syndrome or due to HITas antiphospholipid antibody syndrome or due to HIT
Occur more often with wide-necked aneurysms (dt Occur more often with wide-necked aneurysms (dt increased exposed surface area of thrombogenic coil increased exposed surface area of thrombogenic coil material)material)
Current regimen of endovascular Current regimen of endovascular managementmanagement
The The glycoprotein IIbIIIa antagonist tirofiban glycoprotein IIbIIIa antagonist tirofiban (04 (04 microgkgmin bolus for 30 minutes followed by infusion of microgkgmin bolus for 30 minutes followed by infusion of 0125 ugkgmin until the thrombus dissolved) 0125 ugkgmin until the thrombus dissolved)
Intraarterial thrombolysis with Intraarterial thrombolysis with urokinase or r- TPA urokinase or r- TPA increase of intravenous (IV) heparin (measured by increase of intravenous (IV) heparin (measured by
ACT) ACT) Intravenous aspirin Intravenous aspirin
Coil-related platelet aggregation (white clot) is Coil-related platelet aggregation (white clot) is unlikely to respond to fibrinolytics but has a high risk unlikely to respond to fibrinolytics but has a high risk of hemorrhage (In ISAT) all 5 patients who had of hemorrhage (In ISAT) all 5 patients who had received thrombolytic therapy with tPA to treat a received thrombolytic therapy with tPA to treat a thromboembolic complication after endovascular thromboembolic complication after endovascular treatment rebleed and all of these patients died)treatment rebleed and all of these patients died)
IntracranialIntracranial Stenting Stenting Metallic foreign body such as stent will accumulate Metallic foreign body such as stent will accumulate
thrombus in the absence of platelet inhibitionthrombus in the absence of platelet inhibition Antiplatelet drugs are important to prevent peri or Antiplatelet drugs are important to prevent peri or
post-interventional thromboembolic eventspost-interventional thromboembolic events Optimal treatment regimens has not been determined Optimal treatment regimens has not been determined
but usually but usually Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-
procedureprocedureOrOr
Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on
morning of proceduremorning of procedure
If need to use stent is not pre-planned thanIf need to use stent is not pre-planned than
Abciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkgAbciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkg IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)
Glycoprotein IIbIIIa inhibitor are not used routinely during elective Glycoprotein IIbIIIa inhibitor are not used routinely during elective stenting procedure dt increased risk of ICH stenting procedure dt increased risk of ICH
Carotid StentingCarotid Stenting
Pre-procedurePre-procedure
Double Antiplatelet therapy is routinely given Double Antiplatelet therapy is routinely given beginning at least 3beginning at least 3
days before the proceduredays before the procedure
Aspirin 325mgd+Clopidogrel 75mgdAspirin 325mgd+Clopidogrel 75mgd During procedureDuring procedure
Heparin is given with target clotting time of 250-Heparin is given with target clotting time of 250-300sec300sec
Post-procedure Post-procedure
Aspirin 325mg is continued indefinitely and Aspirin 325mg is continued indefinitely and
Clopidogrel 75mgd for at least 6 weeks Clopidogrel 75mgd for at least 6 weeks
Inclusion criteria for Local ThrombolysisInclusion criteria for Local Thrombolysis a)a) Patients in severe clinical grade on admission Patients in severe clinical grade on admission
with evidence of dural venous sinus with evidence of dural venous sinus thrombosis and restrictive venous outflow on thrombosis and restrictive venous outflow on cerebral angiogramcerebral angiogram
b)b) Patients in clinical grade 3 worsening on Patients in clinical grade 3 worsening on heparin therapy Restriction to venous heparin therapy Restriction to venous outflow was defined as an increase in brain outflow was defined as an increase in brain circulation time gt 12 s delay in the drainage circulation time gt 12 s delay in the drainage of cortical veins with cortical veins hanging of cortical veins with cortical veins hanging in spacein space
Treatment Options for Venous Thrombosis
CT Grading for Venous ThrombosisCT Grading for Venous Thrombosis Grade I no parenchymal change Grade I no parenchymal change
(hyperdense (hyperdense sinuses cortical veins empty sinuses cortical veins empty delta sign)delta sign)
Grade II non hemorrhagic venous infarct Grade II non hemorrhagic venous infarct without mass effect without mass effect
Grade III non-hemorrhagic infarct with Grade III non-hemorrhagic infarct with mass effectmass effect
Grade IV hemorrhagic venous infarct (max Grade IV hemorrhagic venous infarct (max diameter lt 3 cm) with no mass effectdiameter lt 3 cm) with no mass effect
Grade V hemorrhagic venous infarct (max Grade V hemorrhagic venous infarct (max diameter gt 3 cm) with mass effect diameter gt 3 cm) with mass effect
Local ThrombolysisLocal Thrombolysis
Femoral Jugular access was secured and a guiding Femoral Jugular access was secured and a guiding catheter was placed in the jugular bulb catheter was placed in the jugular bulb Mechanical Mechanical clot maceration clot maceration was done with the guidewire was done with the guidewire following which a microcatheter (was navigated and following which a microcatheter (was navigated and placed in the thrombosed segment of sinus confirmed placed in the thrombosed segment of sinus confirmed on a selective venogram on a selective venogram
Urokinase infusion Bolus dose of 2-6 lacs followed Urokinase infusion Bolus dose of 2-6 lacs followed by 60000 to 100000 units per hour along with by 60000 to 100000 units per hour along with periodic check venogram Along with maintenance periodic check venogram Along with maintenance systemic infusion of Heparinsystemic infusion of Heparin Other agents such as Other agents such as streptokinase altepase or rTPAstreptokinase altepase or rTPA can be also used can be also used
After thrombolysis patient should subjected to oral After thrombolysis patient should subjected to oral anticoagulation for six monthsanticoagulation for six months
Low-molecular-weight Low-molecular-weight heparinheparin
PharmacologyPharmacologyLMWH as its name suggests is a glycosaminoglycan that is approximatelyLMWH as its name suggests is a glycosaminoglycan that is approximately
one third the molecular weight of UFH It is derived from UFH through one third the molecular weight of UFH It is derived from UFH through variousvarious
depolymerization processes LMWH binds to antithrombin which in turn depolymerization processes LMWH binds to antithrombin which in turn
Neutralizes actors Xa and IIa Because LMWH lacks many of the longer Neutralizes actors Xa and IIa Because LMWH lacks many of the longer chains chains
required for binding to thrombin it has less ability to neutralize thrombin required for binding to thrombin it has less ability to neutralize thrombin
relativeto its ability to neutralize factor Xa LMWH also has less relativeto its ability to neutralize factor Xa LMWH also has less nonspecific nonspecific
binding to other proteins There is greater bioavailability with more binding to other proteins There is greater bioavailability with more predictable predictable
pharmacokinetics that eliminates the need for monitoring The smaller pharmacokinetics that eliminates the need for monitoring The smaller size also size also
allows for enhanced subcutaneous absorption when compared with UFHallows for enhanced subcutaneous absorption when compared with UFH
Three LMWH preparations are Three LMWH preparations are currently approved for use in the currently approved for use in the United States (1) enoxaparin (2) United States (1) enoxaparin (2) dalteparin and (3) tinzaparin dalteparin and (3) tinzaparin
They are all administered They are all administered subcutaneously at intervals of either subcutaneously at intervals of either once or twice daily for both once or twice daily for both prophylaxis and treatment dosesprophylaxis and treatment doses
Few Experiences of Few Experiences of ThrombolysisThrombolysis
Vickey 25 Yrs male patient presented Vickey 25 Yrs male patient presented with 12with 12thth day HO severe headache with day HO severe headache with right sided hemiplegiaright sided hemiplegia
MRI shows thrombosis of the superior MRI shows thrombosis of the superior sagittal left transverse left sigmoid sagittal left transverse left sigmoid sinuses and cortical veins in the fronto-sinuses and cortical veins in the fronto-parietal regions with eo haemorrhagic parietal regions with eo haemorrhagic infarct in the left cerebral hemisphere infarct in the left cerebral hemisphere with mass effect( Grade ndashV)with mass effect( Grade ndashV)
Sashi Srivastava 64 yrs FSashi Srivastava 64 yrs F In a follow up case of MRD with infra-renal In a follow up case of MRD with infra-renal
aortic abdominal and bilateral renal artery aortic abdominal and bilateral renal artery thrombosis renal angiogram shows filling thrombosis renal angiogram shows filling defects in the right Renal artery defects in the right Renal artery
Initially Renal angioplasty was done Initially Renal angioplasty was done Following angioplasty few thrombi are seem Following angioplasty few thrombi are seem to extends into the segmental branches and to extends into the segmental branches and causing blockage So Thrombolysis was causing blockage So Thrombolysis was plane to dissolve the run-out thrombi with plane to dissolve the run-out thrombi with urokinase urokinase
Rakesh 34yrsMRakesh 34yrsM Left SFA pseudoaneurysm with Left SFA pseudoaneurysm with
Covered stent placementCovered stent placement Pre operative antiplatelets with post Pre operative antiplatelets with post
procedure heparin Tirofiban procedure heparin Tirofiban followed by aspirin and clopidogrel followed by aspirin and clopidogrel were usedwere used
IAT may be a treatment option for selected patients IAT may be a treatment option for selected patients Possible selection criteria include Possible selection criteria include
presentation between 3 and 6 hours from symptom onsetpresentation between 3 and 6 hours from symptom onset major cerebral artery occlusion major cerebral artery occlusion severe neurologic deficits severe neurologic deficits high risk of systemic hemorrhage with IV rt-PA (eg recent high risk of systemic hemorrhage with IV rt-PA (eg recent
surgery) surgery) The MERCI (Mechanical Embolus Removal in Cerebral The MERCI (Mechanical Embolus Removal in Cerebral
Ischemia) retrievalIschemia) retrieval system system
Has been FDA-approved for recanalizing acutely occluded Has been FDA-approved for recanalizing acutely occluded cerebral arteries cerebral arteries
In the Multi-MERCI study patients who did not improve In the Multi-MERCI study patients who did not improve immediately after IV rt-PA underwent mechanical immediately after IV rt-PA underwent mechanical embolectomy within 8 hours of symptom onset embolectomy within 8 hours of symptom onset
Partial or complete recanalization occurred in 74 of Partial or complete recanalization occurred in 74 of patientspatients
with a symptomatic intracerebral hemorrhage (sICH) rate of with a symptomatic intracerebral hemorrhage (sICH) rate of 67 67
Mechanical embolectomy with the MERCI retriever may be a Mechanical embolectomy with the MERCI retriever may be a feasible and safe option for patients after IV rt-PAfeasible and safe option for patients after IV rt-PA
Penumbra stroke systemPenumbra stroke system This device combines two methods of clot This device combines two methods of clot
extraction aspiration and mechanical extraction aspiration and mechanical extraction extraction
First the clot is aspirated then a thrombus First the clot is aspirated then a thrombus removal ring can be used if necessary to removal ring can be used if necessary to remove remaining clot remove remaining clot
successful recanalizing 82successful recanalizing 82 Bridging therapyBridging therapy
06 mgkg IV rt-PA followed by IAT with IA rt-06 mgkg IV rt-PA followed by IAT with IA rt-PA (up to 20 mg)PA (up to 20 mg)
achieved a higher recanalization rateachieved a higher recanalization rate
Criteria for thrombolysis with rTPACriteria for thrombolysis with rTPA
Inclusion criteriaInclusion criteria Clinical signs and symptoms consistent with ischemic Clinical signs and symptoms consistent with ischemic
strokestroke Patient last seen normal within 3 hoursPatient last seen normal within 3 hours Measurable neurologic deficitMeasurable neurologic deficit
Exclusion criteriaExclusion criteria Any hemorrhage on neuroimaging (CT or MRI)Any hemorrhage on neuroimaging (CT or MRI) Symptoms suggestive of subarachnoid hemorrhageSymptoms suggestive of subarachnoid hemorrhage Seizure at stroke onset that is thought to contribute to Seizure at stroke onset that is thought to contribute to
neurologic deficitneurologic deficit Hypodensity greater than one third cerebral hemisphere Hypodensity greater than one third cerebral hemisphere
on CTon CT SBP greater than 185 mm Hg or DBP greater than 110 SBP greater than 185 mm Hg or DBP greater than 110
mm Hgmm Hg International normalized ratio (INR) greater than 17International normalized ratio (INR) greater than 17
Ischemic Stroke Ischemic Stroke Treatment ndash 2006Treatment ndash 2006
IV tissue plasminogen activator (tPA)IV tissue plasminogen activator (tPA) ndash ndash Only FDA-approved acute stroke drugOnly FDA-approved acute stroke drug ndash ndash 3 hour treatment window3 hour treatment window
MERCI - Concentric clot retrieval MERCI - Concentric clot retrieval devicedevice ndash ndash Rescue therapy - approved 2004Rescue therapy - approved 2004 ndash ndash Device approval (not outcomes-based)Device approval (not outcomes-based)
Off label approachesOff label approaches ndash ndash IV tPA after 3 hoursIV tPA after 3 hours ndash ndash IV-IA tPA sequential strategiesIV-IA tPA sequential strategies ndash ndash IA tPA clot angioplasty fragmentationIA tPA clot angioplasty fragmentation ndash ndash Ultrasound-assisted tPA lysisUltrasound-assisted tPA lysis
rt-PA Trials NINDSrt-PA Trials NINDS
Acute stroke - 624 patientsAcute stroke - 624 patients Treat within 3 hrsTreat within 3 hrs Intravenous 09 mgkg rt-PA vs placeboIntravenous 09 mgkg rt-PA vs placebo Hemorrhage 64 tPA 06 placeboHemorrhage 64 tPA 06 placebo Neurologic recovery better with tPA 30 Neurologic recovery better with tPA 30
more like to have minimal or no disabilitymore like to have minimal or no disability
First proven approved treatment for First proven approved treatment for strokestroke
Limitations of tPALimitations of tPA Only 4 of acute strokes receive tPAOnly 4 of acute strokes receive tPA (Kleindorfer et al Stroke 2004 35 e27-e29)(Kleindorfer et al Stroke 2004 35 e27-e29)
Only 22 of patients present within 3 hoursOnly 22 of patients present within 3 hours1048707 1048707 51 of these ineligible due to51 of these ineligible due to
bull bull Mild severityMild severity bull bull Medical or surgical historyMedical or surgical history bull bull Blood testsBlood tests
Sustained recanalization only 13Sustained recanalization only 13 (Alexandrov et al NEJM 2004 351 2170-8)(Alexandrov et al NEJM 2004 351 2170-8)
Concern for hemorrhageConcern for hemorrhage tPA potentiates apoptotic injury tPA potentiates apoptotic injury (Liu et al Nature Med 2004 101379-83)(Liu et al Nature Med 2004 101379-83)
PROACT II IA Lysis TrialPROACT II IA Lysis Trial Baseline 24 hours 8 days
Baseline 60 minutes 120 minutes
9mg IAProurokinase
Desmoteplase Trials DEDAS Desmoteplase Trials DEDAS DIASDIAS
Trial OverviewTrial Overview Double blind randomized placebo Double blind randomized placebo
controlled trialscontrolled trials IV delivery 3-9 hour time windowIV delivery 3-9 hour time window Plasminogen activator ndash from Plasminogen activator ndash from vampire bat vampire bat
salivasaliva Selection based on PWI-DWI MismatchSelection based on PWI-DWI Mismatch
MRI InclusionMRI Inclusion PWI defect at least 2 cm AND ~20 larger PWI defect at least 2 cm AND ~20 larger
than DWIthan DWI PWI should be obvious even visible on PWI should be obvious even visible on
raw imagesraw imagesMRI ExclusionMRI Exclusion
DWI gt 13 MCADWI gt 13 MCA MRA ICA occlusionMRA ICA occlusion
Desmoteplase ndash DIAS Desmoteplase ndash DIAS ResultsResults
Mechanical Thrombolysis Mechanical Thrombolysis devicesdevices
mechanical thrombolysis potentially extends the treatment mechanical thrombolysis potentially extends the treatment window because they act promptly at the site of the thrombuswindow because they act promptly at the site of the thrombus
The devices can retrieve large clots that pharmaceutical agents The devices can retrieve large clots that pharmaceutical agents may not successfully lysemay not successfully lyse
Patients treated with IV tPA may be considered for treatment of Patients treated with IV tPA may be considered for treatment of residual clot with some of these devicesresidual clot with some of these devices
suction-creating saline jets suction-creating saline jets laser energy ultrasound laser energy ultrasound a corkscrew apparatus to treat strokesa corkscrew apparatus to treat strokes The AngioJet systemThe AngioJet system uses saline jets that are directed back into the catheter to uses saline jets that are directed back into the catheter to
create a low-pressure zone around the catheter tip inducing create a low-pressure zone around the catheter tip inducing suction suction
The clot is pulled into the exhaust lumen and removed from the The clot is pulled into the exhaust lumen and removed from the vessel Although US Food and Drug Administration (FDA) has vessel Although US Food and Drug Administration (FDA) has approved this device for use in arteriovenous dialysis grafts and approved this device for use in arteriovenous dialysis grafts and fistulae and for the treatment of coronary arteries saphenous fistulae and for the treatment of coronary arteries saphenous vein grafts and peripheral vessels clinical trials for the vein grafts and peripheral vessels clinical trials for the treatment of acute stroke are no longer in progress treatment of acute stroke are no longer in progress
Most devices are used in cerebral vessels that 2-5 mm
The Latis laser device The Latis laser device used laser energy to ablate clots used laser energy to ablate clots Arteries 2-5 mm in diameter could be Arteries 2-5 mm in diameter could be
treated including the ICA M1 or M2 treated including the ICA M1 or M2 branch of the MCA A1 branch of the branch of the MCA A1 branch of the anterior cerebral artery (ACA) basilar anterior cerebral artery (ACA) basilar artery posterior cerebral artery (PCA) artery posterior cerebral artery (PCA) and vertebral and vertebral
Patients could receive treatment as late Patients could receive treatment as late as 8 hours after symptom onset in the as 8 hours after symptom onset in the anterior circulation and within 24 hours in anterior circulation and within 24 hours in the posterior circulation the posterior circulation
Endovascular Photo Acoustic Endovascular Photo Acoustic Recanalization (EPAR) Recanalization (EPAR)
A laser power source generated energy for the A laser power source generated energy for the systemsystem
The energy was delivered by means of The energy was delivered by means of fiberoptics to the tip of the catheter at the fiberoptics to the tip of the catheter at the treatment sitetreatment site
Absorption of laser light by darkly pigmented Absorption of laser light by darkly pigmented materials (ie the clot) occurred inside the 1-mm materials (ie the clot) occurred inside the 1-mm catheter tipcatheter tip
the system was designed to minimize scattering the system was designed to minimize scattering of laser light of laser light
Absorption converted photo energy to acoustic Absorption converted photo energy to acoustic energy which then emulsified the clot inside the energy which then emulsified the clot inside the catheter tip catheter tip
EKOS ultrasound( the EKOS ultrasound( the Ultrasound Thrombolytic Ultrasound Thrombolytic
Infusion Catheter) Infusion Catheter) combines the use of a distal ultrasound transducer with combines the use of a distal ultrasound transducer with
infusion of a thrombolytic agent through the infusion of a thrombolytic agent through the microcathetermicrocatheter
Ultrasound changes the structure of the clot to Ultrasound changes the structure of the clot to temporarily increase its permeability while providing an temporarily increase its permeability while providing an acoustic pressure gradient to move the drug into the clot acoustic pressure gradient to move the drug into the clot to speed its dissolution to speed its dissolution
The EKOS catheter is placed in the proximal portion of the The EKOS catheter is placed in the proximal portion of the clot clot
After a 2-mg bolus of tPA was injected through the After a 2-mg bolus of tPA was injected through the catheter catheter
the patient received a continuous infusion of IA tPA 03 the patient received a continuous infusion of IA tPA 03 mgmin to a maximum of 20 mg and simultaneous mgmin to a maximum of 20 mg and simultaneous ultrasound transmission for as long as 60 minutes ultrasound transmission for as long as 60 minutes
One patient was treated with a total of 4 units of One patient was treated with a total of 4 units of recombinant reteplase (Retavase) hand-injected over 60 recombinant reteplase (Retavase) hand-injected over 60 minutes minutes
Penumbra system Penumbra system The Penumbra system (Penumbra Inc) provides a dual The Penumbra system (Penumbra Inc) provides a dual
approach to clot extraction using aspiration followed by approach to clot extraction using aspiration followed by clot retrieval with a ring device if needed clot retrieval with a ring device if needed
Mechanical Embolus Removal in Cerebral Ischemia Mechanical Embolus Removal in Cerebral Ischemia (MERCI)(MERCI)
a corkscrew-like apparatus to remove blood clots from a corkscrew-like apparatus to remove blood clots from the brain in patients experiencing an ischemic stroke the brain in patients experiencing an ischemic stroke
The corkscrew itself resides in the catheter tip which The corkscrew itself resides in the catheter tip which shields it from the wall of the vessel until it is ready to be shields it from the wall of the vessel until it is ready to be burrowed into the clot Once lodged in the clot the device burrowed into the clot Once lodged in the clot the device and clot are withdrawn from the vessel and clot are withdrawn from the vessel
Snarelike devicesSnarelike devices Snares such as the Neuronet snare (Guidant Snares such as the Neuronet snare (Guidant
Endovascular Santa Clara CA) have been developed Endovascular Santa Clara CA) have been developed specifically for use in the treatment of strokes specifically for use in the treatment of strokes
These devices are simple in design and do not require the These devices are simple in design and do not require the clot to be amenable to emulsification clot to be amenable to emulsification
X-Sizer deviceX-Sizer device a device with small moving blades at the a device with small moving blades at the
catheter tip catheter tip This device the X-Sizer device (EndiCor Medical This device the X-Sizer device (EndiCor Medical
San Clemente CA) can be used to excise the San Clemente CA) can be used to excise the thrombus and aspirate it thrombus and aspirate it
The device was being evaluated in randomized The device was being evaluated in randomized studies of coronary vessels and in a registry of studies of coronary vessels and in a registry of patients with acute myocardial infarctionpatients with acute myocardial infarction
Although the manufacturer had modified the Although the manufacturer had modified the device for use in cerebral vessels a safety and device for use in cerebral vessels a safety and feasibility study was indefinitely suspended after feasibility study was indefinitely suspended after only 1 patient was treated with the device in only 1 patient was treated with the device in Europe Europe
Suction thrombectomySuction thrombectomy This method of mechanical thrombolysis is one of the This method of mechanical thrombolysis is one of the
simplestsimplest In this readily available technique suction is applied with In this readily available technique suction is applied with
a syringe to remove thrombus in the ICA a syringe to remove thrombus in the ICA It requires no other devicesIt requires no other devices A catheter with a large inner diameter (Brite Tip Cordis A catheter with a large inner diameter (Brite Tip Cordis
Corporation Miami FL) was placed in the symptomatic Corporation Miami FL) was placed in the symptomatic vessel and navigated over a guidewire into the thrombusvessel and navigated over a guidewire into the thrombus
A 60-mL syringe was used to aspirate the thrombus A 60-mL syringe was used to aspirate the thrombus Each patient required angioplasty and stenting of carotid Each patient required angioplasty and stenting of carotid
bifurcation stenosis and received daily aspirin and bifurcation stenosis and received daily aspirin and ticlopidine after the procedure No complications ticlopidine after the procedure No complications occurred occurred
Summary Acute Stroke Summary Acute Stroke ImagingImaging
PhysiologyPhysiology importance collaterals importance collaterals
ndash ndashGrowing role for perfusion Growing role for perfusion assessmentassessment
tPAtPA guidelines amp limitations guidelines amp limitations Signs on CT amp MRSigns on CT amp MR follow physiology follow physiology Stroke trialsStroke trials PWI-DWI mismatch PWI-DWI mismatch
ndash ndashTreat based on physiology not timeTreat based on physiology not time ProtocolsProtocols should be fast and should be fast and
comprehensivecomprehensive
OPTIMIZING WARFARIN THERAPYOPTIMIZING WARFARIN THERAPY
Use of large loading dose may lead to hemorrhage and Use of large loading dose may lead to hemorrhage and other complicationsother complications
Initial dose 2-5 mg once dailyInitial dose 2-5 mg once daily Maintenance dose 2-10 mg once dailyMaintenance dose 2-10 mg once daily If Immediate anticoagulation is requiredIf Immediate anticoagulation is required Heparin IS Heparin IS
started along with loading dose of warfarin 10 mg started along with loading dose of warfarin 10 mg Heparin is usually discontinued after 4-5 days Heparin is usually discontinued after 4-5 days Before Before discontinuing INR should be in therapeutic range for 2 discontinuing INR should be in therapeutic range for 2 consecutive daysconsecutive days
Daily monitoring of INR until INR is in therapeutic Daily monitoring of INR until INR is in therapeutic range then 3 times weekly for 1-2 weeks then less often range then 3 times weekly for 1-2 weeks then less often (every 4 to 6 weeks)(every 4 to 6 weeks)
OPTIMAL THERAPEUTIC RANGEOPTIMAL THERAPEUTIC RANGE
IndicationIndication INRINR
Prophylaxis of venous Prophylaxis of venous thromboembolismthromboembolism
20-3020-30
Treatment of venous Treatment of venous thromboembolismthromboembolism
20-3020-30
Atrial fibrillationAtrial fibrillation 20-3020-30
Mitral valve stenosisMitral valve stenosis 20-3020-30
Heart valve replacementHeart valve replacement
Bioprosthetic valveBioprosthetic valve
Mechanical valveMechanical valve
20-3020-30
25-3525-35
Myocardial infarctionMyocardial infarction 20-3020-30
25-35 25-35 (high risk patients)(high risk patients)
FACTORS INFLUENCING DOSE RESPONSEFACTORS INFLUENCING DOSE RESPONSE
Poor patient compliancePoor patient compliance Concomitant medicationsConcomitant medications Levels of dietary vitamin KLevels of dietary vitamin K Alcohol Inaccurate lab testingAlcohol Inaccurate lab testing Inaccurate lab testingInaccurate lab testing Hepatic dysfunctionHepatic dysfunction FeverFever
Contraindication for WarfarinContraindication for Warfarin
Hypersensitivity to warfarinHypersensitivity to warfarin Hemorrhagic tendencyHemorrhagic tendency Condition with risk of hemorrhageCondition with risk of hemorrhage Inadequate laboratory techniquesInadequate laboratory techniques Protein C amp S deficiencyProtein C amp S deficiency Vitamin K deficiencyVitamin K deficiency
SIDE EFFECTSSIDE EFFECTS
Hemorrhage Hemorrhage Skin necrosisSkin necrosis Purple toe syndromePurple toe syndrome Microembolization Microembolization TeratogenecityTeratogenecity Agranulocytosis leukopenia Agranulocytosis leukopenia Diarrhoeanausea anorexiaDiarrhoeanausea anorexia
MONITORING OF WARFARIN THERAPYMONITORING OF WARFARIN THERAPY
Prothrombin timeProthrombin time PT ratioPT ratio INR (International Normalized Ratio)INR (International Normalized Ratio)
PROTHROMBIN TIME (PT)PROTHROMBIN TIME (PT)
Time required for blood to coagulate Time required for blood to coagulate is called PT ( normal value ~10sec)is called PT ( normal value ~10sec)
Performed by adding a mixture of Performed by adding a mixture of calcium and thromboplastin to calcium and thromboplastin to citrated plasmacitrated plasma
As a control a normal blood sample is As a control a normal blood sample is tested continuouslytested continuously
PT ratio (PTR) = PT ratio (PTR) = Patientrsquos PTPatientrsquos PT Control PTControl PT
PROBLEMS WITH PTPTRPROBLEMS WITH PTPTR
Thromboplastins are extracts from Thromboplastins are extracts from brain lung or placenta of animalsbrain lung or placenta of animals
Thromboplastins from various Thromboplastins from various manufacturers differ in their manufacturers differ in their sensitivity to prolong PTsensitivity to prolong PT
May result in false control of May result in false control of anticoagulant therapyanticoagulant therapy
INTERNATIONAL NORMALISED RATIO (INR)INTERNATIONAL NORMALISED RATIO (INR)
International Normalized Ratio (INR) International Normalized Ratio (INR) a PT test with a a PT test with a formula based ratio to normalize the often variable source formula based ratio to normalize the often variable source of tissue factor (human rabbit recombinant)of tissue factor (human rabbit recombinant)
INR = [PTINR = [PTptpt] ] ISIISI
[PT[PTRefRef]]
PTPTpt pt ndash prothrombin time of patientndash prothrombin time of patient
PTPTRef Ref ndash prothrombin time of normal pooled samplendash prothrombin time of normal pooled sample
ISI ndash International Sensitivity IndexISI ndash International Sensitivity Index
Warfarin is given orally and titrated to achieve an INR of Warfarin is given orally and titrated to achieve an INR of typically 20 ndash 30typically 20 ndash 30
Heparin versus WarfarinHeparin versus Warfarin
Drug ActionMechan-ism
Moni-toring
Effective
HeparinDirect
Inhibition ofThrombin
ATIIIcofactor
APTTACT
Immediate
WarfarinDecreasesProductionof factors
Vitamin K PTDelay
3-5 days
INR
Recanalization or Antegrade Recanalization or Antegrade Reperfusion StrategiesReperfusion Strategies
Recanalization strategies focus on removing Recanalization strategies focus on removing andor dissolving the occlusive thrombus to re-andor dissolving the occlusive thrombus to re-establish antegrade flow Strategies may be establish antegrade flow Strategies may be classified into 7 different categories on the classified into 7 different categories on the basis of their primary mechanism of action basis of their primary mechanism of action 1) 1) IV andor intraarterial thrombolysis (IAT) IV andor intraarterial thrombolysis (IAT) 2) endovascular thrombectomy2) endovascular thrombectomy3) endovascular thromboaspiration 3) endovascular thromboaspiration 4) endovascular mechanical thrombus disruption or 4) endovascular mechanical thrombus disruption or
thromborrhexisthromborrhexis5) 5) transcranial or endovascular augmented transcranial or endovascular augmented
fibrinolysis fibrinolysis 6) endovascular thrombus entrapment and 6) endovascular thrombus entrapment and 7) temporary endovascular bypass7) temporary endovascular bypass
IAT in Acute Ischemic StrokeIAT in Acute Ischemic Stroke
IAT advantages over IV thrombolysisIAT advantages over IV thrombolysis Coaxial microcatheter techniques the occluded intracranial Coaxial microcatheter techniques the occluded intracranial
vessel is directly accessible and the fibrinolytic agent can be vessel is directly accessible and the fibrinolytic agent can be infused directly into the thrombusinfused directly into the thrombus
This permits a smaller dose of fibrinolytic agent to reach a This permits a smaller dose of fibrinolytic agent to reach a higher local concentration than that reached by systemic higher local concentration than that reached by systemic infusioninfusion
Allows more complete recanalization with lower total doses of Allows more complete recanalization with lower total doses of thrombolytic thrombolytic
With the smaller dose complications from systemic fibrinolytic With the smaller dose complications from systemic fibrinolytic effects including intracranial hemorrhage (ICH) can effects including intracranial hemorrhage (ICH) can theoretically be reduced theoretically be reduced
Treatment window for endovascular techniques can be Treatment window for endovascular techniques can be extended beyond the typical IV window of 3 hours extended beyond the typical IV window of 3 hours
IA techniques have led to higher recanalization rates than IV IA techniques have led to higher recanalization rates than IV thrombolysisthrombolysis
Major disadvantagesMajor disadvantages Relative complexity of the procedure the level Relative complexity of the procedure the level
of required technical expertise and its of required technical expertise and its relatively low availability relatively low availability
Delays in initiating treatmentDelays in initiating treatment InvasiveInvasive
ThrombolyticsThrombolytics
Plasminogen activators
Fibrinolytics
1 Plasminogen Activators 1 Plasminogen Activators drugs act by converting the inactive proenzyme drugs act by converting the inactive proenzyme plasminogen into the active enzyme plasmin Plasmin plasminogen into the active enzyme plasmin Plasmin digests fibrinogen fibrin monomers and cross-linked digests fibrinogen fibrin monomers and cross-linked fibrin (as found in a thrombus) into fibrin degradation fibrin (as found in a thrombus) into fibrin degradation productsproducts
First-Generation Agents First-Generation Agents StreptokinaseStreptokinase a protein derived from group C a protein derived from group C
szlig-hemolytic streptococci has a half-life of 16ndashszlig-hemolytic streptococci has a half-life of 16ndash90 minutes and low fibrin specificity This drug 90 minutes and low fibrin specificity This drug proved to have a very narrow therapeutic proved to have a very narrow therapeutic window and significant rates of ICH and window and significant rates of ICH and systemic hemorrhage18systemic hemorrhage18
UrokinaseUrokinase is a serine protease with a plasma is a serine protease with a plasma half life of 14 minutes and low fibrin specificity half life of 14 minutes and low fibrin specificity
The urokinase dose used in cerebral IAT has The urokinase dose used in cerebral IAT has ranged from 002 to 2 X106unitsranged from 002 to 2 X106units
Second-Generation Agents Second-Generation Agents Alteplase (rtPA) Alteplase (rtPA)
is a serine is a serine protease with a plasma half-life of 35 protease with a plasma half-life of 35 minutes and a high degree of fibrin affinity and minutes and a high degree of fibrin affinity and specificity specificity
Dose used in cerebral IAT has ranged between 20 Dose used in cerebral IAT has ranged between 20 and 60 mgand 60 mg
Disadvantages of alteplase include its relatively short Disadvantages of alteplase include its relatively short halflife and limited penetration into the clot matrix halflife and limited penetration into the clot matrix because of strong binding with surface fibrin which because of strong binding with surface fibrin which could delay recanalization and increase the risk of could delay recanalization and increase the risk of recurrent occlusion recurrent occlusion
Prourokinase (r-prourokinase) Prourokinase (r-prourokinase) is the proenzyme precursor of urokinase is the proenzyme precursor of urokinase T12 of 7 minutes and high fibrin specificity T12 of 7 minutes and high fibrin specificity
Third-Generation AgentsThird-Generation Agents
ReteplaseReteplase is a structurally modified is a structurally modified form of alteplase form of alteplase
with a longer half-life (15ndash18 minutes) In with a longer half-life (15ndash18 minutes) In addition it does not bind as highly to fibrin addition it does not bind as highly to fibrin unbound reteplase can thus theoretically better unbound reteplase can thus theoretically better penetrate the clot and potentially penetrate the clot and potentially improve in improve in vivo fibrinolytic activity vivo fibrinolytic activity
TenecteplaseTenecteplase is another modified form of rtPA with a longer is another modified form of rtPA with a longer
half-life (17 minutes)half-life (17 minutes) greater fibrin specificity and greater greater fibrin specificity and greater
resistance to plasminogen activator inhibitor-1 resistance to plasminogen activator inhibitor-1 IV tenecteplase in acute ischemic stroke IV tenecteplase in acute ischemic stroke
suggest that the drug is safe and promisingsuggest that the drug is safe and promising
Newer plasminogen activatorNewer plasminogen activator
DesmoteplaseDesmoteplase is a genetically engineered is a genetically engineered version of the clot-dissolving factor version of the clot-dissolving factor
found in the saliva found in the saliva of the vampire bat Desmodus rotundusof the vampire bat Desmodus rotundus moremore potent and more selective for fibrin-bound potent and more selective for fibrin-bound
plasminogen than any other known plasminogen plasminogen than any other known plasminogen activatoractivator
Unlike tissue plasminogen activator (tPA) desmoteplase Unlike tissue plasminogen activator (tPA) desmoteplase is not activated by fibrinogen or -amyloid proteins is not activated by fibrinogen or -amyloid proteins factors that may exacerbate the risk for ICH factors that may exacerbate the risk for ICH
The effect of IV administration of desmoteplase 3ndash9 The effect of IV administration of desmoteplase 3ndash9 hours after symptom onset in patients with stroke who hours after symptom onset in patients with stroke who present with mismatch on MR imaging or CT perfusion present with mismatch on MR imaging or CT perfusion
3 DefibrinogenatingFibrinogenolytic 3 DefibrinogenatingFibrinogenolytic Agents Agents
AncrodAncrod(Viprinex)(Viprinex) is is the purified fraction of the Malayan pit viper venomthe purified fraction of the Malayan pit viper venom It acts by directly cleaving and inactivating fibrinogen It acts by directly cleaving and inactivating fibrinogen
and thus indirectly promoting anticoagulation and thus indirectly promoting anticoagulation The reduction in the blood levels of fibrinogen also The reduction in the blood levels of fibrinogen also
leads to a reduced blood viscosity which may improve leads to a reduced blood viscosity which may improve blood flow to the affected areas of the brain blood flow to the affected areas of the brain
In the Stroke Treatment with Ancrod Trial 500 In the Stroke Treatment with Ancrod Trial 500 patients with stroke presenting within 3 hours of patients with stroke presenting within 3 hours of symptom onset were randomized to receive ancrod (symptom onset were randomized to receive ancrod (n n 248) or a placebo (n 252) Good outcome (Barthel 248) or a placebo (n 252) Good outcome (Barthel Index 95ndash100 at 3 months) was achieved in 4221 Index 95ndash100 at 3 months) was achieved in 4221 and 344 of the patients respectively and 344 of the patients respectively
2 Direct Fibrinolytics2 Direct Fibrinolytics
Microplasmin (Microplasmin (ThromboGenics Heverlee Belgium)ThromboGenics Heverlee Belgium) is a truncated form of plasmin that is more resistant to the effects is a truncated form of plasmin that is more resistant to the effects
of antiplasmin of antiplasmin microplasmin can be used upto 4ndash12 hours after stroke onset microplasmin can be used upto 4ndash12 hours after stroke onset There was no evidence of increased bleeding risk with There was no evidence of increased bleeding risk with
microplasminmicroplasmin
Alfimeprase (Nuvelo San Carlos Calif)Alfimeprase (Nuvelo San Carlos Calif) is a recombinant truncated form of fibrolase a fibrinolytic zinc metalloproteinase is a recombinant truncated form of fibrolase a fibrinolytic zinc metalloproteinase
isolated from the venom of the southern copperhead snake isolated from the venom of the southern copperhead snake It degrades fibrin directly and achieves thrombolysis independent It degrades fibrin directly and achieves thrombolysis independent
of plasmin formationof plasmin formation its thrombolytic activity appears to be localized to the site of its thrombolytic activity appears to be localized to the site of
delivery These properties should theoretically result in faster delivery These properties should theoretically result in faster recanalization and lower hemorrhagic conversion riskrecanalization and lower hemorrhagic conversion risk
Anti-fibrinolyticsAnti-fibrinolytics
to limit fibrinolytic activityto limit fibrinolytic activity -aminocaproic acid (EACA) -aminocaproic acid (EACA) competitively inhibitscompetitively inhibits plasminogen and plasminogen activators from plasminogen and plasminogen activators from
binding to fibrinbinding to fibrin
alpha2-antiplasminalpha2-antiplasmin a serine protease inhibitor that a serine protease inhibitor that neutralizes any free circulating plasminneutralizes any free circulating plasmin
Plasminogen activator inhibitor-1Plasminogen activator inhibitor-1 a serine protease a serine protease inhibitor that inhibits tissue-type plasminogen inhibitor that inhibits tissue-type plasminogen activatoractivator
Glycoprotein (GP) IIbIIIa antagonistsGlycoprotein (GP) IIbIIIa antagonists
such as ReoPro (abciximab) Integrilin such as ReoPro (abciximab) Integrilin (eptifibatide) or Aggrastat (tirofiban) in (eptifibatide) or Aggrastat (tirofiban) in ischemic stroke remains investigational ischemic stroke remains investigational Deshmukh et al38 reported 21 patients with Deshmukh et al38 reported 21 patients with large-vessel occlusion refractory to IAT with large-vessel occlusion refractory to IAT with rtPA who were treated with IV andor IA rtPA who were treated with IV andor IA abciximab eptifibatide or tirofiban abciximab eptifibatide or tirofiban
IA Mechanical Approaches in Acute Ischemic Stroke IA Mechanical Approaches in Acute Ischemic Stroke Mechanical strategies have several advantagesMechanical strategies have several advantages First they lessen and may even preclude the use of chemical First they lessen and may even preclude the use of chemical
thrombolytics in this manner very likely reducing the risk of ICHthrombolytics in this manner very likely reducing the risk of ICH Second by avoiding the use of chemical thrombolytics it is Second by avoiding the use of chemical thrombolytics it is
possible to extend the treatment window beyond the limit of 6ndash8 possible to extend the treatment window beyond the limit of 6ndash8 hours hours
Third mechanically fragmenting a clot increases the surface area Third mechanically fragmenting a clot increases the surface area accessible to fibrinolytic agents and allows inflow of fresh accessible to fibrinolytic agents and allows inflow of fresh plasminogen which in turn may increase the speed of plasminogen which in turn may increase the speed of thrombolysis thrombolysis
Finally clot-retrieval devices may provide faster recanalization Finally clot-retrieval devices may provide faster recanalization
The disadvantages of the mechanical The disadvantages of the mechanical approaches approaches technical difficulty of navigating mechanical technical difficulty of navigating mechanical
devices into the intracranial circulation excessive devices into the intracranial circulation excessive trauma to the vasculature (potentially leading to trauma to the vasculature (potentially leading to vasospasm vessel dissection perforation or vasospasm vessel dissection perforation or rupture) rupture)
fragmented thrombus causing distal embolization fragmented thrombus causing distal embolization into previously unaffected territories into previously unaffected territories
Nevertheless the advantages of mechanical stroke Nevertheless the advantages of mechanical stroke therapy appear to significantly outweigh its therapy appear to significantly outweigh its disadvantages and risksdisadvantages and risks
Contraindications to Thrombolytic Contraindications to Thrombolytic agents agents
Recent thoracic abdominal or Recent thoracic abdominal or intracranial surgeryintracranial surgery
Recent haemorrhagic CVA Head injury Recent haemorrhagic CVA Head injury or neoplasmor neoplasm
Bleeding ulcerBleeding ulcer Anticipated invasive procedures (arterial Anticipated invasive procedures (arterial
punctures biopsies)punctures biopsies) Concurrent hemostatic dysfunctionConcurrent hemostatic dysfunction
Monitoring of thrombolytic Monitoring of thrombolytic therapytherapy
Thrombin time Measures the availability of functional
fibrinogen Normal thrombin time is 10-14 sec Prolonged when fibrinogen level is below
75-100 mgdl
Half Life of ThrombolyticsHalf Life of ThrombolyticsAgent Administration Half Life
Streptokinase IA 60-80min
Urokinase IAIV 9-12min
rTPA IAIV 6min
Abciximab(Reopro) IAIV 12hour
Aspirin POIV 15-20min
Heparin IVSC 60min
Coumadin PO 15-25 days
Anti Platelet DrugsAnti Platelet DrugsDrug Drug Mechanism Mechanism UsesUsesAspirinAspirin Permanently inhibits Permanently inhibits
COX-1 and COX-2COX-1 and COX-2CADCAD
Stroke-TIAsStroke-TIAs
NSAIDsNSAIDs Reversibly inhibits Reversibly inhibits COX-1COX-1
LimitedLimited
DipyridamoleDipyridamole Inhibits PDE increases Inhibits PDE increases cAMPcAMP
TIAsTIAs
ThenopyridinesThenopyridines
(Ticlopidine(Ticlopidine
ClopidrgrelClopidrgrel))
Inhibits ADP Inhibits ADP
PlatAg PlatAg
TIAsStrokeTIAsStroke
CAD PVDCAD PVD
Abciximab (ReoPro)Abciximab (ReoPro)
Eptifibatide (Integrilin)Eptifibatide (Integrilin)
TirofibanTirofiban
GP IIBIIIA InhibitorsGP IIBIIIA Inhibitors
Stroke- TIAs Stroke- TIAs
MonitoringMonitoring
Bleeding timeBleeding time
Optical aggregometryOptical aggregometry
Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay
Bleeding timeBleeding time
Requires a skin incision (usually made on the ear lobe or Requires a skin incision (usually made on the ear lobe or forearm offorearm of
a depth that results in disruption of capillary loops and a depth that results in disruption of capillary loops and small vessels)small vessels)
AdvantagesAdvantages Universally availableUniversally available Relatively simple techniquesRelatively simple techniques Can be performed bedsideCan be performed bedside
DisadvantagesDisadvantages Insensitive inaccurate non-specific techniqueInsensitive inaccurate non-specific technique
Poorly reproducible (as depends on multiple variables)Poorly reproducible (as depends on multiple variables)
Optical aggregometryOptical aggregometry
Gold standard assay for platelet functionGold standard assay for platelet function Agonist induced aggregation is measuredAgonist induced aggregation is measured Different agonist are available for different Different agonist are available for different
agentsagents However require unique expertise and are not However require unique expertise and are not
universally availableuniversally available Aspirin measured with ADP or AA(gt70 Aspirin measured with ADP or AA(gt70
aggregation so resistance)aggregation so resistance) Clopidogrel( ADP gt 90 aggregation means Clopidogrel( ADP gt 90 aggregation means
resistance) resistance)
Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay
Can be performed bed sideCan be performed bed side Different assay devices with different Different assay devices with different
agonist are used for each of different agonist are used for each of different antiplatelet agents antiplatelet agents
For Aspirin AA is used (result is reported as aspirin For Aspirin AA is used (result is reported as aspirin reaction units [ARU] ARUgt 550 indicates non-reaction units [ARU] ARUgt 550 indicates non-responsiveness)responsiveness)
Verify IIbIIIa assay device uses TRAP as agonist for Verify IIbIIIa assay device uses TRAP as agonist for Abciximab and TirofibanAbciximab and Tirofiban
Practical Applications Practical Applications related to specific related to specific
Neurovascular Neurovascular interventionsinterventions
Acute ischemic StrokeAcute ischemic Stroke When an artery occludes neurons are affected When an artery occludes neurons are affected
differently depending upon the amount of residual blood differently depending upon the amount of residual blood flowflow
Normal cerebral blood flow is greater than 50 mL100 Normal cerebral blood flow is greater than 50 mL100 mgminmgmin
Once blood flow decreases to less than 20 mL100 Once blood flow decreases to less than 20 mL100 mgmin infarction occursmgmin infarction occurs
If blood flow decreases to less than 10 mL100 mgmin If blood flow decreases to less than 10 mL100 mgmin irreversible neuronal death occurs rapidly irreversible neuronal death occurs rapidly
Blood flow between 11 and 20 mL100 mgmin is thought Blood flow between 11 and 20 mL100 mgmin is thought to represent the ischemic penumbra an area where the to represent the ischemic penumbra an area where the cells are functionally silent because of ischemia but are cells are functionally silent because of ischemia but are still able to recover if blood flow is restored still able to recover if blood flow is restored
Many acute stroke therapies are targeted toward Many acute stroke therapies are targeted toward restoring flow or function to the ischemic penumbrarestoring flow or function to the ischemic penumbra
Therapeutic window in Therapeutic window in management of acute Ischemic management of acute Ischemic
StrokeStrokeThe early diagnosis of ischemic stroke is critical to the The early diagnosis of ischemic stroke is critical to the
with only a narrow therapeutic window in the first few with only a narrow therapeutic window in the first few hours following stroke ictushours following stroke ictus
Diagnosis in the first 3 hours postictus provides the Diagnosis in the first 3 hours postictus provides the opportunity for intravenous or intraarterial thrombolysis opportunity for intravenous or intraarterial thrombolysis and intra-arterial clot mechanical treatment which and intra-arterial clot mechanical treatment which improve the outcome improve the outcome
Diagnosis in the time period between 3 and 6 hours Diagnosis in the time period between 3 and 6 hours provides an opportunity for intra-arterial thrombolysis provides an opportunity for intra-arterial thrombolysis and mechanical treatment and mechanical treatment
Involvement of the posterior circulation especially the Involvement of the posterior circulation especially the basilar artery is treated by some regardless of time of basilar artery is treated by some regardless of time of onset or up until 12 to 24 hours in some practices This is onset or up until 12 to 24 hours in some practices This is related to the potentially high mortality and morbidity related to the potentially high mortality and morbidity associated with basilar artery thrombosisassociated with basilar artery thrombosis
Infarct evaluation on angiographyInfarct evaluation on angiography(CT angiography and catheter (CT angiography and catheter
angiography)angiography)CTA is an excellent first-line examination for CTA is an excellent first-line examination for
evaluation of the head and neck arteries evaluation of the head and neck arteries In comparison with catheter angiography In comparison with catheter angiography
what it gives up in resolution and dynamic what it gives up in resolution and dynamic properties it makes up for with rapid properties it makes up for with rapid acquisition of a 3-D dataset and the potential acquisition of a 3-D dataset and the potential for assessment of whole-brain perfusion and for assessment of whole-brain perfusion and better parenchymal evaluationbetter parenchymal evaluation
Moreover CTA illustrates not only arterial Moreover CTA illustrates not only arterial stenosis or occlusion but also the vessel wall stenosis or occlusion but also the vessel wall This factor is most important for evaluation of This factor is most important for evaluation of intramural dissection and thrombosed intramural dissection and thrombosed aneurysms which may both complicate aneurysms which may both complicate evaluation of stroke patientsevaluation of stroke patients
Early angiographic signs of strokes Early angiographic signs of strokes both CTA both CTA and DSA and DSA
Vessel occlusion or cutoff related to Vessel occlusion or cutoff related to thromboembolithromboemboli
aneurysms aneurysms arterial dissection arterial dissection Meniscus or flattened shape to clot Meniscus or flattened shape to clot
(recent) versus reverse meniscus (older)(recent) versus reverse meniscus (older) tram track (nonocclusive or recanalized tram track (nonocclusive or recanalized
clot) clot) delayed (antegrade) flow (manifest as delayed (antegrade) flow (manifest as
decreased whole-brain perfusion on CTA)decreased whole-brain perfusion on CTA) retrograde collateral flowretrograde collateral flow
Non-occlusive left MCA thrombus on 3-D imaging performed from CTA source data and was confirmed at catheter angiography
Therapy to be started within a 6-hr Therapy to be started within a 6-hr time to treatment (TTT) window time to treatment (TTT) window (while in case of IV thrombolysis (while in case of IV thrombolysis therapy to be started with in 3hrs)therapy to be started with in 3hrs)
Exclusion criteria Exclusion criteria Rapidly improving neurologic deficit or Rapidly improving neurologic deficit or Sustained blood pressure of gt180100 Sustained blood pressure of gt180100 Hemorrhage is detected on CTHemorrhage is detected on CT Infarct involving gt more than 13 rd Infarct involving gt more than 13 rd
territory of MCAterritory of MCA MRADWI-Perfusion mismatchlt 20MRADWI-Perfusion mismatchlt 20 Definite hypodensity on CTDefinite hypodensity on CT
Intra-arterial Thrombolysis
Fibrinolytics + AntiplateletsFibrinolytics + Antiplatelets
PlasminogenPlasminogen activators through fibrinolysis exposes activators through fibrinolysis exposes free thrombin and paradoxically stimulatesfree thrombin and paradoxically stimulates platelet platelet aggregation which leads to formation of aaggregation which leads to formation of a platelet platelet thrombus (white clot) thrombus (white clot)
This new thrombus is relatively resistant to This new thrombus is relatively resistant to fibrinolyticsfibrinolytics
So new regimen in case of acute stroke isSo new regimen in case of acute stroke is fibrinolytics + antiplatelet drugsfibrinolytics + antiplatelet drugs
rtPA + IIbIIIa inhibitors( tirofiban rtPA + IIbIIIa inhibitors( tirofiban abciximab) orabciximab) or
Urokinase + IIbIIIa Urokinase + IIbIIIa inhibitors( tirofiban abciximab)inhibitors( tirofiban abciximab)
Intra-arterial Thrombolysis Tirofiban (04 microgkgmin bolus for 3 min followed by Tirofiban (04 microgkgmin bolus for 3 min followed by
0125 ugkgmin)0125 ugkgmin)
++
Heparin (2000ndash3000 IU bolus followed by Heparin (2000ndash3000 IU bolus followed by 1000 IUhour infusion 1000 IUhour infusion
with ACT maintained bw 200-300) throughout the with ACT maintained bw 200-300) throughout the interventional procedure and for 24ndash48 hours thereafter when interventional procedure and for 24ndash48 hours thereafter when there is neither intraprocedural bleeding nor suspicion of there is neither intraprocedural bleeding nor suspicion of increased risk of bleeding increased risk of bleeding
Maximum dose of Urokinase Maximum dose of Urokinase Anterior circulation stroke - 500000 IU (mean 400000 Anterior circulation stroke - 500000 IU (mean 400000
IU range 300000ndash500000 IU)IU range 300000ndash500000 IU) Posterior circulation stroke -1000000 IU (mean 837000 Posterior circulation stroke -1000000 IU (mean 837000
IU range 300000ndash1000000 IU)IU range 300000ndash1000000 IU)American Journal of NeuroradiologyAmerican Journal of Neuroradiology 262595-2601 2005262595-2601 2005
Intravenous ThrombolysisIntravenous Thrombolysis
The first method to restore cerebral The first method to restore cerebral perfusion is clot lysis with the goal perfusion is clot lysis with the goal of re-establishing blood flow to the of re-establishing blood flow to the affected tissue affected tissue
IV thrombolysis rt-PA is the only IV thrombolysis rt-PA is the only FDA- approved treatment for AIS FDA- approved treatment for AIS
Fibrinolysis is enhanced powerfully Fibrinolysis is enhanced powerfully by rt-PAby rt-PA
Intravenous rTPA Intravenous rTPA administration administration protocolprotocol
Total dose of rt-PA 09 mgkg (maximum dose Total dose of rt-PA 09 mgkg (maximum dose 90 mg)90 mg)
Give 10 as initial IV bolusGive 10 as initial IV bolus Infuse remainder over 1 hourInfuse remainder over 1 hour Admit patient to an ICU or stroke unit for Admit patient to an ICU or stroke unit for
monitoringmonitoring Neurologic assessments every 15 minutes Neurologic assessments every 15 minutes
during infusion then every 30 minutes for next during infusion then every 30 minutes for next 6 hours then every hour until 24hours after 6 hours then every hour until 24hours after treatmenttreatment
Favorable Outcome vs Treatment Time Favorable Outcome vs Treatment Time with IV rTPAwith IV rTPA
Protocol limit = 3 hrs
Benefit ~ 45 hrs
Thromboembolism During coilingThromboembolism During coiling Most feared and frequent complication Most feared and frequent complication Reported incidence - Approx 7 Reported incidence - Approx 7 SourcesSources of Thromboembolism are of Thromboembolism are
- Clots at the aneurysmal neck during or immediately- Clots at the aneurysmal neck during or immediately after after embolization embolization
- Thrombus forming on catheters during- Thrombus forming on catheters during proceduresprocedures
- Stenosis of an adjacent artery dt coil mass- Stenosis of an adjacent artery dt coil mass or herniationor herniation
- Migration of intraaneurysmal- Migration of intraaneurysmal thrombus during coil thrombus during coil placement placement
- Slow flow dt vasospasm - Slow flow dt vasospasm
- Rare and unlikely causes are hypercoagulable- Rare and unlikely causes are hypercoagulable state such state such as antiphospholipid antibody syndrome or due to HITas antiphospholipid antibody syndrome or due to HIT
Occur more often with wide-necked aneurysms (dt Occur more often with wide-necked aneurysms (dt increased exposed surface area of thrombogenic coil increased exposed surface area of thrombogenic coil material)material)
Current regimen of endovascular Current regimen of endovascular managementmanagement
The The glycoprotein IIbIIIa antagonist tirofiban glycoprotein IIbIIIa antagonist tirofiban (04 (04 microgkgmin bolus for 30 minutes followed by infusion of microgkgmin bolus for 30 minutes followed by infusion of 0125 ugkgmin until the thrombus dissolved) 0125 ugkgmin until the thrombus dissolved)
Intraarterial thrombolysis with Intraarterial thrombolysis with urokinase or r- TPA urokinase or r- TPA increase of intravenous (IV) heparin (measured by increase of intravenous (IV) heparin (measured by
ACT) ACT) Intravenous aspirin Intravenous aspirin
Coil-related platelet aggregation (white clot) is Coil-related platelet aggregation (white clot) is unlikely to respond to fibrinolytics but has a high risk unlikely to respond to fibrinolytics but has a high risk of hemorrhage (In ISAT) all 5 patients who had of hemorrhage (In ISAT) all 5 patients who had received thrombolytic therapy with tPA to treat a received thrombolytic therapy with tPA to treat a thromboembolic complication after endovascular thromboembolic complication after endovascular treatment rebleed and all of these patients died)treatment rebleed and all of these patients died)
IntracranialIntracranial Stenting Stenting Metallic foreign body such as stent will accumulate Metallic foreign body such as stent will accumulate
thrombus in the absence of platelet inhibitionthrombus in the absence of platelet inhibition Antiplatelet drugs are important to prevent peri or Antiplatelet drugs are important to prevent peri or
post-interventional thromboembolic eventspost-interventional thromboembolic events Optimal treatment regimens has not been determined Optimal treatment regimens has not been determined
but usually but usually Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-
procedureprocedureOrOr
Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on
morning of proceduremorning of procedure
If need to use stent is not pre-planned thanIf need to use stent is not pre-planned than
Abciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkgAbciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkg IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)
Glycoprotein IIbIIIa inhibitor are not used routinely during elective Glycoprotein IIbIIIa inhibitor are not used routinely during elective stenting procedure dt increased risk of ICH stenting procedure dt increased risk of ICH
Carotid StentingCarotid Stenting
Pre-procedurePre-procedure
Double Antiplatelet therapy is routinely given Double Antiplatelet therapy is routinely given beginning at least 3beginning at least 3
days before the proceduredays before the procedure
Aspirin 325mgd+Clopidogrel 75mgdAspirin 325mgd+Clopidogrel 75mgd During procedureDuring procedure
Heparin is given with target clotting time of 250-Heparin is given with target clotting time of 250-300sec300sec
Post-procedure Post-procedure
Aspirin 325mg is continued indefinitely and Aspirin 325mg is continued indefinitely and
Clopidogrel 75mgd for at least 6 weeks Clopidogrel 75mgd for at least 6 weeks
Inclusion criteria for Local ThrombolysisInclusion criteria for Local Thrombolysis a)a) Patients in severe clinical grade on admission Patients in severe clinical grade on admission
with evidence of dural venous sinus with evidence of dural venous sinus thrombosis and restrictive venous outflow on thrombosis and restrictive venous outflow on cerebral angiogramcerebral angiogram
b)b) Patients in clinical grade 3 worsening on Patients in clinical grade 3 worsening on heparin therapy Restriction to venous heparin therapy Restriction to venous outflow was defined as an increase in brain outflow was defined as an increase in brain circulation time gt 12 s delay in the drainage circulation time gt 12 s delay in the drainage of cortical veins with cortical veins hanging of cortical veins with cortical veins hanging in spacein space
Treatment Options for Venous Thrombosis
CT Grading for Venous ThrombosisCT Grading for Venous Thrombosis Grade I no parenchymal change Grade I no parenchymal change
(hyperdense (hyperdense sinuses cortical veins empty sinuses cortical veins empty delta sign)delta sign)
Grade II non hemorrhagic venous infarct Grade II non hemorrhagic venous infarct without mass effect without mass effect
Grade III non-hemorrhagic infarct with Grade III non-hemorrhagic infarct with mass effectmass effect
Grade IV hemorrhagic venous infarct (max Grade IV hemorrhagic venous infarct (max diameter lt 3 cm) with no mass effectdiameter lt 3 cm) with no mass effect
Grade V hemorrhagic venous infarct (max Grade V hemorrhagic venous infarct (max diameter gt 3 cm) with mass effect diameter gt 3 cm) with mass effect
Local ThrombolysisLocal Thrombolysis
Femoral Jugular access was secured and a guiding Femoral Jugular access was secured and a guiding catheter was placed in the jugular bulb catheter was placed in the jugular bulb Mechanical Mechanical clot maceration clot maceration was done with the guidewire was done with the guidewire following which a microcatheter (was navigated and following which a microcatheter (was navigated and placed in the thrombosed segment of sinus confirmed placed in the thrombosed segment of sinus confirmed on a selective venogram on a selective venogram
Urokinase infusion Bolus dose of 2-6 lacs followed Urokinase infusion Bolus dose of 2-6 lacs followed by 60000 to 100000 units per hour along with by 60000 to 100000 units per hour along with periodic check venogram Along with maintenance periodic check venogram Along with maintenance systemic infusion of Heparinsystemic infusion of Heparin Other agents such as Other agents such as streptokinase altepase or rTPAstreptokinase altepase or rTPA can be also used can be also used
After thrombolysis patient should subjected to oral After thrombolysis patient should subjected to oral anticoagulation for six monthsanticoagulation for six months
Low-molecular-weight Low-molecular-weight heparinheparin
PharmacologyPharmacologyLMWH as its name suggests is a glycosaminoglycan that is approximatelyLMWH as its name suggests is a glycosaminoglycan that is approximately
one third the molecular weight of UFH It is derived from UFH through one third the molecular weight of UFH It is derived from UFH through variousvarious
depolymerization processes LMWH binds to antithrombin which in turn depolymerization processes LMWH binds to antithrombin which in turn
Neutralizes actors Xa and IIa Because LMWH lacks many of the longer Neutralizes actors Xa and IIa Because LMWH lacks many of the longer chains chains
required for binding to thrombin it has less ability to neutralize thrombin required for binding to thrombin it has less ability to neutralize thrombin
relativeto its ability to neutralize factor Xa LMWH also has less relativeto its ability to neutralize factor Xa LMWH also has less nonspecific nonspecific
binding to other proteins There is greater bioavailability with more binding to other proteins There is greater bioavailability with more predictable predictable
pharmacokinetics that eliminates the need for monitoring The smaller pharmacokinetics that eliminates the need for monitoring The smaller size also size also
allows for enhanced subcutaneous absorption when compared with UFHallows for enhanced subcutaneous absorption when compared with UFH
Three LMWH preparations are Three LMWH preparations are currently approved for use in the currently approved for use in the United States (1) enoxaparin (2) United States (1) enoxaparin (2) dalteparin and (3) tinzaparin dalteparin and (3) tinzaparin
They are all administered They are all administered subcutaneously at intervals of either subcutaneously at intervals of either once or twice daily for both once or twice daily for both prophylaxis and treatment dosesprophylaxis and treatment doses
Few Experiences of Few Experiences of ThrombolysisThrombolysis
Vickey 25 Yrs male patient presented Vickey 25 Yrs male patient presented with 12with 12thth day HO severe headache with day HO severe headache with right sided hemiplegiaright sided hemiplegia
MRI shows thrombosis of the superior MRI shows thrombosis of the superior sagittal left transverse left sigmoid sagittal left transverse left sigmoid sinuses and cortical veins in the fronto-sinuses and cortical veins in the fronto-parietal regions with eo haemorrhagic parietal regions with eo haemorrhagic infarct in the left cerebral hemisphere infarct in the left cerebral hemisphere with mass effect( Grade ndashV)with mass effect( Grade ndashV)
Sashi Srivastava 64 yrs FSashi Srivastava 64 yrs F In a follow up case of MRD with infra-renal In a follow up case of MRD with infra-renal
aortic abdominal and bilateral renal artery aortic abdominal and bilateral renal artery thrombosis renal angiogram shows filling thrombosis renal angiogram shows filling defects in the right Renal artery defects in the right Renal artery
Initially Renal angioplasty was done Initially Renal angioplasty was done Following angioplasty few thrombi are seem Following angioplasty few thrombi are seem to extends into the segmental branches and to extends into the segmental branches and causing blockage So Thrombolysis was causing blockage So Thrombolysis was plane to dissolve the run-out thrombi with plane to dissolve the run-out thrombi with urokinase urokinase
Rakesh 34yrsMRakesh 34yrsM Left SFA pseudoaneurysm with Left SFA pseudoaneurysm with
Covered stent placementCovered stent placement Pre operative antiplatelets with post Pre operative antiplatelets with post
procedure heparin Tirofiban procedure heparin Tirofiban followed by aspirin and clopidogrel followed by aspirin and clopidogrel were usedwere used
IAT may be a treatment option for selected patients IAT may be a treatment option for selected patients Possible selection criteria include Possible selection criteria include
presentation between 3 and 6 hours from symptom onsetpresentation between 3 and 6 hours from symptom onset major cerebral artery occlusion major cerebral artery occlusion severe neurologic deficits severe neurologic deficits high risk of systemic hemorrhage with IV rt-PA (eg recent high risk of systemic hemorrhage with IV rt-PA (eg recent
surgery) surgery) The MERCI (Mechanical Embolus Removal in Cerebral The MERCI (Mechanical Embolus Removal in Cerebral
Ischemia) retrievalIschemia) retrieval system system
Has been FDA-approved for recanalizing acutely occluded Has been FDA-approved for recanalizing acutely occluded cerebral arteries cerebral arteries
In the Multi-MERCI study patients who did not improve In the Multi-MERCI study patients who did not improve immediately after IV rt-PA underwent mechanical immediately after IV rt-PA underwent mechanical embolectomy within 8 hours of symptom onset embolectomy within 8 hours of symptom onset
Partial or complete recanalization occurred in 74 of Partial or complete recanalization occurred in 74 of patientspatients
with a symptomatic intracerebral hemorrhage (sICH) rate of with a symptomatic intracerebral hemorrhage (sICH) rate of 67 67
Mechanical embolectomy with the MERCI retriever may be a Mechanical embolectomy with the MERCI retriever may be a feasible and safe option for patients after IV rt-PAfeasible and safe option for patients after IV rt-PA
Penumbra stroke systemPenumbra stroke system This device combines two methods of clot This device combines two methods of clot
extraction aspiration and mechanical extraction aspiration and mechanical extraction extraction
First the clot is aspirated then a thrombus First the clot is aspirated then a thrombus removal ring can be used if necessary to removal ring can be used if necessary to remove remaining clot remove remaining clot
successful recanalizing 82successful recanalizing 82 Bridging therapyBridging therapy
06 mgkg IV rt-PA followed by IAT with IA rt-06 mgkg IV rt-PA followed by IAT with IA rt-PA (up to 20 mg)PA (up to 20 mg)
achieved a higher recanalization rateachieved a higher recanalization rate
Criteria for thrombolysis with rTPACriteria for thrombolysis with rTPA
Inclusion criteriaInclusion criteria Clinical signs and symptoms consistent with ischemic Clinical signs and symptoms consistent with ischemic
strokestroke Patient last seen normal within 3 hoursPatient last seen normal within 3 hours Measurable neurologic deficitMeasurable neurologic deficit
Exclusion criteriaExclusion criteria Any hemorrhage on neuroimaging (CT or MRI)Any hemorrhage on neuroimaging (CT or MRI) Symptoms suggestive of subarachnoid hemorrhageSymptoms suggestive of subarachnoid hemorrhage Seizure at stroke onset that is thought to contribute to Seizure at stroke onset that is thought to contribute to
neurologic deficitneurologic deficit Hypodensity greater than one third cerebral hemisphere Hypodensity greater than one third cerebral hemisphere
on CTon CT SBP greater than 185 mm Hg or DBP greater than 110 SBP greater than 185 mm Hg or DBP greater than 110
mm Hgmm Hg International normalized ratio (INR) greater than 17International normalized ratio (INR) greater than 17
Ischemic Stroke Ischemic Stroke Treatment ndash 2006Treatment ndash 2006
IV tissue plasminogen activator (tPA)IV tissue plasminogen activator (tPA) ndash ndash Only FDA-approved acute stroke drugOnly FDA-approved acute stroke drug ndash ndash 3 hour treatment window3 hour treatment window
MERCI - Concentric clot retrieval MERCI - Concentric clot retrieval devicedevice ndash ndash Rescue therapy - approved 2004Rescue therapy - approved 2004 ndash ndash Device approval (not outcomes-based)Device approval (not outcomes-based)
Off label approachesOff label approaches ndash ndash IV tPA after 3 hoursIV tPA after 3 hours ndash ndash IV-IA tPA sequential strategiesIV-IA tPA sequential strategies ndash ndash IA tPA clot angioplasty fragmentationIA tPA clot angioplasty fragmentation ndash ndash Ultrasound-assisted tPA lysisUltrasound-assisted tPA lysis
rt-PA Trials NINDSrt-PA Trials NINDS
Acute stroke - 624 patientsAcute stroke - 624 patients Treat within 3 hrsTreat within 3 hrs Intravenous 09 mgkg rt-PA vs placeboIntravenous 09 mgkg rt-PA vs placebo Hemorrhage 64 tPA 06 placeboHemorrhage 64 tPA 06 placebo Neurologic recovery better with tPA 30 Neurologic recovery better with tPA 30
more like to have minimal or no disabilitymore like to have minimal or no disability
First proven approved treatment for First proven approved treatment for strokestroke
Limitations of tPALimitations of tPA Only 4 of acute strokes receive tPAOnly 4 of acute strokes receive tPA (Kleindorfer et al Stroke 2004 35 e27-e29)(Kleindorfer et al Stroke 2004 35 e27-e29)
Only 22 of patients present within 3 hoursOnly 22 of patients present within 3 hours1048707 1048707 51 of these ineligible due to51 of these ineligible due to
bull bull Mild severityMild severity bull bull Medical or surgical historyMedical or surgical history bull bull Blood testsBlood tests
Sustained recanalization only 13Sustained recanalization only 13 (Alexandrov et al NEJM 2004 351 2170-8)(Alexandrov et al NEJM 2004 351 2170-8)
Concern for hemorrhageConcern for hemorrhage tPA potentiates apoptotic injury tPA potentiates apoptotic injury (Liu et al Nature Med 2004 101379-83)(Liu et al Nature Med 2004 101379-83)
PROACT II IA Lysis TrialPROACT II IA Lysis Trial Baseline 24 hours 8 days
Baseline 60 minutes 120 minutes
9mg IAProurokinase
Desmoteplase Trials DEDAS Desmoteplase Trials DEDAS DIASDIAS
Trial OverviewTrial Overview Double blind randomized placebo Double blind randomized placebo
controlled trialscontrolled trials IV delivery 3-9 hour time windowIV delivery 3-9 hour time window Plasminogen activator ndash from Plasminogen activator ndash from vampire bat vampire bat
salivasaliva Selection based on PWI-DWI MismatchSelection based on PWI-DWI Mismatch
MRI InclusionMRI Inclusion PWI defect at least 2 cm AND ~20 larger PWI defect at least 2 cm AND ~20 larger
than DWIthan DWI PWI should be obvious even visible on PWI should be obvious even visible on
raw imagesraw imagesMRI ExclusionMRI Exclusion
DWI gt 13 MCADWI gt 13 MCA MRA ICA occlusionMRA ICA occlusion
Desmoteplase ndash DIAS Desmoteplase ndash DIAS ResultsResults
Mechanical Thrombolysis Mechanical Thrombolysis devicesdevices
mechanical thrombolysis potentially extends the treatment mechanical thrombolysis potentially extends the treatment window because they act promptly at the site of the thrombuswindow because they act promptly at the site of the thrombus
The devices can retrieve large clots that pharmaceutical agents The devices can retrieve large clots that pharmaceutical agents may not successfully lysemay not successfully lyse
Patients treated with IV tPA may be considered for treatment of Patients treated with IV tPA may be considered for treatment of residual clot with some of these devicesresidual clot with some of these devices
suction-creating saline jets suction-creating saline jets laser energy ultrasound laser energy ultrasound a corkscrew apparatus to treat strokesa corkscrew apparatus to treat strokes The AngioJet systemThe AngioJet system uses saline jets that are directed back into the catheter to uses saline jets that are directed back into the catheter to
create a low-pressure zone around the catheter tip inducing create a low-pressure zone around the catheter tip inducing suction suction
The clot is pulled into the exhaust lumen and removed from the The clot is pulled into the exhaust lumen and removed from the vessel Although US Food and Drug Administration (FDA) has vessel Although US Food and Drug Administration (FDA) has approved this device for use in arteriovenous dialysis grafts and approved this device for use in arteriovenous dialysis grafts and fistulae and for the treatment of coronary arteries saphenous fistulae and for the treatment of coronary arteries saphenous vein grafts and peripheral vessels clinical trials for the vein grafts and peripheral vessels clinical trials for the treatment of acute stroke are no longer in progress treatment of acute stroke are no longer in progress
Most devices are used in cerebral vessels that 2-5 mm
The Latis laser device The Latis laser device used laser energy to ablate clots used laser energy to ablate clots Arteries 2-5 mm in diameter could be Arteries 2-5 mm in diameter could be
treated including the ICA M1 or M2 treated including the ICA M1 or M2 branch of the MCA A1 branch of the branch of the MCA A1 branch of the anterior cerebral artery (ACA) basilar anterior cerebral artery (ACA) basilar artery posterior cerebral artery (PCA) artery posterior cerebral artery (PCA) and vertebral and vertebral
Patients could receive treatment as late Patients could receive treatment as late as 8 hours after symptom onset in the as 8 hours after symptom onset in the anterior circulation and within 24 hours in anterior circulation and within 24 hours in the posterior circulation the posterior circulation
Endovascular Photo Acoustic Endovascular Photo Acoustic Recanalization (EPAR) Recanalization (EPAR)
A laser power source generated energy for the A laser power source generated energy for the systemsystem
The energy was delivered by means of The energy was delivered by means of fiberoptics to the tip of the catheter at the fiberoptics to the tip of the catheter at the treatment sitetreatment site
Absorption of laser light by darkly pigmented Absorption of laser light by darkly pigmented materials (ie the clot) occurred inside the 1-mm materials (ie the clot) occurred inside the 1-mm catheter tipcatheter tip
the system was designed to minimize scattering the system was designed to minimize scattering of laser light of laser light
Absorption converted photo energy to acoustic Absorption converted photo energy to acoustic energy which then emulsified the clot inside the energy which then emulsified the clot inside the catheter tip catheter tip
EKOS ultrasound( the EKOS ultrasound( the Ultrasound Thrombolytic Ultrasound Thrombolytic
Infusion Catheter) Infusion Catheter) combines the use of a distal ultrasound transducer with combines the use of a distal ultrasound transducer with
infusion of a thrombolytic agent through the infusion of a thrombolytic agent through the microcathetermicrocatheter
Ultrasound changes the structure of the clot to Ultrasound changes the structure of the clot to temporarily increase its permeability while providing an temporarily increase its permeability while providing an acoustic pressure gradient to move the drug into the clot acoustic pressure gradient to move the drug into the clot to speed its dissolution to speed its dissolution
The EKOS catheter is placed in the proximal portion of the The EKOS catheter is placed in the proximal portion of the clot clot
After a 2-mg bolus of tPA was injected through the After a 2-mg bolus of tPA was injected through the catheter catheter
the patient received a continuous infusion of IA tPA 03 the patient received a continuous infusion of IA tPA 03 mgmin to a maximum of 20 mg and simultaneous mgmin to a maximum of 20 mg and simultaneous ultrasound transmission for as long as 60 minutes ultrasound transmission for as long as 60 minutes
One patient was treated with a total of 4 units of One patient was treated with a total of 4 units of recombinant reteplase (Retavase) hand-injected over 60 recombinant reteplase (Retavase) hand-injected over 60 minutes minutes
Penumbra system Penumbra system The Penumbra system (Penumbra Inc) provides a dual The Penumbra system (Penumbra Inc) provides a dual
approach to clot extraction using aspiration followed by approach to clot extraction using aspiration followed by clot retrieval with a ring device if needed clot retrieval with a ring device if needed
Mechanical Embolus Removal in Cerebral Ischemia Mechanical Embolus Removal in Cerebral Ischemia (MERCI)(MERCI)
a corkscrew-like apparatus to remove blood clots from a corkscrew-like apparatus to remove blood clots from the brain in patients experiencing an ischemic stroke the brain in patients experiencing an ischemic stroke
The corkscrew itself resides in the catheter tip which The corkscrew itself resides in the catheter tip which shields it from the wall of the vessel until it is ready to be shields it from the wall of the vessel until it is ready to be burrowed into the clot Once lodged in the clot the device burrowed into the clot Once lodged in the clot the device and clot are withdrawn from the vessel and clot are withdrawn from the vessel
Snarelike devicesSnarelike devices Snares such as the Neuronet snare (Guidant Snares such as the Neuronet snare (Guidant
Endovascular Santa Clara CA) have been developed Endovascular Santa Clara CA) have been developed specifically for use in the treatment of strokes specifically for use in the treatment of strokes
These devices are simple in design and do not require the These devices are simple in design and do not require the clot to be amenable to emulsification clot to be amenable to emulsification
X-Sizer deviceX-Sizer device a device with small moving blades at the a device with small moving blades at the
catheter tip catheter tip This device the X-Sizer device (EndiCor Medical This device the X-Sizer device (EndiCor Medical
San Clemente CA) can be used to excise the San Clemente CA) can be used to excise the thrombus and aspirate it thrombus and aspirate it
The device was being evaluated in randomized The device was being evaluated in randomized studies of coronary vessels and in a registry of studies of coronary vessels and in a registry of patients with acute myocardial infarctionpatients with acute myocardial infarction
Although the manufacturer had modified the Although the manufacturer had modified the device for use in cerebral vessels a safety and device for use in cerebral vessels a safety and feasibility study was indefinitely suspended after feasibility study was indefinitely suspended after only 1 patient was treated with the device in only 1 patient was treated with the device in Europe Europe
Suction thrombectomySuction thrombectomy This method of mechanical thrombolysis is one of the This method of mechanical thrombolysis is one of the
simplestsimplest In this readily available technique suction is applied with In this readily available technique suction is applied with
a syringe to remove thrombus in the ICA a syringe to remove thrombus in the ICA It requires no other devicesIt requires no other devices A catheter with a large inner diameter (Brite Tip Cordis A catheter with a large inner diameter (Brite Tip Cordis
Corporation Miami FL) was placed in the symptomatic Corporation Miami FL) was placed in the symptomatic vessel and navigated over a guidewire into the thrombusvessel and navigated over a guidewire into the thrombus
A 60-mL syringe was used to aspirate the thrombus A 60-mL syringe was used to aspirate the thrombus Each patient required angioplasty and stenting of carotid Each patient required angioplasty and stenting of carotid
bifurcation stenosis and received daily aspirin and bifurcation stenosis and received daily aspirin and ticlopidine after the procedure No complications ticlopidine after the procedure No complications occurred occurred
Summary Acute Stroke Summary Acute Stroke ImagingImaging
PhysiologyPhysiology importance collaterals importance collaterals
ndash ndashGrowing role for perfusion Growing role for perfusion assessmentassessment
tPAtPA guidelines amp limitations guidelines amp limitations Signs on CT amp MRSigns on CT amp MR follow physiology follow physiology Stroke trialsStroke trials PWI-DWI mismatch PWI-DWI mismatch
ndash ndashTreat based on physiology not timeTreat based on physiology not time ProtocolsProtocols should be fast and should be fast and
comprehensivecomprehensive
OPTIMAL THERAPEUTIC RANGEOPTIMAL THERAPEUTIC RANGE
IndicationIndication INRINR
Prophylaxis of venous Prophylaxis of venous thromboembolismthromboembolism
20-3020-30
Treatment of venous Treatment of venous thromboembolismthromboembolism
20-3020-30
Atrial fibrillationAtrial fibrillation 20-3020-30
Mitral valve stenosisMitral valve stenosis 20-3020-30
Heart valve replacementHeart valve replacement
Bioprosthetic valveBioprosthetic valve
Mechanical valveMechanical valve
20-3020-30
25-3525-35
Myocardial infarctionMyocardial infarction 20-3020-30
25-35 25-35 (high risk patients)(high risk patients)
FACTORS INFLUENCING DOSE RESPONSEFACTORS INFLUENCING DOSE RESPONSE
Poor patient compliancePoor patient compliance Concomitant medicationsConcomitant medications Levels of dietary vitamin KLevels of dietary vitamin K Alcohol Inaccurate lab testingAlcohol Inaccurate lab testing Inaccurate lab testingInaccurate lab testing Hepatic dysfunctionHepatic dysfunction FeverFever
Contraindication for WarfarinContraindication for Warfarin
Hypersensitivity to warfarinHypersensitivity to warfarin Hemorrhagic tendencyHemorrhagic tendency Condition with risk of hemorrhageCondition with risk of hemorrhage Inadequate laboratory techniquesInadequate laboratory techniques Protein C amp S deficiencyProtein C amp S deficiency Vitamin K deficiencyVitamin K deficiency
SIDE EFFECTSSIDE EFFECTS
Hemorrhage Hemorrhage Skin necrosisSkin necrosis Purple toe syndromePurple toe syndrome Microembolization Microembolization TeratogenecityTeratogenecity Agranulocytosis leukopenia Agranulocytosis leukopenia Diarrhoeanausea anorexiaDiarrhoeanausea anorexia
MONITORING OF WARFARIN THERAPYMONITORING OF WARFARIN THERAPY
Prothrombin timeProthrombin time PT ratioPT ratio INR (International Normalized Ratio)INR (International Normalized Ratio)
PROTHROMBIN TIME (PT)PROTHROMBIN TIME (PT)
Time required for blood to coagulate Time required for blood to coagulate is called PT ( normal value ~10sec)is called PT ( normal value ~10sec)
Performed by adding a mixture of Performed by adding a mixture of calcium and thromboplastin to calcium and thromboplastin to citrated plasmacitrated plasma
As a control a normal blood sample is As a control a normal blood sample is tested continuouslytested continuously
PT ratio (PTR) = PT ratio (PTR) = Patientrsquos PTPatientrsquos PT Control PTControl PT
PROBLEMS WITH PTPTRPROBLEMS WITH PTPTR
Thromboplastins are extracts from Thromboplastins are extracts from brain lung or placenta of animalsbrain lung or placenta of animals
Thromboplastins from various Thromboplastins from various manufacturers differ in their manufacturers differ in their sensitivity to prolong PTsensitivity to prolong PT
May result in false control of May result in false control of anticoagulant therapyanticoagulant therapy
INTERNATIONAL NORMALISED RATIO (INR)INTERNATIONAL NORMALISED RATIO (INR)
International Normalized Ratio (INR) International Normalized Ratio (INR) a PT test with a a PT test with a formula based ratio to normalize the often variable source formula based ratio to normalize the often variable source of tissue factor (human rabbit recombinant)of tissue factor (human rabbit recombinant)
INR = [PTINR = [PTptpt] ] ISIISI
[PT[PTRefRef]]
PTPTpt pt ndash prothrombin time of patientndash prothrombin time of patient
PTPTRef Ref ndash prothrombin time of normal pooled samplendash prothrombin time of normal pooled sample
ISI ndash International Sensitivity IndexISI ndash International Sensitivity Index
Warfarin is given orally and titrated to achieve an INR of Warfarin is given orally and titrated to achieve an INR of typically 20 ndash 30typically 20 ndash 30
Heparin versus WarfarinHeparin versus Warfarin
Drug ActionMechan-ism
Moni-toring
Effective
HeparinDirect
Inhibition ofThrombin
ATIIIcofactor
APTTACT
Immediate
WarfarinDecreasesProductionof factors
Vitamin K PTDelay
3-5 days
INR
Recanalization or Antegrade Recanalization or Antegrade Reperfusion StrategiesReperfusion Strategies
Recanalization strategies focus on removing Recanalization strategies focus on removing andor dissolving the occlusive thrombus to re-andor dissolving the occlusive thrombus to re-establish antegrade flow Strategies may be establish antegrade flow Strategies may be classified into 7 different categories on the classified into 7 different categories on the basis of their primary mechanism of action basis of their primary mechanism of action 1) 1) IV andor intraarterial thrombolysis (IAT) IV andor intraarterial thrombolysis (IAT) 2) endovascular thrombectomy2) endovascular thrombectomy3) endovascular thromboaspiration 3) endovascular thromboaspiration 4) endovascular mechanical thrombus disruption or 4) endovascular mechanical thrombus disruption or
thromborrhexisthromborrhexis5) 5) transcranial or endovascular augmented transcranial or endovascular augmented
fibrinolysis fibrinolysis 6) endovascular thrombus entrapment and 6) endovascular thrombus entrapment and 7) temporary endovascular bypass7) temporary endovascular bypass
IAT in Acute Ischemic StrokeIAT in Acute Ischemic Stroke
IAT advantages over IV thrombolysisIAT advantages over IV thrombolysis Coaxial microcatheter techniques the occluded intracranial Coaxial microcatheter techniques the occluded intracranial
vessel is directly accessible and the fibrinolytic agent can be vessel is directly accessible and the fibrinolytic agent can be infused directly into the thrombusinfused directly into the thrombus
This permits a smaller dose of fibrinolytic agent to reach a This permits a smaller dose of fibrinolytic agent to reach a higher local concentration than that reached by systemic higher local concentration than that reached by systemic infusioninfusion
Allows more complete recanalization with lower total doses of Allows more complete recanalization with lower total doses of thrombolytic thrombolytic
With the smaller dose complications from systemic fibrinolytic With the smaller dose complications from systemic fibrinolytic effects including intracranial hemorrhage (ICH) can effects including intracranial hemorrhage (ICH) can theoretically be reduced theoretically be reduced
Treatment window for endovascular techniques can be Treatment window for endovascular techniques can be extended beyond the typical IV window of 3 hours extended beyond the typical IV window of 3 hours
IA techniques have led to higher recanalization rates than IV IA techniques have led to higher recanalization rates than IV thrombolysisthrombolysis
Major disadvantagesMajor disadvantages Relative complexity of the procedure the level Relative complexity of the procedure the level
of required technical expertise and its of required technical expertise and its relatively low availability relatively low availability
Delays in initiating treatmentDelays in initiating treatment InvasiveInvasive
ThrombolyticsThrombolytics
Plasminogen activators
Fibrinolytics
1 Plasminogen Activators 1 Plasminogen Activators drugs act by converting the inactive proenzyme drugs act by converting the inactive proenzyme plasminogen into the active enzyme plasmin Plasmin plasminogen into the active enzyme plasmin Plasmin digests fibrinogen fibrin monomers and cross-linked digests fibrinogen fibrin monomers and cross-linked fibrin (as found in a thrombus) into fibrin degradation fibrin (as found in a thrombus) into fibrin degradation productsproducts
First-Generation Agents First-Generation Agents StreptokinaseStreptokinase a protein derived from group C a protein derived from group C
szlig-hemolytic streptococci has a half-life of 16ndashszlig-hemolytic streptococci has a half-life of 16ndash90 minutes and low fibrin specificity This drug 90 minutes and low fibrin specificity This drug proved to have a very narrow therapeutic proved to have a very narrow therapeutic window and significant rates of ICH and window and significant rates of ICH and systemic hemorrhage18systemic hemorrhage18
UrokinaseUrokinase is a serine protease with a plasma is a serine protease with a plasma half life of 14 minutes and low fibrin specificity half life of 14 minutes and low fibrin specificity
The urokinase dose used in cerebral IAT has The urokinase dose used in cerebral IAT has ranged from 002 to 2 X106unitsranged from 002 to 2 X106units
Second-Generation Agents Second-Generation Agents Alteplase (rtPA) Alteplase (rtPA)
is a serine is a serine protease with a plasma half-life of 35 protease with a plasma half-life of 35 minutes and a high degree of fibrin affinity and minutes and a high degree of fibrin affinity and specificity specificity
Dose used in cerebral IAT has ranged between 20 Dose used in cerebral IAT has ranged between 20 and 60 mgand 60 mg
Disadvantages of alteplase include its relatively short Disadvantages of alteplase include its relatively short halflife and limited penetration into the clot matrix halflife and limited penetration into the clot matrix because of strong binding with surface fibrin which because of strong binding with surface fibrin which could delay recanalization and increase the risk of could delay recanalization and increase the risk of recurrent occlusion recurrent occlusion
Prourokinase (r-prourokinase) Prourokinase (r-prourokinase) is the proenzyme precursor of urokinase is the proenzyme precursor of urokinase T12 of 7 minutes and high fibrin specificity T12 of 7 minutes and high fibrin specificity
Third-Generation AgentsThird-Generation Agents
ReteplaseReteplase is a structurally modified is a structurally modified form of alteplase form of alteplase
with a longer half-life (15ndash18 minutes) In with a longer half-life (15ndash18 minutes) In addition it does not bind as highly to fibrin addition it does not bind as highly to fibrin unbound reteplase can thus theoretically better unbound reteplase can thus theoretically better penetrate the clot and potentially penetrate the clot and potentially improve in improve in vivo fibrinolytic activity vivo fibrinolytic activity
TenecteplaseTenecteplase is another modified form of rtPA with a longer is another modified form of rtPA with a longer
half-life (17 minutes)half-life (17 minutes) greater fibrin specificity and greater greater fibrin specificity and greater
resistance to plasminogen activator inhibitor-1 resistance to plasminogen activator inhibitor-1 IV tenecteplase in acute ischemic stroke IV tenecteplase in acute ischemic stroke
suggest that the drug is safe and promisingsuggest that the drug is safe and promising
Newer plasminogen activatorNewer plasminogen activator
DesmoteplaseDesmoteplase is a genetically engineered is a genetically engineered version of the clot-dissolving factor version of the clot-dissolving factor
found in the saliva found in the saliva of the vampire bat Desmodus rotundusof the vampire bat Desmodus rotundus moremore potent and more selective for fibrin-bound potent and more selective for fibrin-bound
plasminogen than any other known plasminogen plasminogen than any other known plasminogen activatoractivator
Unlike tissue plasminogen activator (tPA) desmoteplase Unlike tissue plasminogen activator (tPA) desmoteplase is not activated by fibrinogen or -amyloid proteins is not activated by fibrinogen or -amyloid proteins factors that may exacerbate the risk for ICH factors that may exacerbate the risk for ICH
The effect of IV administration of desmoteplase 3ndash9 The effect of IV administration of desmoteplase 3ndash9 hours after symptom onset in patients with stroke who hours after symptom onset in patients with stroke who present with mismatch on MR imaging or CT perfusion present with mismatch on MR imaging or CT perfusion
3 DefibrinogenatingFibrinogenolytic 3 DefibrinogenatingFibrinogenolytic Agents Agents
AncrodAncrod(Viprinex)(Viprinex) is is the purified fraction of the Malayan pit viper venomthe purified fraction of the Malayan pit viper venom It acts by directly cleaving and inactivating fibrinogen It acts by directly cleaving and inactivating fibrinogen
and thus indirectly promoting anticoagulation and thus indirectly promoting anticoagulation The reduction in the blood levels of fibrinogen also The reduction in the blood levels of fibrinogen also
leads to a reduced blood viscosity which may improve leads to a reduced blood viscosity which may improve blood flow to the affected areas of the brain blood flow to the affected areas of the brain
In the Stroke Treatment with Ancrod Trial 500 In the Stroke Treatment with Ancrod Trial 500 patients with stroke presenting within 3 hours of patients with stroke presenting within 3 hours of symptom onset were randomized to receive ancrod (symptom onset were randomized to receive ancrod (n n 248) or a placebo (n 252) Good outcome (Barthel 248) or a placebo (n 252) Good outcome (Barthel Index 95ndash100 at 3 months) was achieved in 4221 Index 95ndash100 at 3 months) was achieved in 4221 and 344 of the patients respectively and 344 of the patients respectively
2 Direct Fibrinolytics2 Direct Fibrinolytics
Microplasmin (Microplasmin (ThromboGenics Heverlee Belgium)ThromboGenics Heverlee Belgium) is a truncated form of plasmin that is more resistant to the effects is a truncated form of plasmin that is more resistant to the effects
of antiplasmin of antiplasmin microplasmin can be used upto 4ndash12 hours after stroke onset microplasmin can be used upto 4ndash12 hours after stroke onset There was no evidence of increased bleeding risk with There was no evidence of increased bleeding risk with
microplasminmicroplasmin
Alfimeprase (Nuvelo San Carlos Calif)Alfimeprase (Nuvelo San Carlos Calif) is a recombinant truncated form of fibrolase a fibrinolytic zinc metalloproteinase is a recombinant truncated form of fibrolase a fibrinolytic zinc metalloproteinase
isolated from the venom of the southern copperhead snake isolated from the venom of the southern copperhead snake It degrades fibrin directly and achieves thrombolysis independent It degrades fibrin directly and achieves thrombolysis independent
of plasmin formationof plasmin formation its thrombolytic activity appears to be localized to the site of its thrombolytic activity appears to be localized to the site of
delivery These properties should theoretically result in faster delivery These properties should theoretically result in faster recanalization and lower hemorrhagic conversion riskrecanalization and lower hemorrhagic conversion risk
Anti-fibrinolyticsAnti-fibrinolytics
to limit fibrinolytic activityto limit fibrinolytic activity -aminocaproic acid (EACA) -aminocaproic acid (EACA) competitively inhibitscompetitively inhibits plasminogen and plasminogen activators from plasminogen and plasminogen activators from
binding to fibrinbinding to fibrin
alpha2-antiplasminalpha2-antiplasmin a serine protease inhibitor that a serine protease inhibitor that neutralizes any free circulating plasminneutralizes any free circulating plasmin
Plasminogen activator inhibitor-1Plasminogen activator inhibitor-1 a serine protease a serine protease inhibitor that inhibits tissue-type plasminogen inhibitor that inhibits tissue-type plasminogen activatoractivator
Glycoprotein (GP) IIbIIIa antagonistsGlycoprotein (GP) IIbIIIa antagonists
such as ReoPro (abciximab) Integrilin such as ReoPro (abciximab) Integrilin (eptifibatide) or Aggrastat (tirofiban) in (eptifibatide) or Aggrastat (tirofiban) in ischemic stroke remains investigational ischemic stroke remains investigational Deshmukh et al38 reported 21 patients with Deshmukh et al38 reported 21 patients with large-vessel occlusion refractory to IAT with large-vessel occlusion refractory to IAT with rtPA who were treated with IV andor IA rtPA who were treated with IV andor IA abciximab eptifibatide or tirofiban abciximab eptifibatide or tirofiban
IA Mechanical Approaches in Acute Ischemic Stroke IA Mechanical Approaches in Acute Ischemic Stroke Mechanical strategies have several advantagesMechanical strategies have several advantages First they lessen and may even preclude the use of chemical First they lessen and may even preclude the use of chemical
thrombolytics in this manner very likely reducing the risk of ICHthrombolytics in this manner very likely reducing the risk of ICH Second by avoiding the use of chemical thrombolytics it is Second by avoiding the use of chemical thrombolytics it is
possible to extend the treatment window beyond the limit of 6ndash8 possible to extend the treatment window beyond the limit of 6ndash8 hours hours
Third mechanically fragmenting a clot increases the surface area Third mechanically fragmenting a clot increases the surface area accessible to fibrinolytic agents and allows inflow of fresh accessible to fibrinolytic agents and allows inflow of fresh plasminogen which in turn may increase the speed of plasminogen which in turn may increase the speed of thrombolysis thrombolysis
Finally clot-retrieval devices may provide faster recanalization Finally clot-retrieval devices may provide faster recanalization
The disadvantages of the mechanical The disadvantages of the mechanical approaches approaches technical difficulty of navigating mechanical technical difficulty of navigating mechanical
devices into the intracranial circulation excessive devices into the intracranial circulation excessive trauma to the vasculature (potentially leading to trauma to the vasculature (potentially leading to vasospasm vessel dissection perforation or vasospasm vessel dissection perforation or rupture) rupture)
fragmented thrombus causing distal embolization fragmented thrombus causing distal embolization into previously unaffected territories into previously unaffected territories
Nevertheless the advantages of mechanical stroke Nevertheless the advantages of mechanical stroke therapy appear to significantly outweigh its therapy appear to significantly outweigh its disadvantages and risksdisadvantages and risks
Contraindications to Thrombolytic Contraindications to Thrombolytic agents agents
Recent thoracic abdominal or Recent thoracic abdominal or intracranial surgeryintracranial surgery
Recent haemorrhagic CVA Head injury Recent haemorrhagic CVA Head injury or neoplasmor neoplasm
Bleeding ulcerBleeding ulcer Anticipated invasive procedures (arterial Anticipated invasive procedures (arterial
punctures biopsies)punctures biopsies) Concurrent hemostatic dysfunctionConcurrent hemostatic dysfunction
Monitoring of thrombolytic Monitoring of thrombolytic therapytherapy
Thrombin time Measures the availability of functional
fibrinogen Normal thrombin time is 10-14 sec Prolonged when fibrinogen level is below
75-100 mgdl
Half Life of ThrombolyticsHalf Life of ThrombolyticsAgent Administration Half Life
Streptokinase IA 60-80min
Urokinase IAIV 9-12min
rTPA IAIV 6min
Abciximab(Reopro) IAIV 12hour
Aspirin POIV 15-20min
Heparin IVSC 60min
Coumadin PO 15-25 days
Anti Platelet DrugsAnti Platelet DrugsDrug Drug Mechanism Mechanism UsesUsesAspirinAspirin Permanently inhibits Permanently inhibits
COX-1 and COX-2COX-1 and COX-2CADCAD
Stroke-TIAsStroke-TIAs
NSAIDsNSAIDs Reversibly inhibits Reversibly inhibits COX-1COX-1
LimitedLimited
DipyridamoleDipyridamole Inhibits PDE increases Inhibits PDE increases cAMPcAMP
TIAsTIAs
ThenopyridinesThenopyridines
(Ticlopidine(Ticlopidine
ClopidrgrelClopidrgrel))
Inhibits ADP Inhibits ADP
PlatAg PlatAg
TIAsStrokeTIAsStroke
CAD PVDCAD PVD
Abciximab (ReoPro)Abciximab (ReoPro)
Eptifibatide (Integrilin)Eptifibatide (Integrilin)
TirofibanTirofiban
GP IIBIIIA InhibitorsGP IIBIIIA Inhibitors
Stroke- TIAs Stroke- TIAs
MonitoringMonitoring
Bleeding timeBleeding time
Optical aggregometryOptical aggregometry
Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay
Bleeding timeBleeding time
Requires a skin incision (usually made on the ear lobe or Requires a skin incision (usually made on the ear lobe or forearm offorearm of
a depth that results in disruption of capillary loops and a depth that results in disruption of capillary loops and small vessels)small vessels)
AdvantagesAdvantages Universally availableUniversally available Relatively simple techniquesRelatively simple techniques Can be performed bedsideCan be performed bedside
DisadvantagesDisadvantages Insensitive inaccurate non-specific techniqueInsensitive inaccurate non-specific technique
Poorly reproducible (as depends on multiple variables)Poorly reproducible (as depends on multiple variables)
Optical aggregometryOptical aggregometry
Gold standard assay for platelet functionGold standard assay for platelet function Agonist induced aggregation is measuredAgonist induced aggregation is measured Different agonist are available for different Different agonist are available for different
agentsagents However require unique expertise and are not However require unique expertise and are not
universally availableuniversally available Aspirin measured with ADP or AA(gt70 Aspirin measured with ADP or AA(gt70
aggregation so resistance)aggregation so resistance) Clopidogrel( ADP gt 90 aggregation means Clopidogrel( ADP gt 90 aggregation means
resistance) resistance)
Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay
Can be performed bed sideCan be performed bed side Different assay devices with different Different assay devices with different
agonist are used for each of different agonist are used for each of different antiplatelet agents antiplatelet agents
For Aspirin AA is used (result is reported as aspirin For Aspirin AA is used (result is reported as aspirin reaction units [ARU] ARUgt 550 indicates non-reaction units [ARU] ARUgt 550 indicates non-responsiveness)responsiveness)
Verify IIbIIIa assay device uses TRAP as agonist for Verify IIbIIIa assay device uses TRAP as agonist for Abciximab and TirofibanAbciximab and Tirofiban
Practical Applications Practical Applications related to specific related to specific
Neurovascular Neurovascular interventionsinterventions
Acute ischemic StrokeAcute ischemic Stroke When an artery occludes neurons are affected When an artery occludes neurons are affected
differently depending upon the amount of residual blood differently depending upon the amount of residual blood flowflow
Normal cerebral blood flow is greater than 50 mL100 Normal cerebral blood flow is greater than 50 mL100 mgminmgmin
Once blood flow decreases to less than 20 mL100 Once blood flow decreases to less than 20 mL100 mgmin infarction occursmgmin infarction occurs
If blood flow decreases to less than 10 mL100 mgmin If blood flow decreases to less than 10 mL100 mgmin irreversible neuronal death occurs rapidly irreversible neuronal death occurs rapidly
Blood flow between 11 and 20 mL100 mgmin is thought Blood flow between 11 and 20 mL100 mgmin is thought to represent the ischemic penumbra an area where the to represent the ischemic penumbra an area where the cells are functionally silent because of ischemia but are cells are functionally silent because of ischemia but are still able to recover if blood flow is restored still able to recover if blood flow is restored
Many acute stroke therapies are targeted toward Many acute stroke therapies are targeted toward restoring flow or function to the ischemic penumbrarestoring flow or function to the ischemic penumbra
Therapeutic window in Therapeutic window in management of acute Ischemic management of acute Ischemic
StrokeStrokeThe early diagnosis of ischemic stroke is critical to the The early diagnosis of ischemic stroke is critical to the
with only a narrow therapeutic window in the first few with only a narrow therapeutic window in the first few hours following stroke ictushours following stroke ictus
Diagnosis in the first 3 hours postictus provides the Diagnosis in the first 3 hours postictus provides the opportunity for intravenous or intraarterial thrombolysis opportunity for intravenous or intraarterial thrombolysis and intra-arterial clot mechanical treatment which and intra-arterial clot mechanical treatment which improve the outcome improve the outcome
Diagnosis in the time period between 3 and 6 hours Diagnosis in the time period between 3 and 6 hours provides an opportunity for intra-arterial thrombolysis provides an opportunity for intra-arterial thrombolysis and mechanical treatment and mechanical treatment
Involvement of the posterior circulation especially the Involvement of the posterior circulation especially the basilar artery is treated by some regardless of time of basilar artery is treated by some regardless of time of onset or up until 12 to 24 hours in some practices This is onset or up until 12 to 24 hours in some practices This is related to the potentially high mortality and morbidity related to the potentially high mortality and morbidity associated with basilar artery thrombosisassociated with basilar artery thrombosis
Infarct evaluation on angiographyInfarct evaluation on angiography(CT angiography and catheter (CT angiography and catheter
angiography)angiography)CTA is an excellent first-line examination for CTA is an excellent first-line examination for
evaluation of the head and neck arteries evaluation of the head and neck arteries In comparison with catheter angiography In comparison with catheter angiography
what it gives up in resolution and dynamic what it gives up in resolution and dynamic properties it makes up for with rapid properties it makes up for with rapid acquisition of a 3-D dataset and the potential acquisition of a 3-D dataset and the potential for assessment of whole-brain perfusion and for assessment of whole-brain perfusion and better parenchymal evaluationbetter parenchymal evaluation
Moreover CTA illustrates not only arterial Moreover CTA illustrates not only arterial stenosis or occlusion but also the vessel wall stenosis or occlusion but also the vessel wall This factor is most important for evaluation of This factor is most important for evaluation of intramural dissection and thrombosed intramural dissection and thrombosed aneurysms which may both complicate aneurysms which may both complicate evaluation of stroke patientsevaluation of stroke patients
Early angiographic signs of strokes Early angiographic signs of strokes both CTA both CTA and DSA and DSA
Vessel occlusion or cutoff related to Vessel occlusion or cutoff related to thromboembolithromboemboli
aneurysms aneurysms arterial dissection arterial dissection Meniscus or flattened shape to clot Meniscus or flattened shape to clot
(recent) versus reverse meniscus (older)(recent) versus reverse meniscus (older) tram track (nonocclusive or recanalized tram track (nonocclusive or recanalized
clot) clot) delayed (antegrade) flow (manifest as delayed (antegrade) flow (manifest as
decreased whole-brain perfusion on CTA)decreased whole-brain perfusion on CTA) retrograde collateral flowretrograde collateral flow
Non-occlusive left MCA thrombus on 3-D imaging performed from CTA source data and was confirmed at catheter angiography
Therapy to be started within a 6-hr Therapy to be started within a 6-hr time to treatment (TTT) window time to treatment (TTT) window (while in case of IV thrombolysis (while in case of IV thrombolysis therapy to be started with in 3hrs)therapy to be started with in 3hrs)
Exclusion criteria Exclusion criteria Rapidly improving neurologic deficit or Rapidly improving neurologic deficit or Sustained blood pressure of gt180100 Sustained blood pressure of gt180100 Hemorrhage is detected on CTHemorrhage is detected on CT Infarct involving gt more than 13 rd Infarct involving gt more than 13 rd
territory of MCAterritory of MCA MRADWI-Perfusion mismatchlt 20MRADWI-Perfusion mismatchlt 20 Definite hypodensity on CTDefinite hypodensity on CT
Intra-arterial Thrombolysis
Fibrinolytics + AntiplateletsFibrinolytics + Antiplatelets
PlasminogenPlasminogen activators through fibrinolysis exposes activators through fibrinolysis exposes free thrombin and paradoxically stimulatesfree thrombin and paradoxically stimulates platelet platelet aggregation which leads to formation of aaggregation which leads to formation of a platelet platelet thrombus (white clot) thrombus (white clot)
This new thrombus is relatively resistant to This new thrombus is relatively resistant to fibrinolyticsfibrinolytics
So new regimen in case of acute stroke isSo new regimen in case of acute stroke is fibrinolytics + antiplatelet drugsfibrinolytics + antiplatelet drugs
rtPA + IIbIIIa inhibitors( tirofiban rtPA + IIbIIIa inhibitors( tirofiban abciximab) orabciximab) or
Urokinase + IIbIIIa Urokinase + IIbIIIa inhibitors( tirofiban abciximab)inhibitors( tirofiban abciximab)
Intra-arterial Thrombolysis Tirofiban (04 microgkgmin bolus for 3 min followed by Tirofiban (04 microgkgmin bolus for 3 min followed by
0125 ugkgmin)0125 ugkgmin)
++
Heparin (2000ndash3000 IU bolus followed by Heparin (2000ndash3000 IU bolus followed by 1000 IUhour infusion 1000 IUhour infusion
with ACT maintained bw 200-300) throughout the with ACT maintained bw 200-300) throughout the interventional procedure and for 24ndash48 hours thereafter when interventional procedure and for 24ndash48 hours thereafter when there is neither intraprocedural bleeding nor suspicion of there is neither intraprocedural bleeding nor suspicion of increased risk of bleeding increased risk of bleeding
Maximum dose of Urokinase Maximum dose of Urokinase Anterior circulation stroke - 500000 IU (mean 400000 Anterior circulation stroke - 500000 IU (mean 400000
IU range 300000ndash500000 IU)IU range 300000ndash500000 IU) Posterior circulation stroke -1000000 IU (mean 837000 Posterior circulation stroke -1000000 IU (mean 837000
IU range 300000ndash1000000 IU)IU range 300000ndash1000000 IU)American Journal of NeuroradiologyAmerican Journal of Neuroradiology 262595-2601 2005262595-2601 2005
Intravenous ThrombolysisIntravenous Thrombolysis
The first method to restore cerebral The first method to restore cerebral perfusion is clot lysis with the goal perfusion is clot lysis with the goal of re-establishing blood flow to the of re-establishing blood flow to the affected tissue affected tissue
IV thrombolysis rt-PA is the only IV thrombolysis rt-PA is the only FDA- approved treatment for AIS FDA- approved treatment for AIS
Fibrinolysis is enhanced powerfully Fibrinolysis is enhanced powerfully by rt-PAby rt-PA
Intravenous rTPA Intravenous rTPA administration administration protocolprotocol
Total dose of rt-PA 09 mgkg (maximum dose Total dose of rt-PA 09 mgkg (maximum dose 90 mg)90 mg)
Give 10 as initial IV bolusGive 10 as initial IV bolus Infuse remainder over 1 hourInfuse remainder over 1 hour Admit patient to an ICU or stroke unit for Admit patient to an ICU or stroke unit for
monitoringmonitoring Neurologic assessments every 15 minutes Neurologic assessments every 15 minutes
during infusion then every 30 minutes for next during infusion then every 30 minutes for next 6 hours then every hour until 24hours after 6 hours then every hour until 24hours after treatmenttreatment
Favorable Outcome vs Treatment Time Favorable Outcome vs Treatment Time with IV rTPAwith IV rTPA
Protocol limit = 3 hrs
Benefit ~ 45 hrs
Thromboembolism During coilingThromboembolism During coiling Most feared and frequent complication Most feared and frequent complication Reported incidence - Approx 7 Reported incidence - Approx 7 SourcesSources of Thromboembolism are of Thromboembolism are
- Clots at the aneurysmal neck during or immediately- Clots at the aneurysmal neck during or immediately after after embolization embolization
- Thrombus forming on catheters during- Thrombus forming on catheters during proceduresprocedures
- Stenosis of an adjacent artery dt coil mass- Stenosis of an adjacent artery dt coil mass or herniationor herniation
- Migration of intraaneurysmal- Migration of intraaneurysmal thrombus during coil thrombus during coil placement placement
- Slow flow dt vasospasm - Slow flow dt vasospasm
- Rare and unlikely causes are hypercoagulable- Rare and unlikely causes are hypercoagulable state such state such as antiphospholipid antibody syndrome or due to HITas antiphospholipid antibody syndrome or due to HIT
Occur more often with wide-necked aneurysms (dt Occur more often with wide-necked aneurysms (dt increased exposed surface area of thrombogenic coil increased exposed surface area of thrombogenic coil material)material)
Current regimen of endovascular Current regimen of endovascular managementmanagement
The The glycoprotein IIbIIIa antagonist tirofiban glycoprotein IIbIIIa antagonist tirofiban (04 (04 microgkgmin bolus for 30 minutes followed by infusion of microgkgmin bolus for 30 minutes followed by infusion of 0125 ugkgmin until the thrombus dissolved) 0125 ugkgmin until the thrombus dissolved)
Intraarterial thrombolysis with Intraarterial thrombolysis with urokinase or r- TPA urokinase or r- TPA increase of intravenous (IV) heparin (measured by increase of intravenous (IV) heparin (measured by
ACT) ACT) Intravenous aspirin Intravenous aspirin
Coil-related platelet aggregation (white clot) is Coil-related platelet aggregation (white clot) is unlikely to respond to fibrinolytics but has a high risk unlikely to respond to fibrinolytics but has a high risk of hemorrhage (In ISAT) all 5 patients who had of hemorrhage (In ISAT) all 5 patients who had received thrombolytic therapy with tPA to treat a received thrombolytic therapy with tPA to treat a thromboembolic complication after endovascular thromboembolic complication after endovascular treatment rebleed and all of these patients died)treatment rebleed and all of these patients died)
IntracranialIntracranial Stenting Stenting Metallic foreign body such as stent will accumulate Metallic foreign body such as stent will accumulate
thrombus in the absence of platelet inhibitionthrombus in the absence of platelet inhibition Antiplatelet drugs are important to prevent peri or Antiplatelet drugs are important to prevent peri or
post-interventional thromboembolic eventspost-interventional thromboembolic events Optimal treatment regimens has not been determined Optimal treatment regimens has not been determined
but usually but usually Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-
procedureprocedureOrOr
Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on
morning of proceduremorning of procedure
If need to use stent is not pre-planned thanIf need to use stent is not pre-planned than
Abciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkgAbciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkg IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)
Glycoprotein IIbIIIa inhibitor are not used routinely during elective Glycoprotein IIbIIIa inhibitor are not used routinely during elective stenting procedure dt increased risk of ICH stenting procedure dt increased risk of ICH
Carotid StentingCarotid Stenting
Pre-procedurePre-procedure
Double Antiplatelet therapy is routinely given Double Antiplatelet therapy is routinely given beginning at least 3beginning at least 3
days before the proceduredays before the procedure
Aspirin 325mgd+Clopidogrel 75mgdAspirin 325mgd+Clopidogrel 75mgd During procedureDuring procedure
Heparin is given with target clotting time of 250-Heparin is given with target clotting time of 250-300sec300sec
Post-procedure Post-procedure
Aspirin 325mg is continued indefinitely and Aspirin 325mg is continued indefinitely and
Clopidogrel 75mgd for at least 6 weeks Clopidogrel 75mgd for at least 6 weeks
Inclusion criteria for Local ThrombolysisInclusion criteria for Local Thrombolysis a)a) Patients in severe clinical grade on admission Patients in severe clinical grade on admission
with evidence of dural venous sinus with evidence of dural venous sinus thrombosis and restrictive venous outflow on thrombosis and restrictive venous outflow on cerebral angiogramcerebral angiogram
b)b) Patients in clinical grade 3 worsening on Patients in clinical grade 3 worsening on heparin therapy Restriction to venous heparin therapy Restriction to venous outflow was defined as an increase in brain outflow was defined as an increase in brain circulation time gt 12 s delay in the drainage circulation time gt 12 s delay in the drainage of cortical veins with cortical veins hanging of cortical veins with cortical veins hanging in spacein space
Treatment Options for Venous Thrombosis
CT Grading for Venous ThrombosisCT Grading for Venous Thrombosis Grade I no parenchymal change Grade I no parenchymal change
(hyperdense (hyperdense sinuses cortical veins empty sinuses cortical veins empty delta sign)delta sign)
Grade II non hemorrhagic venous infarct Grade II non hemorrhagic venous infarct without mass effect without mass effect
Grade III non-hemorrhagic infarct with Grade III non-hemorrhagic infarct with mass effectmass effect
Grade IV hemorrhagic venous infarct (max Grade IV hemorrhagic venous infarct (max diameter lt 3 cm) with no mass effectdiameter lt 3 cm) with no mass effect
Grade V hemorrhagic venous infarct (max Grade V hemorrhagic venous infarct (max diameter gt 3 cm) with mass effect diameter gt 3 cm) with mass effect
Local ThrombolysisLocal Thrombolysis
Femoral Jugular access was secured and a guiding Femoral Jugular access was secured and a guiding catheter was placed in the jugular bulb catheter was placed in the jugular bulb Mechanical Mechanical clot maceration clot maceration was done with the guidewire was done with the guidewire following which a microcatheter (was navigated and following which a microcatheter (was navigated and placed in the thrombosed segment of sinus confirmed placed in the thrombosed segment of sinus confirmed on a selective venogram on a selective venogram
Urokinase infusion Bolus dose of 2-6 lacs followed Urokinase infusion Bolus dose of 2-6 lacs followed by 60000 to 100000 units per hour along with by 60000 to 100000 units per hour along with periodic check venogram Along with maintenance periodic check venogram Along with maintenance systemic infusion of Heparinsystemic infusion of Heparin Other agents such as Other agents such as streptokinase altepase or rTPAstreptokinase altepase or rTPA can be also used can be also used
After thrombolysis patient should subjected to oral After thrombolysis patient should subjected to oral anticoagulation for six monthsanticoagulation for six months
Low-molecular-weight Low-molecular-weight heparinheparin
PharmacologyPharmacologyLMWH as its name suggests is a glycosaminoglycan that is approximatelyLMWH as its name suggests is a glycosaminoglycan that is approximately
one third the molecular weight of UFH It is derived from UFH through one third the molecular weight of UFH It is derived from UFH through variousvarious
depolymerization processes LMWH binds to antithrombin which in turn depolymerization processes LMWH binds to antithrombin which in turn
Neutralizes actors Xa and IIa Because LMWH lacks many of the longer Neutralizes actors Xa and IIa Because LMWH lacks many of the longer chains chains
required for binding to thrombin it has less ability to neutralize thrombin required for binding to thrombin it has less ability to neutralize thrombin
relativeto its ability to neutralize factor Xa LMWH also has less relativeto its ability to neutralize factor Xa LMWH also has less nonspecific nonspecific
binding to other proteins There is greater bioavailability with more binding to other proteins There is greater bioavailability with more predictable predictable
pharmacokinetics that eliminates the need for monitoring The smaller pharmacokinetics that eliminates the need for monitoring The smaller size also size also
allows for enhanced subcutaneous absorption when compared with UFHallows for enhanced subcutaneous absorption when compared with UFH
Three LMWH preparations are Three LMWH preparations are currently approved for use in the currently approved for use in the United States (1) enoxaparin (2) United States (1) enoxaparin (2) dalteparin and (3) tinzaparin dalteparin and (3) tinzaparin
They are all administered They are all administered subcutaneously at intervals of either subcutaneously at intervals of either once or twice daily for both once or twice daily for both prophylaxis and treatment dosesprophylaxis and treatment doses
Few Experiences of Few Experiences of ThrombolysisThrombolysis
Vickey 25 Yrs male patient presented Vickey 25 Yrs male patient presented with 12with 12thth day HO severe headache with day HO severe headache with right sided hemiplegiaright sided hemiplegia
MRI shows thrombosis of the superior MRI shows thrombosis of the superior sagittal left transverse left sigmoid sagittal left transverse left sigmoid sinuses and cortical veins in the fronto-sinuses and cortical veins in the fronto-parietal regions with eo haemorrhagic parietal regions with eo haemorrhagic infarct in the left cerebral hemisphere infarct in the left cerebral hemisphere with mass effect( Grade ndashV)with mass effect( Grade ndashV)
Sashi Srivastava 64 yrs FSashi Srivastava 64 yrs F In a follow up case of MRD with infra-renal In a follow up case of MRD with infra-renal
aortic abdominal and bilateral renal artery aortic abdominal and bilateral renal artery thrombosis renal angiogram shows filling thrombosis renal angiogram shows filling defects in the right Renal artery defects in the right Renal artery
Initially Renal angioplasty was done Initially Renal angioplasty was done Following angioplasty few thrombi are seem Following angioplasty few thrombi are seem to extends into the segmental branches and to extends into the segmental branches and causing blockage So Thrombolysis was causing blockage So Thrombolysis was plane to dissolve the run-out thrombi with plane to dissolve the run-out thrombi with urokinase urokinase
Rakesh 34yrsMRakesh 34yrsM Left SFA pseudoaneurysm with Left SFA pseudoaneurysm with
Covered stent placementCovered stent placement Pre operative antiplatelets with post Pre operative antiplatelets with post
procedure heparin Tirofiban procedure heparin Tirofiban followed by aspirin and clopidogrel followed by aspirin and clopidogrel were usedwere used
IAT may be a treatment option for selected patients IAT may be a treatment option for selected patients Possible selection criteria include Possible selection criteria include
presentation between 3 and 6 hours from symptom onsetpresentation between 3 and 6 hours from symptom onset major cerebral artery occlusion major cerebral artery occlusion severe neurologic deficits severe neurologic deficits high risk of systemic hemorrhage with IV rt-PA (eg recent high risk of systemic hemorrhage with IV rt-PA (eg recent
surgery) surgery) The MERCI (Mechanical Embolus Removal in Cerebral The MERCI (Mechanical Embolus Removal in Cerebral
Ischemia) retrievalIschemia) retrieval system system
Has been FDA-approved for recanalizing acutely occluded Has been FDA-approved for recanalizing acutely occluded cerebral arteries cerebral arteries
In the Multi-MERCI study patients who did not improve In the Multi-MERCI study patients who did not improve immediately after IV rt-PA underwent mechanical immediately after IV rt-PA underwent mechanical embolectomy within 8 hours of symptom onset embolectomy within 8 hours of symptom onset
Partial or complete recanalization occurred in 74 of Partial or complete recanalization occurred in 74 of patientspatients
with a symptomatic intracerebral hemorrhage (sICH) rate of with a symptomatic intracerebral hemorrhage (sICH) rate of 67 67
Mechanical embolectomy with the MERCI retriever may be a Mechanical embolectomy with the MERCI retriever may be a feasible and safe option for patients after IV rt-PAfeasible and safe option for patients after IV rt-PA
Penumbra stroke systemPenumbra stroke system This device combines two methods of clot This device combines two methods of clot
extraction aspiration and mechanical extraction aspiration and mechanical extraction extraction
First the clot is aspirated then a thrombus First the clot is aspirated then a thrombus removal ring can be used if necessary to removal ring can be used if necessary to remove remaining clot remove remaining clot
successful recanalizing 82successful recanalizing 82 Bridging therapyBridging therapy
06 mgkg IV rt-PA followed by IAT with IA rt-06 mgkg IV rt-PA followed by IAT with IA rt-PA (up to 20 mg)PA (up to 20 mg)
achieved a higher recanalization rateachieved a higher recanalization rate
Criteria for thrombolysis with rTPACriteria for thrombolysis with rTPA
Inclusion criteriaInclusion criteria Clinical signs and symptoms consistent with ischemic Clinical signs and symptoms consistent with ischemic
strokestroke Patient last seen normal within 3 hoursPatient last seen normal within 3 hours Measurable neurologic deficitMeasurable neurologic deficit
Exclusion criteriaExclusion criteria Any hemorrhage on neuroimaging (CT or MRI)Any hemorrhage on neuroimaging (CT or MRI) Symptoms suggestive of subarachnoid hemorrhageSymptoms suggestive of subarachnoid hemorrhage Seizure at stroke onset that is thought to contribute to Seizure at stroke onset that is thought to contribute to
neurologic deficitneurologic deficit Hypodensity greater than one third cerebral hemisphere Hypodensity greater than one third cerebral hemisphere
on CTon CT SBP greater than 185 mm Hg or DBP greater than 110 SBP greater than 185 mm Hg or DBP greater than 110
mm Hgmm Hg International normalized ratio (INR) greater than 17International normalized ratio (INR) greater than 17
Ischemic Stroke Ischemic Stroke Treatment ndash 2006Treatment ndash 2006
IV tissue plasminogen activator (tPA)IV tissue plasminogen activator (tPA) ndash ndash Only FDA-approved acute stroke drugOnly FDA-approved acute stroke drug ndash ndash 3 hour treatment window3 hour treatment window
MERCI - Concentric clot retrieval MERCI - Concentric clot retrieval devicedevice ndash ndash Rescue therapy - approved 2004Rescue therapy - approved 2004 ndash ndash Device approval (not outcomes-based)Device approval (not outcomes-based)
Off label approachesOff label approaches ndash ndash IV tPA after 3 hoursIV tPA after 3 hours ndash ndash IV-IA tPA sequential strategiesIV-IA tPA sequential strategies ndash ndash IA tPA clot angioplasty fragmentationIA tPA clot angioplasty fragmentation ndash ndash Ultrasound-assisted tPA lysisUltrasound-assisted tPA lysis
rt-PA Trials NINDSrt-PA Trials NINDS
Acute stroke - 624 patientsAcute stroke - 624 patients Treat within 3 hrsTreat within 3 hrs Intravenous 09 mgkg rt-PA vs placeboIntravenous 09 mgkg rt-PA vs placebo Hemorrhage 64 tPA 06 placeboHemorrhage 64 tPA 06 placebo Neurologic recovery better with tPA 30 Neurologic recovery better with tPA 30
more like to have minimal or no disabilitymore like to have minimal or no disability
First proven approved treatment for First proven approved treatment for strokestroke
Limitations of tPALimitations of tPA Only 4 of acute strokes receive tPAOnly 4 of acute strokes receive tPA (Kleindorfer et al Stroke 2004 35 e27-e29)(Kleindorfer et al Stroke 2004 35 e27-e29)
Only 22 of patients present within 3 hoursOnly 22 of patients present within 3 hours1048707 1048707 51 of these ineligible due to51 of these ineligible due to
bull bull Mild severityMild severity bull bull Medical or surgical historyMedical or surgical history bull bull Blood testsBlood tests
Sustained recanalization only 13Sustained recanalization only 13 (Alexandrov et al NEJM 2004 351 2170-8)(Alexandrov et al NEJM 2004 351 2170-8)
Concern for hemorrhageConcern for hemorrhage tPA potentiates apoptotic injury tPA potentiates apoptotic injury (Liu et al Nature Med 2004 101379-83)(Liu et al Nature Med 2004 101379-83)
PROACT II IA Lysis TrialPROACT II IA Lysis Trial Baseline 24 hours 8 days
Baseline 60 minutes 120 minutes
9mg IAProurokinase
Desmoteplase Trials DEDAS Desmoteplase Trials DEDAS DIASDIAS
Trial OverviewTrial Overview Double blind randomized placebo Double blind randomized placebo
controlled trialscontrolled trials IV delivery 3-9 hour time windowIV delivery 3-9 hour time window Plasminogen activator ndash from Plasminogen activator ndash from vampire bat vampire bat
salivasaliva Selection based on PWI-DWI MismatchSelection based on PWI-DWI Mismatch
MRI InclusionMRI Inclusion PWI defect at least 2 cm AND ~20 larger PWI defect at least 2 cm AND ~20 larger
than DWIthan DWI PWI should be obvious even visible on PWI should be obvious even visible on
raw imagesraw imagesMRI ExclusionMRI Exclusion
DWI gt 13 MCADWI gt 13 MCA MRA ICA occlusionMRA ICA occlusion
Desmoteplase ndash DIAS Desmoteplase ndash DIAS ResultsResults
Mechanical Thrombolysis Mechanical Thrombolysis devicesdevices
mechanical thrombolysis potentially extends the treatment mechanical thrombolysis potentially extends the treatment window because they act promptly at the site of the thrombuswindow because they act promptly at the site of the thrombus
The devices can retrieve large clots that pharmaceutical agents The devices can retrieve large clots that pharmaceutical agents may not successfully lysemay not successfully lyse
Patients treated with IV tPA may be considered for treatment of Patients treated with IV tPA may be considered for treatment of residual clot with some of these devicesresidual clot with some of these devices
suction-creating saline jets suction-creating saline jets laser energy ultrasound laser energy ultrasound a corkscrew apparatus to treat strokesa corkscrew apparatus to treat strokes The AngioJet systemThe AngioJet system uses saline jets that are directed back into the catheter to uses saline jets that are directed back into the catheter to
create a low-pressure zone around the catheter tip inducing create a low-pressure zone around the catheter tip inducing suction suction
The clot is pulled into the exhaust lumen and removed from the The clot is pulled into the exhaust lumen and removed from the vessel Although US Food and Drug Administration (FDA) has vessel Although US Food and Drug Administration (FDA) has approved this device for use in arteriovenous dialysis grafts and approved this device for use in arteriovenous dialysis grafts and fistulae and for the treatment of coronary arteries saphenous fistulae and for the treatment of coronary arteries saphenous vein grafts and peripheral vessels clinical trials for the vein grafts and peripheral vessels clinical trials for the treatment of acute stroke are no longer in progress treatment of acute stroke are no longer in progress
Most devices are used in cerebral vessels that 2-5 mm
The Latis laser device The Latis laser device used laser energy to ablate clots used laser energy to ablate clots Arteries 2-5 mm in diameter could be Arteries 2-5 mm in diameter could be
treated including the ICA M1 or M2 treated including the ICA M1 or M2 branch of the MCA A1 branch of the branch of the MCA A1 branch of the anterior cerebral artery (ACA) basilar anterior cerebral artery (ACA) basilar artery posterior cerebral artery (PCA) artery posterior cerebral artery (PCA) and vertebral and vertebral
Patients could receive treatment as late Patients could receive treatment as late as 8 hours after symptom onset in the as 8 hours after symptom onset in the anterior circulation and within 24 hours in anterior circulation and within 24 hours in the posterior circulation the posterior circulation
Endovascular Photo Acoustic Endovascular Photo Acoustic Recanalization (EPAR) Recanalization (EPAR)
A laser power source generated energy for the A laser power source generated energy for the systemsystem
The energy was delivered by means of The energy was delivered by means of fiberoptics to the tip of the catheter at the fiberoptics to the tip of the catheter at the treatment sitetreatment site
Absorption of laser light by darkly pigmented Absorption of laser light by darkly pigmented materials (ie the clot) occurred inside the 1-mm materials (ie the clot) occurred inside the 1-mm catheter tipcatheter tip
the system was designed to minimize scattering the system was designed to minimize scattering of laser light of laser light
Absorption converted photo energy to acoustic Absorption converted photo energy to acoustic energy which then emulsified the clot inside the energy which then emulsified the clot inside the catheter tip catheter tip
EKOS ultrasound( the EKOS ultrasound( the Ultrasound Thrombolytic Ultrasound Thrombolytic
Infusion Catheter) Infusion Catheter) combines the use of a distal ultrasound transducer with combines the use of a distal ultrasound transducer with
infusion of a thrombolytic agent through the infusion of a thrombolytic agent through the microcathetermicrocatheter
Ultrasound changes the structure of the clot to Ultrasound changes the structure of the clot to temporarily increase its permeability while providing an temporarily increase its permeability while providing an acoustic pressure gradient to move the drug into the clot acoustic pressure gradient to move the drug into the clot to speed its dissolution to speed its dissolution
The EKOS catheter is placed in the proximal portion of the The EKOS catheter is placed in the proximal portion of the clot clot
After a 2-mg bolus of tPA was injected through the After a 2-mg bolus of tPA was injected through the catheter catheter
the patient received a continuous infusion of IA tPA 03 the patient received a continuous infusion of IA tPA 03 mgmin to a maximum of 20 mg and simultaneous mgmin to a maximum of 20 mg and simultaneous ultrasound transmission for as long as 60 minutes ultrasound transmission for as long as 60 minutes
One patient was treated with a total of 4 units of One patient was treated with a total of 4 units of recombinant reteplase (Retavase) hand-injected over 60 recombinant reteplase (Retavase) hand-injected over 60 minutes minutes
Penumbra system Penumbra system The Penumbra system (Penumbra Inc) provides a dual The Penumbra system (Penumbra Inc) provides a dual
approach to clot extraction using aspiration followed by approach to clot extraction using aspiration followed by clot retrieval with a ring device if needed clot retrieval with a ring device if needed
Mechanical Embolus Removal in Cerebral Ischemia Mechanical Embolus Removal in Cerebral Ischemia (MERCI)(MERCI)
a corkscrew-like apparatus to remove blood clots from a corkscrew-like apparatus to remove blood clots from the brain in patients experiencing an ischemic stroke the brain in patients experiencing an ischemic stroke
The corkscrew itself resides in the catheter tip which The corkscrew itself resides in the catheter tip which shields it from the wall of the vessel until it is ready to be shields it from the wall of the vessel until it is ready to be burrowed into the clot Once lodged in the clot the device burrowed into the clot Once lodged in the clot the device and clot are withdrawn from the vessel and clot are withdrawn from the vessel
Snarelike devicesSnarelike devices Snares such as the Neuronet snare (Guidant Snares such as the Neuronet snare (Guidant
Endovascular Santa Clara CA) have been developed Endovascular Santa Clara CA) have been developed specifically for use in the treatment of strokes specifically for use in the treatment of strokes
These devices are simple in design and do not require the These devices are simple in design and do not require the clot to be amenable to emulsification clot to be amenable to emulsification
X-Sizer deviceX-Sizer device a device with small moving blades at the a device with small moving blades at the
catheter tip catheter tip This device the X-Sizer device (EndiCor Medical This device the X-Sizer device (EndiCor Medical
San Clemente CA) can be used to excise the San Clemente CA) can be used to excise the thrombus and aspirate it thrombus and aspirate it
The device was being evaluated in randomized The device was being evaluated in randomized studies of coronary vessels and in a registry of studies of coronary vessels and in a registry of patients with acute myocardial infarctionpatients with acute myocardial infarction
Although the manufacturer had modified the Although the manufacturer had modified the device for use in cerebral vessels a safety and device for use in cerebral vessels a safety and feasibility study was indefinitely suspended after feasibility study was indefinitely suspended after only 1 patient was treated with the device in only 1 patient was treated with the device in Europe Europe
Suction thrombectomySuction thrombectomy This method of mechanical thrombolysis is one of the This method of mechanical thrombolysis is one of the
simplestsimplest In this readily available technique suction is applied with In this readily available technique suction is applied with
a syringe to remove thrombus in the ICA a syringe to remove thrombus in the ICA It requires no other devicesIt requires no other devices A catheter with a large inner diameter (Brite Tip Cordis A catheter with a large inner diameter (Brite Tip Cordis
Corporation Miami FL) was placed in the symptomatic Corporation Miami FL) was placed in the symptomatic vessel and navigated over a guidewire into the thrombusvessel and navigated over a guidewire into the thrombus
A 60-mL syringe was used to aspirate the thrombus A 60-mL syringe was used to aspirate the thrombus Each patient required angioplasty and stenting of carotid Each patient required angioplasty and stenting of carotid
bifurcation stenosis and received daily aspirin and bifurcation stenosis and received daily aspirin and ticlopidine after the procedure No complications ticlopidine after the procedure No complications occurred occurred
Summary Acute Stroke Summary Acute Stroke ImagingImaging
PhysiologyPhysiology importance collaterals importance collaterals
ndash ndashGrowing role for perfusion Growing role for perfusion assessmentassessment
tPAtPA guidelines amp limitations guidelines amp limitations Signs on CT amp MRSigns on CT amp MR follow physiology follow physiology Stroke trialsStroke trials PWI-DWI mismatch PWI-DWI mismatch
ndash ndashTreat based on physiology not timeTreat based on physiology not time ProtocolsProtocols should be fast and should be fast and
comprehensivecomprehensive
FACTORS INFLUENCING DOSE RESPONSEFACTORS INFLUENCING DOSE RESPONSE
Poor patient compliancePoor patient compliance Concomitant medicationsConcomitant medications Levels of dietary vitamin KLevels of dietary vitamin K Alcohol Inaccurate lab testingAlcohol Inaccurate lab testing Inaccurate lab testingInaccurate lab testing Hepatic dysfunctionHepatic dysfunction FeverFever
Contraindication for WarfarinContraindication for Warfarin
Hypersensitivity to warfarinHypersensitivity to warfarin Hemorrhagic tendencyHemorrhagic tendency Condition with risk of hemorrhageCondition with risk of hemorrhage Inadequate laboratory techniquesInadequate laboratory techniques Protein C amp S deficiencyProtein C amp S deficiency Vitamin K deficiencyVitamin K deficiency
SIDE EFFECTSSIDE EFFECTS
Hemorrhage Hemorrhage Skin necrosisSkin necrosis Purple toe syndromePurple toe syndrome Microembolization Microembolization TeratogenecityTeratogenecity Agranulocytosis leukopenia Agranulocytosis leukopenia Diarrhoeanausea anorexiaDiarrhoeanausea anorexia
MONITORING OF WARFARIN THERAPYMONITORING OF WARFARIN THERAPY
Prothrombin timeProthrombin time PT ratioPT ratio INR (International Normalized Ratio)INR (International Normalized Ratio)
PROTHROMBIN TIME (PT)PROTHROMBIN TIME (PT)
Time required for blood to coagulate Time required for blood to coagulate is called PT ( normal value ~10sec)is called PT ( normal value ~10sec)
Performed by adding a mixture of Performed by adding a mixture of calcium and thromboplastin to calcium and thromboplastin to citrated plasmacitrated plasma
As a control a normal blood sample is As a control a normal blood sample is tested continuouslytested continuously
PT ratio (PTR) = PT ratio (PTR) = Patientrsquos PTPatientrsquos PT Control PTControl PT
PROBLEMS WITH PTPTRPROBLEMS WITH PTPTR
Thromboplastins are extracts from Thromboplastins are extracts from brain lung or placenta of animalsbrain lung or placenta of animals
Thromboplastins from various Thromboplastins from various manufacturers differ in their manufacturers differ in their sensitivity to prolong PTsensitivity to prolong PT
May result in false control of May result in false control of anticoagulant therapyanticoagulant therapy
INTERNATIONAL NORMALISED RATIO (INR)INTERNATIONAL NORMALISED RATIO (INR)
International Normalized Ratio (INR) International Normalized Ratio (INR) a PT test with a a PT test with a formula based ratio to normalize the often variable source formula based ratio to normalize the often variable source of tissue factor (human rabbit recombinant)of tissue factor (human rabbit recombinant)
INR = [PTINR = [PTptpt] ] ISIISI
[PT[PTRefRef]]
PTPTpt pt ndash prothrombin time of patientndash prothrombin time of patient
PTPTRef Ref ndash prothrombin time of normal pooled samplendash prothrombin time of normal pooled sample
ISI ndash International Sensitivity IndexISI ndash International Sensitivity Index
Warfarin is given orally and titrated to achieve an INR of Warfarin is given orally and titrated to achieve an INR of typically 20 ndash 30typically 20 ndash 30
Heparin versus WarfarinHeparin versus Warfarin
Drug ActionMechan-ism
Moni-toring
Effective
HeparinDirect
Inhibition ofThrombin
ATIIIcofactor
APTTACT
Immediate
WarfarinDecreasesProductionof factors
Vitamin K PTDelay
3-5 days
INR
Recanalization or Antegrade Recanalization or Antegrade Reperfusion StrategiesReperfusion Strategies
Recanalization strategies focus on removing Recanalization strategies focus on removing andor dissolving the occlusive thrombus to re-andor dissolving the occlusive thrombus to re-establish antegrade flow Strategies may be establish antegrade flow Strategies may be classified into 7 different categories on the classified into 7 different categories on the basis of their primary mechanism of action basis of their primary mechanism of action 1) 1) IV andor intraarterial thrombolysis (IAT) IV andor intraarterial thrombolysis (IAT) 2) endovascular thrombectomy2) endovascular thrombectomy3) endovascular thromboaspiration 3) endovascular thromboaspiration 4) endovascular mechanical thrombus disruption or 4) endovascular mechanical thrombus disruption or
thromborrhexisthromborrhexis5) 5) transcranial or endovascular augmented transcranial or endovascular augmented
fibrinolysis fibrinolysis 6) endovascular thrombus entrapment and 6) endovascular thrombus entrapment and 7) temporary endovascular bypass7) temporary endovascular bypass
IAT in Acute Ischemic StrokeIAT in Acute Ischemic Stroke
IAT advantages over IV thrombolysisIAT advantages over IV thrombolysis Coaxial microcatheter techniques the occluded intracranial Coaxial microcatheter techniques the occluded intracranial
vessel is directly accessible and the fibrinolytic agent can be vessel is directly accessible and the fibrinolytic agent can be infused directly into the thrombusinfused directly into the thrombus
This permits a smaller dose of fibrinolytic agent to reach a This permits a smaller dose of fibrinolytic agent to reach a higher local concentration than that reached by systemic higher local concentration than that reached by systemic infusioninfusion
Allows more complete recanalization with lower total doses of Allows more complete recanalization with lower total doses of thrombolytic thrombolytic
With the smaller dose complications from systemic fibrinolytic With the smaller dose complications from systemic fibrinolytic effects including intracranial hemorrhage (ICH) can effects including intracranial hemorrhage (ICH) can theoretically be reduced theoretically be reduced
Treatment window for endovascular techniques can be Treatment window for endovascular techniques can be extended beyond the typical IV window of 3 hours extended beyond the typical IV window of 3 hours
IA techniques have led to higher recanalization rates than IV IA techniques have led to higher recanalization rates than IV thrombolysisthrombolysis
Major disadvantagesMajor disadvantages Relative complexity of the procedure the level Relative complexity of the procedure the level
of required technical expertise and its of required technical expertise and its relatively low availability relatively low availability
Delays in initiating treatmentDelays in initiating treatment InvasiveInvasive
ThrombolyticsThrombolytics
Plasminogen activators
Fibrinolytics
1 Plasminogen Activators 1 Plasminogen Activators drugs act by converting the inactive proenzyme drugs act by converting the inactive proenzyme plasminogen into the active enzyme plasmin Plasmin plasminogen into the active enzyme plasmin Plasmin digests fibrinogen fibrin monomers and cross-linked digests fibrinogen fibrin monomers and cross-linked fibrin (as found in a thrombus) into fibrin degradation fibrin (as found in a thrombus) into fibrin degradation productsproducts
First-Generation Agents First-Generation Agents StreptokinaseStreptokinase a protein derived from group C a protein derived from group C
szlig-hemolytic streptococci has a half-life of 16ndashszlig-hemolytic streptococci has a half-life of 16ndash90 minutes and low fibrin specificity This drug 90 minutes and low fibrin specificity This drug proved to have a very narrow therapeutic proved to have a very narrow therapeutic window and significant rates of ICH and window and significant rates of ICH and systemic hemorrhage18systemic hemorrhage18
UrokinaseUrokinase is a serine protease with a plasma is a serine protease with a plasma half life of 14 minutes and low fibrin specificity half life of 14 minutes and low fibrin specificity
The urokinase dose used in cerebral IAT has The urokinase dose used in cerebral IAT has ranged from 002 to 2 X106unitsranged from 002 to 2 X106units
Second-Generation Agents Second-Generation Agents Alteplase (rtPA) Alteplase (rtPA)
is a serine is a serine protease with a plasma half-life of 35 protease with a plasma half-life of 35 minutes and a high degree of fibrin affinity and minutes and a high degree of fibrin affinity and specificity specificity
Dose used in cerebral IAT has ranged between 20 Dose used in cerebral IAT has ranged between 20 and 60 mgand 60 mg
Disadvantages of alteplase include its relatively short Disadvantages of alteplase include its relatively short halflife and limited penetration into the clot matrix halflife and limited penetration into the clot matrix because of strong binding with surface fibrin which because of strong binding with surface fibrin which could delay recanalization and increase the risk of could delay recanalization and increase the risk of recurrent occlusion recurrent occlusion
Prourokinase (r-prourokinase) Prourokinase (r-prourokinase) is the proenzyme precursor of urokinase is the proenzyme precursor of urokinase T12 of 7 minutes and high fibrin specificity T12 of 7 minutes and high fibrin specificity
Third-Generation AgentsThird-Generation Agents
ReteplaseReteplase is a structurally modified is a structurally modified form of alteplase form of alteplase
with a longer half-life (15ndash18 minutes) In with a longer half-life (15ndash18 minutes) In addition it does not bind as highly to fibrin addition it does not bind as highly to fibrin unbound reteplase can thus theoretically better unbound reteplase can thus theoretically better penetrate the clot and potentially penetrate the clot and potentially improve in improve in vivo fibrinolytic activity vivo fibrinolytic activity
TenecteplaseTenecteplase is another modified form of rtPA with a longer is another modified form of rtPA with a longer
half-life (17 minutes)half-life (17 minutes) greater fibrin specificity and greater greater fibrin specificity and greater
resistance to plasminogen activator inhibitor-1 resistance to plasminogen activator inhibitor-1 IV tenecteplase in acute ischemic stroke IV tenecteplase in acute ischemic stroke
suggest that the drug is safe and promisingsuggest that the drug is safe and promising
Newer plasminogen activatorNewer plasminogen activator
DesmoteplaseDesmoteplase is a genetically engineered is a genetically engineered version of the clot-dissolving factor version of the clot-dissolving factor
found in the saliva found in the saliva of the vampire bat Desmodus rotundusof the vampire bat Desmodus rotundus moremore potent and more selective for fibrin-bound potent and more selective for fibrin-bound
plasminogen than any other known plasminogen plasminogen than any other known plasminogen activatoractivator
Unlike tissue plasminogen activator (tPA) desmoteplase Unlike tissue plasminogen activator (tPA) desmoteplase is not activated by fibrinogen or -amyloid proteins is not activated by fibrinogen or -amyloid proteins factors that may exacerbate the risk for ICH factors that may exacerbate the risk for ICH
The effect of IV administration of desmoteplase 3ndash9 The effect of IV administration of desmoteplase 3ndash9 hours after symptom onset in patients with stroke who hours after symptom onset in patients with stroke who present with mismatch on MR imaging or CT perfusion present with mismatch on MR imaging or CT perfusion
3 DefibrinogenatingFibrinogenolytic 3 DefibrinogenatingFibrinogenolytic Agents Agents
AncrodAncrod(Viprinex)(Viprinex) is is the purified fraction of the Malayan pit viper venomthe purified fraction of the Malayan pit viper venom It acts by directly cleaving and inactivating fibrinogen It acts by directly cleaving and inactivating fibrinogen
and thus indirectly promoting anticoagulation and thus indirectly promoting anticoagulation The reduction in the blood levels of fibrinogen also The reduction in the blood levels of fibrinogen also
leads to a reduced blood viscosity which may improve leads to a reduced blood viscosity which may improve blood flow to the affected areas of the brain blood flow to the affected areas of the brain
In the Stroke Treatment with Ancrod Trial 500 In the Stroke Treatment with Ancrod Trial 500 patients with stroke presenting within 3 hours of patients with stroke presenting within 3 hours of symptom onset were randomized to receive ancrod (symptom onset were randomized to receive ancrod (n n 248) or a placebo (n 252) Good outcome (Barthel 248) or a placebo (n 252) Good outcome (Barthel Index 95ndash100 at 3 months) was achieved in 4221 Index 95ndash100 at 3 months) was achieved in 4221 and 344 of the patients respectively and 344 of the patients respectively
2 Direct Fibrinolytics2 Direct Fibrinolytics
Microplasmin (Microplasmin (ThromboGenics Heverlee Belgium)ThromboGenics Heverlee Belgium) is a truncated form of plasmin that is more resistant to the effects is a truncated form of plasmin that is more resistant to the effects
of antiplasmin of antiplasmin microplasmin can be used upto 4ndash12 hours after stroke onset microplasmin can be used upto 4ndash12 hours after stroke onset There was no evidence of increased bleeding risk with There was no evidence of increased bleeding risk with
microplasminmicroplasmin
Alfimeprase (Nuvelo San Carlos Calif)Alfimeprase (Nuvelo San Carlos Calif) is a recombinant truncated form of fibrolase a fibrinolytic zinc metalloproteinase is a recombinant truncated form of fibrolase a fibrinolytic zinc metalloproteinase
isolated from the venom of the southern copperhead snake isolated from the venom of the southern copperhead snake It degrades fibrin directly and achieves thrombolysis independent It degrades fibrin directly and achieves thrombolysis independent
of plasmin formationof plasmin formation its thrombolytic activity appears to be localized to the site of its thrombolytic activity appears to be localized to the site of
delivery These properties should theoretically result in faster delivery These properties should theoretically result in faster recanalization and lower hemorrhagic conversion riskrecanalization and lower hemorrhagic conversion risk
Anti-fibrinolyticsAnti-fibrinolytics
to limit fibrinolytic activityto limit fibrinolytic activity -aminocaproic acid (EACA) -aminocaproic acid (EACA) competitively inhibitscompetitively inhibits plasminogen and plasminogen activators from plasminogen and plasminogen activators from
binding to fibrinbinding to fibrin
alpha2-antiplasminalpha2-antiplasmin a serine protease inhibitor that a serine protease inhibitor that neutralizes any free circulating plasminneutralizes any free circulating plasmin
Plasminogen activator inhibitor-1Plasminogen activator inhibitor-1 a serine protease a serine protease inhibitor that inhibits tissue-type plasminogen inhibitor that inhibits tissue-type plasminogen activatoractivator
Glycoprotein (GP) IIbIIIa antagonistsGlycoprotein (GP) IIbIIIa antagonists
such as ReoPro (abciximab) Integrilin such as ReoPro (abciximab) Integrilin (eptifibatide) or Aggrastat (tirofiban) in (eptifibatide) or Aggrastat (tirofiban) in ischemic stroke remains investigational ischemic stroke remains investigational Deshmukh et al38 reported 21 patients with Deshmukh et al38 reported 21 patients with large-vessel occlusion refractory to IAT with large-vessel occlusion refractory to IAT with rtPA who were treated with IV andor IA rtPA who were treated with IV andor IA abciximab eptifibatide or tirofiban abciximab eptifibatide or tirofiban
IA Mechanical Approaches in Acute Ischemic Stroke IA Mechanical Approaches in Acute Ischemic Stroke Mechanical strategies have several advantagesMechanical strategies have several advantages First they lessen and may even preclude the use of chemical First they lessen and may even preclude the use of chemical
thrombolytics in this manner very likely reducing the risk of ICHthrombolytics in this manner very likely reducing the risk of ICH Second by avoiding the use of chemical thrombolytics it is Second by avoiding the use of chemical thrombolytics it is
possible to extend the treatment window beyond the limit of 6ndash8 possible to extend the treatment window beyond the limit of 6ndash8 hours hours
Third mechanically fragmenting a clot increases the surface area Third mechanically fragmenting a clot increases the surface area accessible to fibrinolytic agents and allows inflow of fresh accessible to fibrinolytic agents and allows inflow of fresh plasminogen which in turn may increase the speed of plasminogen which in turn may increase the speed of thrombolysis thrombolysis
Finally clot-retrieval devices may provide faster recanalization Finally clot-retrieval devices may provide faster recanalization
The disadvantages of the mechanical The disadvantages of the mechanical approaches approaches technical difficulty of navigating mechanical technical difficulty of navigating mechanical
devices into the intracranial circulation excessive devices into the intracranial circulation excessive trauma to the vasculature (potentially leading to trauma to the vasculature (potentially leading to vasospasm vessel dissection perforation or vasospasm vessel dissection perforation or rupture) rupture)
fragmented thrombus causing distal embolization fragmented thrombus causing distal embolization into previously unaffected territories into previously unaffected territories
Nevertheless the advantages of mechanical stroke Nevertheless the advantages of mechanical stroke therapy appear to significantly outweigh its therapy appear to significantly outweigh its disadvantages and risksdisadvantages and risks
Contraindications to Thrombolytic Contraindications to Thrombolytic agents agents
Recent thoracic abdominal or Recent thoracic abdominal or intracranial surgeryintracranial surgery
Recent haemorrhagic CVA Head injury Recent haemorrhagic CVA Head injury or neoplasmor neoplasm
Bleeding ulcerBleeding ulcer Anticipated invasive procedures (arterial Anticipated invasive procedures (arterial
punctures biopsies)punctures biopsies) Concurrent hemostatic dysfunctionConcurrent hemostatic dysfunction
Monitoring of thrombolytic Monitoring of thrombolytic therapytherapy
Thrombin time Measures the availability of functional
fibrinogen Normal thrombin time is 10-14 sec Prolonged when fibrinogen level is below
75-100 mgdl
Half Life of ThrombolyticsHalf Life of ThrombolyticsAgent Administration Half Life
Streptokinase IA 60-80min
Urokinase IAIV 9-12min
rTPA IAIV 6min
Abciximab(Reopro) IAIV 12hour
Aspirin POIV 15-20min
Heparin IVSC 60min
Coumadin PO 15-25 days
Anti Platelet DrugsAnti Platelet DrugsDrug Drug Mechanism Mechanism UsesUsesAspirinAspirin Permanently inhibits Permanently inhibits
COX-1 and COX-2COX-1 and COX-2CADCAD
Stroke-TIAsStroke-TIAs
NSAIDsNSAIDs Reversibly inhibits Reversibly inhibits COX-1COX-1
LimitedLimited
DipyridamoleDipyridamole Inhibits PDE increases Inhibits PDE increases cAMPcAMP
TIAsTIAs
ThenopyridinesThenopyridines
(Ticlopidine(Ticlopidine
ClopidrgrelClopidrgrel))
Inhibits ADP Inhibits ADP
PlatAg PlatAg
TIAsStrokeTIAsStroke
CAD PVDCAD PVD
Abciximab (ReoPro)Abciximab (ReoPro)
Eptifibatide (Integrilin)Eptifibatide (Integrilin)
TirofibanTirofiban
GP IIBIIIA InhibitorsGP IIBIIIA Inhibitors
Stroke- TIAs Stroke- TIAs
MonitoringMonitoring
Bleeding timeBleeding time
Optical aggregometryOptical aggregometry
Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay
Bleeding timeBleeding time
Requires a skin incision (usually made on the ear lobe or Requires a skin incision (usually made on the ear lobe or forearm offorearm of
a depth that results in disruption of capillary loops and a depth that results in disruption of capillary loops and small vessels)small vessels)
AdvantagesAdvantages Universally availableUniversally available Relatively simple techniquesRelatively simple techniques Can be performed bedsideCan be performed bedside
DisadvantagesDisadvantages Insensitive inaccurate non-specific techniqueInsensitive inaccurate non-specific technique
Poorly reproducible (as depends on multiple variables)Poorly reproducible (as depends on multiple variables)
Optical aggregometryOptical aggregometry
Gold standard assay for platelet functionGold standard assay for platelet function Agonist induced aggregation is measuredAgonist induced aggregation is measured Different agonist are available for different Different agonist are available for different
agentsagents However require unique expertise and are not However require unique expertise and are not
universally availableuniversally available Aspirin measured with ADP or AA(gt70 Aspirin measured with ADP or AA(gt70
aggregation so resistance)aggregation so resistance) Clopidogrel( ADP gt 90 aggregation means Clopidogrel( ADP gt 90 aggregation means
resistance) resistance)
Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay
Can be performed bed sideCan be performed bed side Different assay devices with different Different assay devices with different
agonist are used for each of different agonist are used for each of different antiplatelet agents antiplatelet agents
For Aspirin AA is used (result is reported as aspirin For Aspirin AA is used (result is reported as aspirin reaction units [ARU] ARUgt 550 indicates non-reaction units [ARU] ARUgt 550 indicates non-responsiveness)responsiveness)
Verify IIbIIIa assay device uses TRAP as agonist for Verify IIbIIIa assay device uses TRAP as agonist for Abciximab and TirofibanAbciximab and Tirofiban
Practical Applications Practical Applications related to specific related to specific
Neurovascular Neurovascular interventionsinterventions
Acute ischemic StrokeAcute ischemic Stroke When an artery occludes neurons are affected When an artery occludes neurons are affected
differently depending upon the amount of residual blood differently depending upon the amount of residual blood flowflow
Normal cerebral blood flow is greater than 50 mL100 Normal cerebral blood flow is greater than 50 mL100 mgminmgmin
Once blood flow decreases to less than 20 mL100 Once blood flow decreases to less than 20 mL100 mgmin infarction occursmgmin infarction occurs
If blood flow decreases to less than 10 mL100 mgmin If blood flow decreases to less than 10 mL100 mgmin irreversible neuronal death occurs rapidly irreversible neuronal death occurs rapidly
Blood flow between 11 and 20 mL100 mgmin is thought Blood flow between 11 and 20 mL100 mgmin is thought to represent the ischemic penumbra an area where the to represent the ischemic penumbra an area where the cells are functionally silent because of ischemia but are cells are functionally silent because of ischemia but are still able to recover if blood flow is restored still able to recover if blood flow is restored
Many acute stroke therapies are targeted toward Many acute stroke therapies are targeted toward restoring flow or function to the ischemic penumbrarestoring flow or function to the ischemic penumbra
Therapeutic window in Therapeutic window in management of acute Ischemic management of acute Ischemic
StrokeStrokeThe early diagnosis of ischemic stroke is critical to the The early diagnosis of ischemic stroke is critical to the
with only a narrow therapeutic window in the first few with only a narrow therapeutic window in the first few hours following stroke ictushours following stroke ictus
Diagnosis in the first 3 hours postictus provides the Diagnosis in the first 3 hours postictus provides the opportunity for intravenous or intraarterial thrombolysis opportunity for intravenous or intraarterial thrombolysis and intra-arterial clot mechanical treatment which and intra-arterial clot mechanical treatment which improve the outcome improve the outcome
Diagnosis in the time period between 3 and 6 hours Diagnosis in the time period between 3 and 6 hours provides an opportunity for intra-arterial thrombolysis provides an opportunity for intra-arterial thrombolysis and mechanical treatment and mechanical treatment
Involvement of the posterior circulation especially the Involvement of the posterior circulation especially the basilar artery is treated by some regardless of time of basilar artery is treated by some regardless of time of onset or up until 12 to 24 hours in some practices This is onset or up until 12 to 24 hours in some practices This is related to the potentially high mortality and morbidity related to the potentially high mortality and morbidity associated with basilar artery thrombosisassociated with basilar artery thrombosis
Infarct evaluation on angiographyInfarct evaluation on angiography(CT angiography and catheter (CT angiography and catheter
angiography)angiography)CTA is an excellent first-line examination for CTA is an excellent first-line examination for
evaluation of the head and neck arteries evaluation of the head and neck arteries In comparison with catheter angiography In comparison with catheter angiography
what it gives up in resolution and dynamic what it gives up in resolution and dynamic properties it makes up for with rapid properties it makes up for with rapid acquisition of a 3-D dataset and the potential acquisition of a 3-D dataset and the potential for assessment of whole-brain perfusion and for assessment of whole-brain perfusion and better parenchymal evaluationbetter parenchymal evaluation
Moreover CTA illustrates not only arterial Moreover CTA illustrates not only arterial stenosis or occlusion but also the vessel wall stenosis or occlusion but also the vessel wall This factor is most important for evaluation of This factor is most important for evaluation of intramural dissection and thrombosed intramural dissection and thrombosed aneurysms which may both complicate aneurysms which may both complicate evaluation of stroke patientsevaluation of stroke patients
Early angiographic signs of strokes Early angiographic signs of strokes both CTA both CTA and DSA and DSA
Vessel occlusion or cutoff related to Vessel occlusion or cutoff related to thromboembolithromboemboli
aneurysms aneurysms arterial dissection arterial dissection Meniscus or flattened shape to clot Meniscus or flattened shape to clot
(recent) versus reverse meniscus (older)(recent) versus reverse meniscus (older) tram track (nonocclusive or recanalized tram track (nonocclusive or recanalized
clot) clot) delayed (antegrade) flow (manifest as delayed (antegrade) flow (manifest as
decreased whole-brain perfusion on CTA)decreased whole-brain perfusion on CTA) retrograde collateral flowretrograde collateral flow
Non-occlusive left MCA thrombus on 3-D imaging performed from CTA source data and was confirmed at catheter angiography
Therapy to be started within a 6-hr Therapy to be started within a 6-hr time to treatment (TTT) window time to treatment (TTT) window (while in case of IV thrombolysis (while in case of IV thrombolysis therapy to be started with in 3hrs)therapy to be started with in 3hrs)
Exclusion criteria Exclusion criteria Rapidly improving neurologic deficit or Rapidly improving neurologic deficit or Sustained blood pressure of gt180100 Sustained blood pressure of gt180100 Hemorrhage is detected on CTHemorrhage is detected on CT Infarct involving gt more than 13 rd Infarct involving gt more than 13 rd
territory of MCAterritory of MCA MRADWI-Perfusion mismatchlt 20MRADWI-Perfusion mismatchlt 20 Definite hypodensity on CTDefinite hypodensity on CT
Intra-arterial Thrombolysis
Fibrinolytics + AntiplateletsFibrinolytics + Antiplatelets
PlasminogenPlasminogen activators through fibrinolysis exposes activators through fibrinolysis exposes free thrombin and paradoxically stimulatesfree thrombin and paradoxically stimulates platelet platelet aggregation which leads to formation of aaggregation which leads to formation of a platelet platelet thrombus (white clot) thrombus (white clot)
This new thrombus is relatively resistant to This new thrombus is relatively resistant to fibrinolyticsfibrinolytics
So new regimen in case of acute stroke isSo new regimen in case of acute stroke is fibrinolytics + antiplatelet drugsfibrinolytics + antiplatelet drugs
rtPA + IIbIIIa inhibitors( tirofiban rtPA + IIbIIIa inhibitors( tirofiban abciximab) orabciximab) or
Urokinase + IIbIIIa Urokinase + IIbIIIa inhibitors( tirofiban abciximab)inhibitors( tirofiban abciximab)
Intra-arterial Thrombolysis Tirofiban (04 microgkgmin bolus for 3 min followed by Tirofiban (04 microgkgmin bolus for 3 min followed by
0125 ugkgmin)0125 ugkgmin)
++
Heparin (2000ndash3000 IU bolus followed by Heparin (2000ndash3000 IU bolus followed by 1000 IUhour infusion 1000 IUhour infusion
with ACT maintained bw 200-300) throughout the with ACT maintained bw 200-300) throughout the interventional procedure and for 24ndash48 hours thereafter when interventional procedure and for 24ndash48 hours thereafter when there is neither intraprocedural bleeding nor suspicion of there is neither intraprocedural bleeding nor suspicion of increased risk of bleeding increased risk of bleeding
Maximum dose of Urokinase Maximum dose of Urokinase Anterior circulation stroke - 500000 IU (mean 400000 Anterior circulation stroke - 500000 IU (mean 400000
IU range 300000ndash500000 IU)IU range 300000ndash500000 IU) Posterior circulation stroke -1000000 IU (mean 837000 Posterior circulation stroke -1000000 IU (mean 837000
IU range 300000ndash1000000 IU)IU range 300000ndash1000000 IU)American Journal of NeuroradiologyAmerican Journal of Neuroradiology 262595-2601 2005262595-2601 2005
Intravenous ThrombolysisIntravenous Thrombolysis
The first method to restore cerebral The first method to restore cerebral perfusion is clot lysis with the goal perfusion is clot lysis with the goal of re-establishing blood flow to the of re-establishing blood flow to the affected tissue affected tissue
IV thrombolysis rt-PA is the only IV thrombolysis rt-PA is the only FDA- approved treatment for AIS FDA- approved treatment for AIS
Fibrinolysis is enhanced powerfully Fibrinolysis is enhanced powerfully by rt-PAby rt-PA
Intravenous rTPA Intravenous rTPA administration administration protocolprotocol
Total dose of rt-PA 09 mgkg (maximum dose Total dose of rt-PA 09 mgkg (maximum dose 90 mg)90 mg)
Give 10 as initial IV bolusGive 10 as initial IV bolus Infuse remainder over 1 hourInfuse remainder over 1 hour Admit patient to an ICU or stroke unit for Admit patient to an ICU or stroke unit for
monitoringmonitoring Neurologic assessments every 15 minutes Neurologic assessments every 15 minutes
during infusion then every 30 minutes for next during infusion then every 30 minutes for next 6 hours then every hour until 24hours after 6 hours then every hour until 24hours after treatmenttreatment
Favorable Outcome vs Treatment Time Favorable Outcome vs Treatment Time with IV rTPAwith IV rTPA
Protocol limit = 3 hrs
Benefit ~ 45 hrs
Thromboembolism During coilingThromboembolism During coiling Most feared and frequent complication Most feared and frequent complication Reported incidence - Approx 7 Reported incidence - Approx 7 SourcesSources of Thromboembolism are of Thromboembolism are
- Clots at the aneurysmal neck during or immediately- Clots at the aneurysmal neck during or immediately after after embolization embolization
- Thrombus forming on catheters during- Thrombus forming on catheters during proceduresprocedures
- Stenosis of an adjacent artery dt coil mass- Stenosis of an adjacent artery dt coil mass or herniationor herniation
- Migration of intraaneurysmal- Migration of intraaneurysmal thrombus during coil thrombus during coil placement placement
- Slow flow dt vasospasm - Slow flow dt vasospasm
- Rare and unlikely causes are hypercoagulable- Rare and unlikely causes are hypercoagulable state such state such as antiphospholipid antibody syndrome or due to HITas antiphospholipid antibody syndrome or due to HIT
Occur more often with wide-necked aneurysms (dt Occur more often with wide-necked aneurysms (dt increased exposed surface area of thrombogenic coil increased exposed surface area of thrombogenic coil material)material)
Current regimen of endovascular Current regimen of endovascular managementmanagement
The The glycoprotein IIbIIIa antagonist tirofiban glycoprotein IIbIIIa antagonist tirofiban (04 (04 microgkgmin bolus for 30 minutes followed by infusion of microgkgmin bolus for 30 minutes followed by infusion of 0125 ugkgmin until the thrombus dissolved) 0125 ugkgmin until the thrombus dissolved)
Intraarterial thrombolysis with Intraarterial thrombolysis with urokinase or r- TPA urokinase or r- TPA increase of intravenous (IV) heparin (measured by increase of intravenous (IV) heparin (measured by
ACT) ACT) Intravenous aspirin Intravenous aspirin
Coil-related platelet aggregation (white clot) is Coil-related platelet aggregation (white clot) is unlikely to respond to fibrinolytics but has a high risk unlikely to respond to fibrinolytics but has a high risk of hemorrhage (In ISAT) all 5 patients who had of hemorrhage (In ISAT) all 5 patients who had received thrombolytic therapy with tPA to treat a received thrombolytic therapy with tPA to treat a thromboembolic complication after endovascular thromboembolic complication after endovascular treatment rebleed and all of these patients died)treatment rebleed and all of these patients died)
IntracranialIntracranial Stenting Stenting Metallic foreign body such as stent will accumulate Metallic foreign body such as stent will accumulate
thrombus in the absence of platelet inhibitionthrombus in the absence of platelet inhibition Antiplatelet drugs are important to prevent peri or Antiplatelet drugs are important to prevent peri or
post-interventional thromboembolic eventspost-interventional thromboembolic events Optimal treatment regimens has not been determined Optimal treatment regimens has not been determined
but usually but usually Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-
procedureprocedureOrOr
Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on
morning of proceduremorning of procedure
If need to use stent is not pre-planned thanIf need to use stent is not pre-planned than
Abciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkgAbciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkg IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)
Glycoprotein IIbIIIa inhibitor are not used routinely during elective Glycoprotein IIbIIIa inhibitor are not used routinely during elective stenting procedure dt increased risk of ICH stenting procedure dt increased risk of ICH
Carotid StentingCarotid Stenting
Pre-procedurePre-procedure
Double Antiplatelet therapy is routinely given Double Antiplatelet therapy is routinely given beginning at least 3beginning at least 3
days before the proceduredays before the procedure
Aspirin 325mgd+Clopidogrel 75mgdAspirin 325mgd+Clopidogrel 75mgd During procedureDuring procedure
Heparin is given with target clotting time of 250-Heparin is given with target clotting time of 250-300sec300sec
Post-procedure Post-procedure
Aspirin 325mg is continued indefinitely and Aspirin 325mg is continued indefinitely and
Clopidogrel 75mgd for at least 6 weeks Clopidogrel 75mgd for at least 6 weeks
Inclusion criteria for Local ThrombolysisInclusion criteria for Local Thrombolysis a)a) Patients in severe clinical grade on admission Patients in severe clinical grade on admission
with evidence of dural venous sinus with evidence of dural venous sinus thrombosis and restrictive venous outflow on thrombosis and restrictive venous outflow on cerebral angiogramcerebral angiogram
b)b) Patients in clinical grade 3 worsening on Patients in clinical grade 3 worsening on heparin therapy Restriction to venous heparin therapy Restriction to venous outflow was defined as an increase in brain outflow was defined as an increase in brain circulation time gt 12 s delay in the drainage circulation time gt 12 s delay in the drainage of cortical veins with cortical veins hanging of cortical veins with cortical veins hanging in spacein space
Treatment Options for Venous Thrombosis
CT Grading for Venous ThrombosisCT Grading for Venous Thrombosis Grade I no parenchymal change Grade I no parenchymal change
(hyperdense (hyperdense sinuses cortical veins empty sinuses cortical veins empty delta sign)delta sign)
Grade II non hemorrhagic venous infarct Grade II non hemorrhagic venous infarct without mass effect without mass effect
Grade III non-hemorrhagic infarct with Grade III non-hemorrhagic infarct with mass effectmass effect
Grade IV hemorrhagic venous infarct (max Grade IV hemorrhagic venous infarct (max diameter lt 3 cm) with no mass effectdiameter lt 3 cm) with no mass effect
Grade V hemorrhagic venous infarct (max Grade V hemorrhagic venous infarct (max diameter gt 3 cm) with mass effect diameter gt 3 cm) with mass effect
Local ThrombolysisLocal Thrombolysis
Femoral Jugular access was secured and a guiding Femoral Jugular access was secured and a guiding catheter was placed in the jugular bulb catheter was placed in the jugular bulb Mechanical Mechanical clot maceration clot maceration was done with the guidewire was done with the guidewire following which a microcatheter (was navigated and following which a microcatheter (was navigated and placed in the thrombosed segment of sinus confirmed placed in the thrombosed segment of sinus confirmed on a selective venogram on a selective venogram
Urokinase infusion Bolus dose of 2-6 lacs followed Urokinase infusion Bolus dose of 2-6 lacs followed by 60000 to 100000 units per hour along with by 60000 to 100000 units per hour along with periodic check venogram Along with maintenance periodic check venogram Along with maintenance systemic infusion of Heparinsystemic infusion of Heparin Other agents such as Other agents such as streptokinase altepase or rTPAstreptokinase altepase or rTPA can be also used can be also used
After thrombolysis patient should subjected to oral After thrombolysis patient should subjected to oral anticoagulation for six monthsanticoagulation for six months
Low-molecular-weight Low-molecular-weight heparinheparin
PharmacologyPharmacologyLMWH as its name suggests is a glycosaminoglycan that is approximatelyLMWH as its name suggests is a glycosaminoglycan that is approximately
one third the molecular weight of UFH It is derived from UFH through one third the molecular weight of UFH It is derived from UFH through variousvarious
depolymerization processes LMWH binds to antithrombin which in turn depolymerization processes LMWH binds to antithrombin which in turn
Neutralizes actors Xa and IIa Because LMWH lacks many of the longer Neutralizes actors Xa and IIa Because LMWH lacks many of the longer chains chains
required for binding to thrombin it has less ability to neutralize thrombin required for binding to thrombin it has less ability to neutralize thrombin
relativeto its ability to neutralize factor Xa LMWH also has less relativeto its ability to neutralize factor Xa LMWH also has less nonspecific nonspecific
binding to other proteins There is greater bioavailability with more binding to other proteins There is greater bioavailability with more predictable predictable
pharmacokinetics that eliminates the need for monitoring The smaller pharmacokinetics that eliminates the need for monitoring The smaller size also size also
allows for enhanced subcutaneous absorption when compared with UFHallows for enhanced subcutaneous absorption when compared with UFH
Three LMWH preparations are Three LMWH preparations are currently approved for use in the currently approved for use in the United States (1) enoxaparin (2) United States (1) enoxaparin (2) dalteparin and (3) tinzaparin dalteparin and (3) tinzaparin
They are all administered They are all administered subcutaneously at intervals of either subcutaneously at intervals of either once or twice daily for both once or twice daily for both prophylaxis and treatment dosesprophylaxis and treatment doses
Few Experiences of Few Experiences of ThrombolysisThrombolysis
Vickey 25 Yrs male patient presented Vickey 25 Yrs male patient presented with 12with 12thth day HO severe headache with day HO severe headache with right sided hemiplegiaright sided hemiplegia
MRI shows thrombosis of the superior MRI shows thrombosis of the superior sagittal left transverse left sigmoid sagittal left transverse left sigmoid sinuses and cortical veins in the fronto-sinuses and cortical veins in the fronto-parietal regions with eo haemorrhagic parietal regions with eo haemorrhagic infarct in the left cerebral hemisphere infarct in the left cerebral hemisphere with mass effect( Grade ndashV)with mass effect( Grade ndashV)
Sashi Srivastava 64 yrs FSashi Srivastava 64 yrs F In a follow up case of MRD with infra-renal In a follow up case of MRD with infra-renal
aortic abdominal and bilateral renal artery aortic abdominal and bilateral renal artery thrombosis renal angiogram shows filling thrombosis renal angiogram shows filling defects in the right Renal artery defects in the right Renal artery
Initially Renal angioplasty was done Initially Renal angioplasty was done Following angioplasty few thrombi are seem Following angioplasty few thrombi are seem to extends into the segmental branches and to extends into the segmental branches and causing blockage So Thrombolysis was causing blockage So Thrombolysis was plane to dissolve the run-out thrombi with plane to dissolve the run-out thrombi with urokinase urokinase
Rakesh 34yrsMRakesh 34yrsM Left SFA pseudoaneurysm with Left SFA pseudoaneurysm with
Covered stent placementCovered stent placement Pre operative antiplatelets with post Pre operative antiplatelets with post
procedure heparin Tirofiban procedure heparin Tirofiban followed by aspirin and clopidogrel followed by aspirin and clopidogrel were usedwere used
IAT may be a treatment option for selected patients IAT may be a treatment option for selected patients Possible selection criteria include Possible selection criteria include
presentation between 3 and 6 hours from symptom onsetpresentation between 3 and 6 hours from symptom onset major cerebral artery occlusion major cerebral artery occlusion severe neurologic deficits severe neurologic deficits high risk of systemic hemorrhage with IV rt-PA (eg recent high risk of systemic hemorrhage with IV rt-PA (eg recent
surgery) surgery) The MERCI (Mechanical Embolus Removal in Cerebral The MERCI (Mechanical Embolus Removal in Cerebral
Ischemia) retrievalIschemia) retrieval system system
Has been FDA-approved for recanalizing acutely occluded Has been FDA-approved for recanalizing acutely occluded cerebral arteries cerebral arteries
In the Multi-MERCI study patients who did not improve In the Multi-MERCI study patients who did not improve immediately after IV rt-PA underwent mechanical immediately after IV rt-PA underwent mechanical embolectomy within 8 hours of symptom onset embolectomy within 8 hours of symptom onset
Partial or complete recanalization occurred in 74 of Partial or complete recanalization occurred in 74 of patientspatients
with a symptomatic intracerebral hemorrhage (sICH) rate of with a symptomatic intracerebral hemorrhage (sICH) rate of 67 67
Mechanical embolectomy with the MERCI retriever may be a Mechanical embolectomy with the MERCI retriever may be a feasible and safe option for patients after IV rt-PAfeasible and safe option for patients after IV rt-PA
Penumbra stroke systemPenumbra stroke system This device combines two methods of clot This device combines two methods of clot
extraction aspiration and mechanical extraction aspiration and mechanical extraction extraction
First the clot is aspirated then a thrombus First the clot is aspirated then a thrombus removal ring can be used if necessary to removal ring can be used if necessary to remove remaining clot remove remaining clot
successful recanalizing 82successful recanalizing 82 Bridging therapyBridging therapy
06 mgkg IV rt-PA followed by IAT with IA rt-06 mgkg IV rt-PA followed by IAT with IA rt-PA (up to 20 mg)PA (up to 20 mg)
achieved a higher recanalization rateachieved a higher recanalization rate
Criteria for thrombolysis with rTPACriteria for thrombolysis with rTPA
Inclusion criteriaInclusion criteria Clinical signs and symptoms consistent with ischemic Clinical signs and symptoms consistent with ischemic
strokestroke Patient last seen normal within 3 hoursPatient last seen normal within 3 hours Measurable neurologic deficitMeasurable neurologic deficit
Exclusion criteriaExclusion criteria Any hemorrhage on neuroimaging (CT or MRI)Any hemorrhage on neuroimaging (CT or MRI) Symptoms suggestive of subarachnoid hemorrhageSymptoms suggestive of subarachnoid hemorrhage Seizure at stroke onset that is thought to contribute to Seizure at stroke onset that is thought to contribute to
neurologic deficitneurologic deficit Hypodensity greater than one third cerebral hemisphere Hypodensity greater than one third cerebral hemisphere
on CTon CT SBP greater than 185 mm Hg or DBP greater than 110 SBP greater than 185 mm Hg or DBP greater than 110
mm Hgmm Hg International normalized ratio (INR) greater than 17International normalized ratio (INR) greater than 17
Ischemic Stroke Ischemic Stroke Treatment ndash 2006Treatment ndash 2006
IV tissue plasminogen activator (tPA)IV tissue plasminogen activator (tPA) ndash ndash Only FDA-approved acute stroke drugOnly FDA-approved acute stroke drug ndash ndash 3 hour treatment window3 hour treatment window
MERCI - Concentric clot retrieval MERCI - Concentric clot retrieval devicedevice ndash ndash Rescue therapy - approved 2004Rescue therapy - approved 2004 ndash ndash Device approval (not outcomes-based)Device approval (not outcomes-based)
Off label approachesOff label approaches ndash ndash IV tPA after 3 hoursIV tPA after 3 hours ndash ndash IV-IA tPA sequential strategiesIV-IA tPA sequential strategies ndash ndash IA tPA clot angioplasty fragmentationIA tPA clot angioplasty fragmentation ndash ndash Ultrasound-assisted tPA lysisUltrasound-assisted tPA lysis
rt-PA Trials NINDSrt-PA Trials NINDS
Acute stroke - 624 patientsAcute stroke - 624 patients Treat within 3 hrsTreat within 3 hrs Intravenous 09 mgkg rt-PA vs placeboIntravenous 09 mgkg rt-PA vs placebo Hemorrhage 64 tPA 06 placeboHemorrhage 64 tPA 06 placebo Neurologic recovery better with tPA 30 Neurologic recovery better with tPA 30
more like to have minimal or no disabilitymore like to have minimal or no disability
First proven approved treatment for First proven approved treatment for strokestroke
Limitations of tPALimitations of tPA Only 4 of acute strokes receive tPAOnly 4 of acute strokes receive tPA (Kleindorfer et al Stroke 2004 35 e27-e29)(Kleindorfer et al Stroke 2004 35 e27-e29)
Only 22 of patients present within 3 hoursOnly 22 of patients present within 3 hours1048707 1048707 51 of these ineligible due to51 of these ineligible due to
bull bull Mild severityMild severity bull bull Medical or surgical historyMedical or surgical history bull bull Blood testsBlood tests
Sustained recanalization only 13Sustained recanalization only 13 (Alexandrov et al NEJM 2004 351 2170-8)(Alexandrov et al NEJM 2004 351 2170-8)
Concern for hemorrhageConcern for hemorrhage tPA potentiates apoptotic injury tPA potentiates apoptotic injury (Liu et al Nature Med 2004 101379-83)(Liu et al Nature Med 2004 101379-83)
PROACT II IA Lysis TrialPROACT II IA Lysis Trial Baseline 24 hours 8 days
Baseline 60 minutes 120 minutes
9mg IAProurokinase
Desmoteplase Trials DEDAS Desmoteplase Trials DEDAS DIASDIAS
Trial OverviewTrial Overview Double blind randomized placebo Double blind randomized placebo
controlled trialscontrolled trials IV delivery 3-9 hour time windowIV delivery 3-9 hour time window Plasminogen activator ndash from Plasminogen activator ndash from vampire bat vampire bat
salivasaliva Selection based on PWI-DWI MismatchSelection based on PWI-DWI Mismatch
MRI InclusionMRI Inclusion PWI defect at least 2 cm AND ~20 larger PWI defect at least 2 cm AND ~20 larger
than DWIthan DWI PWI should be obvious even visible on PWI should be obvious even visible on
raw imagesraw imagesMRI ExclusionMRI Exclusion
DWI gt 13 MCADWI gt 13 MCA MRA ICA occlusionMRA ICA occlusion
Desmoteplase ndash DIAS Desmoteplase ndash DIAS ResultsResults
Mechanical Thrombolysis Mechanical Thrombolysis devicesdevices
mechanical thrombolysis potentially extends the treatment mechanical thrombolysis potentially extends the treatment window because they act promptly at the site of the thrombuswindow because they act promptly at the site of the thrombus
The devices can retrieve large clots that pharmaceutical agents The devices can retrieve large clots that pharmaceutical agents may not successfully lysemay not successfully lyse
Patients treated with IV tPA may be considered for treatment of Patients treated with IV tPA may be considered for treatment of residual clot with some of these devicesresidual clot with some of these devices
suction-creating saline jets suction-creating saline jets laser energy ultrasound laser energy ultrasound a corkscrew apparatus to treat strokesa corkscrew apparatus to treat strokes The AngioJet systemThe AngioJet system uses saline jets that are directed back into the catheter to uses saline jets that are directed back into the catheter to
create a low-pressure zone around the catheter tip inducing create a low-pressure zone around the catheter tip inducing suction suction
The clot is pulled into the exhaust lumen and removed from the The clot is pulled into the exhaust lumen and removed from the vessel Although US Food and Drug Administration (FDA) has vessel Although US Food and Drug Administration (FDA) has approved this device for use in arteriovenous dialysis grafts and approved this device for use in arteriovenous dialysis grafts and fistulae and for the treatment of coronary arteries saphenous fistulae and for the treatment of coronary arteries saphenous vein grafts and peripheral vessels clinical trials for the vein grafts and peripheral vessels clinical trials for the treatment of acute stroke are no longer in progress treatment of acute stroke are no longer in progress
Most devices are used in cerebral vessels that 2-5 mm
The Latis laser device The Latis laser device used laser energy to ablate clots used laser energy to ablate clots Arteries 2-5 mm in diameter could be Arteries 2-5 mm in diameter could be
treated including the ICA M1 or M2 treated including the ICA M1 or M2 branch of the MCA A1 branch of the branch of the MCA A1 branch of the anterior cerebral artery (ACA) basilar anterior cerebral artery (ACA) basilar artery posterior cerebral artery (PCA) artery posterior cerebral artery (PCA) and vertebral and vertebral
Patients could receive treatment as late Patients could receive treatment as late as 8 hours after symptom onset in the as 8 hours after symptom onset in the anterior circulation and within 24 hours in anterior circulation and within 24 hours in the posterior circulation the posterior circulation
Endovascular Photo Acoustic Endovascular Photo Acoustic Recanalization (EPAR) Recanalization (EPAR)
A laser power source generated energy for the A laser power source generated energy for the systemsystem
The energy was delivered by means of The energy was delivered by means of fiberoptics to the tip of the catheter at the fiberoptics to the tip of the catheter at the treatment sitetreatment site
Absorption of laser light by darkly pigmented Absorption of laser light by darkly pigmented materials (ie the clot) occurred inside the 1-mm materials (ie the clot) occurred inside the 1-mm catheter tipcatheter tip
the system was designed to minimize scattering the system was designed to minimize scattering of laser light of laser light
Absorption converted photo energy to acoustic Absorption converted photo energy to acoustic energy which then emulsified the clot inside the energy which then emulsified the clot inside the catheter tip catheter tip
EKOS ultrasound( the EKOS ultrasound( the Ultrasound Thrombolytic Ultrasound Thrombolytic
Infusion Catheter) Infusion Catheter) combines the use of a distal ultrasound transducer with combines the use of a distal ultrasound transducer with
infusion of a thrombolytic agent through the infusion of a thrombolytic agent through the microcathetermicrocatheter
Ultrasound changes the structure of the clot to Ultrasound changes the structure of the clot to temporarily increase its permeability while providing an temporarily increase its permeability while providing an acoustic pressure gradient to move the drug into the clot acoustic pressure gradient to move the drug into the clot to speed its dissolution to speed its dissolution
The EKOS catheter is placed in the proximal portion of the The EKOS catheter is placed in the proximal portion of the clot clot
After a 2-mg bolus of tPA was injected through the After a 2-mg bolus of tPA was injected through the catheter catheter
the patient received a continuous infusion of IA tPA 03 the patient received a continuous infusion of IA tPA 03 mgmin to a maximum of 20 mg and simultaneous mgmin to a maximum of 20 mg and simultaneous ultrasound transmission for as long as 60 minutes ultrasound transmission for as long as 60 minutes
One patient was treated with a total of 4 units of One patient was treated with a total of 4 units of recombinant reteplase (Retavase) hand-injected over 60 recombinant reteplase (Retavase) hand-injected over 60 minutes minutes
Penumbra system Penumbra system The Penumbra system (Penumbra Inc) provides a dual The Penumbra system (Penumbra Inc) provides a dual
approach to clot extraction using aspiration followed by approach to clot extraction using aspiration followed by clot retrieval with a ring device if needed clot retrieval with a ring device if needed
Mechanical Embolus Removal in Cerebral Ischemia Mechanical Embolus Removal in Cerebral Ischemia (MERCI)(MERCI)
a corkscrew-like apparatus to remove blood clots from a corkscrew-like apparatus to remove blood clots from the brain in patients experiencing an ischemic stroke the brain in patients experiencing an ischemic stroke
The corkscrew itself resides in the catheter tip which The corkscrew itself resides in the catheter tip which shields it from the wall of the vessel until it is ready to be shields it from the wall of the vessel until it is ready to be burrowed into the clot Once lodged in the clot the device burrowed into the clot Once lodged in the clot the device and clot are withdrawn from the vessel and clot are withdrawn from the vessel
Snarelike devicesSnarelike devices Snares such as the Neuronet snare (Guidant Snares such as the Neuronet snare (Guidant
Endovascular Santa Clara CA) have been developed Endovascular Santa Clara CA) have been developed specifically for use in the treatment of strokes specifically for use in the treatment of strokes
These devices are simple in design and do not require the These devices are simple in design and do not require the clot to be amenable to emulsification clot to be amenable to emulsification
X-Sizer deviceX-Sizer device a device with small moving blades at the a device with small moving blades at the
catheter tip catheter tip This device the X-Sizer device (EndiCor Medical This device the X-Sizer device (EndiCor Medical
San Clemente CA) can be used to excise the San Clemente CA) can be used to excise the thrombus and aspirate it thrombus and aspirate it
The device was being evaluated in randomized The device was being evaluated in randomized studies of coronary vessels and in a registry of studies of coronary vessels and in a registry of patients with acute myocardial infarctionpatients with acute myocardial infarction
Although the manufacturer had modified the Although the manufacturer had modified the device for use in cerebral vessels a safety and device for use in cerebral vessels a safety and feasibility study was indefinitely suspended after feasibility study was indefinitely suspended after only 1 patient was treated with the device in only 1 patient was treated with the device in Europe Europe
Suction thrombectomySuction thrombectomy This method of mechanical thrombolysis is one of the This method of mechanical thrombolysis is one of the
simplestsimplest In this readily available technique suction is applied with In this readily available technique suction is applied with
a syringe to remove thrombus in the ICA a syringe to remove thrombus in the ICA It requires no other devicesIt requires no other devices A catheter with a large inner diameter (Brite Tip Cordis A catheter with a large inner diameter (Brite Tip Cordis
Corporation Miami FL) was placed in the symptomatic Corporation Miami FL) was placed in the symptomatic vessel and navigated over a guidewire into the thrombusvessel and navigated over a guidewire into the thrombus
A 60-mL syringe was used to aspirate the thrombus A 60-mL syringe was used to aspirate the thrombus Each patient required angioplasty and stenting of carotid Each patient required angioplasty and stenting of carotid
bifurcation stenosis and received daily aspirin and bifurcation stenosis and received daily aspirin and ticlopidine after the procedure No complications ticlopidine after the procedure No complications occurred occurred
Summary Acute Stroke Summary Acute Stroke ImagingImaging
PhysiologyPhysiology importance collaterals importance collaterals
ndash ndashGrowing role for perfusion Growing role for perfusion assessmentassessment
tPAtPA guidelines amp limitations guidelines amp limitations Signs on CT amp MRSigns on CT amp MR follow physiology follow physiology Stroke trialsStroke trials PWI-DWI mismatch PWI-DWI mismatch
ndash ndashTreat based on physiology not timeTreat based on physiology not time ProtocolsProtocols should be fast and should be fast and
comprehensivecomprehensive
Contraindication for WarfarinContraindication for Warfarin
Hypersensitivity to warfarinHypersensitivity to warfarin Hemorrhagic tendencyHemorrhagic tendency Condition with risk of hemorrhageCondition with risk of hemorrhage Inadequate laboratory techniquesInadequate laboratory techniques Protein C amp S deficiencyProtein C amp S deficiency Vitamin K deficiencyVitamin K deficiency
SIDE EFFECTSSIDE EFFECTS
Hemorrhage Hemorrhage Skin necrosisSkin necrosis Purple toe syndromePurple toe syndrome Microembolization Microembolization TeratogenecityTeratogenecity Agranulocytosis leukopenia Agranulocytosis leukopenia Diarrhoeanausea anorexiaDiarrhoeanausea anorexia
MONITORING OF WARFARIN THERAPYMONITORING OF WARFARIN THERAPY
Prothrombin timeProthrombin time PT ratioPT ratio INR (International Normalized Ratio)INR (International Normalized Ratio)
PROTHROMBIN TIME (PT)PROTHROMBIN TIME (PT)
Time required for blood to coagulate Time required for blood to coagulate is called PT ( normal value ~10sec)is called PT ( normal value ~10sec)
Performed by adding a mixture of Performed by adding a mixture of calcium and thromboplastin to calcium and thromboplastin to citrated plasmacitrated plasma
As a control a normal blood sample is As a control a normal blood sample is tested continuouslytested continuously
PT ratio (PTR) = PT ratio (PTR) = Patientrsquos PTPatientrsquos PT Control PTControl PT
PROBLEMS WITH PTPTRPROBLEMS WITH PTPTR
Thromboplastins are extracts from Thromboplastins are extracts from brain lung or placenta of animalsbrain lung or placenta of animals
Thromboplastins from various Thromboplastins from various manufacturers differ in their manufacturers differ in their sensitivity to prolong PTsensitivity to prolong PT
May result in false control of May result in false control of anticoagulant therapyanticoagulant therapy
INTERNATIONAL NORMALISED RATIO (INR)INTERNATIONAL NORMALISED RATIO (INR)
International Normalized Ratio (INR) International Normalized Ratio (INR) a PT test with a a PT test with a formula based ratio to normalize the often variable source formula based ratio to normalize the often variable source of tissue factor (human rabbit recombinant)of tissue factor (human rabbit recombinant)
INR = [PTINR = [PTptpt] ] ISIISI
[PT[PTRefRef]]
PTPTpt pt ndash prothrombin time of patientndash prothrombin time of patient
PTPTRef Ref ndash prothrombin time of normal pooled samplendash prothrombin time of normal pooled sample
ISI ndash International Sensitivity IndexISI ndash International Sensitivity Index
Warfarin is given orally and titrated to achieve an INR of Warfarin is given orally and titrated to achieve an INR of typically 20 ndash 30typically 20 ndash 30
Heparin versus WarfarinHeparin versus Warfarin
Drug ActionMechan-ism
Moni-toring
Effective
HeparinDirect
Inhibition ofThrombin
ATIIIcofactor
APTTACT
Immediate
WarfarinDecreasesProductionof factors
Vitamin K PTDelay
3-5 days
INR
Recanalization or Antegrade Recanalization or Antegrade Reperfusion StrategiesReperfusion Strategies
Recanalization strategies focus on removing Recanalization strategies focus on removing andor dissolving the occlusive thrombus to re-andor dissolving the occlusive thrombus to re-establish antegrade flow Strategies may be establish antegrade flow Strategies may be classified into 7 different categories on the classified into 7 different categories on the basis of their primary mechanism of action basis of their primary mechanism of action 1) 1) IV andor intraarterial thrombolysis (IAT) IV andor intraarterial thrombolysis (IAT) 2) endovascular thrombectomy2) endovascular thrombectomy3) endovascular thromboaspiration 3) endovascular thromboaspiration 4) endovascular mechanical thrombus disruption or 4) endovascular mechanical thrombus disruption or
thromborrhexisthromborrhexis5) 5) transcranial or endovascular augmented transcranial or endovascular augmented
fibrinolysis fibrinolysis 6) endovascular thrombus entrapment and 6) endovascular thrombus entrapment and 7) temporary endovascular bypass7) temporary endovascular bypass
IAT in Acute Ischemic StrokeIAT in Acute Ischemic Stroke
IAT advantages over IV thrombolysisIAT advantages over IV thrombolysis Coaxial microcatheter techniques the occluded intracranial Coaxial microcatheter techniques the occluded intracranial
vessel is directly accessible and the fibrinolytic agent can be vessel is directly accessible and the fibrinolytic agent can be infused directly into the thrombusinfused directly into the thrombus
This permits a smaller dose of fibrinolytic agent to reach a This permits a smaller dose of fibrinolytic agent to reach a higher local concentration than that reached by systemic higher local concentration than that reached by systemic infusioninfusion
Allows more complete recanalization with lower total doses of Allows more complete recanalization with lower total doses of thrombolytic thrombolytic
With the smaller dose complications from systemic fibrinolytic With the smaller dose complications from systemic fibrinolytic effects including intracranial hemorrhage (ICH) can effects including intracranial hemorrhage (ICH) can theoretically be reduced theoretically be reduced
Treatment window for endovascular techniques can be Treatment window for endovascular techniques can be extended beyond the typical IV window of 3 hours extended beyond the typical IV window of 3 hours
IA techniques have led to higher recanalization rates than IV IA techniques have led to higher recanalization rates than IV thrombolysisthrombolysis
Major disadvantagesMajor disadvantages Relative complexity of the procedure the level Relative complexity of the procedure the level
of required technical expertise and its of required technical expertise and its relatively low availability relatively low availability
Delays in initiating treatmentDelays in initiating treatment InvasiveInvasive
ThrombolyticsThrombolytics
Plasminogen activators
Fibrinolytics
1 Plasminogen Activators 1 Plasminogen Activators drugs act by converting the inactive proenzyme drugs act by converting the inactive proenzyme plasminogen into the active enzyme plasmin Plasmin plasminogen into the active enzyme plasmin Plasmin digests fibrinogen fibrin monomers and cross-linked digests fibrinogen fibrin monomers and cross-linked fibrin (as found in a thrombus) into fibrin degradation fibrin (as found in a thrombus) into fibrin degradation productsproducts
First-Generation Agents First-Generation Agents StreptokinaseStreptokinase a protein derived from group C a protein derived from group C
szlig-hemolytic streptococci has a half-life of 16ndashszlig-hemolytic streptococci has a half-life of 16ndash90 minutes and low fibrin specificity This drug 90 minutes and low fibrin specificity This drug proved to have a very narrow therapeutic proved to have a very narrow therapeutic window and significant rates of ICH and window and significant rates of ICH and systemic hemorrhage18systemic hemorrhage18
UrokinaseUrokinase is a serine protease with a plasma is a serine protease with a plasma half life of 14 minutes and low fibrin specificity half life of 14 minutes and low fibrin specificity
The urokinase dose used in cerebral IAT has The urokinase dose used in cerebral IAT has ranged from 002 to 2 X106unitsranged from 002 to 2 X106units
Second-Generation Agents Second-Generation Agents Alteplase (rtPA) Alteplase (rtPA)
is a serine is a serine protease with a plasma half-life of 35 protease with a plasma half-life of 35 minutes and a high degree of fibrin affinity and minutes and a high degree of fibrin affinity and specificity specificity
Dose used in cerebral IAT has ranged between 20 Dose used in cerebral IAT has ranged between 20 and 60 mgand 60 mg
Disadvantages of alteplase include its relatively short Disadvantages of alteplase include its relatively short halflife and limited penetration into the clot matrix halflife and limited penetration into the clot matrix because of strong binding with surface fibrin which because of strong binding with surface fibrin which could delay recanalization and increase the risk of could delay recanalization and increase the risk of recurrent occlusion recurrent occlusion
Prourokinase (r-prourokinase) Prourokinase (r-prourokinase) is the proenzyme precursor of urokinase is the proenzyme precursor of urokinase T12 of 7 minutes and high fibrin specificity T12 of 7 minutes and high fibrin specificity
Third-Generation AgentsThird-Generation Agents
ReteplaseReteplase is a structurally modified is a structurally modified form of alteplase form of alteplase
with a longer half-life (15ndash18 minutes) In with a longer half-life (15ndash18 minutes) In addition it does not bind as highly to fibrin addition it does not bind as highly to fibrin unbound reteplase can thus theoretically better unbound reteplase can thus theoretically better penetrate the clot and potentially penetrate the clot and potentially improve in improve in vivo fibrinolytic activity vivo fibrinolytic activity
TenecteplaseTenecteplase is another modified form of rtPA with a longer is another modified form of rtPA with a longer
half-life (17 minutes)half-life (17 minutes) greater fibrin specificity and greater greater fibrin specificity and greater
resistance to plasminogen activator inhibitor-1 resistance to plasminogen activator inhibitor-1 IV tenecteplase in acute ischemic stroke IV tenecteplase in acute ischemic stroke
suggest that the drug is safe and promisingsuggest that the drug is safe and promising
Newer plasminogen activatorNewer plasminogen activator
DesmoteplaseDesmoteplase is a genetically engineered is a genetically engineered version of the clot-dissolving factor version of the clot-dissolving factor
found in the saliva found in the saliva of the vampire bat Desmodus rotundusof the vampire bat Desmodus rotundus moremore potent and more selective for fibrin-bound potent and more selective for fibrin-bound
plasminogen than any other known plasminogen plasminogen than any other known plasminogen activatoractivator
Unlike tissue plasminogen activator (tPA) desmoteplase Unlike tissue plasminogen activator (tPA) desmoteplase is not activated by fibrinogen or -amyloid proteins is not activated by fibrinogen or -amyloid proteins factors that may exacerbate the risk for ICH factors that may exacerbate the risk for ICH
The effect of IV administration of desmoteplase 3ndash9 The effect of IV administration of desmoteplase 3ndash9 hours after symptom onset in patients with stroke who hours after symptom onset in patients with stroke who present with mismatch on MR imaging or CT perfusion present with mismatch on MR imaging or CT perfusion
3 DefibrinogenatingFibrinogenolytic 3 DefibrinogenatingFibrinogenolytic Agents Agents
AncrodAncrod(Viprinex)(Viprinex) is is the purified fraction of the Malayan pit viper venomthe purified fraction of the Malayan pit viper venom It acts by directly cleaving and inactivating fibrinogen It acts by directly cleaving and inactivating fibrinogen
and thus indirectly promoting anticoagulation and thus indirectly promoting anticoagulation The reduction in the blood levels of fibrinogen also The reduction in the blood levels of fibrinogen also
leads to a reduced blood viscosity which may improve leads to a reduced blood viscosity which may improve blood flow to the affected areas of the brain blood flow to the affected areas of the brain
In the Stroke Treatment with Ancrod Trial 500 In the Stroke Treatment with Ancrod Trial 500 patients with stroke presenting within 3 hours of patients with stroke presenting within 3 hours of symptom onset were randomized to receive ancrod (symptom onset were randomized to receive ancrod (n n 248) or a placebo (n 252) Good outcome (Barthel 248) or a placebo (n 252) Good outcome (Barthel Index 95ndash100 at 3 months) was achieved in 4221 Index 95ndash100 at 3 months) was achieved in 4221 and 344 of the patients respectively and 344 of the patients respectively
2 Direct Fibrinolytics2 Direct Fibrinolytics
Microplasmin (Microplasmin (ThromboGenics Heverlee Belgium)ThromboGenics Heverlee Belgium) is a truncated form of plasmin that is more resistant to the effects is a truncated form of plasmin that is more resistant to the effects
of antiplasmin of antiplasmin microplasmin can be used upto 4ndash12 hours after stroke onset microplasmin can be used upto 4ndash12 hours after stroke onset There was no evidence of increased bleeding risk with There was no evidence of increased bleeding risk with
microplasminmicroplasmin
Alfimeprase (Nuvelo San Carlos Calif)Alfimeprase (Nuvelo San Carlos Calif) is a recombinant truncated form of fibrolase a fibrinolytic zinc metalloproteinase is a recombinant truncated form of fibrolase a fibrinolytic zinc metalloproteinase
isolated from the venom of the southern copperhead snake isolated from the venom of the southern copperhead snake It degrades fibrin directly and achieves thrombolysis independent It degrades fibrin directly and achieves thrombolysis independent
of plasmin formationof plasmin formation its thrombolytic activity appears to be localized to the site of its thrombolytic activity appears to be localized to the site of
delivery These properties should theoretically result in faster delivery These properties should theoretically result in faster recanalization and lower hemorrhagic conversion riskrecanalization and lower hemorrhagic conversion risk
Anti-fibrinolyticsAnti-fibrinolytics
to limit fibrinolytic activityto limit fibrinolytic activity -aminocaproic acid (EACA) -aminocaproic acid (EACA) competitively inhibitscompetitively inhibits plasminogen and plasminogen activators from plasminogen and plasminogen activators from
binding to fibrinbinding to fibrin
alpha2-antiplasminalpha2-antiplasmin a serine protease inhibitor that a serine protease inhibitor that neutralizes any free circulating plasminneutralizes any free circulating plasmin
Plasminogen activator inhibitor-1Plasminogen activator inhibitor-1 a serine protease a serine protease inhibitor that inhibits tissue-type plasminogen inhibitor that inhibits tissue-type plasminogen activatoractivator
Glycoprotein (GP) IIbIIIa antagonistsGlycoprotein (GP) IIbIIIa antagonists
such as ReoPro (abciximab) Integrilin such as ReoPro (abciximab) Integrilin (eptifibatide) or Aggrastat (tirofiban) in (eptifibatide) or Aggrastat (tirofiban) in ischemic stroke remains investigational ischemic stroke remains investigational Deshmukh et al38 reported 21 patients with Deshmukh et al38 reported 21 patients with large-vessel occlusion refractory to IAT with large-vessel occlusion refractory to IAT with rtPA who were treated with IV andor IA rtPA who were treated with IV andor IA abciximab eptifibatide or tirofiban abciximab eptifibatide or tirofiban
IA Mechanical Approaches in Acute Ischemic Stroke IA Mechanical Approaches in Acute Ischemic Stroke Mechanical strategies have several advantagesMechanical strategies have several advantages First they lessen and may even preclude the use of chemical First they lessen and may even preclude the use of chemical
thrombolytics in this manner very likely reducing the risk of ICHthrombolytics in this manner very likely reducing the risk of ICH Second by avoiding the use of chemical thrombolytics it is Second by avoiding the use of chemical thrombolytics it is
possible to extend the treatment window beyond the limit of 6ndash8 possible to extend the treatment window beyond the limit of 6ndash8 hours hours
Third mechanically fragmenting a clot increases the surface area Third mechanically fragmenting a clot increases the surface area accessible to fibrinolytic agents and allows inflow of fresh accessible to fibrinolytic agents and allows inflow of fresh plasminogen which in turn may increase the speed of plasminogen which in turn may increase the speed of thrombolysis thrombolysis
Finally clot-retrieval devices may provide faster recanalization Finally clot-retrieval devices may provide faster recanalization
The disadvantages of the mechanical The disadvantages of the mechanical approaches approaches technical difficulty of navigating mechanical technical difficulty of navigating mechanical
devices into the intracranial circulation excessive devices into the intracranial circulation excessive trauma to the vasculature (potentially leading to trauma to the vasculature (potentially leading to vasospasm vessel dissection perforation or vasospasm vessel dissection perforation or rupture) rupture)
fragmented thrombus causing distal embolization fragmented thrombus causing distal embolization into previously unaffected territories into previously unaffected territories
Nevertheless the advantages of mechanical stroke Nevertheless the advantages of mechanical stroke therapy appear to significantly outweigh its therapy appear to significantly outweigh its disadvantages and risksdisadvantages and risks
Contraindications to Thrombolytic Contraindications to Thrombolytic agents agents
Recent thoracic abdominal or Recent thoracic abdominal or intracranial surgeryintracranial surgery
Recent haemorrhagic CVA Head injury Recent haemorrhagic CVA Head injury or neoplasmor neoplasm
Bleeding ulcerBleeding ulcer Anticipated invasive procedures (arterial Anticipated invasive procedures (arterial
punctures biopsies)punctures biopsies) Concurrent hemostatic dysfunctionConcurrent hemostatic dysfunction
Monitoring of thrombolytic Monitoring of thrombolytic therapytherapy
Thrombin time Measures the availability of functional
fibrinogen Normal thrombin time is 10-14 sec Prolonged when fibrinogen level is below
75-100 mgdl
Half Life of ThrombolyticsHalf Life of ThrombolyticsAgent Administration Half Life
Streptokinase IA 60-80min
Urokinase IAIV 9-12min
rTPA IAIV 6min
Abciximab(Reopro) IAIV 12hour
Aspirin POIV 15-20min
Heparin IVSC 60min
Coumadin PO 15-25 days
Anti Platelet DrugsAnti Platelet DrugsDrug Drug Mechanism Mechanism UsesUsesAspirinAspirin Permanently inhibits Permanently inhibits
COX-1 and COX-2COX-1 and COX-2CADCAD
Stroke-TIAsStroke-TIAs
NSAIDsNSAIDs Reversibly inhibits Reversibly inhibits COX-1COX-1
LimitedLimited
DipyridamoleDipyridamole Inhibits PDE increases Inhibits PDE increases cAMPcAMP
TIAsTIAs
ThenopyridinesThenopyridines
(Ticlopidine(Ticlopidine
ClopidrgrelClopidrgrel))
Inhibits ADP Inhibits ADP
PlatAg PlatAg
TIAsStrokeTIAsStroke
CAD PVDCAD PVD
Abciximab (ReoPro)Abciximab (ReoPro)
Eptifibatide (Integrilin)Eptifibatide (Integrilin)
TirofibanTirofiban
GP IIBIIIA InhibitorsGP IIBIIIA Inhibitors
Stroke- TIAs Stroke- TIAs
MonitoringMonitoring
Bleeding timeBleeding time
Optical aggregometryOptical aggregometry
Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay
Bleeding timeBleeding time
Requires a skin incision (usually made on the ear lobe or Requires a skin incision (usually made on the ear lobe or forearm offorearm of
a depth that results in disruption of capillary loops and a depth that results in disruption of capillary loops and small vessels)small vessels)
AdvantagesAdvantages Universally availableUniversally available Relatively simple techniquesRelatively simple techniques Can be performed bedsideCan be performed bedside
DisadvantagesDisadvantages Insensitive inaccurate non-specific techniqueInsensitive inaccurate non-specific technique
Poorly reproducible (as depends on multiple variables)Poorly reproducible (as depends on multiple variables)
Optical aggregometryOptical aggregometry
Gold standard assay for platelet functionGold standard assay for platelet function Agonist induced aggregation is measuredAgonist induced aggregation is measured Different agonist are available for different Different agonist are available for different
agentsagents However require unique expertise and are not However require unique expertise and are not
universally availableuniversally available Aspirin measured with ADP or AA(gt70 Aspirin measured with ADP or AA(gt70
aggregation so resistance)aggregation so resistance) Clopidogrel( ADP gt 90 aggregation means Clopidogrel( ADP gt 90 aggregation means
resistance) resistance)
Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay
Can be performed bed sideCan be performed bed side Different assay devices with different Different assay devices with different
agonist are used for each of different agonist are used for each of different antiplatelet agents antiplatelet agents
For Aspirin AA is used (result is reported as aspirin For Aspirin AA is used (result is reported as aspirin reaction units [ARU] ARUgt 550 indicates non-reaction units [ARU] ARUgt 550 indicates non-responsiveness)responsiveness)
Verify IIbIIIa assay device uses TRAP as agonist for Verify IIbIIIa assay device uses TRAP as agonist for Abciximab and TirofibanAbciximab and Tirofiban
Practical Applications Practical Applications related to specific related to specific
Neurovascular Neurovascular interventionsinterventions
Acute ischemic StrokeAcute ischemic Stroke When an artery occludes neurons are affected When an artery occludes neurons are affected
differently depending upon the amount of residual blood differently depending upon the amount of residual blood flowflow
Normal cerebral blood flow is greater than 50 mL100 Normal cerebral blood flow is greater than 50 mL100 mgminmgmin
Once blood flow decreases to less than 20 mL100 Once blood flow decreases to less than 20 mL100 mgmin infarction occursmgmin infarction occurs
If blood flow decreases to less than 10 mL100 mgmin If blood flow decreases to less than 10 mL100 mgmin irreversible neuronal death occurs rapidly irreversible neuronal death occurs rapidly
Blood flow between 11 and 20 mL100 mgmin is thought Blood flow between 11 and 20 mL100 mgmin is thought to represent the ischemic penumbra an area where the to represent the ischemic penumbra an area where the cells are functionally silent because of ischemia but are cells are functionally silent because of ischemia but are still able to recover if blood flow is restored still able to recover if blood flow is restored
Many acute stroke therapies are targeted toward Many acute stroke therapies are targeted toward restoring flow or function to the ischemic penumbrarestoring flow or function to the ischemic penumbra
Therapeutic window in Therapeutic window in management of acute Ischemic management of acute Ischemic
StrokeStrokeThe early diagnosis of ischemic stroke is critical to the The early diagnosis of ischemic stroke is critical to the
with only a narrow therapeutic window in the first few with only a narrow therapeutic window in the first few hours following stroke ictushours following stroke ictus
Diagnosis in the first 3 hours postictus provides the Diagnosis in the first 3 hours postictus provides the opportunity for intravenous or intraarterial thrombolysis opportunity for intravenous or intraarterial thrombolysis and intra-arterial clot mechanical treatment which and intra-arterial clot mechanical treatment which improve the outcome improve the outcome
Diagnosis in the time period between 3 and 6 hours Diagnosis in the time period between 3 and 6 hours provides an opportunity for intra-arterial thrombolysis provides an opportunity for intra-arterial thrombolysis and mechanical treatment and mechanical treatment
Involvement of the posterior circulation especially the Involvement of the posterior circulation especially the basilar artery is treated by some regardless of time of basilar artery is treated by some regardless of time of onset or up until 12 to 24 hours in some practices This is onset or up until 12 to 24 hours in some practices This is related to the potentially high mortality and morbidity related to the potentially high mortality and morbidity associated with basilar artery thrombosisassociated with basilar artery thrombosis
Infarct evaluation on angiographyInfarct evaluation on angiography(CT angiography and catheter (CT angiography and catheter
angiography)angiography)CTA is an excellent first-line examination for CTA is an excellent first-line examination for
evaluation of the head and neck arteries evaluation of the head and neck arteries In comparison with catheter angiography In comparison with catheter angiography
what it gives up in resolution and dynamic what it gives up in resolution and dynamic properties it makes up for with rapid properties it makes up for with rapid acquisition of a 3-D dataset and the potential acquisition of a 3-D dataset and the potential for assessment of whole-brain perfusion and for assessment of whole-brain perfusion and better parenchymal evaluationbetter parenchymal evaluation
Moreover CTA illustrates not only arterial Moreover CTA illustrates not only arterial stenosis or occlusion but also the vessel wall stenosis or occlusion but also the vessel wall This factor is most important for evaluation of This factor is most important for evaluation of intramural dissection and thrombosed intramural dissection and thrombosed aneurysms which may both complicate aneurysms which may both complicate evaluation of stroke patientsevaluation of stroke patients
Early angiographic signs of strokes Early angiographic signs of strokes both CTA both CTA and DSA and DSA
Vessel occlusion or cutoff related to Vessel occlusion or cutoff related to thromboembolithromboemboli
aneurysms aneurysms arterial dissection arterial dissection Meniscus or flattened shape to clot Meniscus or flattened shape to clot
(recent) versus reverse meniscus (older)(recent) versus reverse meniscus (older) tram track (nonocclusive or recanalized tram track (nonocclusive or recanalized
clot) clot) delayed (antegrade) flow (manifest as delayed (antegrade) flow (manifest as
decreased whole-brain perfusion on CTA)decreased whole-brain perfusion on CTA) retrograde collateral flowretrograde collateral flow
Non-occlusive left MCA thrombus on 3-D imaging performed from CTA source data and was confirmed at catheter angiography
Therapy to be started within a 6-hr Therapy to be started within a 6-hr time to treatment (TTT) window time to treatment (TTT) window (while in case of IV thrombolysis (while in case of IV thrombolysis therapy to be started with in 3hrs)therapy to be started with in 3hrs)
Exclusion criteria Exclusion criteria Rapidly improving neurologic deficit or Rapidly improving neurologic deficit or Sustained blood pressure of gt180100 Sustained blood pressure of gt180100 Hemorrhage is detected on CTHemorrhage is detected on CT Infarct involving gt more than 13 rd Infarct involving gt more than 13 rd
territory of MCAterritory of MCA MRADWI-Perfusion mismatchlt 20MRADWI-Perfusion mismatchlt 20 Definite hypodensity on CTDefinite hypodensity on CT
Intra-arterial Thrombolysis
Fibrinolytics + AntiplateletsFibrinolytics + Antiplatelets
PlasminogenPlasminogen activators through fibrinolysis exposes activators through fibrinolysis exposes free thrombin and paradoxically stimulatesfree thrombin and paradoxically stimulates platelet platelet aggregation which leads to formation of aaggregation which leads to formation of a platelet platelet thrombus (white clot) thrombus (white clot)
This new thrombus is relatively resistant to This new thrombus is relatively resistant to fibrinolyticsfibrinolytics
So new regimen in case of acute stroke isSo new regimen in case of acute stroke is fibrinolytics + antiplatelet drugsfibrinolytics + antiplatelet drugs
rtPA + IIbIIIa inhibitors( tirofiban rtPA + IIbIIIa inhibitors( tirofiban abciximab) orabciximab) or
Urokinase + IIbIIIa Urokinase + IIbIIIa inhibitors( tirofiban abciximab)inhibitors( tirofiban abciximab)
Intra-arterial Thrombolysis Tirofiban (04 microgkgmin bolus for 3 min followed by Tirofiban (04 microgkgmin bolus for 3 min followed by
0125 ugkgmin)0125 ugkgmin)
++
Heparin (2000ndash3000 IU bolus followed by Heparin (2000ndash3000 IU bolus followed by 1000 IUhour infusion 1000 IUhour infusion
with ACT maintained bw 200-300) throughout the with ACT maintained bw 200-300) throughout the interventional procedure and for 24ndash48 hours thereafter when interventional procedure and for 24ndash48 hours thereafter when there is neither intraprocedural bleeding nor suspicion of there is neither intraprocedural bleeding nor suspicion of increased risk of bleeding increased risk of bleeding
Maximum dose of Urokinase Maximum dose of Urokinase Anterior circulation stroke - 500000 IU (mean 400000 Anterior circulation stroke - 500000 IU (mean 400000
IU range 300000ndash500000 IU)IU range 300000ndash500000 IU) Posterior circulation stroke -1000000 IU (mean 837000 Posterior circulation stroke -1000000 IU (mean 837000
IU range 300000ndash1000000 IU)IU range 300000ndash1000000 IU)American Journal of NeuroradiologyAmerican Journal of Neuroradiology 262595-2601 2005262595-2601 2005
Intravenous ThrombolysisIntravenous Thrombolysis
The first method to restore cerebral The first method to restore cerebral perfusion is clot lysis with the goal perfusion is clot lysis with the goal of re-establishing blood flow to the of re-establishing blood flow to the affected tissue affected tissue
IV thrombolysis rt-PA is the only IV thrombolysis rt-PA is the only FDA- approved treatment for AIS FDA- approved treatment for AIS
Fibrinolysis is enhanced powerfully Fibrinolysis is enhanced powerfully by rt-PAby rt-PA
Intravenous rTPA Intravenous rTPA administration administration protocolprotocol
Total dose of rt-PA 09 mgkg (maximum dose Total dose of rt-PA 09 mgkg (maximum dose 90 mg)90 mg)
Give 10 as initial IV bolusGive 10 as initial IV bolus Infuse remainder over 1 hourInfuse remainder over 1 hour Admit patient to an ICU or stroke unit for Admit patient to an ICU or stroke unit for
monitoringmonitoring Neurologic assessments every 15 minutes Neurologic assessments every 15 minutes
during infusion then every 30 minutes for next during infusion then every 30 minutes for next 6 hours then every hour until 24hours after 6 hours then every hour until 24hours after treatmenttreatment
Favorable Outcome vs Treatment Time Favorable Outcome vs Treatment Time with IV rTPAwith IV rTPA
Protocol limit = 3 hrs
Benefit ~ 45 hrs
Thromboembolism During coilingThromboembolism During coiling Most feared and frequent complication Most feared and frequent complication Reported incidence - Approx 7 Reported incidence - Approx 7 SourcesSources of Thromboembolism are of Thromboembolism are
- Clots at the aneurysmal neck during or immediately- Clots at the aneurysmal neck during or immediately after after embolization embolization
- Thrombus forming on catheters during- Thrombus forming on catheters during proceduresprocedures
- Stenosis of an adjacent artery dt coil mass- Stenosis of an adjacent artery dt coil mass or herniationor herniation
- Migration of intraaneurysmal- Migration of intraaneurysmal thrombus during coil thrombus during coil placement placement
- Slow flow dt vasospasm - Slow flow dt vasospasm
- Rare and unlikely causes are hypercoagulable- Rare and unlikely causes are hypercoagulable state such state such as antiphospholipid antibody syndrome or due to HITas antiphospholipid antibody syndrome or due to HIT
Occur more often with wide-necked aneurysms (dt Occur more often with wide-necked aneurysms (dt increased exposed surface area of thrombogenic coil increased exposed surface area of thrombogenic coil material)material)
Current regimen of endovascular Current regimen of endovascular managementmanagement
The The glycoprotein IIbIIIa antagonist tirofiban glycoprotein IIbIIIa antagonist tirofiban (04 (04 microgkgmin bolus for 30 minutes followed by infusion of microgkgmin bolus for 30 minutes followed by infusion of 0125 ugkgmin until the thrombus dissolved) 0125 ugkgmin until the thrombus dissolved)
Intraarterial thrombolysis with Intraarterial thrombolysis with urokinase or r- TPA urokinase or r- TPA increase of intravenous (IV) heparin (measured by increase of intravenous (IV) heparin (measured by
ACT) ACT) Intravenous aspirin Intravenous aspirin
Coil-related platelet aggregation (white clot) is Coil-related platelet aggregation (white clot) is unlikely to respond to fibrinolytics but has a high risk unlikely to respond to fibrinolytics but has a high risk of hemorrhage (In ISAT) all 5 patients who had of hemorrhage (In ISAT) all 5 patients who had received thrombolytic therapy with tPA to treat a received thrombolytic therapy with tPA to treat a thromboembolic complication after endovascular thromboembolic complication after endovascular treatment rebleed and all of these patients died)treatment rebleed and all of these patients died)
IntracranialIntracranial Stenting Stenting Metallic foreign body such as stent will accumulate Metallic foreign body such as stent will accumulate
thrombus in the absence of platelet inhibitionthrombus in the absence of platelet inhibition Antiplatelet drugs are important to prevent peri or Antiplatelet drugs are important to prevent peri or
post-interventional thromboembolic eventspost-interventional thromboembolic events Optimal treatment regimens has not been determined Optimal treatment regimens has not been determined
but usually but usually Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-
procedureprocedureOrOr
Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on
morning of proceduremorning of procedure
If need to use stent is not pre-planned thanIf need to use stent is not pre-planned than
Abciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkgAbciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkg IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)
Glycoprotein IIbIIIa inhibitor are not used routinely during elective Glycoprotein IIbIIIa inhibitor are not used routinely during elective stenting procedure dt increased risk of ICH stenting procedure dt increased risk of ICH
Carotid StentingCarotid Stenting
Pre-procedurePre-procedure
Double Antiplatelet therapy is routinely given Double Antiplatelet therapy is routinely given beginning at least 3beginning at least 3
days before the proceduredays before the procedure
Aspirin 325mgd+Clopidogrel 75mgdAspirin 325mgd+Clopidogrel 75mgd During procedureDuring procedure
Heparin is given with target clotting time of 250-Heparin is given with target clotting time of 250-300sec300sec
Post-procedure Post-procedure
Aspirin 325mg is continued indefinitely and Aspirin 325mg is continued indefinitely and
Clopidogrel 75mgd for at least 6 weeks Clopidogrel 75mgd for at least 6 weeks
Inclusion criteria for Local ThrombolysisInclusion criteria for Local Thrombolysis a)a) Patients in severe clinical grade on admission Patients in severe clinical grade on admission
with evidence of dural venous sinus with evidence of dural venous sinus thrombosis and restrictive venous outflow on thrombosis and restrictive venous outflow on cerebral angiogramcerebral angiogram
b)b) Patients in clinical grade 3 worsening on Patients in clinical grade 3 worsening on heparin therapy Restriction to venous heparin therapy Restriction to venous outflow was defined as an increase in brain outflow was defined as an increase in brain circulation time gt 12 s delay in the drainage circulation time gt 12 s delay in the drainage of cortical veins with cortical veins hanging of cortical veins with cortical veins hanging in spacein space
Treatment Options for Venous Thrombosis
CT Grading for Venous ThrombosisCT Grading for Venous Thrombosis Grade I no parenchymal change Grade I no parenchymal change
(hyperdense (hyperdense sinuses cortical veins empty sinuses cortical veins empty delta sign)delta sign)
Grade II non hemorrhagic venous infarct Grade II non hemorrhagic venous infarct without mass effect without mass effect
Grade III non-hemorrhagic infarct with Grade III non-hemorrhagic infarct with mass effectmass effect
Grade IV hemorrhagic venous infarct (max Grade IV hemorrhagic venous infarct (max diameter lt 3 cm) with no mass effectdiameter lt 3 cm) with no mass effect
Grade V hemorrhagic venous infarct (max Grade V hemorrhagic venous infarct (max diameter gt 3 cm) with mass effect diameter gt 3 cm) with mass effect
Local ThrombolysisLocal Thrombolysis
Femoral Jugular access was secured and a guiding Femoral Jugular access was secured and a guiding catheter was placed in the jugular bulb catheter was placed in the jugular bulb Mechanical Mechanical clot maceration clot maceration was done with the guidewire was done with the guidewire following which a microcatheter (was navigated and following which a microcatheter (was navigated and placed in the thrombosed segment of sinus confirmed placed in the thrombosed segment of sinus confirmed on a selective venogram on a selective venogram
Urokinase infusion Bolus dose of 2-6 lacs followed Urokinase infusion Bolus dose of 2-6 lacs followed by 60000 to 100000 units per hour along with by 60000 to 100000 units per hour along with periodic check venogram Along with maintenance periodic check venogram Along with maintenance systemic infusion of Heparinsystemic infusion of Heparin Other agents such as Other agents such as streptokinase altepase or rTPAstreptokinase altepase or rTPA can be also used can be also used
After thrombolysis patient should subjected to oral After thrombolysis patient should subjected to oral anticoagulation for six monthsanticoagulation for six months
Low-molecular-weight Low-molecular-weight heparinheparin
PharmacologyPharmacologyLMWH as its name suggests is a glycosaminoglycan that is approximatelyLMWH as its name suggests is a glycosaminoglycan that is approximately
one third the molecular weight of UFH It is derived from UFH through one third the molecular weight of UFH It is derived from UFH through variousvarious
depolymerization processes LMWH binds to antithrombin which in turn depolymerization processes LMWH binds to antithrombin which in turn
Neutralizes actors Xa and IIa Because LMWH lacks many of the longer Neutralizes actors Xa and IIa Because LMWH lacks many of the longer chains chains
required for binding to thrombin it has less ability to neutralize thrombin required for binding to thrombin it has less ability to neutralize thrombin
relativeto its ability to neutralize factor Xa LMWH also has less relativeto its ability to neutralize factor Xa LMWH also has less nonspecific nonspecific
binding to other proteins There is greater bioavailability with more binding to other proteins There is greater bioavailability with more predictable predictable
pharmacokinetics that eliminates the need for monitoring The smaller pharmacokinetics that eliminates the need for monitoring The smaller size also size also
allows for enhanced subcutaneous absorption when compared with UFHallows for enhanced subcutaneous absorption when compared with UFH
Three LMWH preparations are Three LMWH preparations are currently approved for use in the currently approved for use in the United States (1) enoxaparin (2) United States (1) enoxaparin (2) dalteparin and (3) tinzaparin dalteparin and (3) tinzaparin
They are all administered They are all administered subcutaneously at intervals of either subcutaneously at intervals of either once or twice daily for both once or twice daily for both prophylaxis and treatment dosesprophylaxis and treatment doses
Few Experiences of Few Experiences of ThrombolysisThrombolysis
Vickey 25 Yrs male patient presented Vickey 25 Yrs male patient presented with 12with 12thth day HO severe headache with day HO severe headache with right sided hemiplegiaright sided hemiplegia
MRI shows thrombosis of the superior MRI shows thrombosis of the superior sagittal left transverse left sigmoid sagittal left transverse left sigmoid sinuses and cortical veins in the fronto-sinuses and cortical veins in the fronto-parietal regions with eo haemorrhagic parietal regions with eo haemorrhagic infarct in the left cerebral hemisphere infarct in the left cerebral hemisphere with mass effect( Grade ndashV)with mass effect( Grade ndashV)
Sashi Srivastava 64 yrs FSashi Srivastava 64 yrs F In a follow up case of MRD with infra-renal In a follow up case of MRD with infra-renal
aortic abdominal and bilateral renal artery aortic abdominal and bilateral renal artery thrombosis renal angiogram shows filling thrombosis renal angiogram shows filling defects in the right Renal artery defects in the right Renal artery
Initially Renal angioplasty was done Initially Renal angioplasty was done Following angioplasty few thrombi are seem Following angioplasty few thrombi are seem to extends into the segmental branches and to extends into the segmental branches and causing blockage So Thrombolysis was causing blockage So Thrombolysis was plane to dissolve the run-out thrombi with plane to dissolve the run-out thrombi with urokinase urokinase
Rakesh 34yrsMRakesh 34yrsM Left SFA pseudoaneurysm with Left SFA pseudoaneurysm with
Covered stent placementCovered stent placement Pre operative antiplatelets with post Pre operative antiplatelets with post
procedure heparin Tirofiban procedure heparin Tirofiban followed by aspirin and clopidogrel followed by aspirin and clopidogrel were usedwere used
IAT may be a treatment option for selected patients IAT may be a treatment option for selected patients Possible selection criteria include Possible selection criteria include
presentation between 3 and 6 hours from symptom onsetpresentation between 3 and 6 hours from symptom onset major cerebral artery occlusion major cerebral artery occlusion severe neurologic deficits severe neurologic deficits high risk of systemic hemorrhage with IV rt-PA (eg recent high risk of systemic hemorrhage with IV rt-PA (eg recent
surgery) surgery) The MERCI (Mechanical Embolus Removal in Cerebral The MERCI (Mechanical Embolus Removal in Cerebral
Ischemia) retrievalIschemia) retrieval system system
Has been FDA-approved for recanalizing acutely occluded Has been FDA-approved for recanalizing acutely occluded cerebral arteries cerebral arteries
In the Multi-MERCI study patients who did not improve In the Multi-MERCI study patients who did not improve immediately after IV rt-PA underwent mechanical immediately after IV rt-PA underwent mechanical embolectomy within 8 hours of symptom onset embolectomy within 8 hours of symptom onset
Partial or complete recanalization occurred in 74 of Partial or complete recanalization occurred in 74 of patientspatients
with a symptomatic intracerebral hemorrhage (sICH) rate of with a symptomatic intracerebral hemorrhage (sICH) rate of 67 67
Mechanical embolectomy with the MERCI retriever may be a Mechanical embolectomy with the MERCI retriever may be a feasible and safe option for patients after IV rt-PAfeasible and safe option for patients after IV rt-PA
Penumbra stroke systemPenumbra stroke system This device combines two methods of clot This device combines two methods of clot
extraction aspiration and mechanical extraction aspiration and mechanical extraction extraction
First the clot is aspirated then a thrombus First the clot is aspirated then a thrombus removal ring can be used if necessary to removal ring can be used if necessary to remove remaining clot remove remaining clot
successful recanalizing 82successful recanalizing 82 Bridging therapyBridging therapy
06 mgkg IV rt-PA followed by IAT with IA rt-06 mgkg IV rt-PA followed by IAT with IA rt-PA (up to 20 mg)PA (up to 20 mg)
achieved a higher recanalization rateachieved a higher recanalization rate
Criteria for thrombolysis with rTPACriteria for thrombolysis with rTPA
Inclusion criteriaInclusion criteria Clinical signs and symptoms consistent with ischemic Clinical signs and symptoms consistent with ischemic
strokestroke Patient last seen normal within 3 hoursPatient last seen normal within 3 hours Measurable neurologic deficitMeasurable neurologic deficit
Exclusion criteriaExclusion criteria Any hemorrhage on neuroimaging (CT or MRI)Any hemorrhage on neuroimaging (CT or MRI) Symptoms suggestive of subarachnoid hemorrhageSymptoms suggestive of subarachnoid hemorrhage Seizure at stroke onset that is thought to contribute to Seizure at stroke onset that is thought to contribute to
neurologic deficitneurologic deficit Hypodensity greater than one third cerebral hemisphere Hypodensity greater than one third cerebral hemisphere
on CTon CT SBP greater than 185 mm Hg or DBP greater than 110 SBP greater than 185 mm Hg or DBP greater than 110
mm Hgmm Hg International normalized ratio (INR) greater than 17International normalized ratio (INR) greater than 17
Ischemic Stroke Ischemic Stroke Treatment ndash 2006Treatment ndash 2006
IV tissue plasminogen activator (tPA)IV tissue plasminogen activator (tPA) ndash ndash Only FDA-approved acute stroke drugOnly FDA-approved acute stroke drug ndash ndash 3 hour treatment window3 hour treatment window
MERCI - Concentric clot retrieval MERCI - Concentric clot retrieval devicedevice ndash ndash Rescue therapy - approved 2004Rescue therapy - approved 2004 ndash ndash Device approval (not outcomes-based)Device approval (not outcomes-based)
Off label approachesOff label approaches ndash ndash IV tPA after 3 hoursIV tPA after 3 hours ndash ndash IV-IA tPA sequential strategiesIV-IA tPA sequential strategies ndash ndash IA tPA clot angioplasty fragmentationIA tPA clot angioplasty fragmentation ndash ndash Ultrasound-assisted tPA lysisUltrasound-assisted tPA lysis
rt-PA Trials NINDSrt-PA Trials NINDS
Acute stroke - 624 patientsAcute stroke - 624 patients Treat within 3 hrsTreat within 3 hrs Intravenous 09 mgkg rt-PA vs placeboIntravenous 09 mgkg rt-PA vs placebo Hemorrhage 64 tPA 06 placeboHemorrhage 64 tPA 06 placebo Neurologic recovery better with tPA 30 Neurologic recovery better with tPA 30
more like to have minimal or no disabilitymore like to have minimal or no disability
First proven approved treatment for First proven approved treatment for strokestroke
Limitations of tPALimitations of tPA Only 4 of acute strokes receive tPAOnly 4 of acute strokes receive tPA (Kleindorfer et al Stroke 2004 35 e27-e29)(Kleindorfer et al Stroke 2004 35 e27-e29)
Only 22 of patients present within 3 hoursOnly 22 of patients present within 3 hours1048707 1048707 51 of these ineligible due to51 of these ineligible due to
bull bull Mild severityMild severity bull bull Medical or surgical historyMedical or surgical history bull bull Blood testsBlood tests
Sustained recanalization only 13Sustained recanalization only 13 (Alexandrov et al NEJM 2004 351 2170-8)(Alexandrov et al NEJM 2004 351 2170-8)
Concern for hemorrhageConcern for hemorrhage tPA potentiates apoptotic injury tPA potentiates apoptotic injury (Liu et al Nature Med 2004 101379-83)(Liu et al Nature Med 2004 101379-83)
PROACT II IA Lysis TrialPROACT II IA Lysis Trial Baseline 24 hours 8 days
Baseline 60 minutes 120 minutes
9mg IAProurokinase
Desmoteplase Trials DEDAS Desmoteplase Trials DEDAS DIASDIAS
Trial OverviewTrial Overview Double blind randomized placebo Double blind randomized placebo
controlled trialscontrolled trials IV delivery 3-9 hour time windowIV delivery 3-9 hour time window Plasminogen activator ndash from Plasminogen activator ndash from vampire bat vampire bat
salivasaliva Selection based on PWI-DWI MismatchSelection based on PWI-DWI Mismatch
MRI InclusionMRI Inclusion PWI defect at least 2 cm AND ~20 larger PWI defect at least 2 cm AND ~20 larger
than DWIthan DWI PWI should be obvious even visible on PWI should be obvious even visible on
raw imagesraw imagesMRI ExclusionMRI Exclusion
DWI gt 13 MCADWI gt 13 MCA MRA ICA occlusionMRA ICA occlusion
Desmoteplase ndash DIAS Desmoteplase ndash DIAS ResultsResults
Mechanical Thrombolysis Mechanical Thrombolysis devicesdevices
mechanical thrombolysis potentially extends the treatment mechanical thrombolysis potentially extends the treatment window because they act promptly at the site of the thrombuswindow because they act promptly at the site of the thrombus
The devices can retrieve large clots that pharmaceutical agents The devices can retrieve large clots that pharmaceutical agents may not successfully lysemay not successfully lyse
Patients treated with IV tPA may be considered for treatment of Patients treated with IV tPA may be considered for treatment of residual clot with some of these devicesresidual clot with some of these devices
suction-creating saline jets suction-creating saline jets laser energy ultrasound laser energy ultrasound a corkscrew apparatus to treat strokesa corkscrew apparatus to treat strokes The AngioJet systemThe AngioJet system uses saline jets that are directed back into the catheter to uses saline jets that are directed back into the catheter to
create a low-pressure zone around the catheter tip inducing create a low-pressure zone around the catheter tip inducing suction suction
The clot is pulled into the exhaust lumen and removed from the The clot is pulled into the exhaust lumen and removed from the vessel Although US Food and Drug Administration (FDA) has vessel Although US Food and Drug Administration (FDA) has approved this device for use in arteriovenous dialysis grafts and approved this device for use in arteriovenous dialysis grafts and fistulae and for the treatment of coronary arteries saphenous fistulae and for the treatment of coronary arteries saphenous vein grafts and peripheral vessels clinical trials for the vein grafts and peripheral vessels clinical trials for the treatment of acute stroke are no longer in progress treatment of acute stroke are no longer in progress
Most devices are used in cerebral vessels that 2-5 mm
The Latis laser device The Latis laser device used laser energy to ablate clots used laser energy to ablate clots Arteries 2-5 mm in diameter could be Arteries 2-5 mm in diameter could be
treated including the ICA M1 or M2 treated including the ICA M1 or M2 branch of the MCA A1 branch of the branch of the MCA A1 branch of the anterior cerebral artery (ACA) basilar anterior cerebral artery (ACA) basilar artery posterior cerebral artery (PCA) artery posterior cerebral artery (PCA) and vertebral and vertebral
Patients could receive treatment as late Patients could receive treatment as late as 8 hours after symptom onset in the as 8 hours after symptom onset in the anterior circulation and within 24 hours in anterior circulation and within 24 hours in the posterior circulation the posterior circulation
Endovascular Photo Acoustic Endovascular Photo Acoustic Recanalization (EPAR) Recanalization (EPAR)
A laser power source generated energy for the A laser power source generated energy for the systemsystem
The energy was delivered by means of The energy was delivered by means of fiberoptics to the tip of the catheter at the fiberoptics to the tip of the catheter at the treatment sitetreatment site
Absorption of laser light by darkly pigmented Absorption of laser light by darkly pigmented materials (ie the clot) occurred inside the 1-mm materials (ie the clot) occurred inside the 1-mm catheter tipcatheter tip
the system was designed to minimize scattering the system was designed to minimize scattering of laser light of laser light
Absorption converted photo energy to acoustic Absorption converted photo energy to acoustic energy which then emulsified the clot inside the energy which then emulsified the clot inside the catheter tip catheter tip
EKOS ultrasound( the EKOS ultrasound( the Ultrasound Thrombolytic Ultrasound Thrombolytic
Infusion Catheter) Infusion Catheter) combines the use of a distal ultrasound transducer with combines the use of a distal ultrasound transducer with
infusion of a thrombolytic agent through the infusion of a thrombolytic agent through the microcathetermicrocatheter
Ultrasound changes the structure of the clot to Ultrasound changes the structure of the clot to temporarily increase its permeability while providing an temporarily increase its permeability while providing an acoustic pressure gradient to move the drug into the clot acoustic pressure gradient to move the drug into the clot to speed its dissolution to speed its dissolution
The EKOS catheter is placed in the proximal portion of the The EKOS catheter is placed in the proximal portion of the clot clot
After a 2-mg bolus of tPA was injected through the After a 2-mg bolus of tPA was injected through the catheter catheter
the patient received a continuous infusion of IA tPA 03 the patient received a continuous infusion of IA tPA 03 mgmin to a maximum of 20 mg and simultaneous mgmin to a maximum of 20 mg and simultaneous ultrasound transmission for as long as 60 minutes ultrasound transmission for as long as 60 minutes
One patient was treated with a total of 4 units of One patient was treated with a total of 4 units of recombinant reteplase (Retavase) hand-injected over 60 recombinant reteplase (Retavase) hand-injected over 60 minutes minutes
Penumbra system Penumbra system The Penumbra system (Penumbra Inc) provides a dual The Penumbra system (Penumbra Inc) provides a dual
approach to clot extraction using aspiration followed by approach to clot extraction using aspiration followed by clot retrieval with a ring device if needed clot retrieval with a ring device if needed
Mechanical Embolus Removal in Cerebral Ischemia Mechanical Embolus Removal in Cerebral Ischemia (MERCI)(MERCI)
a corkscrew-like apparatus to remove blood clots from a corkscrew-like apparatus to remove blood clots from the brain in patients experiencing an ischemic stroke the brain in patients experiencing an ischemic stroke
The corkscrew itself resides in the catheter tip which The corkscrew itself resides in the catheter tip which shields it from the wall of the vessel until it is ready to be shields it from the wall of the vessel until it is ready to be burrowed into the clot Once lodged in the clot the device burrowed into the clot Once lodged in the clot the device and clot are withdrawn from the vessel and clot are withdrawn from the vessel
Snarelike devicesSnarelike devices Snares such as the Neuronet snare (Guidant Snares such as the Neuronet snare (Guidant
Endovascular Santa Clara CA) have been developed Endovascular Santa Clara CA) have been developed specifically for use in the treatment of strokes specifically for use in the treatment of strokes
These devices are simple in design and do not require the These devices are simple in design and do not require the clot to be amenable to emulsification clot to be amenable to emulsification
X-Sizer deviceX-Sizer device a device with small moving blades at the a device with small moving blades at the
catheter tip catheter tip This device the X-Sizer device (EndiCor Medical This device the X-Sizer device (EndiCor Medical
San Clemente CA) can be used to excise the San Clemente CA) can be used to excise the thrombus and aspirate it thrombus and aspirate it
The device was being evaluated in randomized The device was being evaluated in randomized studies of coronary vessels and in a registry of studies of coronary vessels and in a registry of patients with acute myocardial infarctionpatients with acute myocardial infarction
Although the manufacturer had modified the Although the manufacturer had modified the device for use in cerebral vessels a safety and device for use in cerebral vessels a safety and feasibility study was indefinitely suspended after feasibility study was indefinitely suspended after only 1 patient was treated with the device in only 1 patient was treated with the device in Europe Europe
Suction thrombectomySuction thrombectomy This method of mechanical thrombolysis is one of the This method of mechanical thrombolysis is one of the
simplestsimplest In this readily available technique suction is applied with In this readily available technique suction is applied with
a syringe to remove thrombus in the ICA a syringe to remove thrombus in the ICA It requires no other devicesIt requires no other devices A catheter with a large inner diameter (Brite Tip Cordis A catheter with a large inner diameter (Brite Tip Cordis
Corporation Miami FL) was placed in the symptomatic Corporation Miami FL) was placed in the symptomatic vessel and navigated over a guidewire into the thrombusvessel and navigated over a guidewire into the thrombus
A 60-mL syringe was used to aspirate the thrombus A 60-mL syringe was used to aspirate the thrombus Each patient required angioplasty and stenting of carotid Each patient required angioplasty and stenting of carotid
bifurcation stenosis and received daily aspirin and bifurcation stenosis and received daily aspirin and ticlopidine after the procedure No complications ticlopidine after the procedure No complications occurred occurred
Summary Acute Stroke Summary Acute Stroke ImagingImaging
PhysiologyPhysiology importance collaterals importance collaterals
ndash ndashGrowing role for perfusion Growing role for perfusion assessmentassessment
tPAtPA guidelines amp limitations guidelines amp limitations Signs on CT amp MRSigns on CT amp MR follow physiology follow physiology Stroke trialsStroke trials PWI-DWI mismatch PWI-DWI mismatch
ndash ndashTreat based on physiology not timeTreat based on physiology not time ProtocolsProtocols should be fast and should be fast and
comprehensivecomprehensive
SIDE EFFECTSSIDE EFFECTS
Hemorrhage Hemorrhage Skin necrosisSkin necrosis Purple toe syndromePurple toe syndrome Microembolization Microembolization TeratogenecityTeratogenecity Agranulocytosis leukopenia Agranulocytosis leukopenia Diarrhoeanausea anorexiaDiarrhoeanausea anorexia
MONITORING OF WARFARIN THERAPYMONITORING OF WARFARIN THERAPY
Prothrombin timeProthrombin time PT ratioPT ratio INR (International Normalized Ratio)INR (International Normalized Ratio)
PROTHROMBIN TIME (PT)PROTHROMBIN TIME (PT)
Time required for blood to coagulate Time required for blood to coagulate is called PT ( normal value ~10sec)is called PT ( normal value ~10sec)
Performed by adding a mixture of Performed by adding a mixture of calcium and thromboplastin to calcium and thromboplastin to citrated plasmacitrated plasma
As a control a normal blood sample is As a control a normal blood sample is tested continuouslytested continuously
PT ratio (PTR) = PT ratio (PTR) = Patientrsquos PTPatientrsquos PT Control PTControl PT
PROBLEMS WITH PTPTRPROBLEMS WITH PTPTR
Thromboplastins are extracts from Thromboplastins are extracts from brain lung or placenta of animalsbrain lung or placenta of animals
Thromboplastins from various Thromboplastins from various manufacturers differ in their manufacturers differ in their sensitivity to prolong PTsensitivity to prolong PT
May result in false control of May result in false control of anticoagulant therapyanticoagulant therapy
INTERNATIONAL NORMALISED RATIO (INR)INTERNATIONAL NORMALISED RATIO (INR)
International Normalized Ratio (INR) International Normalized Ratio (INR) a PT test with a a PT test with a formula based ratio to normalize the often variable source formula based ratio to normalize the often variable source of tissue factor (human rabbit recombinant)of tissue factor (human rabbit recombinant)
INR = [PTINR = [PTptpt] ] ISIISI
[PT[PTRefRef]]
PTPTpt pt ndash prothrombin time of patientndash prothrombin time of patient
PTPTRef Ref ndash prothrombin time of normal pooled samplendash prothrombin time of normal pooled sample
ISI ndash International Sensitivity IndexISI ndash International Sensitivity Index
Warfarin is given orally and titrated to achieve an INR of Warfarin is given orally and titrated to achieve an INR of typically 20 ndash 30typically 20 ndash 30
Heparin versus WarfarinHeparin versus Warfarin
Drug ActionMechan-ism
Moni-toring
Effective
HeparinDirect
Inhibition ofThrombin
ATIIIcofactor
APTTACT
Immediate
WarfarinDecreasesProductionof factors
Vitamin K PTDelay
3-5 days
INR
Recanalization or Antegrade Recanalization or Antegrade Reperfusion StrategiesReperfusion Strategies
Recanalization strategies focus on removing Recanalization strategies focus on removing andor dissolving the occlusive thrombus to re-andor dissolving the occlusive thrombus to re-establish antegrade flow Strategies may be establish antegrade flow Strategies may be classified into 7 different categories on the classified into 7 different categories on the basis of their primary mechanism of action basis of their primary mechanism of action 1) 1) IV andor intraarterial thrombolysis (IAT) IV andor intraarterial thrombolysis (IAT) 2) endovascular thrombectomy2) endovascular thrombectomy3) endovascular thromboaspiration 3) endovascular thromboaspiration 4) endovascular mechanical thrombus disruption or 4) endovascular mechanical thrombus disruption or
thromborrhexisthromborrhexis5) 5) transcranial or endovascular augmented transcranial or endovascular augmented
fibrinolysis fibrinolysis 6) endovascular thrombus entrapment and 6) endovascular thrombus entrapment and 7) temporary endovascular bypass7) temporary endovascular bypass
IAT in Acute Ischemic StrokeIAT in Acute Ischemic Stroke
IAT advantages over IV thrombolysisIAT advantages over IV thrombolysis Coaxial microcatheter techniques the occluded intracranial Coaxial microcatheter techniques the occluded intracranial
vessel is directly accessible and the fibrinolytic agent can be vessel is directly accessible and the fibrinolytic agent can be infused directly into the thrombusinfused directly into the thrombus
This permits a smaller dose of fibrinolytic agent to reach a This permits a smaller dose of fibrinolytic agent to reach a higher local concentration than that reached by systemic higher local concentration than that reached by systemic infusioninfusion
Allows more complete recanalization with lower total doses of Allows more complete recanalization with lower total doses of thrombolytic thrombolytic
With the smaller dose complications from systemic fibrinolytic With the smaller dose complications from systemic fibrinolytic effects including intracranial hemorrhage (ICH) can effects including intracranial hemorrhage (ICH) can theoretically be reduced theoretically be reduced
Treatment window for endovascular techniques can be Treatment window for endovascular techniques can be extended beyond the typical IV window of 3 hours extended beyond the typical IV window of 3 hours
IA techniques have led to higher recanalization rates than IV IA techniques have led to higher recanalization rates than IV thrombolysisthrombolysis
Major disadvantagesMajor disadvantages Relative complexity of the procedure the level Relative complexity of the procedure the level
of required technical expertise and its of required technical expertise and its relatively low availability relatively low availability
Delays in initiating treatmentDelays in initiating treatment InvasiveInvasive
ThrombolyticsThrombolytics
Plasminogen activators
Fibrinolytics
1 Plasminogen Activators 1 Plasminogen Activators drugs act by converting the inactive proenzyme drugs act by converting the inactive proenzyme plasminogen into the active enzyme plasmin Plasmin plasminogen into the active enzyme plasmin Plasmin digests fibrinogen fibrin monomers and cross-linked digests fibrinogen fibrin monomers and cross-linked fibrin (as found in a thrombus) into fibrin degradation fibrin (as found in a thrombus) into fibrin degradation productsproducts
First-Generation Agents First-Generation Agents StreptokinaseStreptokinase a protein derived from group C a protein derived from group C
szlig-hemolytic streptococci has a half-life of 16ndashszlig-hemolytic streptococci has a half-life of 16ndash90 minutes and low fibrin specificity This drug 90 minutes and low fibrin specificity This drug proved to have a very narrow therapeutic proved to have a very narrow therapeutic window and significant rates of ICH and window and significant rates of ICH and systemic hemorrhage18systemic hemorrhage18
UrokinaseUrokinase is a serine protease with a plasma is a serine protease with a plasma half life of 14 minutes and low fibrin specificity half life of 14 minutes and low fibrin specificity
The urokinase dose used in cerebral IAT has The urokinase dose used in cerebral IAT has ranged from 002 to 2 X106unitsranged from 002 to 2 X106units
Second-Generation Agents Second-Generation Agents Alteplase (rtPA) Alteplase (rtPA)
is a serine is a serine protease with a plasma half-life of 35 protease with a plasma half-life of 35 minutes and a high degree of fibrin affinity and minutes and a high degree of fibrin affinity and specificity specificity
Dose used in cerebral IAT has ranged between 20 Dose used in cerebral IAT has ranged between 20 and 60 mgand 60 mg
Disadvantages of alteplase include its relatively short Disadvantages of alteplase include its relatively short halflife and limited penetration into the clot matrix halflife and limited penetration into the clot matrix because of strong binding with surface fibrin which because of strong binding with surface fibrin which could delay recanalization and increase the risk of could delay recanalization and increase the risk of recurrent occlusion recurrent occlusion
Prourokinase (r-prourokinase) Prourokinase (r-prourokinase) is the proenzyme precursor of urokinase is the proenzyme precursor of urokinase T12 of 7 minutes and high fibrin specificity T12 of 7 minutes and high fibrin specificity
Third-Generation AgentsThird-Generation Agents
ReteplaseReteplase is a structurally modified is a structurally modified form of alteplase form of alteplase
with a longer half-life (15ndash18 minutes) In with a longer half-life (15ndash18 minutes) In addition it does not bind as highly to fibrin addition it does not bind as highly to fibrin unbound reteplase can thus theoretically better unbound reteplase can thus theoretically better penetrate the clot and potentially penetrate the clot and potentially improve in improve in vivo fibrinolytic activity vivo fibrinolytic activity
TenecteplaseTenecteplase is another modified form of rtPA with a longer is another modified form of rtPA with a longer
half-life (17 minutes)half-life (17 minutes) greater fibrin specificity and greater greater fibrin specificity and greater
resistance to plasminogen activator inhibitor-1 resistance to plasminogen activator inhibitor-1 IV tenecteplase in acute ischemic stroke IV tenecteplase in acute ischemic stroke
suggest that the drug is safe and promisingsuggest that the drug is safe and promising
Newer plasminogen activatorNewer plasminogen activator
DesmoteplaseDesmoteplase is a genetically engineered is a genetically engineered version of the clot-dissolving factor version of the clot-dissolving factor
found in the saliva found in the saliva of the vampire bat Desmodus rotundusof the vampire bat Desmodus rotundus moremore potent and more selective for fibrin-bound potent and more selective for fibrin-bound
plasminogen than any other known plasminogen plasminogen than any other known plasminogen activatoractivator
Unlike tissue plasminogen activator (tPA) desmoteplase Unlike tissue plasminogen activator (tPA) desmoteplase is not activated by fibrinogen or -amyloid proteins is not activated by fibrinogen or -amyloid proteins factors that may exacerbate the risk for ICH factors that may exacerbate the risk for ICH
The effect of IV administration of desmoteplase 3ndash9 The effect of IV administration of desmoteplase 3ndash9 hours after symptom onset in patients with stroke who hours after symptom onset in patients with stroke who present with mismatch on MR imaging or CT perfusion present with mismatch on MR imaging or CT perfusion
3 DefibrinogenatingFibrinogenolytic 3 DefibrinogenatingFibrinogenolytic Agents Agents
AncrodAncrod(Viprinex)(Viprinex) is is the purified fraction of the Malayan pit viper venomthe purified fraction of the Malayan pit viper venom It acts by directly cleaving and inactivating fibrinogen It acts by directly cleaving and inactivating fibrinogen
and thus indirectly promoting anticoagulation and thus indirectly promoting anticoagulation The reduction in the blood levels of fibrinogen also The reduction in the blood levels of fibrinogen also
leads to a reduced blood viscosity which may improve leads to a reduced blood viscosity which may improve blood flow to the affected areas of the brain blood flow to the affected areas of the brain
In the Stroke Treatment with Ancrod Trial 500 In the Stroke Treatment with Ancrod Trial 500 patients with stroke presenting within 3 hours of patients with stroke presenting within 3 hours of symptom onset were randomized to receive ancrod (symptom onset were randomized to receive ancrod (n n 248) or a placebo (n 252) Good outcome (Barthel 248) or a placebo (n 252) Good outcome (Barthel Index 95ndash100 at 3 months) was achieved in 4221 Index 95ndash100 at 3 months) was achieved in 4221 and 344 of the patients respectively and 344 of the patients respectively
2 Direct Fibrinolytics2 Direct Fibrinolytics
Microplasmin (Microplasmin (ThromboGenics Heverlee Belgium)ThromboGenics Heverlee Belgium) is a truncated form of plasmin that is more resistant to the effects is a truncated form of plasmin that is more resistant to the effects
of antiplasmin of antiplasmin microplasmin can be used upto 4ndash12 hours after stroke onset microplasmin can be used upto 4ndash12 hours after stroke onset There was no evidence of increased bleeding risk with There was no evidence of increased bleeding risk with
microplasminmicroplasmin
Alfimeprase (Nuvelo San Carlos Calif)Alfimeprase (Nuvelo San Carlos Calif) is a recombinant truncated form of fibrolase a fibrinolytic zinc metalloproteinase is a recombinant truncated form of fibrolase a fibrinolytic zinc metalloproteinase
isolated from the venom of the southern copperhead snake isolated from the venom of the southern copperhead snake It degrades fibrin directly and achieves thrombolysis independent It degrades fibrin directly and achieves thrombolysis independent
of plasmin formationof plasmin formation its thrombolytic activity appears to be localized to the site of its thrombolytic activity appears to be localized to the site of
delivery These properties should theoretically result in faster delivery These properties should theoretically result in faster recanalization and lower hemorrhagic conversion riskrecanalization and lower hemorrhagic conversion risk
Anti-fibrinolyticsAnti-fibrinolytics
to limit fibrinolytic activityto limit fibrinolytic activity -aminocaproic acid (EACA) -aminocaproic acid (EACA) competitively inhibitscompetitively inhibits plasminogen and plasminogen activators from plasminogen and plasminogen activators from
binding to fibrinbinding to fibrin
alpha2-antiplasminalpha2-antiplasmin a serine protease inhibitor that a serine protease inhibitor that neutralizes any free circulating plasminneutralizes any free circulating plasmin
Plasminogen activator inhibitor-1Plasminogen activator inhibitor-1 a serine protease a serine protease inhibitor that inhibits tissue-type plasminogen inhibitor that inhibits tissue-type plasminogen activatoractivator
Glycoprotein (GP) IIbIIIa antagonistsGlycoprotein (GP) IIbIIIa antagonists
such as ReoPro (abciximab) Integrilin such as ReoPro (abciximab) Integrilin (eptifibatide) or Aggrastat (tirofiban) in (eptifibatide) or Aggrastat (tirofiban) in ischemic stroke remains investigational ischemic stroke remains investigational Deshmukh et al38 reported 21 patients with Deshmukh et al38 reported 21 patients with large-vessel occlusion refractory to IAT with large-vessel occlusion refractory to IAT with rtPA who were treated with IV andor IA rtPA who were treated with IV andor IA abciximab eptifibatide or tirofiban abciximab eptifibatide or tirofiban
IA Mechanical Approaches in Acute Ischemic Stroke IA Mechanical Approaches in Acute Ischemic Stroke Mechanical strategies have several advantagesMechanical strategies have several advantages First they lessen and may even preclude the use of chemical First they lessen and may even preclude the use of chemical
thrombolytics in this manner very likely reducing the risk of ICHthrombolytics in this manner very likely reducing the risk of ICH Second by avoiding the use of chemical thrombolytics it is Second by avoiding the use of chemical thrombolytics it is
possible to extend the treatment window beyond the limit of 6ndash8 possible to extend the treatment window beyond the limit of 6ndash8 hours hours
Third mechanically fragmenting a clot increases the surface area Third mechanically fragmenting a clot increases the surface area accessible to fibrinolytic agents and allows inflow of fresh accessible to fibrinolytic agents and allows inflow of fresh plasminogen which in turn may increase the speed of plasminogen which in turn may increase the speed of thrombolysis thrombolysis
Finally clot-retrieval devices may provide faster recanalization Finally clot-retrieval devices may provide faster recanalization
The disadvantages of the mechanical The disadvantages of the mechanical approaches approaches technical difficulty of navigating mechanical technical difficulty of navigating mechanical
devices into the intracranial circulation excessive devices into the intracranial circulation excessive trauma to the vasculature (potentially leading to trauma to the vasculature (potentially leading to vasospasm vessel dissection perforation or vasospasm vessel dissection perforation or rupture) rupture)
fragmented thrombus causing distal embolization fragmented thrombus causing distal embolization into previously unaffected territories into previously unaffected territories
Nevertheless the advantages of mechanical stroke Nevertheless the advantages of mechanical stroke therapy appear to significantly outweigh its therapy appear to significantly outweigh its disadvantages and risksdisadvantages and risks
Contraindications to Thrombolytic Contraindications to Thrombolytic agents agents
Recent thoracic abdominal or Recent thoracic abdominal or intracranial surgeryintracranial surgery
Recent haemorrhagic CVA Head injury Recent haemorrhagic CVA Head injury or neoplasmor neoplasm
Bleeding ulcerBleeding ulcer Anticipated invasive procedures (arterial Anticipated invasive procedures (arterial
punctures biopsies)punctures biopsies) Concurrent hemostatic dysfunctionConcurrent hemostatic dysfunction
Monitoring of thrombolytic Monitoring of thrombolytic therapytherapy
Thrombin time Measures the availability of functional
fibrinogen Normal thrombin time is 10-14 sec Prolonged when fibrinogen level is below
75-100 mgdl
Half Life of ThrombolyticsHalf Life of ThrombolyticsAgent Administration Half Life
Streptokinase IA 60-80min
Urokinase IAIV 9-12min
rTPA IAIV 6min
Abciximab(Reopro) IAIV 12hour
Aspirin POIV 15-20min
Heparin IVSC 60min
Coumadin PO 15-25 days
Anti Platelet DrugsAnti Platelet DrugsDrug Drug Mechanism Mechanism UsesUsesAspirinAspirin Permanently inhibits Permanently inhibits
COX-1 and COX-2COX-1 and COX-2CADCAD
Stroke-TIAsStroke-TIAs
NSAIDsNSAIDs Reversibly inhibits Reversibly inhibits COX-1COX-1
LimitedLimited
DipyridamoleDipyridamole Inhibits PDE increases Inhibits PDE increases cAMPcAMP
TIAsTIAs
ThenopyridinesThenopyridines
(Ticlopidine(Ticlopidine
ClopidrgrelClopidrgrel))
Inhibits ADP Inhibits ADP
PlatAg PlatAg
TIAsStrokeTIAsStroke
CAD PVDCAD PVD
Abciximab (ReoPro)Abciximab (ReoPro)
Eptifibatide (Integrilin)Eptifibatide (Integrilin)
TirofibanTirofiban
GP IIBIIIA InhibitorsGP IIBIIIA Inhibitors
Stroke- TIAs Stroke- TIAs
MonitoringMonitoring
Bleeding timeBleeding time
Optical aggregometryOptical aggregometry
Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay
Bleeding timeBleeding time
Requires a skin incision (usually made on the ear lobe or Requires a skin incision (usually made on the ear lobe or forearm offorearm of
a depth that results in disruption of capillary loops and a depth that results in disruption of capillary loops and small vessels)small vessels)
AdvantagesAdvantages Universally availableUniversally available Relatively simple techniquesRelatively simple techniques Can be performed bedsideCan be performed bedside
DisadvantagesDisadvantages Insensitive inaccurate non-specific techniqueInsensitive inaccurate non-specific technique
Poorly reproducible (as depends on multiple variables)Poorly reproducible (as depends on multiple variables)
Optical aggregometryOptical aggregometry
Gold standard assay for platelet functionGold standard assay for platelet function Agonist induced aggregation is measuredAgonist induced aggregation is measured Different agonist are available for different Different agonist are available for different
agentsagents However require unique expertise and are not However require unique expertise and are not
universally availableuniversally available Aspirin measured with ADP or AA(gt70 Aspirin measured with ADP or AA(gt70
aggregation so resistance)aggregation so resistance) Clopidogrel( ADP gt 90 aggregation means Clopidogrel( ADP gt 90 aggregation means
resistance) resistance)
Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay
Can be performed bed sideCan be performed bed side Different assay devices with different Different assay devices with different
agonist are used for each of different agonist are used for each of different antiplatelet agents antiplatelet agents
For Aspirin AA is used (result is reported as aspirin For Aspirin AA is used (result is reported as aspirin reaction units [ARU] ARUgt 550 indicates non-reaction units [ARU] ARUgt 550 indicates non-responsiveness)responsiveness)
Verify IIbIIIa assay device uses TRAP as agonist for Verify IIbIIIa assay device uses TRAP as agonist for Abciximab and TirofibanAbciximab and Tirofiban
Practical Applications Practical Applications related to specific related to specific
Neurovascular Neurovascular interventionsinterventions
Acute ischemic StrokeAcute ischemic Stroke When an artery occludes neurons are affected When an artery occludes neurons are affected
differently depending upon the amount of residual blood differently depending upon the amount of residual blood flowflow
Normal cerebral blood flow is greater than 50 mL100 Normal cerebral blood flow is greater than 50 mL100 mgminmgmin
Once blood flow decreases to less than 20 mL100 Once blood flow decreases to less than 20 mL100 mgmin infarction occursmgmin infarction occurs
If blood flow decreases to less than 10 mL100 mgmin If blood flow decreases to less than 10 mL100 mgmin irreversible neuronal death occurs rapidly irreversible neuronal death occurs rapidly
Blood flow between 11 and 20 mL100 mgmin is thought Blood flow between 11 and 20 mL100 mgmin is thought to represent the ischemic penumbra an area where the to represent the ischemic penumbra an area where the cells are functionally silent because of ischemia but are cells are functionally silent because of ischemia but are still able to recover if blood flow is restored still able to recover if blood flow is restored
Many acute stroke therapies are targeted toward Many acute stroke therapies are targeted toward restoring flow or function to the ischemic penumbrarestoring flow or function to the ischemic penumbra
Therapeutic window in Therapeutic window in management of acute Ischemic management of acute Ischemic
StrokeStrokeThe early diagnosis of ischemic stroke is critical to the The early diagnosis of ischemic stroke is critical to the
with only a narrow therapeutic window in the first few with only a narrow therapeutic window in the first few hours following stroke ictushours following stroke ictus
Diagnosis in the first 3 hours postictus provides the Diagnosis in the first 3 hours postictus provides the opportunity for intravenous or intraarterial thrombolysis opportunity for intravenous or intraarterial thrombolysis and intra-arterial clot mechanical treatment which and intra-arterial clot mechanical treatment which improve the outcome improve the outcome
Diagnosis in the time period between 3 and 6 hours Diagnosis in the time period between 3 and 6 hours provides an opportunity for intra-arterial thrombolysis provides an opportunity for intra-arterial thrombolysis and mechanical treatment and mechanical treatment
Involvement of the posterior circulation especially the Involvement of the posterior circulation especially the basilar artery is treated by some regardless of time of basilar artery is treated by some regardless of time of onset or up until 12 to 24 hours in some practices This is onset or up until 12 to 24 hours in some practices This is related to the potentially high mortality and morbidity related to the potentially high mortality and morbidity associated with basilar artery thrombosisassociated with basilar artery thrombosis
Infarct evaluation on angiographyInfarct evaluation on angiography(CT angiography and catheter (CT angiography and catheter
angiography)angiography)CTA is an excellent first-line examination for CTA is an excellent first-line examination for
evaluation of the head and neck arteries evaluation of the head and neck arteries In comparison with catheter angiography In comparison with catheter angiography
what it gives up in resolution and dynamic what it gives up in resolution and dynamic properties it makes up for with rapid properties it makes up for with rapid acquisition of a 3-D dataset and the potential acquisition of a 3-D dataset and the potential for assessment of whole-brain perfusion and for assessment of whole-brain perfusion and better parenchymal evaluationbetter parenchymal evaluation
Moreover CTA illustrates not only arterial Moreover CTA illustrates not only arterial stenosis or occlusion but also the vessel wall stenosis or occlusion but also the vessel wall This factor is most important for evaluation of This factor is most important for evaluation of intramural dissection and thrombosed intramural dissection and thrombosed aneurysms which may both complicate aneurysms which may both complicate evaluation of stroke patientsevaluation of stroke patients
Early angiographic signs of strokes Early angiographic signs of strokes both CTA both CTA and DSA and DSA
Vessel occlusion or cutoff related to Vessel occlusion or cutoff related to thromboembolithromboemboli
aneurysms aneurysms arterial dissection arterial dissection Meniscus or flattened shape to clot Meniscus or flattened shape to clot
(recent) versus reverse meniscus (older)(recent) versus reverse meniscus (older) tram track (nonocclusive or recanalized tram track (nonocclusive or recanalized
clot) clot) delayed (antegrade) flow (manifest as delayed (antegrade) flow (manifest as
decreased whole-brain perfusion on CTA)decreased whole-brain perfusion on CTA) retrograde collateral flowretrograde collateral flow
Non-occlusive left MCA thrombus on 3-D imaging performed from CTA source data and was confirmed at catheter angiography
Therapy to be started within a 6-hr Therapy to be started within a 6-hr time to treatment (TTT) window time to treatment (TTT) window (while in case of IV thrombolysis (while in case of IV thrombolysis therapy to be started with in 3hrs)therapy to be started with in 3hrs)
Exclusion criteria Exclusion criteria Rapidly improving neurologic deficit or Rapidly improving neurologic deficit or Sustained blood pressure of gt180100 Sustained blood pressure of gt180100 Hemorrhage is detected on CTHemorrhage is detected on CT Infarct involving gt more than 13 rd Infarct involving gt more than 13 rd
territory of MCAterritory of MCA MRADWI-Perfusion mismatchlt 20MRADWI-Perfusion mismatchlt 20 Definite hypodensity on CTDefinite hypodensity on CT
Intra-arterial Thrombolysis
Fibrinolytics + AntiplateletsFibrinolytics + Antiplatelets
PlasminogenPlasminogen activators through fibrinolysis exposes activators through fibrinolysis exposes free thrombin and paradoxically stimulatesfree thrombin and paradoxically stimulates platelet platelet aggregation which leads to formation of aaggregation which leads to formation of a platelet platelet thrombus (white clot) thrombus (white clot)
This new thrombus is relatively resistant to This new thrombus is relatively resistant to fibrinolyticsfibrinolytics
So new regimen in case of acute stroke isSo new regimen in case of acute stroke is fibrinolytics + antiplatelet drugsfibrinolytics + antiplatelet drugs
rtPA + IIbIIIa inhibitors( tirofiban rtPA + IIbIIIa inhibitors( tirofiban abciximab) orabciximab) or
Urokinase + IIbIIIa Urokinase + IIbIIIa inhibitors( tirofiban abciximab)inhibitors( tirofiban abciximab)
Intra-arterial Thrombolysis Tirofiban (04 microgkgmin bolus for 3 min followed by Tirofiban (04 microgkgmin bolus for 3 min followed by
0125 ugkgmin)0125 ugkgmin)
++
Heparin (2000ndash3000 IU bolus followed by Heparin (2000ndash3000 IU bolus followed by 1000 IUhour infusion 1000 IUhour infusion
with ACT maintained bw 200-300) throughout the with ACT maintained bw 200-300) throughout the interventional procedure and for 24ndash48 hours thereafter when interventional procedure and for 24ndash48 hours thereafter when there is neither intraprocedural bleeding nor suspicion of there is neither intraprocedural bleeding nor suspicion of increased risk of bleeding increased risk of bleeding
Maximum dose of Urokinase Maximum dose of Urokinase Anterior circulation stroke - 500000 IU (mean 400000 Anterior circulation stroke - 500000 IU (mean 400000
IU range 300000ndash500000 IU)IU range 300000ndash500000 IU) Posterior circulation stroke -1000000 IU (mean 837000 Posterior circulation stroke -1000000 IU (mean 837000
IU range 300000ndash1000000 IU)IU range 300000ndash1000000 IU)American Journal of NeuroradiologyAmerican Journal of Neuroradiology 262595-2601 2005262595-2601 2005
Intravenous ThrombolysisIntravenous Thrombolysis
The first method to restore cerebral The first method to restore cerebral perfusion is clot lysis with the goal perfusion is clot lysis with the goal of re-establishing blood flow to the of re-establishing blood flow to the affected tissue affected tissue
IV thrombolysis rt-PA is the only IV thrombolysis rt-PA is the only FDA- approved treatment for AIS FDA- approved treatment for AIS
Fibrinolysis is enhanced powerfully Fibrinolysis is enhanced powerfully by rt-PAby rt-PA
Intravenous rTPA Intravenous rTPA administration administration protocolprotocol
Total dose of rt-PA 09 mgkg (maximum dose Total dose of rt-PA 09 mgkg (maximum dose 90 mg)90 mg)
Give 10 as initial IV bolusGive 10 as initial IV bolus Infuse remainder over 1 hourInfuse remainder over 1 hour Admit patient to an ICU or stroke unit for Admit patient to an ICU or stroke unit for
monitoringmonitoring Neurologic assessments every 15 minutes Neurologic assessments every 15 minutes
during infusion then every 30 minutes for next during infusion then every 30 minutes for next 6 hours then every hour until 24hours after 6 hours then every hour until 24hours after treatmenttreatment
Favorable Outcome vs Treatment Time Favorable Outcome vs Treatment Time with IV rTPAwith IV rTPA
Protocol limit = 3 hrs
Benefit ~ 45 hrs
Thromboembolism During coilingThromboembolism During coiling Most feared and frequent complication Most feared and frequent complication Reported incidence - Approx 7 Reported incidence - Approx 7 SourcesSources of Thromboembolism are of Thromboembolism are
- Clots at the aneurysmal neck during or immediately- Clots at the aneurysmal neck during or immediately after after embolization embolization
- Thrombus forming on catheters during- Thrombus forming on catheters during proceduresprocedures
- Stenosis of an adjacent artery dt coil mass- Stenosis of an adjacent artery dt coil mass or herniationor herniation
- Migration of intraaneurysmal- Migration of intraaneurysmal thrombus during coil thrombus during coil placement placement
- Slow flow dt vasospasm - Slow flow dt vasospasm
- Rare and unlikely causes are hypercoagulable- Rare and unlikely causes are hypercoagulable state such state such as antiphospholipid antibody syndrome or due to HITas antiphospholipid antibody syndrome or due to HIT
Occur more often with wide-necked aneurysms (dt Occur more often with wide-necked aneurysms (dt increased exposed surface area of thrombogenic coil increased exposed surface area of thrombogenic coil material)material)
Current regimen of endovascular Current regimen of endovascular managementmanagement
The The glycoprotein IIbIIIa antagonist tirofiban glycoprotein IIbIIIa antagonist tirofiban (04 (04 microgkgmin bolus for 30 minutes followed by infusion of microgkgmin bolus for 30 minutes followed by infusion of 0125 ugkgmin until the thrombus dissolved) 0125 ugkgmin until the thrombus dissolved)
Intraarterial thrombolysis with Intraarterial thrombolysis with urokinase or r- TPA urokinase or r- TPA increase of intravenous (IV) heparin (measured by increase of intravenous (IV) heparin (measured by
ACT) ACT) Intravenous aspirin Intravenous aspirin
Coil-related platelet aggregation (white clot) is Coil-related platelet aggregation (white clot) is unlikely to respond to fibrinolytics but has a high risk unlikely to respond to fibrinolytics but has a high risk of hemorrhage (In ISAT) all 5 patients who had of hemorrhage (In ISAT) all 5 patients who had received thrombolytic therapy with tPA to treat a received thrombolytic therapy with tPA to treat a thromboembolic complication after endovascular thromboembolic complication after endovascular treatment rebleed and all of these patients died)treatment rebleed and all of these patients died)
IntracranialIntracranial Stenting Stenting Metallic foreign body such as stent will accumulate Metallic foreign body such as stent will accumulate
thrombus in the absence of platelet inhibitionthrombus in the absence of platelet inhibition Antiplatelet drugs are important to prevent peri or Antiplatelet drugs are important to prevent peri or
post-interventional thromboembolic eventspost-interventional thromboembolic events Optimal treatment regimens has not been determined Optimal treatment regimens has not been determined
but usually but usually Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-
procedureprocedureOrOr
Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on
morning of proceduremorning of procedure
If need to use stent is not pre-planned thanIf need to use stent is not pre-planned than
Abciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkgAbciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkg IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)
Glycoprotein IIbIIIa inhibitor are not used routinely during elective Glycoprotein IIbIIIa inhibitor are not used routinely during elective stenting procedure dt increased risk of ICH stenting procedure dt increased risk of ICH
Carotid StentingCarotid Stenting
Pre-procedurePre-procedure
Double Antiplatelet therapy is routinely given Double Antiplatelet therapy is routinely given beginning at least 3beginning at least 3
days before the proceduredays before the procedure
Aspirin 325mgd+Clopidogrel 75mgdAspirin 325mgd+Clopidogrel 75mgd During procedureDuring procedure
Heparin is given with target clotting time of 250-Heparin is given with target clotting time of 250-300sec300sec
Post-procedure Post-procedure
Aspirin 325mg is continued indefinitely and Aspirin 325mg is continued indefinitely and
Clopidogrel 75mgd for at least 6 weeks Clopidogrel 75mgd for at least 6 weeks
Inclusion criteria for Local ThrombolysisInclusion criteria for Local Thrombolysis a)a) Patients in severe clinical grade on admission Patients in severe clinical grade on admission
with evidence of dural venous sinus with evidence of dural venous sinus thrombosis and restrictive venous outflow on thrombosis and restrictive venous outflow on cerebral angiogramcerebral angiogram
b)b) Patients in clinical grade 3 worsening on Patients in clinical grade 3 worsening on heparin therapy Restriction to venous heparin therapy Restriction to venous outflow was defined as an increase in brain outflow was defined as an increase in brain circulation time gt 12 s delay in the drainage circulation time gt 12 s delay in the drainage of cortical veins with cortical veins hanging of cortical veins with cortical veins hanging in spacein space
Treatment Options for Venous Thrombosis
CT Grading for Venous ThrombosisCT Grading for Venous Thrombosis Grade I no parenchymal change Grade I no parenchymal change
(hyperdense (hyperdense sinuses cortical veins empty sinuses cortical veins empty delta sign)delta sign)
Grade II non hemorrhagic venous infarct Grade II non hemorrhagic venous infarct without mass effect without mass effect
Grade III non-hemorrhagic infarct with Grade III non-hemorrhagic infarct with mass effectmass effect
Grade IV hemorrhagic venous infarct (max Grade IV hemorrhagic venous infarct (max diameter lt 3 cm) with no mass effectdiameter lt 3 cm) with no mass effect
Grade V hemorrhagic venous infarct (max Grade V hemorrhagic venous infarct (max diameter gt 3 cm) with mass effect diameter gt 3 cm) with mass effect
Local ThrombolysisLocal Thrombolysis
Femoral Jugular access was secured and a guiding Femoral Jugular access was secured and a guiding catheter was placed in the jugular bulb catheter was placed in the jugular bulb Mechanical Mechanical clot maceration clot maceration was done with the guidewire was done with the guidewire following which a microcatheter (was navigated and following which a microcatheter (was navigated and placed in the thrombosed segment of sinus confirmed placed in the thrombosed segment of sinus confirmed on a selective venogram on a selective venogram
Urokinase infusion Bolus dose of 2-6 lacs followed Urokinase infusion Bolus dose of 2-6 lacs followed by 60000 to 100000 units per hour along with by 60000 to 100000 units per hour along with periodic check venogram Along with maintenance periodic check venogram Along with maintenance systemic infusion of Heparinsystemic infusion of Heparin Other agents such as Other agents such as streptokinase altepase or rTPAstreptokinase altepase or rTPA can be also used can be also used
After thrombolysis patient should subjected to oral After thrombolysis patient should subjected to oral anticoagulation for six monthsanticoagulation for six months
Low-molecular-weight Low-molecular-weight heparinheparin
PharmacologyPharmacologyLMWH as its name suggests is a glycosaminoglycan that is approximatelyLMWH as its name suggests is a glycosaminoglycan that is approximately
one third the molecular weight of UFH It is derived from UFH through one third the molecular weight of UFH It is derived from UFH through variousvarious
depolymerization processes LMWH binds to antithrombin which in turn depolymerization processes LMWH binds to antithrombin which in turn
Neutralizes actors Xa and IIa Because LMWH lacks many of the longer Neutralizes actors Xa and IIa Because LMWH lacks many of the longer chains chains
required for binding to thrombin it has less ability to neutralize thrombin required for binding to thrombin it has less ability to neutralize thrombin
relativeto its ability to neutralize factor Xa LMWH also has less relativeto its ability to neutralize factor Xa LMWH also has less nonspecific nonspecific
binding to other proteins There is greater bioavailability with more binding to other proteins There is greater bioavailability with more predictable predictable
pharmacokinetics that eliminates the need for monitoring The smaller pharmacokinetics that eliminates the need for monitoring The smaller size also size also
allows for enhanced subcutaneous absorption when compared with UFHallows for enhanced subcutaneous absorption when compared with UFH
Three LMWH preparations are Three LMWH preparations are currently approved for use in the currently approved for use in the United States (1) enoxaparin (2) United States (1) enoxaparin (2) dalteparin and (3) tinzaparin dalteparin and (3) tinzaparin
They are all administered They are all administered subcutaneously at intervals of either subcutaneously at intervals of either once or twice daily for both once or twice daily for both prophylaxis and treatment dosesprophylaxis and treatment doses
Few Experiences of Few Experiences of ThrombolysisThrombolysis
Vickey 25 Yrs male patient presented Vickey 25 Yrs male patient presented with 12with 12thth day HO severe headache with day HO severe headache with right sided hemiplegiaright sided hemiplegia
MRI shows thrombosis of the superior MRI shows thrombosis of the superior sagittal left transverse left sigmoid sagittal left transverse left sigmoid sinuses and cortical veins in the fronto-sinuses and cortical veins in the fronto-parietal regions with eo haemorrhagic parietal regions with eo haemorrhagic infarct in the left cerebral hemisphere infarct in the left cerebral hemisphere with mass effect( Grade ndashV)with mass effect( Grade ndashV)
Sashi Srivastava 64 yrs FSashi Srivastava 64 yrs F In a follow up case of MRD with infra-renal In a follow up case of MRD with infra-renal
aortic abdominal and bilateral renal artery aortic abdominal and bilateral renal artery thrombosis renal angiogram shows filling thrombosis renal angiogram shows filling defects in the right Renal artery defects in the right Renal artery
Initially Renal angioplasty was done Initially Renal angioplasty was done Following angioplasty few thrombi are seem Following angioplasty few thrombi are seem to extends into the segmental branches and to extends into the segmental branches and causing blockage So Thrombolysis was causing blockage So Thrombolysis was plane to dissolve the run-out thrombi with plane to dissolve the run-out thrombi with urokinase urokinase
Rakesh 34yrsMRakesh 34yrsM Left SFA pseudoaneurysm with Left SFA pseudoaneurysm with
Covered stent placementCovered stent placement Pre operative antiplatelets with post Pre operative antiplatelets with post
procedure heparin Tirofiban procedure heparin Tirofiban followed by aspirin and clopidogrel followed by aspirin and clopidogrel were usedwere used
IAT may be a treatment option for selected patients IAT may be a treatment option for selected patients Possible selection criteria include Possible selection criteria include
presentation between 3 and 6 hours from symptom onsetpresentation between 3 and 6 hours from symptom onset major cerebral artery occlusion major cerebral artery occlusion severe neurologic deficits severe neurologic deficits high risk of systemic hemorrhage with IV rt-PA (eg recent high risk of systemic hemorrhage with IV rt-PA (eg recent
surgery) surgery) The MERCI (Mechanical Embolus Removal in Cerebral The MERCI (Mechanical Embolus Removal in Cerebral
Ischemia) retrievalIschemia) retrieval system system
Has been FDA-approved for recanalizing acutely occluded Has been FDA-approved for recanalizing acutely occluded cerebral arteries cerebral arteries
In the Multi-MERCI study patients who did not improve In the Multi-MERCI study patients who did not improve immediately after IV rt-PA underwent mechanical immediately after IV rt-PA underwent mechanical embolectomy within 8 hours of symptom onset embolectomy within 8 hours of symptom onset
Partial or complete recanalization occurred in 74 of Partial or complete recanalization occurred in 74 of patientspatients
with a symptomatic intracerebral hemorrhage (sICH) rate of with a symptomatic intracerebral hemorrhage (sICH) rate of 67 67
Mechanical embolectomy with the MERCI retriever may be a Mechanical embolectomy with the MERCI retriever may be a feasible and safe option for patients after IV rt-PAfeasible and safe option for patients after IV rt-PA
Penumbra stroke systemPenumbra stroke system This device combines two methods of clot This device combines two methods of clot
extraction aspiration and mechanical extraction aspiration and mechanical extraction extraction
First the clot is aspirated then a thrombus First the clot is aspirated then a thrombus removal ring can be used if necessary to removal ring can be used if necessary to remove remaining clot remove remaining clot
successful recanalizing 82successful recanalizing 82 Bridging therapyBridging therapy
06 mgkg IV rt-PA followed by IAT with IA rt-06 mgkg IV rt-PA followed by IAT with IA rt-PA (up to 20 mg)PA (up to 20 mg)
achieved a higher recanalization rateachieved a higher recanalization rate
Criteria for thrombolysis with rTPACriteria for thrombolysis with rTPA
Inclusion criteriaInclusion criteria Clinical signs and symptoms consistent with ischemic Clinical signs and symptoms consistent with ischemic
strokestroke Patient last seen normal within 3 hoursPatient last seen normal within 3 hours Measurable neurologic deficitMeasurable neurologic deficit
Exclusion criteriaExclusion criteria Any hemorrhage on neuroimaging (CT or MRI)Any hemorrhage on neuroimaging (CT or MRI) Symptoms suggestive of subarachnoid hemorrhageSymptoms suggestive of subarachnoid hemorrhage Seizure at stroke onset that is thought to contribute to Seizure at stroke onset that is thought to contribute to
neurologic deficitneurologic deficit Hypodensity greater than one third cerebral hemisphere Hypodensity greater than one third cerebral hemisphere
on CTon CT SBP greater than 185 mm Hg or DBP greater than 110 SBP greater than 185 mm Hg or DBP greater than 110
mm Hgmm Hg International normalized ratio (INR) greater than 17International normalized ratio (INR) greater than 17
Ischemic Stroke Ischemic Stroke Treatment ndash 2006Treatment ndash 2006
IV tissue plasminogen activator (tPA)IV tissue plasminogen activator (tPA) ndash ndash Only FDA-approved acute stroke drugOnly FDA-approved acute stroke drug ndash ndash 3 hour treatment window3 hour treatment window
MERCI - Concentric clot retrieval MERCI - Concentric clot retrieval devicedevice ndash ndash Rescue therapy - approved 2004Rescue therapy - approved 2004 ndash ndash Device approval (not outcomes-based)Device approval (not outcomes-based)
Off label approachesOff label approaches ndash ndash IV tPA after 3 hoursIV tPA after 3 hours ndash ndash IV-IA tPA sequential strategiesIV-IA tPA sequential strategies ndash ndash IA tPA clot angioplasty fragmentationIA tPA clot angioplasty fragmentation ndash ndash Ultrasound-assisted tPA lysisUltrasound-assisted tPA lysis
rt-PA Trials NINDSrt-PA Trials NINDS
Acute stroke - 624 patientsAcute stroke - 624 patients Treat within 3 hrsTreat within 3 hrs Intravenous 09 mgkg rt-PA vs placeboIntravenous 09 mgkg rt-PA vs placebo Hemorrhage 64 tPA 06 placeboHemorrhage 64 tPA 06 placebo Neurologic recovery better with tPA 30 Neurologic recovery better with tPA 30
more like to have minimal or no disabilitymore like to have minimal or no disability
First proven approved treatment for First proven approved treatment for strokestroke
Limitations of tPALimitations of tPA Only 4 of acute strokes receive tPAOnly 4 of acute strokes receive tPA (Kleindorfer et al Stroke 2004 35 e27-e29)(Kleindorfer et al Stroke 2004 35 e27-e29)
Only 22 of patients present within 3 hoursOnly 22 of patients present within 3 hours1048707 1048707 51 of these ineligible due to51 of these ineligible due to
bull bull Mild severityMild severity bull bull Medical or surgical historyMedical or surgical history bull bull Blood testsBlood tests
Sustained recanalization only 13Sustained recanalization only 13 (Alexandrov et al NEJM 2004 351 2170-8)(Alexandrov et al NEJM 2004 351 2170-8)
Concern for hemorrhageConcern for hemorrhage tPA potentiates apoptotic injury tPA potentiates apoptotic injury (Liu et al Nature Med 2004 101379-83)(Liu et al Nature Med 2004 101379-83)
PROACT II IA Lysis TrialPROACT II IA Lysis Trial Baseline 24 hours 8 days
Baseline 60 minutes 120 minutes
9mg IAProurokinase
Desmoteplase Trials DEDAS Desmoteplase Trials DEDAS DIASDIAS
Trial OverviewTrial Overview Double blind randomized placebo Double blind randomized placebo
controlled trialscontrolled trials IV delivery 3-9 hour time windowIV delivery 3-9 hour time window Plasminogen activator ndash from Plasminogen activator ndash from vampire bat vampire bat
salivasaliva Selection based on PWI-DWI MismatchSelection based on PWI-DWI Mismatch
MRI InclusionMRI Inclusion PWI defect at least 2 cm AND ~20 larger PWI defect at least 2 cm AND ~20 larger
than DWIthan DWI PWI should be obvious even visible on PWI should be obvious even visible on
raw imagesraw imagesMRI ExclusionMRI Exclusion
DWI gt 13 MCADWI gt 13 MCA MRA ICA occlusionMRA ICA occlusion
Desmoteplase ndash DIAS Desmoteplase ndash DIAS ResultsResults
Mechanical Thrombolysis Mechanical Thrombolysis devicesdevices
mechanical thrombolysis potentially extends the treatment mechanical thrombolysis potentially extends the treatment window because they act promptly at the site of the thrombuswindow because they act promptly at the site of the thrombus
The devices can retrieve large clots that pharmaceutical agents The devices can retrieve large clots that pharmaceutical agents may not successfully lysemay not successfully lyse
Patients treated with IV tPA may be considered for treatment of Patients treated with IV tPA may be considered for treatment of residual clot with some of these devicesresidual clot with some of these devices
suction-creating saline jets suction-creating saline jets laser energy ultrasound laser energy ultrasound a corkscrew apparatus to treat strokesa corkscrew apparatus to treat strokes The AngioJet systemThe AngioJet system uses saline jets that are directed back into the catheter to uses saline jets that are directed back into the catheter to
create a low-pressure zone around the catheter tip inducing create a low-pressure zone around the catheter tip inducing suction suction
The clot is pulled into the exhaust lumen and removed from the The clot is pulled into the exhaust lumen and removed from the vessel Although US Food and Drug Administration (FDA) has vessel Although US Food and Drug Administration (FDA) has approved this device for use in arteriovenous dialysis grafts and approved this device for use in arteriovenous dialysis grafts and fistulae and for the treatment of coronary arteries saphenous fistulae and for the treatment of coronary arteries saphenous vein grafts and peripheral vessels clinical trials for the vein grafts and peripheral vessels clinical trials for the treatment of acute stroke are no longer in progress treatment of acute stroke are no longer in progress
Most devices are used in cerebral vessels that 2-5 mm
The Latis laser device The Latis laser device used laser energy to ablate clots used laser energy to ablate clots Arteries 2-5 mm in diameter could be Arteries 2-5 mm in diameter could be
treated including the ICA M1 or M2 treated including the ICA M1 or M2 branch of the MCA A1 branch of the branch of the MCA A1 branch of the anterior cerebral artery (ACA) basilar anterior cerebral artery (ACA) basilar artery posterior cerebral artery (PCA) artery posterior cerebral artery (PCA) and vertebral and vertebral
Patients could receive treatment as late Patients could receive treatment as late as 8 hours after symptom onset in the as 8 hours after symptom onset in the anterior circulation and within 24 hours in anterior circulation and within 24 hours in the posterior circulation the posterior circulation
Endovascular Photo Acoustic Endovascular Photo Acoustic Recanalization (EPAR) Recanalization (EPAR)
A laser power source generated energy for the A laser power source generated energy for the systemsystem
The energy was delivered by means of The energy was delivered by means of fiberoptics to the tip of the catheter at the fiberoptics to the tip of the catheter at the treatment sitetreatment site
Absorption of laser light by darkly pigmented Absorption of laser light by darkly pigmented materials (ie the clot) occurred inside the 1-mm materials (ie the clot) occurred inside the 1-mm catheter tipcatheter tip
the system was designed to minimize scattering the system was designed to minimize scattering of laser light of laser light
Absorption converted photo energy to acoustic Absorption converted photo energy to acoustic energy which then emulsified the clot inside the energy which then emulsified the clot inside the catheter tip catheter tip
EKOS ultrasound( the EKOS ultrasound( the Ultrasound Thrombolytic Ultrasound Thrombolytic
Infusion Catheter) Infusion Catheter) combines the use of a distal ultrasound transducer with combines the use of a distal ultrasound transducer with
infusion of a thrombolytic agent through the infusion of a thrombolytic agent through the microcathetermicrocatheter
Ultrasound changes the structure of the clot to Ultrasound changes the structure of the clot to temporarily increase its permeability while providing an temporarily increase its permeability while providing an acoustic pressure gradient to move the drug into the clot acoustic pressure gradient to move the drug into the clot to speed its dissolution to speed its dissolution
The EKOS catheter is placed in the proximal portion of the The EKOS catheter is placed in the proximal portion of the clot clot
After a 2-mg bolus of tPA was injected through the After a 2-mg bolus of tPA was injected through the catheter catheter
the patient received a continuous infusion of IA tPA 03 the patient received a continuous infusion of IA tPA 03 mgmin to a maximum of 20 mg and simultaneous mgmin to a maximum of 20 mg and simultaneous ultrasound transmission for as long as 60 minutes ultrasound transmission for as long as 60 minutes
One patient was treated with a total of 4 units of One patient was treated with a total of 4 units of recombinant reteplase (Retavase) hand-injected over 60 recombinant reteplase (Retavase) hand-injected over 60 minutes minutes
Penumbra system Penumbra system The Penumbra system (Penumbra Inc) provides a dual The Penumbra system (Penumbra Inc) provides a dual
approach to clot extraction using aspiration followed by approach to clot extraction using aspiration followed by clot retrieval with a ring device if needed clot retrieval with a ring device if needed
Mechanical Embolus Removal in Cerebral Ischemia Mechanical Embolus Removal in Cerebral Ischemia (MERCI)(MERCI)
a corkscrew-like apparatus to remove blood clots from a corkscrew-like apparatus to remove blood clots from the brain in patients experiencing an ischemic stroke the brain in patients experiencing an ischemic stroke
The corkscrew itself resides in the catheter tip which The corkscrew itself resides in the catheter tip which shields it from the wall of the vessel until it is ready to be shields it from the wall of the vessel until it is ready to be burrowed into the clot Once lodged in the clot the device burrowed into the clot Once lodged in the clot the device and clot are withdrawn from the vessel and clot are withdrawn from the vessel
Snarelike devicesSnarelike devices Snares such as the Neuronet snare (Guidant Snares such as the Neuronet snare (Guidant
Endovascular Santa Clara CA) have been developed Endovascular Santa Clara CA) have been developed specifically for use in the treatment of strokes specifically for use in the treatment of strokes
These devices are simple in design and do not require the These devices are simple in design and do not require the clot to be amenable to emulsification clot to be amenable to emulsification
X-Sizer deviceX-Sizer device a device with small moving blades at the a device with small moving blades at the
catheter tip catheter tip This device the X-Sizer device (EndiCor Medical This device the X-Sizer device (EndiCor Medical
San Clemente CA) can be used to excise the San Clemente CA) can be used to excise the thrombus and aspirate it thrombus and aspirate it
The device was being evaluated in randomized The device was being evaluated in randomized studies of coronary vessels and in a registry of studies of coronary vessels and in a registry of patients with acute myocardial infarctionpatients with acute myocardial infarction
Although the manufacturer had modified the Although the manufacturer had modified the device for use in cerebral vessels a safety and device for use in cerebral vessels a safety and feasibility study was indefinitely suspended after feasibility study was indefinitely suspended after only 1 patient was treated with the device in only 1 patient was treated with the device in Europe Europe
Suction thrombectomySuction thrombectomy This method of mechanical thrombolysis is one of the This method of mechanical thrombolysis is one of the
simplestsimplest In this readily available technique suction is applied with In this readily available technique suction is applied with
a syringe to remove thrombus in the ICA a syringe to remove thrombus in the ICA It requires no other devicesIt requires no other devices A catheter with a large inner diameter (Brite Tip Cordis A catheter with a large inner diameter (Brite Tip Cordis
Corporation Miami FL) was placed in the symptomatic Corporation Miami FL) was placed in the symptomatic vessel and navigated over a guidewire into the thrombusvessel and navigated over a guidewire into the thrombus
A 60-mL syringe was used to aspirate the thrombus A 60-mL syringe was used to aspirate the thrombus Each patient required angioplasty and stenting of carotid Each patient required angioplasty and stenting of carotid
bifurcation stenosis and received daily aspirin and bifurcation stenosis and received daily aspirin and ticlopidine after the procedure No complications ticlopidine after the procedure No complications occurred occurred
Summary Acute Stroke Summary Acute Stroke ImagingImaging
PhysiologyPhysiology importance collaterals importance collaterals
ndash ndashGrowing role for perfusion Growing role for perfusion assessmentassessment
tPAtPA guidelines amp limitations guidelines amp limitations Signs on CT amp MRSigns on CT amp MR follow physiology follow physiology Stroke trialsStroke trials PWI-DWI mismatch PWI-DWI mismatch
ndash ndashTreat based on physiology not timeTreat based on physiology not time ProtocolsProtocols should be fast and should be fast and
comprehensivecomprehensive
MONITORING OF WARFARIN THERAPYMONITORING OF WARFARIN THERAPY
Prothrombin timeProthrombin time PT ratioPT ratio INR (International Normalized Ratio)INR (International Normalized Ratio)
PROTHROMBIN TIME (PT)PROTHROMBIN TIME (PT)
Time required for blood to coagulate Time required for blood to coagulate is called PT ( normal value ~10sec)is called PT ( normal value ~10sec)
Performed by adding a mixture of Performed by adding a mixture of calcium and thromboplastin to calcium and thromboplastin to citrated plasmacitrated plasma
As a control a normal blood sample is As a control a normal blood sample is tested continuouslytested continuously
PT ratio (PTR) = PT ratio (PTR) = Patientrsquos PTPatientrsquos PT Control PTControl PT
PROBLEMS WITH PTPTRPROBLEMS WITH PTPTR
Thromboplastins are extracts from Thromboplastins are extracts from brain lung or placenta of animalsbrain lung or placenta of animals
Thromboplastins from various Thromboplastins from various manufacturers differ in their manufacturers differ in their sensitivity to prolong PTsensitivity to prolong PT
May result in false control of May result in false control of anticoagulant therapyanticoagulant therapy
INTERNATIONAL NORMALISED RATIO (INR)INTERNATIONAL NORMALISED RATIO (INR)
International Normalized Ratio (INR) International Normalized Ratio (INR) a PT test with a a PT test with a formula based ratio to normalize the often variable source formula based ratio to normalize the often variable source of tissue factor (human rabbit recombinant)of tissue factor (human rabbit recombinant)
INR = [PTINR = [PTptpt] ] ISIISI
[PT[PTRefRef]]
PTPTpt pt ndash prothrombin time of patientndash prothrombin time of patient
PTPTRef Ref ndash prothrombin time of normal pooled samplendash prothrombin time of normal pooled sample
ISI ndash International Sensitivity IndexISI ndash International Sensitivity Index
Warfarin is given orally and titrated to achieve an INR of Warfarin is given orally and titrated to achieve an INR of typically 20 ndash 30typically 20 ndash 30
Heparin versus WarfarinHeparin versus Warfarin
Drug ActionMechan-ism
Moni-toring
Effective
HeparinDirect
Inhibition ofThrombin
ATIIIcofactor
APTTACT
Immediate
WarfarinDecreasesProductionof factors
Vitamin K PTDelay
3-5 days
INR
Recanalization or Antegrade Recanalization or Antegrade Reperfusion StrategiesReperfusion Strategies
Recanalization strategies focus on removing Recanalization strategies focus on removing andor dissolving the occlusive thrombus to re-andor dissolving the occlusive thrombus to re-establish antegrade flow Strategies may be establish antegrade flow Strategies may be classified into 7 different categories on the classified into 7 different categories on the basis of their primary mechanism of action basis of their primary mechanism of action 1) 1) IV andor intraarterial thrombolysis (IAT) IV andor intraarterial thrombolysis (IAT) 2) endovascular thrombectomy2) endovascular thrombectomy3) endovascular thromboaspiration 3) endovascular thromboaspiration 4) endovascular mechanical thrombus disruption or 4) endovascular mechanical thrombus disruption or
thromborrhexisthromborrhexis5) 5) transcranial or endovascular augmented transcranial or endovascular augmented
fibrinolysis fibrinolysis 6) endovascular thrombus entrapment and 6) endovascular thrombus entrapment and 7) temporary endovascular bypass7) temporary endovascular bypass
IAT in Acute Ischemic StrokeIAT in Acute Ischemic Stroke
IAT advantages over IV thrombolysisIAT advantages over IV thrombolysis Coaxial microcatheter techniques the occluded intracranial Coaxial microcatheter techniques the occluded intracranial
vessel is directly accessible and the fibrinolytic agent can be vessel is directly accessible and the fibrinolytic agent can be infused directly into the thrombusinfused directly into the thrombus
This permits a smaller dose of fibrinolytic agent to reach a This permits a smaller dose of fibrinolytic agent to reach a higher local concentration than that reached by systemic higher local concentration than that reached by systemic infusioninfusion
Allows more complete recanalization with lower total doses of Allows more complete recanalization with lower total doses of thrombolytic thrombolytic
With the smaller dose complications from systemic fibrinolytic With the smaller dose complications from systemic fibrinolytic effects including intracranial hemorrhage (ICH) can effects including intracranial hemorrhage (ICH) can theoretically be reduced theoretically be reduced
Treatment window for endovascular techniques can be Treatment window for endovascular techniques can be extended beyond the typical IV window of 3 hours extended beyond the typical IV window of 3 hours
IA techniques have led to higher recanalization rates than IV IA techniques have led to higher recanalization rates than IV thrombolysisthrombolysis
Major disadvantagesMajor disadvantages Relative complexity of the procedure the level Relative complexity of the procedure the level
of required technical expertise and its of required technical expertise and its relatively low availability relatively low availability
Delays in initiating treatmentDelays in initiating treatment InvasiveInvasive
ThrombolyticsThrombolytics
Plasminogen activators
Fibrinolytics
1 Plasminogen Activators 1 Plasminogen Activators drugs act by converting the inactive proenzyme drugs act by converting the inactive proenzyme plasminogen into the active enzyme plasmin Plasmin plasminogen into the active enzyme plasmin Plasmin digests fibrinogen fibrin monomers and cross-linked digests fibrinogen fibrin monomers and cross-linked fibrin (as found in a thrombus) into fibrin degradation fibrin (as found in a thrombus) into fibrin degradation productsproducts
First-Generation Agents First-Generation Agents StreptokinaseStreptokinase a protein derived from group C a protein derived from group C
szlig-hemolytic streptococci has a half-life of 16ndashszlig-hemolytic streptococci has a half-life of 16ndash90 minutes and low fibrin specificity This drug 90 minutes and low fibrin specificity This drug proved to have a very narrow therapeutic proved to have a very narrow therapeutic window and significant rates of ICH and window and significant rates of ICH and systemic hemorrhage18systemic hemorrhage18
UrokinaseUrokinase is a serine protease with a plasma is a serine protease with a plasma half life of 14 minutes and low fibrin specificity half life of 14 minutes and low fibrin specificity
The urokinase dose used in cerebral IAT has The urokinase dose used in cerebral IAT has ranged from 002 to 2 X106unitsranged from 002 to 2 X106units
Second-Generation Agents Second-Generation Agents Alteplase (rtPA) Alteplase (rtPA)
is a serine is a serine protease with a plasma half-life of 35 protease with a plasma half-life of 35 minutes and a high degree of fibrin affinity and minutes and a high degree of fibrin affinity and specificity specificity
Dose used in cerebral IAT has ranged between 20 Dose used in cerebral IAT has ranged between 20 and 60 mgand 60 mg
Disadvantages of alteplase include its relatively short Disadvantages of alteplase include its relatively short halflife and limited penetration into the clot matrix halflife and limited penetration into the clot matrix because of strong binding with surface fibrin which because of strong binding with surface fibrin which could delay recanalization and increase the risk of could delay recanalization and increase the risk of recurrent occlusion recurrent occlusion
Prourokinase (r-prourokinase) Prourokinase (r-prourokinase) is the proenzyme precursor of urokinase is the proenzyme precursor of urokinase T12 of 7 minutes and high fibrin specificity T12 of 7 minutes and high fibrin specificity
Third-Generation AgentsThird-Generation Agents
ReteplaseReteplase is a structurally modified is a structurally modified form of alteplase form of alteplase
with a longer half-life (15ndash18 minutes) In with a longer half-life (15ndash18 minutes) In addition it does not bind as highly to fibrin addition it does not bind as highly to fibrin unbound reteplase can thus theoretically better unbound reteplase can thus theoretically better penetrate the clot and potentially penetrate the clot and potentially improve in improve in vivo fibrinolytic activity vivo fibrinolytic activity
TenecteplaseTenecteplase is another modified form of rtPA with a longer is another modified form of rtPA with a longer
half-life (17 minutes)half-life (17 minutes) greater fibrin specificity and greater greater fibrin specificity and greater
resistance to plasminogen activator inhibitor-1 resistance to plasminogen activator inhibitor-1 IV tenecteplase in acute ischemic stroke IV tenecteplase in acute ischemic stroke
suggest that the drug is safe and promisingsuggest that the drug is safe and promising
Newer plasminogen activatorNewer plasminogen activator
DesmoteplaseDesmoteplase is a genetically engineered is a genetically engineered version of the clot-dissolving factor version of the clot-dissolving factor
found in the saliva found in the saliva of the vampire bat Desmodus rotundusof the vampire bat Desmodus rotundus moremore potent and more selective for fibrin-bound potent and more selective for fibrin-bound
plasminogen than any other known plasminogen plasminogen than any other known plasminogen activatoractivator
Unlike tissue plasminogen activator (tPA) desmoteplase Unlike tissue plasminogen activator (tPA) desmoteplase is not activated by fibrinogen or -amyloid proteins is not activated by fibrinogen or -amyloid proteins factors that may exacerbate the risk for ICH factors that may exacerbate the risk for ICH
The effect of IV administration of desmoteplase 3ndash9 The effect of IV administration of desmoteplase 3ndash9 hours after symptom onset in patients with stroke who hours after symptom onset in patients with stroke who present with mismatch on MR imaging or CT perfusion present with mismatch on MR imaging or CT perfusion
3 DefibrinogenatingFibrinogenolytic 3 DefibrinogenatingFibrinogenolytic Agents Agents
AncrodAncrod(Viprinex)(Viprinex) is is the purified fraction of the Malayan pit viper venomthe purified fraction of the Malayan pit viper venom It acts by directly cleaving and inactivating fibrinogen It acts by directly cleaving and inactivating fibrinogen
and thus indirectly promoting anticoagulation and thus indirectly promoting anticoagulation The reduction in the blood levels of fibrinogen also The reduction in the blood levels of fibrinogen also
leads to a reduced blood viscosity which may improve leads to a reduced blood viscosity which may improve blood flow to the affected areas of the brain blood flow to the affected areas of the brain
In the Stroke Treatment with Ancrod Trial 500 In the Stroke Treatment with Ancrod Trial 500 patients with stroke presenting within 3 hours of patients with stroke presenting within 3 hours of symptom onset were randomized to receive ancrod (symptom onset were randomized to receive ancrod (n n 248) or a placebo (n 252) Good outcome (Barthel 248) or a placebo (n 252) Good outcome (Barthel Index 95ndash100 at 3 months) was achieved in 4221 Index 95ndash100 at 3 months) was achieved in 4221 and 344 of the patients respectively and 344 of the patients respectively
2 Direct Fibrinolytics2 Direct Fibrinolytics
Microplasmin (Microplasmin (ThromboGenics Heverlee Belgium)ThromboGenics Heverlee Belgium) is a truncated form of plasmin that is more resistant to the effects is a truncated form of plasmin that is more resistant to the effects
of antiplasmin of antiplasmin microplasmin can be used upto 4ndash12 hours after stroke onset microplasmin can be used upto 4ndash12 hours after stroke onset There was no evidence of increased bleeding risk with There was no evidence of increased bleeding risk with
microplasminmicroplasmin
Alfimeprase (Nuvelo San Carlos Calif)Alfimeprase (Nuvelo San Carlos Calif) is a recombinant truncated form of fibrolase a fibrinolytic zinc metalloproteinase is a recombinant truncated form of fibrolase a fibrinolytic zinc metalloproteinase
isolated from the venom of the southern copperhead snake isolated from the venom of the southern copperhead snake It degrades fibrin directly and achieves thrombolysis independent It degrades fibrin directly and achieves thrombolysis independent
of plasmin formationof plasmin formation its thrombolytic activity appears to be localized to the site of its thrombolytic activity appears to be localized to the site of
delivery These properties should theoretically result in faster delivery These properties should theoretically result in faster recanalization and lower hemorrhagic conversion riskrecanalization and lower hemorrhagic conversion risk
Anti-fibrinolyticsAnti-fibrinolytics
to limit fibrinolytic activityto limit fibrinolytic activity -aminocaproic acid (EACA) -aminocaproic acid (EACA) competitively inhibitscompetitively inhibits plasminogen and plasminogen activators from plasminogen and plasminogen activators from
binding to fibrinbinding to fibrin
alpha2-antiplasminalpha2-antiplasmin a serine protease inhibitor that a serine protease inhibitor that neutralizes any free circulating plasminneutralizes any free circulating plasmin
Plasminogen activator inhibitor-1Plasminogen activator inhibitor-1 a serine protease a serine protease inhibitor that inhibits tissue-type plasminogen inhibitor that inhibits tissue-type plasminogen activatoractivator
Glycoprotein (GP) IIbIIIa antagonistsGlycoprotein (GP) IIbIIIa antagonists
such as ReoPro (abciximab) Integrilin such as ReoPro (abciximab) Integrilin (eptifibatide) or Aggrastat (tirofiban) in (eptifibatide) or Aggrastat (tirofiban) in ischemic stroke remains investigational ischemic stroke remains investigational Deshmukh et al38 reported 21 patients with Deshmukh et al38 reported 21 patients with large-vessel occlusion refractory to IAT with large-vessel occlusion refractory to IAT with rtPA who were treated with IV andor IA rtPA who were treated with IV andor IA abciximab eptifibatide or tirofiban abciximab eptifibatide or tirofiban
IA Mechanical Approaches in Acute Ischemic Stroke IA Mechanical Approaches in Acute Ischemic Stroke Mechanical strategies have several advantagesMechanical strategies have several advantages First they lessen and may even preclude the use of chemical First they lessen and may even preclude the use of chemical
thrombolytics in this manner very likely reducing the risk of ICHthrombolytics in this manner very likely reducing the risk of ICH Second by avoiding the use of chemical thrombolytics it is Second by avoiding the use of chemical thrombolytics it is
possible to extend the treatment window beyond the limit of 6ndash8 possible to extend the treatment window beyond the limit of 6ndash8 hours hours
Third mechanically fragmenting a clot increases the surface area Third mechanically fragmenting a clot increases the surface area accessible to fibrinolytic agents and allows inflow of fresh accessible to fibrinolytic agents and allows inflow of fresh plasminogen which in turn may increase the speed of plasminogen which in turn may increase the speed of thrombolysis thrombolysis
Finally clot-retrieval devices may provide faster recanalization Finally clot-retrieval devices may provide faster recanalization
The disadvantages of the mechanical The disadvantages of the mechanical approaches approaches technical difficulty of navigating mechanical technical difficulty of navigating mechanical
devices into the intracranial circulation excessive devices into the intracranial circulation excessive trauma to the vasculature (potentially leading to trauma to the vasculature (potentially leading to vasospasm vessel dissection perforation or vasospasm vessel dissection perforation or rupture) rupture)
fragmented thrombus causing distal embolization fragmented thrombus causing distal embolization into previously unaffected territories into previously unaffected territories
Nevertheless the advantages of mechanical stroke Nevertheless the advantages of mechanical stroke therapy appear to significantly outweigh its therapy appear to significantly outweigh its disadvantages and risksdisadvantages and risks
Contraindications to Thrombolytic Contraindications to Thrombolytic agents agents
Recent thoracic abdominal or Recent thoracic abdominal or intracranial surgeryintracranial surgery
Recent haemorrhagic CVA Head injury Recent haemorrhagic CVA Head injury or neoplasmor neoplasm
Bleeding ulcerBleeding ulcer Anticipated invasive procedures (arterial Anticipated invasive procedures (arterial
punctures biopsies)punctures biopsies) Concurrent hemostatic dysfunctionConcurrent hemostatic dysfunction
Monitoring of thrombolytic Monitoring of thrombolytic therapytherapy
Thrombin time Measures the availability of functional
fibrinogen Normal thrombin time is 10-14 sec Prolonged when fibrinogen level is below
75-100 mgdl
Half Life of ThrombolyticsHalf Life of ThrombolyticsAgent Administration Half Life
Streptokinase IA 60-80min
Urokinase IAIV 9-12min
rTPA IAIV 6min
Abciximab(Reopro) IAIV 12hour
Aspirin POIV 15-20min
Heparin IVSC 60min
Coumadin PO 15-25 days
Anti Platelet DrugsAnti Platelet DrugsDrug Drug Mechanism Mechanism UsesUsesAspirinAspirin Permanently inhibits Permanently inhibits
COX-1 and COX-2COX-1 and COX-2CADCAD
Stroke-TIAsStroke-TIAs
NSAIDsNSAIDs Reversibly inhibits Reversibly inhibits COX-1COX-1
LimitedLimited
DipyridamoleDipyridamole Inhibits PDE increases Inhibits PDE increases cAMPcAMP
TIAsTIAs
ThenopyridinesThenopyridines
(Ticlopidine(Ticlopidine
ClopidrgrelClopidrgrel))
Inhibits ADP Inhibits ADP
PlatAg PlatAg
TIAsStrokeTIAsStroke
CAD PVDCAD PVD
Abciximab (ReoPro)Abciximab (ReoPro)
Eptifibatide (Integrilin)Eptifibatide (Integrilin)
TirofibanTirofiban
GP IIBIIIA InhibitorsGP IIBIIIA Inhibitors
Stroke- TIAs Stroke- TIAs
MonitoringMonitoring
Bleeding timeBleeding time
Optical aggregometryOptical aggregometry
Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay
Bleeding timeBleeding time
Requires a skin incision (usually made on the ear lobe or Requires a skin incision (usually made on the ear lobe or forearm offorearm of
a depth that results in disruption of capillary loops and a depth that results in disruption of capillary loops and small vessels)small vessels)
AdvantagesAdvantages Universally availableUniversally available Relatively simple techniquesRelatively simple techniques Can be performed bedsideCan be performed bedside
DisadvantagesDisadvantages Insensitive inaccurate non-specific techniqueInsensitive inaccurate non-specific technique
Poorly reproducible (as depends on multiple variables)Poorly reproducible (as depends on multiple variables)
Optical aggregometryOptical aggregometry
Gold standard assay for platelet functionGold standard assay for platelet function Agonist induced aggregation is measuredAgonist induced aggregation is measured Different agonist are available for different Different agonist are available for different
agentsagents However require unique expertise and are not However require unique expertise and are not
universally availableuniversally available Aspirin measured with ADP or AA(gt70 Aspirin measured with ADP or AA(gt70
aggregation so resistance)aggregation so resistance) Clopidogrel( ADP gt 90 aggregation means Clopidogrel( ADP gt 90 aggregation means
resistance) resistance)
Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay
Can be performed bed sideCan be performed bed side Different assay devices with different Different assay devices with different
agonist are used for each of different agonist are used for each of different antiplatelet agents antiplatelet agents
For Aspirin AA is used (result is reported as aspirin For Aspirin AA is used (result is reported as aspirin reaction units [ARU] ARUgt 550 indicates non-reaction units [ARU] ARUgt 550 indicates non-responsiveness)responsiveness)
Verify IIbIIIa assay device uses TRAP as agonist for Verify IIbIIIa assay device uses TRAP as agonist for Abciximab and TirofibanAbciximab and Tirofiban
Practical Applications Practical Applications related to specific related to specific
Neurovascular Neurovascular interventionsinterventions
Acute ischemic StrokeAcute ischemic Stroke When an artery occludes neurons are affected When an artery occludes neurons are affected
differently depending upon the amount of residual blood differently depending upon the amount of residual blood flowflow
Normal cerebral blood flow is greater than 50 mL100 Normal cerebral blood flow is greater than 50 mL100 mgminmgmin
Once blood flow decreases to less than 20 mL100 Once blood flow decreases to less than 20 mL100 mgmin infarction occursmgmin infarction occurs
If blood flow decreases to less than 10 mL100 mgmin If blood flow decreases to less than 10 mL100 mgmin irreversible neuronal death occurs rapidly irreversible neuronal death occurs rapidly
Blood flow between 11 and 20 mL100 mgmin is thought Blood flow between 11 and 20 mL100 mgmin is thought to represent the ischemic penumbra an area where the to represent the ischemic penumbra an area where the cells are functionally silent because of ischemia but are cells are functionally silent because of ischemia but are still able to recover if blood flow is restored still able to recover if blood flow is restored
Many acute stroke therapies are targeted toward Many acute stroke therapies are targeted toward restoring flow or function to the ischemic penumbrarestoring flow or function to the ischemic penumbra
Therapeutic window in Therapeutic window in management of acute Ischemic management of acute Ischemic
StrokeStrokeThe early diagnosis of ischemic stroke is critical to the The early diagnosis of ischemic stroke is critical to the
with only a narrow therapeutic window in the first few with only a narrow therapeutic window in the first few hours following stroke ictushours following stroke ictus
Diagnosis in the first 3 hours postictus provides the Diagnosis in the first 3 hours postictus provides the opportunity for intravenous or intraarterial thrombolysis opportunity for intravenous or intraarterial thrombolysis and intra-arterial clot mechanical treatment which and intra-arterial clot mechanical treatment which improve the outcome improve the outcome
Diagnosis in the time period between 3 and 6 hours Diagnosis in the time period between 3 and 6 hours provides an opportunity for intra-arterial thrombolysis provides an opportunity for intra-arterial thrombolysis and mechanical treatment and mechanical treatment
Involvement of the posterior circulation especially the Involvement of the posterior circulation especially the basilar artery is treated by some regardless of time of basilar artery is treated by some regardless of time of onset or up until 12 to 24 hours in some practices This is onset or up until 12 to 24 hours in some practices This is related to the potentially high mortality and morbidity related to the potentially high mortality and morbidity associated with basilar artery thrombosisassociated with basilar artery thrombosis
Infarct evaluation on angiographyInfarct evaluation on angiography(CT angiography and catheter (CT angiography and catheter
angiography)angiography)CTA is an excellent first-line examination for CTA is an excellent first-line examination for
evaluation of the head and neck arteries evaluation of the head and neck arteries In comparison with catheter angiography In comparison with catheter angiography
what it gives up in resolution and dynamic what it gives up in resolution and dynamic properties it makes up for with rapid properties it makes up for with rapid acquisition of a 3-D dataset and the potential acquisition of a 3-D dataset and the potential for assessment of whole-brain perfusion and for assessment of whole-brain perfusion and better parenchymal evaluationbetter parenchymal evaluation
Moreover CTA illustrates not only arterial Moreover CTA illustrates not only arterial stenosis or occlusion but also the vessel wall stenosis or occlusion but also the vessel wall This factor is most important for evaluation of This factor is most important for evaluation of intramural dissection and thrombosed intramural dissection and thrombosed aneurysms which may both complicate aneurysms which may both complicate evaluation of stroke patientsevaluation of stroke patients
Early angiographic signs of strokes Early angiographic signs of strokes both CTA both CTA and DSA and DSA
Vessel occlusion or cutoff related to Vessel occlusion or cutoff related to thromboembolithromboemboli
aneurysms aneurysms arterial dissection arterial dissection Meniscus or flattened shape to clot Meniscus or flattened shape to clot
(recent) versus reverse meniscus (older)(recent) versus reverse meniscus (older) tram track (nonocclusive or recanalized tram track (nonocclusive or recanalized
clot) clot) delayed (antegrade) flow (manifest as delayed (antegrade) flow (manifest as
decreased whole-brain perfusion on CTA)decreased whole-brain perfusion on CTA) retrograde collateral flowretrograde collateral flow
Non-occlusive left MCA thrombus on 3-D imaging performed from CTA source data and was confirmed at catheter angiography
Therapy to be started within a 6-hr Therapy to be started within a 6-hr time to treatment (TTT) window time to treatment (TTT) window (while in case of IV thrombolysis (while in case of IV thrombolysis therapy to be started with in 3hrs)therapy to be started with in 3hrs)
Exclusion criteria Exclusion criteria Rapidly improving neurologic deficit or Rapidly improving neurologic deficit or Sustained blood pressure of gt180100 Sustained blood pressure of gt180100 Hemorrhage is detected on CTHemorrhage is detected on CT Infarct involving gt more than 13 rd Infarct involving gt more than 13 rd
territory of MCAterritory of MCA MRADWI-Perfusion mismatchlt 20MRADWI-Perfusion mismatchlt 20 Definite hypodensity on CTDefinite hypodensity on CT
Intra-arterial Thrombolysis
Fibrinolytics + AntiplateletsFibrinolytics + Antiplatelets
PlasminogenPlasminogen activators through fibrinolysis exposes activators through fibrinolysis exposes free thrombin and paradoxically stimulatesfree thrombin and paradoxically stimulates platelet platelet aggregation which leads to formation of aaggregation which leads to formation of a platelet platelet thrombus (white clot) thrombus (white clot)
This new thrombus is relatively resistant to This new thrombus is relatively resistant to fibrinolyticsfibrinolytics
So new regimen in case of acute stroke isSo new regimen in case of acute stroke is fibrinolytics + antiplatelet drugsfibrinolytics + antiplatelet drugs
rtPA + IIbIIIa inhibitors( tirofiban rtPA + IIbIIIa inhibitors( tirofiban abciximab) orabciximab) or
Urokinase + IIbIIIa Urokinase + IIbIIIa inhibitors( tirofiban abciximab)inhibitors( tirofiban abciximab)
Intra-arterial Thrombolysis Tirofiban (04 microgkgmin bolus for 3 min followed by Tirofiban (04 microgkgmin bolus for 3 min followed by
0125 ugkgmin)0125 ugkgmin)
++
Heparin (2000ndash3000 IU bolus followed by Heparin (2000ndash3000 IU bolus followed by 1000 IUhour infusion 1000 IUhour infusion
with ACT maintained bw 200-300) throughout the with ACT maintained bw 200-300) throughout the interventional procedure and for 24ndash48 hours thereafter when interventional procedure and for 24ndash48 hours thereafter when there is neither intraprocedural bleeding nor suspicion of there is neither intraprocedural bleeding nor suspicion of increased risk of bleeding increased risk of bleeding
Maximum dose of Urokinase Maximum dose of Urokinase Anterior circulation stroke - 500000 IU (mean 400000 Anterior circulation stroke - 500000 IU (mean 400000
IU range 300000ndash500000 IU)IU range 300000ndash500000 IU) Posterior circulation stroke -1000000 IU (mean 837000 Posterior circulation stroke -1000000 IU (mean 837000
IU range 300000ndash1000000 IU)IU range 300000ndash1000000 IU)American Journal of NeuroradiologyAmerican Journal of Neuroradiology 262595-2601 2005262595-2601 2005
Intravenous ThrombolysisIntravenous Thrombolysis
The first method to restore cerebral The first method to restore cerebral perfusion is clot lysis with the goal perfusion is clot lysis with the goal of re-establishing blood flow to the of re-establishing blood flow to the affected tissue affected tissue
IV thrombolysis rt-PA is the only IV thrombolysis rt-PA is the only FDA- approved treatment for AIS FDA- approved treatment for AIS
Fibrinolysis is enhanced powerfully Fibrinolysis is enhanced powerfully by rt-PAby rt-PA
Intravenous rTPA Intravenous rTPA administration administration protocolprotocol
Total dose of rt-PA 09 mgkg (maximum dose Total dose of rt-PA 09 mgkg (maximum dose 90 mg)90 mg)
Give 10 as initial IV bolusGive 10 as initial IV bolus Infuse remainder over 1 hourInfuse remainder over 1 hour Admit patient to an ICU or stroke unit for Admit patient to an ICU or stroke unit for
monitoringmonitoring Neurologic assessments every 15 minutes Neurologic assessments every 15 minutes
during infusion then every 30 minutes for next during infusion then every 30 minutes for next 6 hours then every hour until 24hours after 6 hours then every hour until 24hours after treatmenttreatment
Favorable Outcome vs Treatment Time Favorable Outcome vs Treatment Time with IV rTPAwith IV rTPA
Protocol limit = 3 hrs
Benefit ~ 45 hrs
Thromboembolism During coilingThromboembolism During coiling Most feared and frequent complication Most feared and frequent complication Reported incidence - Approx 7 Reported incidence - Approx 7 SourcesSources of Thromboembolism are of Thromboembolism are
- Clots at the aneurysmal neck during or immediately- Clots at the aneurysmal neck during or immediately after after embolization embolization
- Thrombus forming on catheters during- Thrombus forming on catheters during proceduresprocedures
- Stenosis of an adjacent artery dt coil mass- Stenosis of an adjacent artery dt coil mass or herniationor herniation
- Migration of intraaneurysmal- Migration of intraaneurysmal thrombus during coil thrombus during coil placement placement
- Slow flow dt vasospasm - Slow flow dt vasospasm
- Rare and unlikely causes are hypercoagulable- Rare and unlikely causes are hypercoagulable state such state such as antiphospholipid antibody syndrome or due to HITas antiphospholipid antibody syndrome or due to HIT
Occur more often with wide-necked aneurysms (dt Occur more often with wide-necked aneurysms (dt increased exposed surface area of thrombogenic coil increased exposed surface area of thrombogenic coil material)material)
Current regimen of endovascular Current regimen of endovascular managementmanagement
The The glycoprotein IIbIIIa antagonist tirofiban glycoprotein IIbIIIa antagonist tirofiban (04 (04 microgkgmin bolus for 30 minutes followed by infusion of microgkgmin bolus for 30 minutes followed by infusion of 0125 ugkgmin until the thrombus dissolved) 0125 ugkgmin until the thrombus dissolved)
Intraarterial thrombolysis with Intraarterial thrombolysis with urokinase or r- TPA urokinase or r- TPA increase of intravenous (IV) heparin (measured by increase of intravenous (IV) heparin (measured by
ACT) ACT) Intravenous aspirin Intravenous aspirin
Coil-related platelet aggregation (white clot) is Coil-related platelet aggregation (white clot) is unlikely to respond to fibrinolytics but has a high risk unlikely to respond to fibrinolytics but has a high risk of hemorrhage (In ISAT) all 5 patients who had of hemorrhage (In ISAT) all 5 patients who had received thrombolytic therapy with tPA to treat a received thrombolytic therapy with tPA to treat a thromboembolic complication after endovascular thromboembolic complication after endovascular treatment rebleed and all of these patients died)treatment rebleed and all of these patients died)
IntracranialIntracranial Stenting Stenting Metallic foreign body such as stent will accumulate Metallic foreign body such as stent will accumulate
thrombus in the absence of platelet inhibitionthrombus in the absence of platelet inhibition Antiplatelet drugs are important to prevent peri or Antiplatelet drugs are important to prevent peri or
post-interventional thromboembolic eventspost-interventional thromboembolic events Optimal treatment regimens has not been determined Optimal treatment regimens has not been determined
but usually but usually Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-
procedureprocedureOrOr
Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on
morning of proceduremorning of procedure
If need to use stent is not pre-planned thanIf need to use stent is not pre-planned than
Abciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkgAbciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkg IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)
Glycoprotein IIbIIIa inhibitor are not used routinely during elective Glycoprotein IIbIIIa inhibitor are not used routinely during elective stenting procedure dt increased risk of ICH stenting procedure dt increased risk of ICH
Carotid StentingCarotid Stenting
Pre-procedurePre-procedure
Double Antiplatelet therapy is routinely given Double Antiplatelet therapy is routinely given beginning at least 3beginning at least 3
days before the proceduredays before the procedure
Aspirin 325mgd+Clopidogrel 75mgdAspirin 325mgd+Clopidogrel 75mgd During procedureDuring procedure
Heparin is given with target clotting time of 250-Heparin is given with target clotting time of 250-300sec300sec
Post-procedure Post-procedure
Aspirin 325mg is continued indefinitely and Aspirin 325mg is continued indefinitely and
Clopidogrel 75mgd for at least 6 weeks Clopidogrel 75mgd for at least 6 weeks
Inclusion criteria for Local ThrombolysisInclusion criteria for Local Thrombolysis a)a) Patients in severe clinical grade on admission Patients in severe clinical grade on admission
with evidence of dural venous sinus with evidence of dural venous sinus thrombosis and restrictive venous outflow on thrombosis and restrictive venous outflow on cerebral angiogramcerebral angiogram
b)b) Patients in clinical grade 3 worsening on Patients in clinical grade 3 worsening on heparin therapy Restriction to venous heparin therapy Restriction to venous outflow was defined as an increase in brain outflow was defined as an increase in brain circulation time gt 12 s delay in the drainage circulation time gt 12 s delay in the drainage of cortical veins with cortical veins hanging of cortical veins with cortical veins hanging in spacein space
Treatment Options for Venous Thrombosis
CT Grading for Venous ThrombosisCT Grading for Venous Thrombosis Grade I no parenchymal change Grade I no parenchymal change
(hyperdense (hyperdense sinuses cortical veins empty sinuses cortical veins empty delta sign)delta sign)
Grade II non hemorrhagic venous infarct Grade II non hemorrhagic venous infarct without mass effect without mass effect
Grade III non-hemorrhagic infarct with Grade III non-hemorrhagic infarct with mass effectmass effect
Grade IV hemorrhagic venous infarct (max Grade IV hemorrhagic venous infarct (max diameter lt 3 cm) with no mass effectdiameter lt 3 cm) with no mass effect
Grade V hemorrhagic venous infarct (max Grade V hemorrhagic venous infarct (max diameter gt 3 cm) with mass effect diameter gt 3 cm) with mass effect
Local ThrombolysisLocal Thrombolysis
Femoral Jugular access was secured and a guiding Femoral Jugular access was secured and a guiding catheter was placed in the jugular bulb catheter was placed in the jugular bulb Mechanical Mechanical clot maceration clot maceration was done with the guidewire was done with the guidewire following which a microcatheter (was navigated and following which a microcatheter (was navigated and placed in the thrombosed segment of sinus confirmed placed in the thrombosed segment of sinus confirmed on a selective venogram on a selective venogram
Urokinase infusion Bolus dose of 2-6 lacs followed Urokinase infusion Bolus dose of 2-6 lacs followed by 60000 to 100000 units per hour along with by 60000 to 100000 units per hour along with periodic check venogram Along with maintenance periodic check venogram Along with maintenance systemic infusion of Heparinsystemic infusion of Heparin Other agents such as Other agents such as streptokinase altepase or rTPAstreptokinase altepase or rTPA can be also used can be also used
After thrombolysis patient should subjected to oral After thrombolysis patient should subjected to oral anticoagulation for six monthsanticoagulation for six months
Low-molecular-weight Low-molecular-weight heparinheparin
PharmacologyPharmacologyLMWH as its name suggests is a glycosaminoglycan that is approximatelyLMWH as its name suggests is a glycosaminoglycan that is approximately
one third the molecular weight of UFH It is derived from UFH through one third the molecular weight of UFH It is derived from UFH through variousvarious
depolymerization processes LMWH binds to antithrombin which in turn depolymerization processes LMWH binds to antithrombin which in turn
Neutralizes actors Xa and IIa Because LMWH lacks many of the longer Neutralizes actors Xa and IIa Because LMWH lacks many of the longer chains chains
required for binding to thrombin it has less ability to neutralize thrombin required for binding to thrombin it has less ability to neutralize thrombin
relativeto its ability to neutralize factor Xa LMWH also has less relativeto its ability to neutralize factor Xa LMWH also has less nonspecific nonspecific
binding to other proteins There is greater bioavailability with more binding to other proteins There is greater bioavailability with more predictable predictable
pharmacokinetics that eliminates the need for monitoring The smaller pharmacokinetics that eliminates the need for monitoring The smaller size also size also
allows for enhanced subcutaneous absorption when compared with UFHallows for enhanced subcutaneous absorption when compared with UFH
Three LMWH preparations are Three LMWH preparations are currently approved for use in the currently approved for use in the United States (1) enoxaparin (2) United States (1) enoxaparin (2) dalteparin and (3) tinzaparin dalteparin and (3) tinzaparin
They are all administered They are all administered subcutaneously at intervals of either subcutaneously at intervals of either once or twice daily for both once or twice daily for both prophylaxis and treatment dosesprophylaxis and treatment doses
Few Experiences of Few Experiences of ThrombolysisThrombolysis
Vickey 25 Yrs male patient presented Vickey 25 Yrs male patient presented with 12with 12thth day HO severe headache with day HO severe headache with right sided hemiplegiaright sided hemiplegia
MRI shows thrombosis of the superior MRI shows thrombosis of the superior sagittal left transverse left sigmoid sagittal left transverse left sigmoid sinuses and cortical veins in the fronto-sinuses and cortical veins in the fronto-parietal regions with eo haemorrhagic parietal regions with eo haemorrhagic infarct in the left cerebral hemisphere infarct in the left cerebral hemisphere with mass effect( Grade ndashV)with mass effect( Grade ndashV)
Sashi Srivastava 64 yrs FSashi Srivastava 64 yrs F In a follow up case of MRD with infra-renal In a follow up case of MRD with infra-renal
aortic abdominal and bilateral renal artery aortic abdominal and bilateral renal artery thrombosis renal angiogram shows filling thrombosis renal angiogram shows filling defects in the right Renal artery defects in the right Renal artery
Initially Renal angioplasty was done Initially Renal angioplasty was done Following angioplasty few thrombi are seem Following angioplasty few thrombi are seem to extends into the segmental branches and to extends into the segmental branches and causing blockage So Thrombolysis was causing blockage So Thrombolysis was plane to dissolve the run-out thrombi with plane to dissolve the run-out thrombi with urokinase urokinase
Rakesh 34yrsMRakesh 34yrsM Left SFA pseudoaneurysm with Left SFA pseudoaneurysm with
Covered stent placementCovered stent placement Pre operative antiplatelets with post Pre operative antiplatelets with post
procedure heparin Tirofiban procedure heparin Tirofiban followed by aspirin and clopidogrel followed by aspirin and clopidogrel were usedwere used
IAT may be a treatment option for selected patients IAT may be a treatment option for selected patients Possible selection criteria include Possible selection criteria include
presentation between 3 and 6 hours from symptom onsetpresentation between 3 and 6 hours from symptom onset major cerebral artery occlusion major cerebral artery occlusion severe neurologic deficits severe neurologic deficits high risk of systemic hemorrhage with IV rt-PA (eg recent high risk of systemic hemorrhage with IV rt-PA (eg recent
surgery) surgery) The MERCI (Mechanical Embolus Removal in Cerebral The MERCI (Mechanical Embolus Removal in Cerebral
Ischemia) retrievalIschemia) retrieval system system
Has been FDA-approved for recanalizing acutely occluded Has been FDA-approved for recanalizing acutely occluded cerebral arteries cerebral arteries
In the Multi-MERCI study patients who did not improve In the Multi-MERCI study patients who did not improve immediately after IV rt-PA underwent mechanical immediately after IV rt-PA underwent mechanical embolectomy within 8 hours of symptom onset embolectomy within 8 hours of symptom onset
Partial or complete recanalization occurred in 74 of Partial or complete recanalization occurred in 74 of patientspatients
with a symptomatic intracerebral hemorrhage (sICH) rate of with a symptomatic intracerebral hemorrhage (sICH) rate of 67 67
Mechanical embolectomy with the MERCI retriever may be a Mechanical embolectomy with the MERCI retriever may be a feasible and safe option for patients after IV rt-PAfeasible and safe option for patients after IV rt-PA
Penumbra stroke systemPenumbra stroke system This device combines two methods of clot This device combines two methods of clot
extraction aspiration and mechanical extraction aspiration and mechanical extraction extraction
First the clot is aspirated then a thrombus First the clot is aspirated then a thrombus removal ring can be used if necessary to removal ring can be used if necessary to remove remaining clot remove remaining clot
successful recanalizing 82successful recanalizing 82 Bridging therapyBridging therapy
06 mgkg IV rt-PA followed by IAT with IA rt-06 mgkg IV rt-PA followed by IAT with IA rt-PA (up to 20 mg)PA (up to 20 mg)
achieved a higher recanalization rateachieved a higher recanalization rate
Criteria for thrombolysis with rTPACriteria for thrombolysis with rTPA
Inclusion criteriaInclusion criteria Clinical signs and symptoms consistent with ischemic Clinical signs and symptoms consistent with ischemic
strokestroke Patient last seen normal within 3 hoursPatient last seen normal within 3 hours Measurable neurologic deficitMeasurable neurologic deficit
Exclusion criteriaExclusion criteria Any hemorrhage on neuroimaging (CT or MRI)Any hemorrhage on neuroimaging (CT or MRI) Symptoms suggestive of subarachnoid hemorrhageSymptoms suggestive of subarachnoid hemorrhage Seizure at stroke onset that is thought to contribute to Seizure at stroke onset that is thought to contribute to
neurologic deficitneurologic deficit Hypodensity greater than one third cerebral hemisphere Hypodensity greater than one third cerebral hemisphere
on CTon CT SBP greater than 185 mm Hg or DBP greater than 110 SBP greater than 185 mm Hg or DBP greater than 110
mm Hgmm Hg International normalized ratio (INR) greater than 17International normalized ratio (INR) greater than 17
Ischemic Stroke Ischemic Stroke Treatment ndash 2006Treatment ndash 2006
IV tissue plasminogen activator (tPA)IV tissue plasminogen activator (tPA) ndash ndash Only FDA-approved acute stroke drugOnly FDA-approved acute stroke drug ndash ndash 3 hour treatment window3 hour treatment window
MERCI - Concentric clot retrieval MERCI - Concentric clot retrieval devicedevice ndash ndash Rescue therapy - approved 2004Rescue therapy - approved 2004 ndash ndash Device approval (not outcomes-based)Device approval (not outcomes-based)
Off label approachesOff label approaches ndash ndash IV tPA after 3 hoursIV tPA after 3 hours ndash ndash IV-IA tPA sequential strategiesIV-IA tPA sequential strategies ndash ndash IA tPA clot angioplasty fragmentationIA tPA clot angioplasty fragmentation ndash ndash Ultrasound-assisted tPA lysisUltrasound-assisted tPA lysis
rt-PA Trials NINDSrt-PA Trials NINDS
Acute stroke - 624 patientsAcute stroke - 624 patients Treat within 3 hrsTreat within 3 hrs Intravenous 09 mgkg rt-PA vs placeboIntravenous 09 mgkg rt-PA vs placebo Hemorrhage 64 tPA 06 placeboHemorrhage 64 tPA 06 placebo Neurologic recovery better with tPA 30 Neurologic recovery better with tPA 30
more like to have minimal or no disabilitymore like to have minimal or no disability
First proven approved treatment for First proven approved treatment for strokestroke
Limitations of tPALimitations of tPA Only 4 of acute strokes receive tPAOnly 4 of acute strokes receive tPA (Kleindorfer et al Stroke 2004 35 e27-e29)(Kleindorfer et al Stroke 2004 35 e27-e29)
Only 22 of patients present within 3 hoursOnly 22 of patients present within 3 hours1048707 1048707 51 of these ineligible due to51 of these ineligible due to
bull bull Mild severityMild severity bull bull Medical or surgical historyMedical or surgical history bull bull Blood testsBlood tests
Sustained recanalization only 13Sustained recanalization only 13 (Alexandrov et al NEJM 2004 351 2170-8)(Alexandrov et al NEJM 2004 351 2170-8)
Concern for hemorrhageConcern for hemorrhage tPA potentiates apoptotic injury tPA potentiates apoptotic injury (Liu et al Nature Med 2004 101379-83)(Liu et al Nature Med 2004 101379-83)
PROACT II IA Lysis TrialPROACT II IA Lysis Trial Baseline 24 hours 8 days
Baseline 60 minutes 120 minutes
9mg IAProurokinase
Desmoteplase Trials DEDAS Desmoteplase Trials DEDAS DIASDIAS
Trial OverviewTrial Overview Double blind randomized placebo Double blind randomized placebo
controlled trialscontrolled trials IV delivery 3-9 hour time windowIV delivery 3-9 hour time window Plasminogen activator ndash from Plasminogen activator ndash from vampire bat vampire bat
salivasaliva Selection based on PWI-DWI MismatchSelection based on PWI-DWI Mismatch
MRI InclusionMRI Inclusion PWI defect at least 2 cm AND ~20 larger PWI defect at least 2 cm AND ~20 larger
than DWIthan DWI PWI should be obvious even visible on PWI should be obvious even visible on
raw imagesraw imagesMRI ExclusionMRI Exclusion
DWI gt 13 MCADWI gt 13 MCA MRA ICA occlusionMRA ICA occlusion
Desmoteplase ndash DIAS Desmoteplase ndash DIAS ResultsResults
Mechanical Thrombolysis Mechanical Thrombolysis devicesdevices
mechanical thrombolysis potentially extends the treatment mechanical thrombolysis potentially extends the treatment window because they act promptly at the site of the thrombuswindow because they act promptly at the site of the thrombus
The devices can retrieve large clots that pharmaceutical agents The devices can retrieve large clots that pharmaceutical agents may not successfully lysemay not successfully lyse
Patients treated with IV tPA may be considered for treatment of Patients treated with IV tPA may be considered for treatment of residual clot with some of these devicesresidual clot with some of these devices
suction-creating saline jets suction-creating saline jets laser energy ultrasound laser energy ultrasound a corkscrew apparatus to treat strokesa corkscrew apparatus to treat strokes The AngioJet systemThe AngioJet system uses saline jets that are directed back into the catheter to uses saline jets that are directed back into the catheter to
create a low-pressure zone around the catheter tip inducing create a low-pressure zone around the catheter tip inducing suction suction
The clot is pulled into the exhaust lumen and removed from the The clot is pulled into the exhaust lumen and removed from the vessel Although US Food and Drug Administration (FDA) has vessel Although US Food and Drug Administration (FDA) has approved this device for use in arteriovenous dialysis grafts and approved this device for use in arteriovenous dialysis grafts and fistulae and for the treatment of coronary arteries saphenous fistulae and for the treatment of coronary arteries saphenous vein grafts and peripheral vessels clinical trials for the vein grafts and peripheral vessels clinical trials for the treatment of acute stroke are no longer in progress treatment of acute stroke are no longer in progress
Most devices are used in cerebral vessels that 2-5 mm
The Latis laser device The Latis laser device used laser energy to ablate clots used laser energy to ablate clots Arteries 2-5 mm in diameter could be Arteries 2-5 mm in diameter could be
treated including the ICA M1 or M2 treated including the ICA M1 or M2 branch of the MCA A1 branch of the branch of the MCA A1 branch of the anterior cerebral artery (ACA) basilar anterior cerebral artery (ACA) basilar artery posterior cerebral artery (PCA) artery posterior cerebral artery (PCA) and vertebral and vertebral
Patients could receive treatment as late Patients could receive treatment as late as 8 hours after symptom onset in the as 8 hours after symptom onset in the anterior circulation and within 24 hours in anterior circulation and within 24 hours in the posterior circulation the posterior circulation
Endovascular Photo Acoustic Endovascular Photo Acoustic Recanalization (EPAR) Recanalization (EPAR)
A laser power source generated energy for the A laser power source generated energy for the systemsystem
The energy was delivered by means of The energy was delivered by means of fiberoptics to the tip of the catheter at the fiberoptics to the tip of the catheter at the treatment sitetreatment site
Absorption of laser light by darkly pigmented Absorption of laser light by darkly pigmented materials (ie the clot) occurred inside the 1-mm materials (ie the clot) occurred inside the 1-mm catheter tipcatheter tip
the system was designed to minimize scattering the system was designed to minimize scattering of laser light of laser light
Absorption converted photo energy to acoustic Absorption converted photo energy to acoustic energy which then emulsified the clot inside the energy which then emulsified the clot inside the catheter tip catheter tip
EKOS ultrasound( the EKOS ultrasound( the Ultrasound Thrombolytic Ultrasound Thrombolytic
Infusion Catheter) Infusion Catheter) combines the use of a distal ultrasound transducer with combines the use of a distal ultrasound transducer with
infusion of a thrombolytic agent through the infusion of a thrombolytic agent through the microcathetermicrocatheter
Ultrasound changes the structure of the clot to Ultrasound changes the structure of the clot to temporarily increase its permeability while providing an temporarily increase its permeability while providing an acoustic pressure gradient to move the drug into the clot acoustic pressure gradient to move the drug into the clot to speed its dissolution to speed its dissolution
The EKOS catheter is placed in the proximal portion of the The EKOS catheter is placed in the proximal portion of the clot clot
After a 2-mg bolus of tPA was injected through the After a 2-mg bolus of tPA was injected through the catheter catheter
the patient received a continuous infusion of IA tPA 03 the patient received a continuous infusion of IA tPA 03 mgmin to a maximum of 20 mg and simultaneous mgmin to a maximum of 20 mg and simultaneous ultrasound transmission for as long as 60 minutes ultrasound transmission for as long as 60 minutes
One patient was treated with a total of 4 units of One patient was treated with a total of 4 units of recombinant reteplase (Retavase) hand-injected over 60 recombinant reteplase (Retavase) hand-injected over 60 minutes minutes
Penumbra system Penumbra system The Penumbra system (Penumbra Inc) provides a dual The Penumbra system (Penumbra Inc) provides a dual
approach to clot extraction using aspiration followed by approach to clot extraction using aspiration followed by clot retrieval with a ring device if needed clot retrieval with a ring device if needed
Mechanical Embolus Removal in Cerebral Ischemia Mechanical Embolus Removal in Cerebral Ischemia (MERCI)(MERCI)
a corkscrew-like apparatus to remove blood clots from a corkscrew-like apparatus to remove blood clots from the brain in patients experiencing an ischemic stroke the brain in patients experiencing an ischemic stroke
The corkscrew itself resides in the catheter tip which The corkscrew itself resides in the catheter tip which shields it from the wall of the vessel until it is ready to be shields it from the wall of the vessel until it is ready to be burrowed into the clot Once lodged in the clot the device burrowed into the clot Once lodged in the clot the device and clot are withdrawn from the vessel and clot are withdrawn from the vessel
Snarelike devicesSnarelike devices Snares such as the Neuronet snare (Guidant Snares such as the Neuronet snare (Guidant
Endovascular Santa Clara CA) have been developed Endovascular Santa Clara CA) have been developed specifically for use in the treatment of strokes specifically for use in the treatment of strokes
These devices are simple in design and do not require the These devices are simple in design and do not require the clot to be amenable to emulsification clot to be amenable to emulsification
X-Sizer deviceX-Sizer device a device with small moving blades at the a device with small moving blades at the
catheter tip catheter tip This device the X-Sizer device (EndiCor Medical This device the X-Sizer device (EndiCor Medical
San Clemente CA) can be used to excise the San Clemente CA) can be used to excise the thrombus and aspirate it thrombus and aspirate it
The device was being evaluated in randomized The device was being evaluated in randomized studies of coronary vessels and in a registry of studies of coronary vessels and in a registry of patients with acute myocardial infarctionpatients with acute myocardial infarction
Although the manufacturer had modified the Although the manufacturer had modified the device for use in cerebral vessels a safety and device for use in cerebral vessels a safety and feasibility study was indefinitely suspended after feasibility study was indefinitely suspended after only 1 patient was treated with the device in only 1 patient was treated with the device in Europe Europe
Suction thrombectomySuction thrombectomy This method of mechanical thrombolysis is one of the This method of mechanical thrombolysis is one of the
simplestsimplest In this readily available technique suction is applied with In this readily available technique suction is applied with
a syringe to remove thrombus in the ICA a syringe to remove thrombus in the ICA It requires no other devicesIt requires no other devices A catheter with a large inner diameter (Brite Tip Cordis A catheter with a large inner diameter (Brite Tip Cordis
Corporation Miami FL) was placed in the symptomatic Corporation Miami FL) was placed in the symptomatic vessel and navigated over a guidewire into the thrombusvessel and navigated over a guidewire into the thrombus
A 60-mL syringe was used to aspirate the thrombus A 60-mL syringe was used to aspirate the thrombus Each patient required angioplasty and stenting of carotid Each patient required angioplasty and stenting of carotid
bifurcation stenosis and received daily aspirin and bifurcation stenosis and received daily aspirin and ticlopidine after the procedure No complications ticlopidine after the procedure No complications occurred occurred
Summary Acute Stroke Summary Acute Stroke ImagingImaging
PhysiologyPhysiology importance collaterals importance collaterals
ndash ndashGrowing role for perfusion Growing role for perfusion assessmentassessment
tPAtPA guidelines amp limitations guidelines amp limitations Signs on CT amp MRSigns on CT amp MR follow physiology follow physiology Stroke trialsStroke trials PWI-DWI mismatch PWI-DWI mismatch
ndash ndashTreat based on physiology not timeTreat based on physiology not time ProtocolsProtocols should be fast and should be fast and
comprehensivecomprehensive
PROTHROMBIN TIME (PT)PROTHROMBIN TIME (PT)
Time required for blood to coagulate Time required for blood to coagulate is called PT ( normal value ~10sec)is called PT ( normal value ~10sec)
Performed by adding a mixture of Performed by adding a mixture of calcium and thromboplastin to calcium and thromboplastin to citrated plasmacitrated plasma
As a control a normal blood sample is As a control a normal blood sample is tested continuouslytested continuously
PT ratio (PTR) = PT ratio (PTR) = Patientrsquos PTPatientrsquos PT Control PTControl PT
PROBLEMS WITH PTPTRPROBLEMS WITH PTPTR
Thromboplastins are extracts from Thromboplastins are extracts from brain lung or placenta of animalsbrain lung or placenta of animals
Thromboplastins from various Thromboplastins from various manufacturers differ in their manufacturers differ in their sensitivity to prolong PTsensitivity to prolong PT
May result in false control of May result in false control of anticoagulant therapyanticoagulant therapy
INTERNATIONAL NORMALISED RATIO (INR)INTERNATIONAL NORMALISED RATIO (INR)
International Normalized Ratio (INR) International Normalized Ratio (INR) a PT test with a a PT test with a formula based ratio to normalize the often variable source formula based ratio to normalize the often variable source of tissue factor (human rabbit recombinant)of tissue factor (human rabbit recombinant)
INR = [PTINR = [PTptpt] ] ISIISI
[PT[PTRefRef]]
PTPTpt pt ndash prothrombin time of patientndash prothrombin time of patient
PTPTRef Ref ndash prothrombin time of normal pooled samplendash prothrombin time of normal pooled sample
ISI ndash International Sensitivity IndexISI ndash International Sensitivity Index
Warfarin is given orally and titrated to achieve an INR of Warfarin is given orally and titrated to achieve an INR of typically 20 ndash 30typically 20 ndash 30
Heparin versus WarfarinHeparin versus Warfarin
Drug ActionMechan-ism
Moni-toring
Effective
HeparinDirect
Inhibition ofThrombin
ATIIIcofactor
APTTACT
Immediate
WarfarinDecreasesProductionof factors
Vitamin K PTDelay
3-5 days
INR
Recanalization or Antegrade Recanalization or Antegrade Reperfusion StrategiesReperfusion Strategies
Recanalization strategies focus on removing Recanalization strategies focus on removing andor dissolving the occlusive thrombus to re-andor dissolving the occlusive thrombus to re-establish antegrade flow Strategies may be establish antegrade flow Strategies may be classified into 7 different categories on the classified into 7 different categories on the basis of their primary mechanism of action basis of their primary mechanism of action 1) 1) IV andor intraarterial thrombolysis (IAT) IV andor intraarterial thrombolysis (IAT) 2) endovascular thrombectomy2) endovascular thrombectomy3) endovascular thromboaspiration 3) endovascular thromboaspiration 4) endovascular mechanical thrombus disruption or 4) endovascular mechanical thrombus disruption or
thromborrhexisthromborrhexis5) 5) transcranial or endovascular augmented transcranial or endovascular augmented
fibrinolysis fibrinolysis 6) endovascular thrombus entrapment and 6) endovascular thrombus entrapment and 7) temporary endovascular bypass7) temporary endovascular bypass
IAT in Acute Ischemic StrokeIAT in Acute Ischemic Stroke
IAT advantages over IV thrombolysisIAT advantages over IV thrombolysis Coaxial microcatheter techniques the occluded intracranial Coaxial microcatheter techniques the occluded intracranial
vessel is directly accessible and the fibrinolytic agent can be vessel is directly accessible and the fibrinolytic agent can be infused directly into the thrombusinfused directly into the thrombus
This permits a smaller dose of fibrinolytic agent to reach a This permits a smaller dose of fibrinolytic agent to reach a higher local concentration than that reached by systemic higher local concentration than that reached by systemic infusioninfusion
Allows more complete recanalization with lower total doses of Allows more complete recanalization with lower total doses of thrombolytic thrombolytic
With the smaller dose complications from systemic fibrinolytic With the smaller dose complications from systemic fibrinolytic effects including intracranial hemorrhage (ICH) can effects including intracranial hemorrhage (ICH) can theoretically be reduced theoretically be reduced
Treatment window for endovascular techniques can be Treatment window for endovascular techniques can be extended beyond the typical IV window of 3 hours extended beyond the typical IV window of 3 hours
IA techniques have led to higher recanalization rates than IV IA techniques have led to higher recanalization rates than IV thrombolysisthrombolysis
Major disadvantagesMajor disadvantages Relative complexity of the procedure the level Relative complexity of the procedure the level
of required technical expertise and its of required technical expertise and its relatively low availability relatively low availability
Delays in initiating treatmentDelays in initiating treatment InvasiveInvasive
ThrombolyticsThrombolytics
Plasminogen activators
Fibrinolytics
1 Plasminogen Activators 1 Plasminogen Activators drugs act by converting the inactive proenzyme drugs act by converting the inactive proenzyme plasminogen into the active enzyme plasmin Plasmin plasminogen into the active enzyme plasmin Plasmin digests fibrinogen fibrin monomers and cross-linked digests fibrinogen fibrin monomers and cross-linked fibrin (as found in a thrombus) into fibrin degradation fibrin (as found in a thrombus) into fibrin degradation productsproducts
First-Generation Agents First-Generation Agents StreptokinaseStreptokinase a protein derived from group C a protein derived from group C
szlig-hemolytic streptococci has a half-life of 16ndashszlig-hemolytic streptococci has a half-life of 16ndash90 minutes and low fibrin specificity This drug 90 minutes and low fibrin specificity This drug proved to have a very narrow therapeutic proved to have a very narrow therapeutic window and significant rates of ICH and window and significant rates of ICH and systemic hemorrhage18systemic hemorrhage18
UrokinaseUrokinase is a serine protease with a plasma is a serine protease with a plasma half life of 14 minutes and low fibrin specificity half life of 14 minutes and low fibrin specificity
The urokinase dose used in cerebral IAT has The urokinase dose used in cerebral IAT has ranged from 002 to 2 X106unitsranged from 002 to 2 X106units
Second-Generation Agents Second-Generation Agents Alteplase (rtPA) Alteplase (rtPA)
is a serine is a serine protease with a plasma half-life of 35 protease with a plasma half-life of 35 minutes and a high degree of fibrin affinity and minutes and a high degree of fibrin affinity and specificity specificity
Dose used in cerebral IAT has ranged between 20 Dose used in cerebral IAT has ranged between 20 and 60 mgand 60 mg
Disadvantages of alteplase include its relatively short Disadvantages of alteplase include its relatively short halflife and limited penetration into the clot matrix halflife and limited penetration into the clot matrix because of strong binding with surface fibrin which because of strong binding with surface fibrin which could delay recanalization and increase the risk of could delay recanalization and increase the risk of recurrent occlusion recurrent occlusion
Prourokinase (r-prourokinase) Prourokinase (r-prourokinase) is the proenzyme precursor of urokinase is the proenzyme precursor of urokinase T12 of 7 minutes and high fibrin specificity T12 of 7 minutes and high fibrin specificity
Third-Generation AgentsThird-Generation Agents
ReteplaseReteplase is a structurally modified is a structurally modified form of alteplase form of alteplase
with a longer half-life (15ndash18 minutes) In with a longer half-life (15ndash18 minutes) In addition it does not bind as highly to fibrin addition it does not bind as highly to fibrin unbound reteplase can thus theoretically better unbound reteplase can thus theoretically better penetrate the clot and potentially penetrate the clot and potentially improve in improve in vivo fibrinolytic activity vivo fibrinolytic activity
TenecteplaseTenecteplase is another modified form of rtPA with a longer is another modified form of rtPA with a longer
half-life (17 minutes)half-life (17 minutes) greater fibrin specificity and greater greater fibrin specificity and greater
resistance to plasminogen activator inhibitor-1 resistance to plasminogen activator inhibitor-1 IV tenecteplase in acute ischemic stroke IV tenecteplase in acute ischemic stroke
suggest that the drug is safe and promisingsuggest that the drug is safe and promising
Newer plasminogen activatorNewer plasminogen activator
DesmoteplaseDesmoteplase is a genetically engineered is a genetically engineered version of the clot-dissolving factor version of the clot-dissolving factor
found in the saliva found in the saliva of the vampire bat Desmodus rotundusof the vampire bat Desmodus rotundus moremore potent and more selective for fibrin-bound potent and more selective for fibrin-bound
plasminogen than any other known plasminogen plasminogen than any other known plasminogen activatoractivator
Unlike tissue plasminogen activator (tPA) desmoteplase Unlike tissue plasminogen activator (tPA) desmoteplase is not activated by fibrinogen or -amyloid proteins is not activated by fibrinogen or -amyloid proteins factors that may exacerbate the risk for ICH factors that may exacerbate the risk for ICH
The effect of IV administration of desmoteplase 3ndash9 The effect of IV administration of desmoteplase 3ndash9 hours after symptom onset in patients with stroke who hours after symptom onset in patients with stroke who present with mismatch on MR imaging or CT perfusion present with mismatch on MR imaging or CT perfusion
3 DefibrinogenatingFibrinogenolytic 3 DefibrinogenatingFibrinogenolytic Agents Agents
AncrodAncrod(Viprinex)(Viprinex) is is the purified fraction of the Malayan pit viper venomthe purified fraction of the Malayan pit viper venom It acts by directly cleaving and inactivating fibrinogen It acts by directly cleaving and inactivating fibrinogen
and thus indirectly promoting anticoagulation and thus indirectly promoting anticoagulation The reduction in the blood levels of fibrinogen also The reduction in the blood levels of fibrinogen also
leads to a reduced blood viscosity which may improve leads to a reduced blood viscosity which may improve blood flow to the affected areas of the brain blood flow to the affected areas of the brain
In the Stroke Treatment with Ancrod Trial 500 In the Stroke Treatment with Ancrod Trial 500 patients with stroke presenting within 3 hours of patients with stroke presenting within 3 hours of symptom onset were randomized to receive ancrod (symptom onset were randomized to receive ancrod (n n 248) or a placebo (n 252) Good outcome (Barthel 248) or a placebo (n 252) Good outcome (Barthel Index 95ndash100 at 3 months) was achieved in 4221 Index 95ndash100 at 3 months) was achieved in 4221 and 344 of the patients respectively and 344 of the patients respectively
2 Direct Fibrinolytics2 Direct Fibrinolytics
Microplasmin (Microplasmin (ThromboGenics Heverlee Belgium)ThromboGenics Heverlee Belgium) is a truncated form of plasmin that is more resistant to the effects is a truncated form of plasmin that is more resistant to the effects
of antiplasmin of antiplasmin microplasmin can be used upto 4ndash12 hours after stroke onset microplasmin can be used upto 4ndash12 hours after stroke onset There was no evidence of increased bleeding risk with There was no evidence of increased bleeding risk with
microplasminmicroplasmin
Alfimeprase (Nuvelo San Carlos Calif)Alfimeprase (Nuvelo San Carlos Calif) is a recombinant truncated form of fibrolase a fibrinolytic zinc metalloproteinase is a recombinant truncated form of fibrolase a fibrinolytic zinc metalloproteinase
isolated from the venom of the southern copperhead snake isolated from the venom of the southern copperhead snake It degrades fibrin directly and achieves thrombolysis independent It degrades fibrin directly and achieves thrombolysis independent
of plasmin formationof plasmin formation its thrombolytic activity appears to be localized to the site of its thrombolytic activity appears to be localized to the site of
delivery These properties should theoretically result in faster delivery These properties should theoretically result in faster recanalization and lower hemorrhagic conversion riskrecanalization and lower hemorrhagic conversion risk
Anti-fibrinolyticsAnti-fibrinolytics
to limit fibrinolytic activityto limit fibrinolytic activity -aminocaproic acid (EACA) -aminocaproic acid (EACA) competitively inhibitscompetitively inhibits plasminogen and plasminogen activators from plasminogen and plasminogen activators from
binding to fibrinbinding to fibrin
alpha2-antiplasminalpha2-antiplasmin a serine protease inhibitor that a serine protease inhibitor that neutralizes any free circulating plasminneutralizes any free circulating plasmin
Plasminogen activator inhibitor-1Plasminogen activator inhibitor-1 a serine protease a serine protease inhibitor that inhibits tissue-type plasminogen inhibitor that inhibits tissue-type plasminogen activatoractivator
Glycoprotein (GP) IIbIIIa antagonistsGlycoprotein (GP) IIbIIIa antagonists
such as ReoPro (abciximab) Integrilin such as ReoPro (abciximab) Integrilin (eptifibatide) or Aggrastat (tirofiban) in (eptifibatide) or Aggrastat (tirofiban) in ischemic stroke remains investigational ischemic stroke remains investigational Deshmukh et al38 reported 21 patients with Deshmukh et al38 reported 21 patients with large-vessel occlusion refractory to IAT with large-vessel occlusion refractory to IAT with rtPA who were treated with IV andor IA rtPA who were treated with IV andor IA abciximab eptifibatide or tirofiban abciximab eptifibatide or tirofiban
IA Mechanical Approaches in Acute Ischemic Stroke IA Mechanical Approaches in Acute Ischemic Stroke Mechanical strategies have several advantagesMechanical strategies have several advantages First they lessen and may even preclude the use of chemical First they lessen and may even preclude the use of chemical
thrombolytics in this manner very likely reducing the risk of ICHthrombolytics in this manner very likely reducing the risk of ICH Second by avoiding the use of chemical thrombolytics it is Second by avoiding the use of chemical thrombolytics it is
possible to extend the treatment window beyond the limit of 6ndash8 possible to extend the treatment window beyond the limit of 6ndash8 hours hours
Third mechanically fragmenting a clot increases the surface area Third mechanically fragmenting a clot increases the surface area accessible to fibrinolytic agents and allows inflow of fresh accessible to fibrinolytic agents and allows inflow of fresh plasminogen which in turn may increase the speed of plasminogen which in turn may increase the speed of thrombolysis thrombolysis
Finally clot-retrieval devices may provide faster recanalization Finally clot-retrieval devices may provide faster recanalization
The disadvantages of the mechanical The disadvantages of the mechanical approaches approaches technical difficulty of navigating mechanical technical difficulty of navigating mechanical
devices into the intracranial circulation excessive devices into the intracranial circulation excessive trauma to the vasculature (potentially leading to trauma to the vasculature (potentially leading to vasospasm vessel dissection perforation or vasospasm vessel dissection perforation or rupture) rupture)
fragmented thrombus causing distal embolization fragmented thrombus causing distal embolization into previously unaffected territories into previously unaffected territories
Nevertheless the advantages of mechanical stroke Nevertheless the advantages of mechanical stroke therapy appear to significantly outweigh its therapy appear to significantly outweigh its disadvantages and risksdisadvantages and risks
Contraindications to Thrombolytic Contraindications to Thrombolytic agents agents
Recent thoracic abdominal or Recent thoracic abdominal or intracranial surgeryintracranial surgery
Recent haemorrhagic CVA Head injury Recent haemorrhagic CVA Head injury or neoplasmor neoplasm
Bleeding ulcerBleeding ulcer Anticipated invasive procedures (arterial Anticipated invasive procedures (arterial
punctures biopsies)punctures biopsies) Concurrent hemostatic dysfunctionConcurrent hemostatic dysfunction
Monitoring of thrombolytic Monitoring of thrombolytic therapytherapy
Thrombin time Measures the availability of functional
fibrinogen Normal thrombin time is 10-14 sec Prolonged when fibrinogen level is below
75-100 mgdl
Half Life of ThrombolyticsHalf Life of ThrombolyticsAgent Administration Half Life
Streptokinase IA 60-80min
Urokinase IAIV 9-12min
rTPA IAIV 6min
Abciximab(Reopro) IAIV 12hour
Aspirin POIV 15-20min
Heparin IVSC 60min
Coumadin PO 15-25 days
Anti Platelet DrugsAnti Platelet DrugsDrug Drug Mechanism Mechanism UsesUsesAspirinAspirin Permanently inhibits Permanently inhibits
COX-1 and COX-2COX-1 and COX-2CADCAD
Stroke-TIAsStroke-TIAs
NSAIDsNSAIDs Reversibly inhibits Reversibly inhibits COX-1COX-1
LimitedLimited
DipyridamoleDipyridamole Inhibits PDE increases Inhibits PDE increases cAMPcAMP
TIAsTIAs
ThenopyridinesThenopyridines
(Ticlopidine(Ticlopidine
ClopidrgrelClopidrgrel))
Inhibits ADP Inhibits ADP
PlatAg PlatAg
TIAsStrokeTIAsStroke
CAD PVDCAD PVD
Abciximab (ReoPro)Abciximab (ReoPro)
Eptifibatide (Integrilin)Eptifibatide (Integrilin)
TirofibanTirofiban
GP IIBIIIA InhibitorsGP IIBIIIA Inhibitors
Stroke- TIAs Stroke- TIAs
MonitoringMonitoring
Bleeding timeBleeding time
Optical aggregometryOptical aggregometry
Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay
Bleeding timeBleeding time
Requires a skin incision (usually made on the ear lobe or Requires a skin incision (usually made on the ear lobe or forearm offorearm of
a depth that results in disruption of capillary loops and a depth that results in disruption of capillary loops and small vessels)small vessels)
AdvantagesAdvantages Universally availableUniversally available Relatively simple techniquesRelatively simple techniques Can be performed bedsideCan be performed bedside
DisadvantagesDisadvantages Insensitive inaccurate non-specific techniqueInsensitive inaccurate non-specific technique
Poorly reproducible (as depends on multiple variables)Poorly reproducible (as depends on multiple variables)
Optical aggregometryOptical aggregometry
Gold standard assay for platelet functionGold standard assay for platelet function Agonist induced aggregation is measuredAgonist induced aggregation is measured Different agonist are available for different Different agonist are available for different
agentsagents However require unique expertise and are not However require unique expertise and are not
universally availableuniversally available Aspirin measured with ADP or AA(gt70 Aspirin measured with ADP or AA(gt70
aggregation so resistance)aggregation so resistance) Clopidogrel( ADP gt 90 aggregation means Clopidogrel( ADP gt 90 aggregation means
resistance) resistance)
Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay
Can be performed bed sideCan be performed bed side Different assay devices with different Different assay devices with different
agonist are used for each of different agonist are used for each of different antiplatelet agents antiplatelet agents
For Aspirin AA is used (result is reported as aspirin For Aspirin AA is used (result is reported as aspirin reaction units [ARU] ARUgt 550 indicates non-reaction units [ARU] ARUgt 550 indicates non-responsiveness)responsiveness)
Verify IIbIIIa assay device uses TRAP as agonist for Verify IIbIIIa assay device uses TRAP as agonist for Abciximab and TirofibanAbciximab and Tirofiban
Practical Applications Practical Applications related to specific related to specific
Neurovascular Neurovascular interventionsinterventions
Acute ischemic StrokeAcute ischemic Stroke When an artery occludes neurons are affected When an artery occludes neurons are affected
differently depending upon the amount of residual blood differently depending upon the amount of residual blood flowflow
Normal cerebral blood flow is greater than 50 mL100 Normal cerebral blood flow is greater than 50 mL100 mgminmgmin
Once blood flow decreases to less than 20 mL100 Once blood flow decreases to less than 20 mL100 mgmin infarction occursmgmin infarction occurs
If blood flow decreases to less than 10 mL100 mgmin If blood flow decreases to less than 10 mL100 mgmin irreversible neuronal death occurs rapidly irreversible neuronal death occurs rapidly
Blood flow between 11 and 20 mL100 mgmin is thought Blood flow between 11 and 20 mL100 mgmin is thought to represent the ischemic penumbra an area where the to represent the ischemic penumbra an area where the cells are functionally silent because of ischemia but are cells are functionally silent because of ischemia but are still able to recover if blood flow is restored still able to recover if blood flow is restored
Many acute stroke therapies are targeted toward Many acute stroke therapies are targeted toward restoring flow or function to the ischemic penumbrarestoring flow or function to the ischemic penumbra
Therapeutic window in Therapeutic window in management of acute Ischemic management of acute Ischemic
StrokeStrokeThe early diagnosis of ischemic stroke is critical to the The early diagnosis of ischemic stroke is critical to the
with only a narrow therapeutic window in the first few with only a narrow therapeutic window in the first few hours following stroke ictushours following stroke ictus
Diagnosis in the first 3 hours postictus provides the Diagnosis in the first 3 hours postictus provides the opportunity for intravenous or intraarterial thrombolysis opportunity for intravenous or intraarterial thrombolysis and intra-arterial clot mechanical treatment which and intra-arterial clot mechanical treatment which improve the outcome improve the outcome
Diagnosis in the time period between 3 and 6 hours Diagnosis in the time period between 3 and 6 hours provides an opportunity for intra-arterial thrombolysis provides an opportunity for intra-arterial thrombolysis and mechanical treatment and mechanical treatment
Involvement of the posterior circulation especially the Involvement of the posterior circulation especially the basilar artery is treated by some regardless of time of basilar artery is treated by some regardless of time of onset or up until 12 to 24 hours in some practices This is onset or up until 12 to 24 hours in some practices This is related to the potentially high mortality and morbidity related to the potentially high mortality and morbidity associated with basilar artery thrombosisassociated with basilar artery thrombosis
Infarct evaluation on angiographyInfarct evaluation on angiography(CT angiography and catheter (CT angiography and catheter
angiography)angiography)CTA is an excellent first-line examination for CTA is an excellent first-line examination for
evaluation of the head and neck arteries evaluation of the head and neck arteries In comparison with catheter angiography In comparison with catheter angiography
what it gives up in resolution and dynamic what it gives up in resolution and dynamic properties it makes up for with rapid properties it makes up for with rapid acquisition of a 3-D dataset and the potential acquisition of a 3-D dataset and the potential for assessment of whole-brain perfusion and for assessment of whole-brain perfusion and better parenchymal evaluationbetter parenchymal evaluation
Moreover CTA illustrates not only arterial Moreover CTA illustrates not only arterial stenosis or occlusion but also the vessel wall stenosis or occlusion but also the vessel wall This factor is most important for evaluation of This factor is most important for evaluation of intramural dissection and thrombosed intramural dissection and thrombosed aneurysms which may both complicate aneurysms which may both complicate evaluation of stroke patientsevaluation of stroke patients
Early angiographic signs of strokes Early angiographic signs of strokes both CTA both CTA and DSA and DSA
Vessel occlusion or cutoff related to Vessel occlusion or cutoff related to thromboembolithromboemboli
aneurysms aneurysms arterial dissection arterial dissection Meniscus or flattened shape to clot Meniscus or flattened shape to clot
(recent) versus reverse meniscus (older)(recent) versus reverse meniscus (older) tram track (nonocclusive or recanalized tram track (nonocclusive or recanalized
clot) clot) delayed (antegrade) flow (manifest as delayed (antegrade) flow (manifest as
decreased whole-brain perfusion on CTA)decreased whole-brain perfusion on CTA) retrograde collateral flowretrograde collateral flow
Non-occlusive left MCA thrombus on 3-D imaging performed from CTA source data and was confirmed at catheter angiography
Therapy to be started within a 6-hr Therapy to be started within a 6-hr time to treatment (TTT) window time to treatment (TTT) window (while in case of IV thrombolysis (while in case of IV thrombolysis therapy to be started with in 3hrs)therapy to be started with in 3hrs)
Exclusion criteria Exclusion criteria Rapidly improving neurologic deficit or Rapidly improving neurologic deficit or Sustained blood pressure of gt180100 Sustained blood pressure of gt180100 Hemorrhage is detected on CTHemorrhage is detected on CT Infarct involving gt more than 13 rd Infarct involving gt more than 13 rd
territory of MCAterritory of MCA MRADWI-Perfusion mismatchlt 20MRADWI-Perfusion mismatchlt 20 Definite hypodensity on CTDefinite hypodensity on CT
Intra-arterial Thrombolysis
Fibrinolytics + AntiplateletsFibrinolytics + Antiplatelets
PlasminogenPlasminogen activators through fibrinolysis exposes activators through fibrinolysis exposes free thrombin and paradoxically stimulatesfree thrombin and paradoxically stimulates platelet platelet aggregation which leads to formation of aaggregation which leads to formation of a platelet platelet thrombus (white clot) thrombus (white clot)
This new thrombus is relatively resistant to This new thrombus is relatively resistant to fibrinolyticsfibrinolytics
So new regimen in case of acute stroke isSo new regimen in case of acute stroke is fibrinolytics + antiplatelet drugsfibrinolytics + antiplatelet drugs
rtPA + IIbIIIa inhibitors( tirofiban rtPA + IIbIIIa inhibitors( tirofiban abciximab) orabciximab) or
Urokinase + IIbIIIa Urokinase + IIbIIIa inhibitors( tirofiban abciximab)inhibitors( tirofiban abciximab)
Intra-arterial Thrombolysis Tirofiban (04 microgkgmin bolus for 3 min followed by Tirofiban (04 microgkgmin bolus for 3 min followed by
0125 ugkgmin)0125 ugkgmin)
++
Heparin (2000ndash3000 IU bolus followed by Heparin (2000ndash3000 IU bolus followed by 1000 IUhour infusion 1000 IUhour infusion
with ACT maintained bw 200-300) throughout the with ACT maintained bw 200-300) throughout the interventional procedure and for 24ndash48 hours thereafter when interventional procedure and for 24ndash48 hours thereafter when there is neither intraprocedural bleeding nor suspicion of there is neither intraprocedural bleeding nor suspicion of increased risk of bleeding increased risk of bleeding
Maximum dose of Urokinase Maximum dose of Urokinase Anterior circulation stroke - 500000 IU (mean 400000 Anterior circulation stroke - 500000 IU (mean 400000
IU range 300000ndash500000 IU)IU range 300000ndash500000 IU) Posterior circulation stroke -1000000 IU (mean 837000 Posterior circulation stroke -1000000 IU (mean 837000
IU range 300000ndash1000000 IU)IU range 300000ndash1000000 IU)American Journal of NeuroradiologyAmerican Journal of Neuroradiology 262595-2601 2005262595-2601 2005
Intravenous ThrombolysisIntravenous Thrombolysis
The first method to restore cerebral The first method to restore cerebral perfusion is clot lysis with the goal perfusion is clot lysis with the goal of re-establishing blood flow to the of re-establishing blood flow to the affected tissue affected tissue
IV thrombolysis rt-PA is the only IV thrombolysis rt-PA is the only FDA- approved treatment for AIS FDA- approved treatment for AIS
Fibrinolysis is enhanced powerfully Fibrinolysis is enhanced powerfully by rt-PAby rt-PA
Intravenous rTPA Intravenous rTPA administration administration protocolprotocol
Total dose of rt-PA 09 mgkg (maximum dose Total dose of rt-PA 09 mgkg (maximum dose 90 mg)90 mg)
Give 10 as initial IV bolusGive 10 as initial IV bolus Infuse remainder over 1 hourInfuse remainder over 1 hour Admit patient to an ICU or stroke unit for Admit patient to an ICU or stroke unit for
monitoringmonitoring Neurologic assessments every 15 minutes Neurologic assessments every 15 minutes
during infusion then every 30 minutes for next during infusion then every 30 minutes for next 6 hours then every hour until 24hours after 6 hours then every hour until 24hours after treatmenttreatment
Favorable Outcome vs Treatment Time Favorable Outcome vs Treatment Time with IV rTPAwith IV rTPA
Protocol limit = 3 hrs
Benefit ~ 45 hrs
Thromboembolism During coilingThromboembolism During coiling Most feared and frequent complication Most feared and frequent complication Reported incidence - Approx 7 Reported incidence - Approx 7 SourcesSources of Thromboembolism are of Thromboembolism are
- Clots at the aneurysmal neck during or immediately- Clots at the aneurysmal neck during or immediately after after embolization embolization
- Thrombus forming on catheters during- Thrombus forming on catheters during proceduresprocedures
- Stenosis of an adjacent artery dt coil mass- Stenosis of an adjacent artery dt coil mass or herniationor herniation
- Migration of intraaneurysmal- Migration of intraaneurysmal thrombus during coil thrombus during coil placement placement
- Slow flow dt vasospasm - Slow flow dt vasospasm
- Rare and unlikely causes are hypercoagulable- Rare and unlikely causes are hypercoagulable state such state such as antiphospholipid antibody syndrome or due to HITas antiphospholipid antibody syndrome or due to HIT
Occur more often with wide-necked aneurysms (dt Occur more often with wide-necked aneurysms (dt increased exposed surface area of thrombogenic coil increased exposed surface area of thrombogenic coil material)material)
Current regimen of endovascular Current regimen of endovascular managementmanagement
The The glycoprotein IIbIIIa antagonist tirofiban glycoprotein IIbIIIa antagonist tirofiban (04 (04 microgkgmin bolus for 30 minutes followed by infusion of microgkgmin bolus for 30 minutes followed by infusion of 0125 ugkgmin until the thrombus dissolved) 0125 ugkgmin until the thrombus dissolved)
Intraarterial thrombolysis with Intraarterial thrombolysis with urokinase or r- TPA urokinase or r- TPA increase of intravenous (IV) heparin (measured by increase of intravenous (IV) heparin (measured by
ACT) ACT) Intravenous aspirin Intravenous aspirin
Coil-related platelet aggregation (white clot) is Coil-related platelet aggregation (white clot) is unlikely to respond to fibrinolytics but has a high risk unlikely to respond to fibrinolytics but has a high risk of hemorrhage (In ISAT) all 5 patients who had of hemorrhage (In ISAT) all 5 patients who had received thrombolytic therapy with tPA to treat a received thrombolytic therapy with tPA to treat a thromboembolic complication after endovascular thromboembolic complication after endovascular treatment rebleed and all of these patients died)treatment rebleed and all of these patients died)
IntracranialIntracranial Stenting Stenting Metallic foreign body such as stent will accumulate Metallic foreign body such as stent will accumulate
thrombus in the absence of platelet inhibitionthrombus in the absence of platelet inhibition Antiplatelet drugs are important to prevent peri or Antiplatelet drugs are important to prevent peri or
post-interventional thromboembolic eventspost-interventional thromboembolic events Optimal treatment regimens has not been determined Optimal treatment regimens has not been determined
but usually but usually Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-
procedureprocedureOrOr
Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on
morning of proceduremorning of procedure
If need to use stent is not pre-planned thanIf need to use stent is not pre-planned than
Abciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkgAbciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkg IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)
Glycoprotein IIbIIIa inhibitor are not used routinely during elective Glycoprotein IIbIIIa inhibitor are not used routinely during elective stenting procedure dt increased risk of ICH stenting procedure dt increased risk of ICH
Carotid StentingCarotid Stenting
Pre-procedurePre-procedure
Double Antiplatelet therapy is routinely given Double Antiplatelet therapy is routinely given beginning at least 3beginning at least 3
days before the proceduredays before the procedure
Aspirin 325mgd+Clopidogrel 75mgdAspirin 325mgd+Clopidogrel 75mgd During procedureDuring procedure
Heparin is given with target clotting time of 250-Heparin is given with target clotting time of 250-300sec300sec
Post-procedure Post-procedure
Aspirin 325mg is continued indefinitely and Aspirin 325mg is continued indefinitely and
Clopidogrel 75mgd for at least 6 weeks Clopidogrel 75mgd for at least 6 weeks
Inclusion criteria for Local ThrombolysisInclusion criteria for Local Thrombolysis a)a) Patients in severe clinical grade on admission Patients in severe clinical grade on admission
with evidence of dural venous sinus with evidence of dural venous sinus thrombosis and restrictive venous outflow on thrombosis and restrictive venous outflow on cerebral angiogramcerebral angiogram
b)b) Patients in clinical grade 3 worsening on Patients in clinical grade 3 worsening on heparin therapy Restriction to venous heparin therapy Restriction to venous outflow was defined as an increase in brain outflow was defined as an increase in brain circulation time gt 12 s delay in the drainage circulation time gt 12 s delay in the drainage of cortical veins with cortical veins hanging of cortical veins with cortical veins hanging in spacein space
Treatment Options for Venous Thrombosis
CT Grading for Venous ThrombosisCT Grading for Venous Thrombosis Grade I no parenchymal change Grade I no parenchymal change
(hyperdense (hyperdense sinuses cortical veins empty sinuses cortical veins empty delta sign)delta sign)
Grade II non hemorrhagic venous infarct Grade II non hemorrhagic venous infarct without mass effect without mass effect
Grade III non-hemorrhagic infarct with Grade III non-hemorrhagic infarct with mass effectmass effect
Grade IV hemorrhagic venous infarct (max Grade IV hemorrhagic venous infarct (max diameter lt 3 cm) with no mass effectdiameter lt 3 cm) with no mass effect
Grade V hemorrhagic venous infarct (max Grade V hemorrhagic venous infarct (max diameter gt 3 cm) with mass effect diameter gt 3 cm) with mass effect
Local ThrombolysisLocal Thrombolysis
Femoral Jugular access was secured and a guiding Femoral Jugular access was secured and a guiding catheter was placed in the jugular bulb catheter was placed in the jugular bulb Mechanical Mechanical clot maceration clot maceration was done with the guidewire was done with the guidewire following which a microcatheter (was navigated and following which a microcatheter (was navigated and placed in the thrombosed segment of sinus confirmed placed in the thrombosed segment of sinus confirmed on a selective venogram on a selective venogram
Urokinase infusion Bolus dose of 2-6 lacs followed Urokinase infusion Bolus dose of 2-6 lacs followed by 60000 to 100000 units per hour along with by 60000 to 100000 units per hour along with periodic check venogram Along with maintenance periodic check venogram Along with maintenance systemic infusion of Heparinsystemic infusion of Heparin Other agents such as Other agents such as streptokinase altepase or rTPAstreptokinase altepase or rTPA can be also used can be also used
After thrombolysis patient should subjected to oral After thrombolysis patient should subjected to oral anticoagulation for six monthsanticoagulation for six months
Low-molecular-weight Low-molecular-weight heparinheparin
PharmacologyPharmacologyLMWH as its name suggests is a glycosaminoglycan that is approximatelyLMWH as its name suggests is a glycosaminoglycan that is approximately
one third the molecular weight of UFH It is derived from UFH through one third the molecular weight of UFH It is derived from UFH through variousvarious
depolymerization processes LMWH binds to antithrombin which in turn depolymerization processes LMWH binds to antithrombin which in turn
Neutralizes actors Xa and IIa Because LMWH lacks many of the longer Neutralizes actors Xa and IIa Because LMWH lacks many of the longer chains chains
required for binding to thrombin it has less ability to neutralize thrombin required for binding to thrombin it has less ability to neutralize thrombin
relativeto its ability to neutralize factor Xa LMWH also has less relativeto its ability to neutralize factor Xa LMWH also has less nonspecific nonspecific
binding to other proteins There is greater bioavailability with more binding to other proteins There is greater bioavailability with more predictable predictable
pharmacokinetics that eliminates the need for monitoring The smaller pharmacokinetics that eliminates the need for monitoring The smaller size also size also
allows for enhanced subcutaneous absorption when compared with UFHallows for enhanced subcutaneous absorption when compared with UFH
Three LMWH preparations are Three LMWH preparations are currently approved for use in the currently approved for use in the United States (1) enoxaparin (2) United States (1) enoxaparin (2) dalteparin and (3) tinzaparin dalteparin and (3) tinzaparin
They are all administered They are all administered subcutaneously at intervals of either subcutaneously at intervals of either once or twice daily for both once or twice daily for both prophylaxis and treatment dosesprophylaxis and treatment doses
Few Experiences of Few Experiences of ThrombolysisThrombolysis
Vickey 25 Yrs male patient presented Vickey 25 Yrs male patient presented with 12with 12thth day HO severe headache with day HO severe headache with right sided hemiplegiaright sided hemiplegia
MRI shows thrombosis of the superior MRI shows thrombosis of the superior sagittal left transverse left sigmoid sagittal left transverse left sigmoid sinuses and cortical veins in the fronto-sinuses and cortical veins in the fronto-parietal regions with eo haemorrhagic parietal regions with eo haemorrhagic infarct in the left cerebral hemisphere infarct in the left cerebral hemisphere with mass effect( Grade ndashV)with mass effect( Grade ndashV)
Sashi Srivastava 64 yrs FSashi Srivastava 64 yrs F In a follow up case of MRD with infra-renal In a follow up case of MRD with infra-renal
aortic abdominal and bilateral renal artery aortic abdominal and bilateral renal artery thrombosis renal angiogram shows filling thrombosis renal angiogram shows filling defects in the right Renal artery defects in the right Renal artery
Initially Renal angioplasty was done Initially Renal angioplasty was done Following angioplasty few thrombi are seem Following angioplasty few thrombi are seem to extends into the segmental branches and to extends into the segmental branches and causing blockage So Thrombolysis was causing blockage So Thrombolysis was plane to dissolve the run-out thrombi with plane to dissolve the run-out thrombi with urokinase urokinase
Rakesh 34yrsMRakesh 34yrsM Left SFA pseudoaneurysm with Left SFA pseudoaneurysm with
Covered stent placementCovered stent placement Pre operative antiplatelets with post Pre operative antiplatelets with post
procedure heparin Tirofiban procedure heparin Tirofiban followed by aspirin and clopidogrel followed by aspirin and clopidogrel were usedwere used
IAT may be a treatment option for selected patients IAT may be a treatment option for selected patients Possible selection criteria include Possible selection criteria include
presentation between 3 and 6 hours from symptom onsetpresentation between 3 and 6 hours from symptom onset major cerebral artery occlusion major cerebral artery occlusion severe neurologic deficits severe neurologic deficits high risk of systemic hemorrhage with IV rt-PA (eg recent high risk of systemic hemorrhage with IV rt-PA (eg recent
surgery) surgery) The MERCI (Mechanical Embolus Removal in Cerebral The MERCI (Mechanical Embolus Removal in Cerebral
Ischemia) retrievalIschemia) retrieval system system
Has been FDA-approved for recanalizing acutely occluded Has been FDA-approved for recanalizing acutely occluded cerebral arteries cerebral arteries
In the Multi-MERCI study patients who did not improve In the Multi-MERCI study patients who did not improve immediately after IV rt-PA underwent mechanical immediately after IV rt-PA underwent mechanical embolectomy within 8 hours of symptom onset embolectomy within 8 hours of symptom onset
Partial or complete recanalization occurred in 74 of Partial or complete recanalization occurred in 74 of patientspatients
with a symptomatic intracerebral hemorrhage (sICH) rate of with a symptomatic intracerebral hemorrhage (sICH) rate of 67 67
Mechanical embolectomy with the MERCI retriever may be a Mechanical embolectomy with the MERCI retriever may be a feasible and safe option for patients after IV rt-PAfeasible and safe option for patients after IV rt-PA
Penumbra stroke systemPenumbra stroke system This device combines two methods of clot This device combines two methods of clot
extraction aspiration and mechanical extraction aspiration and mechanical extraction extraction
First the clot is aspirated then a thrombus First the clot is aspirated then a thrombus removal ring can be used if necessary to removal ring can be used if necessary to remove remaining clot remove remaining clot
successful recanalizing 82successful recanalizing 82 Bridging therapyBridging therapy
06 mgkg IV rt-PA followed by IAT with IA rt-06 mgkg IV rt-PA followed by IAT with IA rt-PA (up to 20 mg)PA (up to 20 mg)
achieved a higher recanalization rateachieved a higher recanalization rate
Criteria for thrombolysis with rTPACriteria for thrombolysis with rTPA
Inclusion criteriaInclusion criteria Clinical signs and symptoms consistent with ischemic Clinical signs and symptoms consistent with ischemic
strokestroke Patient last seen normal within 3 hoursPatient last seen normal within 3 hours Measurable neurologic deficitMeasurable neurologic deficit
Exclusion criteriaExclusion criteria Any hemorrhage on neuroimaging (CT or MRI)Any hemorrhage on neuroimaging (CT or MRI) Symptoms suggestive of subarachnoid hemorrhageSymptoms suggestive of subarachnoid hemorrhage Seizure at stroke onset that is thought to contribute to Seizure at stroke onset that is thought to contribute to
neurologic deficitneurologic deficit Hypodensity greater than one third cerebral hemisphere Hypodensity greater than one third cerebral hemisphere
on CTon CT SBP greater than 185 mm Hg or DBP greater than 110 SBP greater than 185 mm Hg or DBP greater than 110
mm Hgmm Hg International normalized ratio (INR) greater than 17International normalized ratio (INR) greater than 17
Ischemic Stroke Ischemic Stroke Treatment ndash 2006Treatment ndash 2006
IV tissue plasminogen activator (tPA)IV tissue plasminogen activator (tPA) ndash ndash Only FDA-approved acute stroke drugOnly FDA-approved acute stroke drug ndash ndash 3 hour treatment window3 hour treatment window
MERCI - Concentric clot retrieval MERCI - Concentric clot retrieval devicedevice ndash ndash Rescue therapy - approved 2004Rescue therapy - approved 2004 ndash ndash Device approval (not outcomes-based)Device approval (not outcomes-based)
Off label approachesOff label approaches ndash ndash IV tPA after 3 hoursIV tPA after 3 hours ndash ndash IV-IA tPA sequential strategiesIV-IA tPA sequential strategies ndash ndash IA tPA clot angioplasty fragmentationIA tPA clot angioplasty fragmentation ndash ndash Ultrasound-assisted tPA lysisUltrasound-assisted tPA lysis
rt-PA Trials NINDSrt-PA Trials NINDS
Acute stroke - 624 patientsAcute stroke - 624 patients Treat within 3 hrsTreat within 3 hrs Intravenous 09 mgkg rt-PA vs placeboIntravenous 09 mgkg rt-PA vs placebo Hemorrhage 64 tPA 06 placeboHemorrhage 64 tPA 06 placebo Neurologic recovery better with tPA 30 Neurologic recovery better with tPA 30
more like to have minimal or no disabilitymore like to have minimal or no disability
First proven approved treatment for First proven approved treatment for strokestroke
Limitations of tPALimitations of tPA Only 4 of acute strokes receive tPAOnly 4 of acute strokes receive tPA (Kleindorfer et al Stroke 2004 35 e27-e29)(Kleindorfer et al Stroke 2004 35 e27-e29)
Only 22 of patients present within 3 hoursOnly 22 of patients present within 3 hours1048707 1048707 51 of these ineligible due to51 of these ineligible due to
bull bull Mild severityMild severity bull bull Medical or surgical historyMedical or surgical history bull bull Blood testsBlood tests
Sustained recanalization only 13Sustained recanalization only 13 (Alexandrov et al NEJM 2004 351 2170-8)(Alexandrov et al NEJM 2004 351 2170-8)
Concern for hemorrhageConcern for hemorrhage tPA potentiates apoptotic injury tPA potentiates apoptotic injury (Liu et al Nature Med 2004 101379-83)(Liu et al Nature Med 2004 101379-83)
PROACT II IA Lysis TrialPROACT II IA Lysis Trial Baseline 24 hours 8 days
Baseline 60 minutes 120 minutes
9mg IAProurokinase
Desmoteplase Trials DEDAS Desmoteplase Trials DEDAS DIASDIAS
Trial OverviewTrial Overview Double blind randomized placebo Double blind randomized placebo
controlled trialscontrolled trials IV delivery 3-9 hour time windowIV delivery 3-9 hour time window Plasminogen activator ndash from Plasminogen activator ndash from vampire bat vampire bat
salivasaliva Selection based on PWI-DWI MismatchSelection based on PWI-DWI Mismatch
MRI InclusionMRI Inclusion PWI defect at least 2 cm AND ~20 larger PWI defect at least 2 cm AND ~20 larger
than DWIthan DWI PWI should be obvious even visible on PWI should be obvious even visible on
raw imagesraw imagesMRI ExclusionMRI Exclusion
DWI gt 13 MCADWI gt 13 MCA MRA ICA occlusionMRA ICA occlusion
Desmoteplase ndash DIAS Desmoteplase ndash DIAS ResultsResults
Mechanical Thrombolysis Mechanical Thrombolysis devicesdevices
mechanical thrombolysis potentially extends the treatment mechanical thrombolysis potentially extends the treatment window because they act promptly at the site of the thrombuswindow because they act promptly at the site of the thrombus
The devices can retrieve large clots that pharmaceutical agents The devices can retrieve large clots that pharmaceutical agents may not successfully lysemay not successfully lyse
Patients treated with IV tPA may be considered for treatment of Patients treated with IV tPA may be considered for treatment of residual clot with some of these devicesresidual clot with some of these devices
suction-creating saline jets suction-creating saline jets laser energy ultrasound laser energy ultrasound a corkscrew apparatus to treat strokesa corkscrew apparatus to treat strokes The AngioJet systemThe AngioJet system uses saline jets that are directed back into the catheter to uses saline jets that are directed back into the catheter to
create a low-pressure zone around the catheter tip inducing create a low-pressure zone around the catheter tip inducing suction suction
The clot is pulled into the exhaust lumen and removed from the The clot is pulled into the exhaust lumen and removed from the vessel Although US Food and Drug Administration (FDA) has vessel Although US Food and Drug Administration (FDA) has approved this device for use in arteriovenous dialysis grafts and approved this device for use in arteriovenous dialysis grafts and fistulae and for the treatment of coronary arteries saphenous fistulae and for the treatment of coronary arteries saphenous vein grafts and peripheral vessels clinical trials for the vein grafts and peripheral vessels clinical trials for the treatment of acute stroke are no longer in progress treatment of acute stroke are no longer in progress
Most devices are used in cerebral vessels that 2-5 mm
The Latis laser device The Latis laser device used laser energy to ablate clots used laser energy to ablate clots Arteries 2-5 mm in diameter could be Arteries 2-5 mm in diameter could be
treated including the ICA M1 or M2 treated including the ICA M1 or M2 branch of the MCA A1 branch of the branch of the MCA A1 branch of the anterior cerebral artery (ACA) basilar anterior cerebral artery (ACA) basilar artery posterior cerebral artery (PCA) artery posterior cerebral artery (PCA) and vertebral and vertebral
Patients could receive treatment as late Patients could receive treatment as late as 8 hours after symptom onset in the as 8 hours after symptom onset in the anterior circulation and within 24 hours in anterior circulation and within 24 hours in the posterior circulation the posterior circulation
Endovascular Photo Acoustic Endovascular Photo Acoustic Recanalization (EPAR) Recanalization (EPAR)
A laser power source generated energy for the A laser power source generated energy for the systemsystem
The energy was delivered by means of The energy was delivered by means of fiberoptics to the tip of the catheter at the fiberoptics to the tip of the catheter at the treatment sitetreatment site
Absorption of laser light by darkly pigmented Absorption of laser light by darkly pigmented materials (ie the clot) occurred inside the 1-mm materials (ie the clot) occurred inside the 1-mm catheter tipcatheter tip
the system was designed to minimize scattering the system was designed to minimize scattering of laser light of laser light
Absorption converted photo energy to acoustic Absorption converted photo energy to acoustic energy which then emulsified the clot inside the energy which then emulsified the clot inside the catheter tip catheter tip
EKOS ultrasound( the EKOS ultrasound( the Ultrasound Thrombolytic Ultrasound Thrombolytic
Infusion Catheter) Infusion Catheter) combines the use of a distal ultrasound transducer with combines the use of a distal ultrasound transducer with
infusion of a thrombolytic agent through the infusion of a thrombolytic agent through the microcathetermicrocatheter
Ultrasound changes the structure of the clot to Ultrasound changes the structure of the clot to temporarily increase its permeability while providing an temporarily increase its permeability while providing an acoustic pressure gradient to move the drug into the clot acoustic pressure gradient to move the drug into the clot to speed its dissolution to speed its dissolution
The EKOS catheter is placed in the proximal portion of the The EKOS catheter is placed in the proximal portion of the clot clot
After a 2-mg bolus of tPA was injected through the After a 2-mg bolus of tPA was injected through the catheter catheter
the patient received a continuous infusion of IA tPA 03 the patient received a continuous infusion of IA tPA 03 mgmin to a maximum of 20 mg and simultaneous mgmin to a maximum of 20 mg and simultaneous ultrasound transmission for as long as 60 minutes ultrasound transmission for as long as 60 minutes
One patient was treated with a total of 4 units of One patient was treated with a total of 4 units of recombinant reteplase (Retavase) hand-injected over 60 recombinant reteplase (Retavase) hand-injected over 60 minutes minutes
Penumbra system Penumbra system The Penumbra system (Penumbra Inc) provides a dual The Penumbra system (Penumbra Inc) provides a dual
approach to clot extraction using aspiration followed by approach to clot extraction using aspiration followed by clot retrieval with a ring device if needed clot retrieval with a ring device if needed
Mechanical Embolus Removal in Cerebral Ischemia Mechanical Embolus Removal in Cerebral Ischemia (MERCI)(MERCI)
a corkscrew-like apparatus to remove blood clots from a corkscrew-like apparatus to remove blood clots from the brain in patients experiencing an ischemic stroke the brain in patients experiencing an ischemic stroke
The corkscrew itself resides in the catheter tip which The corkscrew itself resides in the catheter tip which shields it from the wall of the vessel until it is ready to be shields it from the wall of the vessel until it is ready to be burrowed into the clot Once lodged in the clot the device burrowed into the clot Once lodged in the clot the device and clot are withdrawn from the vessel and clot are withdrawn from the vessel
Snarelike devicesSnarelike devices Snares such as the Neuronet snare (Guidant Snares such as the Neuronet snare (Guidant
Endovascular Santa Clara CA) have been developed Endovascular Santa Clara CA) have been developed specifically for use in the treatment of strokes specifically for use in the treatment of strokes
These devices are simple in design and do not require the These devices are simple in design and do not require the clot to be amenable to emulsification clot to be amenable to emulsification
X-Sizer deviceX-Sizer device a device with small moving blades at the a device with small moving blades at the
catheter tip catheter tip This device the X-Sizer device (EndiCor Medical This device the X-Sizer device (EndiCor Medical
San Clemente CA) can be used to excise the San Clemente CA) can be used to excise the thrombus and aspirate it thrombus and aspirate it
The device was being evaluated in randomized The device was being evaluated in randomized studies of coronary vessels and in a registry of studies of coronary vessels and in a registry of patients with acute myocardial infarctionpatients with acute myocardial infarction
Although the manufacturer had modified the Although the manufacturer had modified the device for use in cerebral vessels a safety and device for use in cerebral vessels a safety and feasibility study was indefinitely suspended after feasibility study was indefinitely suspended after only 1 patient was treated with the device in only 1 patient was treated with the device in Europe Europe
Suction thrombectomySuction thrombectomy This method of mechanical thrombolysis is one of the This method of mechanical thrombolysis is one of the
simplestsimplest In this readily available technique suction is applied with In this readily available technique suction is applied with
a syringe to remove thrombus in the ICA a syringe to remove thrombus in the ICA It requires no other devicesIt requires no other devices A catheter with a large inner diameter (Brite Tip Cordis A catheter with a large inner diameter (Brite Tip Cordis
Corporation Miami FL) was placed in the symptomatic Corporation Miami FL) was placed in the symptomatic vessel and navigated over a guidewire into the thrombusvessel and navigated over a guidewire into the thrombus
A 60-mL syringe was used to aspirate the thrombus A 60-mL syringe was used to aspirate the thrombus Each patient required angioplasty and stenting of carotid Each patient required angioplasty and stenting of carotid
bifurcation stenosis and received daily aspirin and bifurcation stenosis and received daily aspirin and ticlopidine after the procedure No complications ticlopidine after the procedure No complications occurred occurred
Summary Acute Stroke Summary Acute Stroke ImagingImaging
PhysiologyPhysiology importance collaterals importance collaterals
ndash ndashGrowing role for perfusion Growing role for perfusion assessmentassessment
tPAtPA guidelines amp limitations guidelines amp limitations Signs on CT amp MRSigns on CT amp MR follow physiology follow physiology Stroke trialsStroke trials PWI-DWI mismatch PWI-DWI mismatch
ndash ndashTreat based on physiology not timeTreat based on physiology not time ProtocolsProtocols should be fast and should be fast and
comprehensivecomprehensive
PROBLEMS WITH PTPTRPROBLEMS WITH PTPTR
Thromboplastins are extracts from Thromboplastins are extracts from brain lung or placenta of animalsbrain lung or placenta of animals
Thromboplastins from various Thromboplastins from various manufacturers differ in their manufacturers differ in their sensitivity to prolong PTsensitivity to prolong PT
May result in false control of May result in false control of anticoagulant therapyanticoagulant therapy
INTERNATIONAL NORMALISED RATIO (INR)INTERNATIONAL NORMALISED RATIO (INR)
International Normalized Ratio (INR) International Normalized Ratio (INR) a PT test with a a PT test with a formula based ratio to normalize the often variable source formula based ratio to normalize the often variable source of tissue factor (human rabbit recombinant)of tissue factor (human rabbit recombinant)
INR = [PTINR = [PTptpt] ] ISIISI
[PT[PTRefRef]]
PTPTpt pt ndash prothrombin time of patientndash prothrombin time of patient
PTPTRef Ref ndash prothrombin time of normal pooled samplendash prothrombin time of normal pooled sample
ISI ndash International Sensitivity IndexISI ndash International Sensitivity Index
Warfarin is given orally and titrated to achieve an INR of Warfarin is given orally and titrated to achieve an INR of typically 20 ndash 30typically 20 ndash 30
Heparin versus WarfarinHeparin versus Warfarin
Drug ActionMechan-ism
Moni-toring
Effective
HeparinDirect
Inhibition ofThrombin
ATIIIcofactor
APTTACT
Immediate
WarfarinDecreasesProductionof factors
Vitamin K PTDelay
3-5 days
INR
Recanalization or Antegrade Recanalization or Antegrade Reperfusion StrategiesReperfusion Strategies
Recanalization strategies focus on removing Recanalization strategies focus on removing andor dissolving the occlusive thrombus to re-andor dissolving the occlusive thrombus to re-establish antegrade flow Strategies may be establish antegrade flow Strategies may be classified into 7 different categories on the classified into 7 different categories on the basis of their primary mechanism of action basis of their primary mechanism of action 1) 1) IV andor intraarterial thrombolysis (IAT) IV andor intraarterial thrombolysis (IAT) 2) endovascular thrombectomy2) endovascular thrombectomy3) endovascular thromboaspiration 3) endovascular thromboaspiration 4) endovascular mechanical thrombus disruption or 4) endovascular mechanical thrombus disruption or
thromborrhexisthromborrhexis5) 5) transcranial or endovascular augmented transcranial or endovascular augmented
fibrinolysis fibrinolysis 6) endovascular thrombus entrapment and 6) endovascular thrombus entrapment and 7) temporary endovascular bypass7) temporary endovascular bypass
IAT in Acute Ischemic StrokeIAT in Acute Ischemic Stroke
IAT advantages over IV thrombolysisIAT advantages over IV thrombolysis Coaxial microcatheter techniques the occluded intracranial Coaxial microcatheter techniques the occluded intracranial
vessel is directly accessible and the fibrinolytic agent can be vessel is directly accessible and the fibrinolytic agent can be infused directly into the thrombusinfused directly into the thrombus
This permits a smaller dose of fibrinolytic agent to reach a This permits a smaller dose of fibrinolytic agent to reach a higher local concentration than that reached by systemic higher local concentration than that reached by systemic infusioninfusion
Allows more complete recanalization with lower total doses of Allows more complete recanalization with lower total doses of thrombolytic thrombolytic
With the smaller dose complications from systemic fibrinolytic With the smaller dose complications from systemic fibrinolytic effects including intracranial hemorrhage (ICH) can effects including intracranial hemorrhage (ICH) can theoretically be reduced theoretically be reduced
Treatment window for endovascular techniques can be Treatment window for endovascular techniques can be extended beyond the typical IV window of 3 hours extended beyond the typical IV window of 3 hours
IA techniques have led to higher recanalization rates than IV IA techniques have led to higher recanalization rates than IV thrombolysisthrombolysis
Major disadvantagesMajor disadvantages Relative complexity of the procedure the level Relative complexity of the procedure the level
of required technical expertise and its of required technical expertise and its relatively low availability relatively low availability
Delays in initiating treatmentDelays in initiating treatment InvasiveInvasive
ThrombolyticsThrombolytics
Plasminogen activators
Fibrinolytics
1 Plasminogen Activators 1 Plasminogen Activators drugs act by converting the inactive proenzyme drugs act by converting the inactive proenzyme plasminogen into the active enzyme plasmin Plasmin plasminogen into the active enzyme plasmin Plasmin digests fibrinogen fibrin monomers and cross-linked digests fibrinogen fibrin monomers and cross-linked fibrin (as found in a thrombus) into fibrin degradation fibrin (as found in a thrombus) into fibrin degradation productsproducts
First-Generation Agents First-Generation Agents StreptokinaseStreptokinase a protein derived from group C a protein derived from group C
szlig-hemolytic streptococci has a half-life of 16ndashszlig-hemolytic streptococci has a half-life of 16ndash90 minutes and low fibrin specificity This drug 90 minutes and low fibrin specificity This drug proved to have a very narrow therapeutic proved to have a very narrow therapeutic window and significant rates of ICH and window and significant rates of ICH and systemic hemorrhage18systemic hemorrhage18
UrokinaseUrokinase is a serine protease with a plasma is a serine protease with a plasma half life of 14 minutes and low fibrin specificity half life of 14 minutes and low fibrin specificity
The urokinase dose used in cerebral IAT has The urokinase dose used in cerebral IAT has ranged from 002 to 2 X106unitsranged from 002 to 2 X106units
Second-Generation Agents Second-Generation Agents Alteplase (rtPA) Alteplase (rtPA)
is a serine is a serine protease with a plasma half-life of 35 protease with a plasma half-life of 35 minutes and a high degree of fibrin affinity and minutes and a high degree of fibrin affinity and specificity specificity
Dose used in cerebral IAT has ranged between 20 Dose used in cerebral IAT has ranged between 20 and 60 mgand 60 mg
Disadvantages of alteplase include its relatively short Disadvantages of alteplase include its relatively short halflife and limited penetration into the clot matrix halflife and limited penetration into the clot matrix because of strong binding with surface fibrin which because of strong binding with surface fibrin which could delay recanalization and increase the risk of could delay recanalization and increase the risk of recurrent occlusion recurrent occlusion
Prourokinase (r-prourokinase) Prourokinase (r-prourokinase) is the proenzyme precursor of urokinase is the proenzyme precursor of urokinase T12 of 7 minutes and high fibrin specificity T12 of 7 minutes and high fibrin specificity
Third-Generation AgentsThird-Generation Agents
ReteplaseReteplase is a structurally modified is a structurally modified form of alteplase form of alteplase
with a longer half-life (15ndash18 minutes) In with a longer half-life (15ndash18 minutes) In addition it does not bind as highly to fibrin addition it does not bind as highly to fibrin unbound reteplase can thus theoretically better unbound reteplase can thus theoretically better penetrate the clot and potentially penetrate the clot and potentially improve in improve in vivo fibrinolytic activity vivo fibrinolytic activity
TenecteplaseTenecteplase is another modified form of rtPA with a longer is another modified form of rtPA with a longer
half-life (17 minutes)half-life (17 minutes) greater fibrin specificity and greater greater fibrin specificity and greater
resistance to plasminogen activator inhibitor-1 resistance to plasminogen activator inhibitor-1 IV tenecteplase in acute ischemic stroke IV tenecteplase in acute ischemic stroke
suggest that the drug is safe and promisingsuggest that the drug is safe and promising
Newer plasminogen activatorNewer plasminogen activator
DesmoteplaseDesmoteplase is a genetically engineered is a genetically engineered version of the clot-dissolving factor version of the clot-dissolving factor
found in the saliva found in the saliva of the vampire bat Desmodus rotundusof the vampire bat Desmodus rotundus moremore potent and more selective for fibrin-bound potent and more selective for fibrin-bound
plasminogen than any other known plasminogen plasminogen than any other known plasminogen activatoractivator
Unlike tissue plasminogen activator (tPA) desmoteplase Unlike tissue plasminogen activator (tPA) desmoteplase is not activated by fibrinogen or -amyloid proteins is not activated by fibrinogen or -amyloid proteins factors that may exacerbate the risk for ICH factors that may exacerbate the risk for ICH
The effect of IV administration of desmoteplase 3ndash9 The effect of IV administration of desmoteplase 3ndash9 hours after symptom onset in patients with stroke who hours after symptom onset in patients with stroke who present with mismatch on MR imaging or CT perfusion present with mismatch on MR imaging or CT perfusion
3 DefibrinogenatingFibrinogenolytic 3 DefibrinogenatingFibrinogenolytic Agents Agents
AncrodAncrod(Viprinex)(Viprinex) is is the purified fraction of the Malayan pit viper venomthe purified fraction of the Malayan pit viper venom It acts by directly cleaving and inactivating fibrinogen It acts by directly cleaving and inactivating fibrinogen
and thus indirectly promoting anticoagulation and thus indirectly promoting anticoagulation The reduction in the blood levels of fibrinogen also The reduction in the blood levels of fibrinogen also
leads to a reduced blood viscosity which may improve leads to a reduced blood viscosity which may improve blood flow to the affected areas of the brain blood flow to the affected areas of the brain
In the Stroke Treatment with Ancrod Trial 500 In the Stroke Treatment with Ancrod Trial 500 patients with stroke presenting within 3 hours of patients with stroke presenting within 3 hours of symptom onset were randomized to receive ancrod (symptom onset were randomized to receive ancrod (n n 248) or a placebo (n 252) Good outcome (Barthel 248) or a placebo (n 252) Good outcome (Barthel Index 95ndash100 at 3 months) was achieved in 4221 Index 95ndash100 at 3 months) was achieved in 4221 and 344 of the patients respectively and 344 of the patients respectively
2 Direct Fibrinolytics2 Direct Fibrinolytics
Microplasmin (Microplasmin (ThromboGenics Heverlee Belgium)ThromboGenics Heverlee Belgium) is a truncated form of plasmin that is more resistant to the effects is a truncated form of plasmin that is more resistant to the effects
of antiplasmin of antiplasmin microplasmin can be used upto 4ndash12 hours after stroke onset microplasmin can be used upto 4ndash12 hours after stroke onset There was no evidence of increased bleeding risk with There was no evidence of increased bleeding risk with
microplasminmicroplasmin
Alfimeprase (Nuvelo San Carlos Calif)Alfimeprase (Nuvelo San Carlos Calif) is a recombinant truncated form of fibrolase a fibrinolytic zinc metalloproteinase is a recombinant truncated form of fibrolase a fibrinolytic zinc metalloproteinase
isolated from the venom of the southern copperhead snake isolated from the venom of the southern copperhead snake It degrades fibrin directly and achieves thrombolysis independent It degrades fibrin directly and achieves thrombolysis independent
of plasmin formationof plasmin formation its thrombolytic activity appears to be localized to the site of its thrombolytic activity appears to be localized to the site of
delivery These properties should theoretically result in faster delivery These properties should theoretically result in faster recanalization and lower hemorrhagic conversion riskrecanalization and lower hemorrhagic conversion risk
Anti-fibrinolyticsAnti-fibrinolytics
to limit fibrinolytic activityto limit fibrinolytic activity -aminocaproic acid (EACA) -aminocaproic acid (EACA) competitively inhibitscompetitively inhibits plasminogen and plasminogen activators from plasminogen and plasminogen activators from
binding to fibrinbinding to fibrin
alpha2-antiplasminalpha2-antiplasmin a serine protease inhibitor that a serine protease inhibitor that neutralizes any free circulating plasminneutralizes any free circulating plasmin
Plasminogen activator inhibitor-1Plasminogen activator inhibitor-1 a serine protease a serine protease inhibitor that inhibits tissue-type plasminogen inhibitor that inhibits tissue-type plasminogen activatoractivator
Glycoprotein (GP) IIbIIIa antagonistsGlycoprotein (GP) IIbIIIa antagonists
such as ReoPro (abciximab) Integrilin such as ReoPro (abciximab) Integrilin (eptifibatide) or Aggrastat (tirofiban) in (eptifibatide) or Aggrastat (tirofiban) in ischemic stroke remains investigational ischemic stroke remains investigational Deshmukh et al38 reported 21 patients with Deshmukh et al38 reported 21 patients with large-vessel occlusion refractory to IAT with large-vessel occlusion refractory to IAT with rtPA who were treated with IV andor IA rtPA who were treated with IV andor IA abciximab eptifibatide or tirofiban abciximab eptifibatide or tirofiban
IA Mechanical Approaches in Acute Ischemic Stroke IA Mechanical Approaches in Acute Ischemic Stroke Mechanical strategies have several advantagesMechanical strategies have several advantages First they lessen and may even preclude the use of chemical First they lessen and may even preclude the use of chemical
thrombolytics in this manner very likely reducing the risk of ICHthrombolytics in this manner very likely reducing the risk of ICH Second by avoiding the use of chemical thrombolytics it is Second by avoiding the use of chemical thrombolytics it is
possible to extend the treatment window beyond the limit of 6ndash8 possible to extend the treatment window beyond the limit of 6ndash8 hours hours
Third mechanically fragmenting a clot increases the surface area Third mechanically fragmenting a clot increases the surface area accessible to fibrinolytic agents and allows inflow of fresh accessible to fibrinolytic agents and allows inflow of fresh plasminogen which in turn may increase the speed of plasminogen which in turn may increase the speed of thrombolysis thrombolysis
Finally clot-retrieval devices may provide faster recanalization Finally clot-retrieval devices may provide faster recanalization
The disadvantages of the mechanical The disadvantages of the mechanical approaches approaches technical difficulty of navigating mechanical technical difficulty of navigating mechanical
devices into the intracranial circulation excessive devices into the intracranial circulation excessive trauma to the vasculature (potentially leading to trauma to the vasculature (potentially leading to vasospasm vessel dissection perforation or vasospasm vessel dissection perforation or rupture) rupture)
fragmented thrombus causing distal embolization fragmented thrombus causing distal embolization into previously unaffected territories into previously unaffected territories
Nevertheless the advantages of mechanical stroke Nevertheless the advantages of mechanical stroke therapy appear to significantly outweigh its therapy appear to significantly outweigh its disadvantages and risksdisadvantages and risks
Contraindications to Thrombolytic Contraindications to Thrombolytic agents agents
Recent thoracic abdominal or Recent thoracic abdominal or intracranial surgeryintracranial surgery
Recent haemorrhagic CVA Head injury Recent haemorrhagic CVA Head injury or neoplasmor neoplasm
Bleeding ulcerBleeding ulcer Anticipated invasive procedures (arterial Anticipated invasive procedures (arterial
punctures biopsies)punctures biopsies) Concurrent hemostatic dysfunctionConcurrent hemostatic dysfunction
Monitoring of thrombolytic Monitoring of thrombolytic therapytherapy
Thrombin time Measures the availability of functional
fibrinogen Normal thrombin time is 10-14 sec Prolonged when fibrinogen level is below
75-100 mgdl
Half Life of ThrombolyticsHalf Life of ThrombolyticsAgent Administration Half Life
Streptokinase IA 60-80min
Urokinase IAIV 9-12min
rTPA IAIV 6min
Abciximab(Reopro) IAIV 12hour
Aspirin POIV 15-20min
Heparin IVSC 60min
Coumadin PO 15-25 days
Anti Platelet DrugsAnti Platelet DrugsDrug Drug Mechanism Mechanism UsesUsesAspirinAspirin Permanently inhibits Permanently inhibits
COX-1 and COX-2COX-1 and COX-2CADCAD
Stroke-TIAsStroke-TIAs
NSAIDsNSAIDs Reversibly inhibits Reversibly inhibits COX-1COX-1
LimitedLimited
DipyridamoleDipyridamole Inhibits PDE increases Inhibits PDE increases cAMPcAMP
TIAsTIAs
ThenopyridinesThenopyridines
(Ticlopidine(Ticlopidine
ClopidrgrelClopidrgrel))
Inhibits ADP Inhibits ADP
PlatAg PlatAg
TIAsStrokeTIAsStroke
CAD PVDCAD PVD
Abciximab (ReoPro)Abciximab (ReoPro)
Eptifibatide (Integrilin)Eptifibatide (Integrilin)
TirofibanTirofiban
GP IIBIIIA InhibitorsGP IIBIIIA Inhibitors
Stroke- TIAs Stroke- TIAs
MonitoringMonitoring
Bleeding timeBleeding time
Optical aggregometryOptical aggregometry
Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay
Bleeding timeBleeding time
Requires a skin incision (usually made on the ear lobe or Requires a skin incision (usually made on the ear lobe or forearm offorearm of
a depth that results in disruption of capillary loops and a depth that results in disruption of capillary loops and small vessels)small vessels)
AdvantagesAdvantages Universally availableUniversally available Relatively simple techniquesRelatively simple techniques Can be performed bedsideCan be performed bedside
DisadvantagesDisadvantages Insensitive inaccurate non-specific techniqueInsensitive inaccurate non-specific technique
Poorly reproducible (as depends on multiple variables)Poorly reproducible (as depends on multiple variables)
Optical aggregometryOptical aggregometry
Gold standard assay for platelet functionGold standard assay for platelet function Agonist induced aggregation is measuredAgonist induced aggregation is measured Different agonist are available for different Different agonist are available for different
agentsagents However require unique expertise and are not However require unique expertise and are not
universally availableuniversally available Aspirin measured with ADP or AA(gt70 Aspirin measured with ADP or AA(gt70
aggregation so resistance)aggregation so resistance) Clopidogrel( ADP gt 90 aggregation means Clopidogrel( ADP gt 90 aggregation means
resistance) resistance)
Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay
Can be performed bed sideCan be performed bed side Different assay devices with different Different assay devices with different
agonist are used for each of different agonist are used for each of different antiplatelet agents antiplatelet agents
For Aspirin AA is used (result is reported as aspirin For Aspirin AA is used (result is reported as aspirin reaction units [ARU] ARUgt 550 indicates non-reaction units [ARU] ARUgt 550 indicates non-responsiveness)responsiveness)
Verify IIbIIIa assay device uses TRAP as agonist for Verify IIbIIIa assay device uses TRAP as agonist for Abciximab and TirofibanAbciximab and Tirofiban
Practical Applications Practical Applications related to specific related to specific
Neurovascular Neurovascular interventionsinterventions
Acute ischemic StrokeAcute ischemic Stroke When an artery occludes neurons are affected When an artery occludes neurons are affected
differently depending upon the amount of residual blood differently depending upon the amount of residual blood flowflow
Normal cerebral blood flow is greater than 50 mL100 Normal cerebral blood flow is greater than 50 mL100 mgminmgmin
Once blood flow decreases to less than 20 mL100 Once blood flow decreases to less than 20 mL100 mgmin infarction occursmgmin infarction occurs
If blood flow decreases to less than 10 mL100 mgmin If blood flow decreases to less than 10 mL100 mgmin irreversible neuronal death occurs rapidly irreversible neuronal death occurs rapidly
Blood flow between 11 and 20 mL100 mgmin is thought Blood flow between 11 and 20 mL100 mgmin is thought to represent the ischemic penumbra an area where the to represent the ischemic penumbra an area where the cells are functionally silent because of ischemia but are cells are functionally silent because of ischemia but are still able to recover if blood flow is restored still able to recover if blood flow is restored
Many acute stroke therapies are targeted toward Many acute stroke therapies are targeted toward restoring flow or function to the ischemic penumbrarestoring flow or function to the ischemic penumbra
Therapeutic window in Therapeutic window in management of acute Ischemic management of acute Ischemic
StrokeStrokeThe early diagnosis of ischemic stroke is critical to the The early diagnosis of ischemic stroke is critical to the
with only a narrow therapeutic window in the first few with only a narrow therapeutic window in the first few hours following stroke ictushours following stroke ictus
Diagnosis in the first 3 hours postictus provides the Diagnosis in the first 3 hours postictus provides the opportunity for intravenous or intraarterial thrombolysis opportunity for intravenous or intraarterial thrombolysis and intra-arterial clot mechanical treatment which and intra-arterial clot mechanical treatment which improve the outcome improve the outcome
Diagnosis in the time period between 3 and 6 hours Diagnosis in the time period between 3 and 6 hours provides an opportunity for intra-arterial thrombolysis provides an opportunity for intra-arterial thrombolysis and mechanical treatment and mechanical treatment
Involvement of the posterior circulation especially the Involvement of the posterior circulation especially the basilar artery is treated by some regardless of time of basilar artery is treated by some regardless of time of onset or up until 12 to 24 hours in some practices This is onset or up until 12 to 24 hours in some practices This is related to the potentially high mortality and morbidity related to the potentially high mortality and morbidity associated with basilar artery thrombosisassociated with basilar artery thrombosis
Infarct evaluation on angiographyInfarct evaluation on angiography(CT angiography and catheter (CT angiography and catheter
angiography)angiography)CTA is an excellent first-line examination for CTA is an excellent first-line examination for
evaluation of the head and neck arteries evaluation of the head and neck arteries In comparison with catheter angiography In comparison with catheter angiography
what it gives up in resolution and dynamic what it gives up in resolution and dynamic properties it makes up for with rapid properties it makes up for with rapid acquisition of a 3-D dataset and the potential acquisition of a 3-D dataset and the potential for assessment of whole-brain perfusion and for assessment of whole-brain perfusion and better parenchymal evaluationbetter parenchymal evaluation
Moreover CTA illustrates not only arterial Moreover CTA illustrates not only arterial stenosis or occlusion but also the vessel wall stenosis or occlusion but also the vessel wall This factor is most important for evaluation of This factor is most important for evaluation of intramural dissection and thrombosed intramural dissection and thrombosed aneurysms which may both complicate aneurysms which may both complicate evaluation of stroke patientsevaluation of stroke patients
Early angiographic signs of strokes Early angiographic signs of strokes both CTA both CTA and DSA and DSA
Vessel occlusion or cutoff related to Vessel occlusion or cutoff related to thromboembolithromboemboli
aneurysms aneurysms arterial dissection arterial dissection Meniscus or flattened shape to clot Meniscus or flattened shape to clot
(recent) versus reverse meniscus (older)(recent) versus reverse meniscus (older) tram track (nonocclusive or recanalized tram track (nonocclusive or recanalized
clot) clot) delayed (antegrade) flow (manifest as delayed (antegrade) flow (manifest as
decreased whole-brain perfusion on CTA)decreased whole-brain perfusion on CTA) retrograde collateral flowretrograde collateral flow
Non-occlusive left MCA thrombus on 3-D imaging performed from CTA source data and was confirmed at catheter angiography
Therapy to be started within a 6-hr Therapy to be started within a 6-hr time to treatment (TTT) window time to treatment (TTT) window (while in case of IV thrombolysis (while in case of IV thrombolysis therapy to be started with in 3hrs)therapy to be started with in 3hrs)
Exclusion criteria Exclusion criteria Rapidly improving neurologic deficit or Rapidly improving neurologic deficit or Sustained blood pressure of gt180100 Sustained blood pressure of gt180100 Hemorrhage is detected on CTHemorrhage is detected on CT Infarct involving gt more than 13 rd Infarct involving gt more than 13 rd
territory of MCAterritory of MCA MRADWI-Perfusion mismatchlt 20MRADWI-Perfusion mismatchlt 20 Definite hypodensity on CTDefinite hypodensity on CT
Intra-arterial Thrombolysis
Fibrinolytics + AntiplateletsFibrinolytics + Antiplatelets
PlasminogenPlasminogen activators through fibrinolysis exposes activators through fibrinolysis exposes free thrombin and paradoxically stimulatesfree thrombin and paradoxically stimulates platelet platelet aggregation which leads to formation of aaggregation which leads to formation of a platelet platelet thrombus (white clot) thrombus (white clot)
This new thrombus is relatively resistant to This new thrombus is relatively resistant to fibrinolyticsfibrinolytics
So new regimen in case of acute stroke isSo new regimen in case of acute stroke is fibrinolytics + antiplatelet drugsfibrinolytics + antiplatelet drugs
rtPA + IIbIIIa inhibitors( tirofiban rtPA + IIbIIIa inhibitors( tirofiban abciximab) orabciximab) or
Urokinase + IIbIIIa Urokinase + IIbIIIa inhibitors( tirofiban abciximab)inhibitors( tirofiban abciximab)
Intra-arterial Thrombolysis Tirofiban (04 microgkgmin bolus for 3 min followed by Tirofiban (04 microgkgmin bolus for 3 min followed by
0125 ugkgmin)0125 ugkgmin)
++
Heparin (2000ndash3000 IU bolus followed by Heparin (2000ndash3000 IU bolus followed by 1000 IUhour infusion 1000 IUhour infusion
with ACT maintained bw 200-300) throughout the with ACT maintained bw 200-300) throughout the interventional procedure and for 24ndash48 hours thereafter when interventional procedure and for 24ndash48 hours thereafter when there is neither intraprocedural bleeding nor suspicion of there is neither intraprocedural bleeding nor suspicion of increased risk of bleeding increased risk of bleeding
Maximum dose of Urokinase Maximum dose of Urokinase Anterior circulation stroke - 500000 IU (mean 400000 Anterior circulation stroke - 500000 IU (mean 400000
IU range 300000ndash500000 IU)IU range 300000ndash500000 IU) Posterior circulation stroke -1000000 IU (mean 837000 Posterior circulation stroke -1000000 IU (mean 837000
IU range 300000ndash1000000 IU)IU range 300000ndash1000000 IU)American Journal of NeuroradiologyAmerican Journal of Neuroradiology 262595-2601 2005262595-2601 2005
Intravenous ThrombolysisIntravenous Thrombolysis
The first method to restore cerebral The first method to restore cerebral perfusion is clot lysis with the goal perfusion is clot lysis with the goal of re-establishing blood flow to the of re-establishing blood flow to the affected tissue affected tissue
IV thrombolysis rt-PA is the only IV thrombolysis rt-PA is the only FDA- approved treatment for AIS FDA- approved treatment for AIS
Fibrinolysis is enhanced powerfully Fibrinolysis is enhanced powerfully by rt-PAby rt-PA
Intravenous rTPA Intravenous rTPA administration administration protocolprotocol
Total dose of rt-PA 09 mgkg (maximum dose Total dose of rt-PA 09 mgkg (maximum dose 90 mg)90 mg)
Give 10 as initial IV bolusGive 10 as initial IV bolus Infuse remainder over 1 hourInfuse remainder over 1 hour Admit patient to an ICU or stroke unit for Admit patient to an ICU or stroke unit for
monitoringmonitoring Neurologic assessments every 15 minutes Neurologic assessments every 15 minutes
during infusion then every 30 minutes for next during infusion then every 30 minutes for next 6 hours then every hour until 24hours after 6 hours then every hour until 24hours after treatmenttreatment
Favorable Outcome vs Treatment Time Favorable Outcome vs Treatment Time with IV rTPAwith IV rTPA
Protocol limit = 3 hrs
Benefit ~ 45 hrs
Thromboembolism During coilingThromboembolism During coiling Most feared and frequent complication Most feared and frequent complication Reported incidence - Approx 7 Reported incidence - Approx 7 SourcesSources of Thromboembolism are of Thromboembolism are
- Clots at the aneurysmal neck during or immediately- Clots at the aneurysmal neck during or immediately after after embolization embolization
- Thrombus forming on catheters during- Thrombus forming on catheters during proceduresprocedures
- Stenosis of an adjacent artery dt coil mass- Stenosis of an adjacent artery dt coil mass or herniationor herniation
- Migration of intraaneurysmal- Migration of intraaneurysmal thrombus during coil thrombus during coil placement placement
- Slow flow dt vasospasm - Slow flow dt vasospasm
- Rare and unlikely causes are hypercoagulable- Rare and unlikely causes are hypercoagulable state such state such as antiphospholipid antibody syndrome or due to HITas antiphospholipid antibody syndrome or due to HIT
Occur more often with wide-necked aneurysms (dt Occur more often with wide-necked aneurysms (dt increased exposed surface area of thrombogenic coil increased exposed surface area of thrombogenic coil material)material)
Current regimen of endovascular Current regimen of endovascular managementmanagement
The The glycoprotein IIbIIIa antagonist tirofiban glycoprotein IIbIIIa antagonist tirofiban (04 (04 microgkgmin bolus for 30 minutes followed by infusion of microgkgmin bolus for 30 minutes followed by infusion of 0125 ugkgmin until the thrombus dissolved) 0125 ugkgmin until the thrombus dissolved)
Intraarterial thrombolysis with Intraarterial thrombolysis with urokinase or r- TPA urokinase or r- TPA increase of intravenous (IV) heparin (measured by increase of intravenous (IV) heparin (measured by
ACT) ACT) Intravenous aspirin Intravenous aspirin
Coil-related platelet aggregation (white clot) is Coil-related platelet aggregation (white clot) is unlikely to respond to fibrinolytics but has a high risk unlikely to respond to fibrinolytics but has a high risk of hemorrhage (In ISAT) all 5 patients who had of hemorrhage (In ISAT) all 5 patients who had received thrombolytic therapy with tPA to treat a received thrombolytic therapy with tPA to treat a thromboembolic complication after endovascular thromboembolic complication after endovascular treatment rebleed and all of these patients died)treatment rebleed and all of these patients died)
IntracranialIntracranial Stenting Stenting Metallic foreign body such as stent will accumulate Metallic foreign body such as stent will accumulate
thrombus in the absence of platelet inhibitionthrombus in the absence of platelet inhibition Antiplatelet drugs are important to prevent peri or Antiplatelet drugs are important to prevent peri or
post-interventional thromboembolic eventspost-interventional thromboembolic events Optimal treatment regimens has not been determined Optimal treatment regimens has not been determined
but usually but usually Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-
procedureprocedureOrOr
Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on
morning of proceduremorning of procedure
If need to use stent is not pre-planned thanIf need to use stent is not pre-planned than
Abciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkgAbciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkg IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)
Glycoprotein IIbIIIa inhibitor are not used routinely during elective Glycoprotein IIbIIIa inhibitor are not used routinely during elective stenting procedure dt increased risk of ICH stenting procedure dt increased risk of ICH
Carotid StentingCarotid Stenting
Pre-procedurePre-procedure
Double Antiplatelet therapy is routinely given Double Antiplatelet therapy is routinely given beginning at least 3beginning at least 3
days before the proceduredays before the procedure
Aspirin 325mgd+Clopidogrel 75mgdAspirin 325mgd+Clopidogrel 75mgd During procedureDuring procedure
Heparin is given with target clotting time of 250-Heparin is given with target clotting time of 250-300sec300sec
Post-procedure Post-procedure
Aspirin 325mg is continued indefinitely and Aspirin 325mg is continued indefinitely and
Clopidogrel 75mgd for at least 6 weeks Clopidogrel 75mgd for at least 6 weeks
Inclusion criteria for Local ThrombolysisInclusion criteria for Local Thrombolysis a)a) Patients in severe clinical grade on admission Patients in severe clinical grade on admission
with evidence of dural venous sinus with evidence of dural venous sinus thrombosis and restrictive venous outflow on thrombosis and restrictive venous outflow on cerebral angiogramcerebral angiogram
b)b) Patients in clinical grade 3 worsening on Patients in clinical grade 3 worsening on heparin therapy Restriction to venous heparin therapy Restriction to venous outflow was defined as an increase in brain outflow was defined as an increase in brain circulation time gt 12 s delay in the drainage circulation time gt 12 s delay in the drainage of cortical veins with cortical veins hanging of cortical veins with cortical veins hanging in spacein space
Treatment Options for Venous Thrombosis
CT Grading for Venous ThrombosisCT Grading for Venous Thrombosis Grade I no parenchymal change Grade I no parenchymal change
(hyperdense (hyperdense sinuses cortical veins empty sinuses cortical veins empty delta sign)delta sign)
Grade II non hemorrhagic venous infarct Grade II non hemorrhagic venous infarct without mass effect without mass effect
Grade III non-hemorrhagic infarct with Grade III non-hemorrhagic infarct with mass effectmass effect
Grade IV hemorrhagic venous infarct (max Grade IV hemorrhagic venous infarct (max diameter lt 3 cm) with no mass effectdiameter lt 3 cm) with no mass effect
Grade V hemorrhagic venous infarct (max Grade V hemorrhagic venous infarct (max diameter gt 3 cm) with mass effect diameter gt 3 cm) with mass effect
Local ThrombolysisLocal Thrombolysis
Femoral Jugular access was secured and a guiding Femoral Jugular access was secured and a guiding catheter was placed in the jugular bulb catheter was placed in the jugular bulb Mechanical Mechanical clot maceration clot maceration was done with the guidewire was done with the guidewire following which a microcatheter (was navigated and following which a microcatheter (was navigated and placed in the thrombosed segment of sinus confirmed placed in the thrombosed segment of sinus confirmed on a selective venogram on a selective venogram
Urokinase infusion Bolus dose of 2-6 lacs followed Urokinase infusion Bolus dose of 2-6 lacs followed by 60000 to 100000 units per hour along with by 60000 to 100000 units per hour along with periodic check venogram Along with maintenance periodic check venogram Along with maintenance systemic infusion of Heparinsystemic infusion of Heparin Other agents such as Other agents such as streptokinase altepase or rTPAstreptokinase altepase or rTPA can be also used can be also used
After thrombolysis patient should subjected to oral After thrombolysis patient should subjected to oral anticoagulation for six monthsanticoagulation for six months
Low-molecular-weight Low-molecular-weight heparinheparin
PharmacologyPharmacologyLMWH as its name suggests is a glycosaminoglycan that is approximatelyLMWH as its name suggests is a glycosaminoglycan that is approximately
one third the molecular weight of UFH It is derived from UFH through one third the molecular weight of UFH It is derived from UFH through variousvarious
depolymerization processes LMWH binds to antithrombin which in turn depolymerization processes LMWH binds to antithrombin which in turn
Neutralizes actors Xa and IIa Because LMWH lacks many of the longer Neutralizes actors Xa and IIa Because LMWH lacks many of the longer chains chains
required for binding to thrombin it has less ability to neutralize thrombin required for binding to thrombin it has less ability to neutralize thrombin
relativeto its ability to neutralize factor Xa LMWH also has less relativeto its ability to neutralize factor Xa LMWH also has less nonspecific nonspecific
binding to other proteins There is greater bioavailability with more binding to other proteins There is greater bioavailability with more predictable predictable
pharmacokinetics that eliminates the need for monitoring The smaller pharmacokinetics that eliminates the need for monitoring The smaller size also size also
allows for enhanced subcutaneous absorption when compared with UFHallows for enhanced subcutaneous absorption when compared with UFH
Three LMWH preparations are Three LMWH preparations are currently approved for use in the currently approved for use in the United States (1) enoxaparin (2) United States (1) enoxaparin (2) dalteparin and (3) tinzaparin dalteparin and (3) tinzaparin
They are all administered They are all administered subcutaneously at intervals of either subcutaneously at intervals of either once or twice daily for both once or twice daily for both prophylaxis and treatment dosesprophylaxis and treatment doses
Few Experiences of Few Experiences of ThrombolysisThrombolysis
Vickey 25 Yrs male patient presented Vickey 25 Yrs male patient presented with 12with 12thth day HO severe headache with day HO severe headache with right sided hemiplegiaright sided hemiplegia
MRI shows thrombosis of the superior MRI shows thrombosis of the superior sagittal left transverse left sigmoid sagittal left transverse left sigmoid sinuses and cortical veins in the fronto-sinuses and cortical veins in the fronto-parietal regions with eo haemorrhagic parietal regions with eo haemorrhagic infarct in the left cerebral hemisphere infarct in the left cerebral hemisphere with mass effect( Grade ndashV)with mass effect( Grade ndashV)
Sashi Srivastava 64 yrs FSashi Srivastava 64 yrs F In a follow up case of MRD with infra-renal In a follow up case of MRD with infra-renal
aortic abdominal and bilateral renal artery aortic abdominal and bilateral renal artery thrombosis renal angiogram shows filling thrombosis renal angiogram shows filling defects in the right Renal artery defects in the right Renal artery
Initially Renal angioplasty was done Initially Renal angioplasty was done Following angioplasty few thrombi are seem Following angioplasty few thrombi are seem to extends into the segmental branches and to extends into the segmental branches and causing blockage So Thrombolysis was causing blockage So Thrombolysis was plane to dissolve the run-out thrombi with plane to dissolve the run-out thrombi with urokinase urokinase
Rakesh 34yrsMRakesh 34yrsM Left SFA pseudoaneurysm with Left SFA pseudoaneurysm with
Covered stent placementCovered stent placement Pre operative antiplatelets with post Pre operative antiplatelets with post
procedure heparin Tirofiban procedure heparin Tirofiban followed by aspirin and clopidogrel followed by aspirin and clopidogrel were usedwere used
IAT may be a treatment option for selected patients IAT may be a treatment option for selected patients Possible selection criteria include Possible selection criteria include
presentation between 3 and 6 hours from symptom onsetpresentation between 3 and 6 hours from symptom onset major cerebral artery occlusion major cerebral artery occlusion severe neurologic deficits severe neurologic deficits high risk of systemic hemorrhage with IV rt-PA (eg recent high risk of systemic hemorrhage with IV rt-PA (eg recent
surgery) surgery) The MERCI (Mechanical Embolus Removal in Cerebral The MERCI (Mechanical Embolus Removal in Cerebral
Ischemia) retrievalIschemia) retrieval system system
Has been FDA-approved for recanalizing acutely occluded Has been FDA-approved for recanalizing acutely occluded cerebral arteries cerebral arteries
In the Multi-MERCI study patients who did not improve In the Multi-MERCI study patients who did not improve immediately after IV rt-PA underwent mechanical immediately after IV rt-PA underwent mechanical embolectomy within 8 hours of symptom onset embolectomy within 8 hours of symptom onset
Partial or complete recanalization occurred in 74 of Partial or complete recanalization occurred in 74 of patientspatients
with a symptomatic intracerebral hemorrhage (sICH) rate of with a symptomatic intracerebral hemorrhage (sICH) rate of 67 67
Mechanical embolectomy with the MERCI retriever may be a Mechanical embolectomy with the MERCI retriever may be a feasible and safe option for patients after IV rt-PAfeasible and safe option for patients after IV rt-PA
Penumbra stroke systemPenumbra stroke system This device combines two methods of clot This device combines two methods of clot
extraction aspiration and mechanical extraction aspiration and mechanical extraction extraction
First the clot is aspirated then a thrombus First the clot is aspirated then a thrombus removal ring can be used if necessary to removal ring can be used if necessary to remove remaining clot remove remaining clot
successful recanalizing 82successful recanalizing 82 Bridging therapyBridging therapy
06 mgkg IV rt-PA followed by IAT with IA rt-06 mgkg IV rt-PA followed by IAT with IA rt-PA (up to 20 mg)PA (up to 20 mg)
achieved a higher recanalization rateachieved a higher recanalization rate
Criteria for thrombolysis with rTPACriteria for thrombolysis with rTPA
Inclusion criteriaInclusion criteria Clinical signs and symptoms consistent with ischemic Clinical signs and symptoms consistent with ischemic
strokestroke Patient last seen normal within 3 hoursPatient last seen normal within 3 hours Measurable neurologic deficitMeasurable neurologic deficit
Exclusion criteriaExclusion criteria Any hemorrhage on neuroimaging (CT or MRI)Any hemorrhage on neuroimaging (CT or MRI) Symptoms suggestive of subarachnoid hemorrhageSymptoms suggestive of subarachnoid hemorrhage Seizure at stroke onset that is thought to contribute to Seizure at stroke onset that is thought to contribute to
neurologic deficitneurologic deficit Hypodensity greater than one third cerebral hemisphere Hypodensity greater than one third cerebral hemisphere
on CTon CT SBP greater than 185 mm Hg or DBP greater than 110 SBP greater than 185 mm Hg or DBP greater than 110
mm Hgmm Hg International normalized ratio (INR) greater than 17International normalized ratio (INR) greater than 17
Ischemic Stroke Ischemic Stroke Treatment ndash 2006Treatment ndash 2006
IV tissue plasminogen activator (tPA)IV tissue plasminogen activator (tPA) ndash ndash Only FDA-approved acute stroke drugOnly FDA-approved acute stroke drug ndash ndash 3 hour treatment window3 hour treatment window
MERCI - Concentric clot retrieval MERCI - Concentric clot retrieval devicedevice ndash ndash Rescue therapy - approved 2004Rescue therapy - approved 2004 ndash ndash Device approval (not outcomes-based)Device approval (not outcomes-based)
Off label approachesOff label approaches ndash ndash IV tPA after 3 hoursIV tPA after 3 hours ndash ndash IV-IA tPA sequential strategiesIV-IA tPA sequential strategies ndash ndash IA tPA clot angioplasty fragmentationIA tPA clot angioplasty fragmentation ndash ndash Ultrasound-assisted tPA lysisUltrasound-assisted tPA lysis
rt-PA Trials NINDSrt-PA Trials NINDS
Acute stroke - 624 patientsAcute stroke - 624 patients Treat within 3 hrsTreat within 3 hrs Intravenous 09 mgkg rt-PA vs placeboIntravenous 09 mgkg rt-PA vs placebo Hemorrhage 64 tPA 06 placeboHemorrhage 64 tPA 06 placebo Neurologic recovery better with tPA 30 Neurologic recovery better with tPA 30
more like to have minimal or no disabilitymore like to have minimal or no disability
First proven approved treatment for First proven approved treatment for strokestroke
Limitations of tPALimitations of tPA Only 4 of acute strokes receive tPAOnly 4 of acute strokes receive tPA (Kleindorfer et al Stroke 2004 35 e27-e29)(Kleindorfer et al Stroke 2004 35 e27-e29)
Only 22 of patients present within 3 hoursOnly 22 of patients present within 3 hours1048707 1048707 51 of these ineligible due to51 of these ineligible due to
bull bull Mild severityMild severity bull bull Medical or surgical historyMedical or surgical history bull bull Blood testsBlood tests
Sustained recanalization only 13Sustained recanalization only 13 (Alexandrov et al NEJM 2004 351 2170-8)(Alexandrov et al NEJM 2004 351 2170-8)
Concern for hemorrhageConcern for hemorrhage tPA potentiates apoptotic injury tPA potentiates apoptotic injury (Liu et al Nature Med 2004 101379-83)(Liu et al Nature Med 2004 101379-83)
PROACT II IA Lysis TrialPROACT II IA Lysis Trial Baseline 24 hours 8 days
Baseline 60 minutes 120 minutes
9mg IAProurokinase
Desmoteplase Trials DEDAS Desmoteplase Trials DEDAS DIASDIAS
Trial OverviewTrial Overview Double blind randomized placebo Double blind randomized placebo
controlled trialscontrolled trials IV delivery 3-9 hour time windowIV delivery 3-9 hour time window Plasminogen activator ndash from Plasminogen activator ndash from vampire bat vampire bat
salivasaliva Selection based on PWI-DWI MismatchSelection based on PWI-DWI Mismatch
MRI InclusionMRI Inclusion PWI defect at least 2 cm AND ~20 larger PWI defect at least 2 cm AND ~20 larger
than DWIthan DWI PWI should be obvious even visible on PWI should be obvious even visible on
raw imagesraw imagesMRI ExclusionMRI Exclusion
DWI gt 13 MCADWI gt 13 MCA MRA ICA occlusionMRA ICA occlusion
Desmoteplase ndash DIAS Desmoteplase ndash DIAS ResultsResults
Mechanical Thrombolysis Mechanical Thrombolysis devicesdevices
mechanical thrombolysis potentially extends the treatment mechanical thrombolysis potentially extends the treatment window because they act promptly at the site of the thrombuswindow because they act promptly at the site of the thrombus
The devices can retrieve large clots that pharmaceutical agents The devices can retrieve large clots that pharmaceutical agents may not successfully lysemay not successfully lyse
Patients treated with IV tPA may be considered for treatment of Patients treated with IV tPA may be considered for treatment of residual clot with some of these devicesresidual clot with some of these devices
suction-creating saline jets suction-creating saline jets laser energy ultrasound laser energy ultrasound a corkscrew apparatus to treat strokesa corkscrew apparatus to treat strokes The AngioJet systemThe AngioJet system uses saline jets that are directed back into the catheter to uses saline jets that are directed back into the catheter to
create a low-pressure zone around the catheter tip inducing create a low-pressure zone around the catheter tip inducing suction suction
The clot is pulled into the exhaust lumen and removed from the The clot is pulled into the exhaust lumen and removed from the vessel Although US Food and Drug Administration (FDA) has vessel Although US Food and Drug Administration (FDA) has approved this device for use in arteriovenous dialysis grafts and approved this device for use in arteriovenous dialysis grafts and fistulae and for the treatment of coronary arteries saphenous fistulae and for the treatment of coronary arteries saphenous vein grafts and peripheral vessels clinical trials for the vein grafts and peripheral vessels clinical trials for the treatment of acute stroke are no longer in progress treatment of acute stroke are no longer in progress
Most devices are used in cerebral vessels that 2-5 mm
The Latis laser device The Latis laser device used laser energy to ablate clots used laser energy to ablate clots Arteries 2-5 mm in diameter could be Arteries 2-5 mm in diameter could be
treated including the ICA M1 or M2 treated including the ICA M1 or M2 branch of the MCA A1 branch of the branch of the MCA A1 branch of the anterior cerebral artery (ACA) basilar anterior cerebral artery (ACA) basilar artery posterior cerebral artery (PCA) artery posterior cerebral artery (PCA) and vertebral and vertebral
Patients could receive treatment as late Patients could receive treatment as late as 8 hours after symptom onset in the as 8 hours after symptom onset in the anterior circulation and within 24 hours in anterior circulation and within 24 hours in the posterior circulation the posterior circulation
Endovascular Photo Acoustic Endovascular Photo Acoustic Recanalization (EPAR) Recanalization (EPAR)
A laser power source generated energy for the A laser power source generated energy for the systemsystem
The energy was delivered by means of The energy was delivered by means of fiberoptics to the tip of the catheter at the fiberoptics to the tip of the catheter at the treatment sitetreatment site
Absorption of laser light by darkly pigmented Absorption of laser light by darkly pigmented materials (ie the clot) occurred inside the 1-mm materials (ie the clot) occurred inside the 1-mm catheter tipcatheter tip
the system was designed to minimize scattering the system was designed to minimize scattering of laser light of laser light
Absorption converted photo energy to acoustic Absorption converted photo energy to acoustic energy which then emulsified the clot inside the energy which then emulsified the clot inside the catheter tip catheter tip
EKOS ultrasound( the EKOS ultrasound( the Ultrasound Thrombolytic Ultrasound Thrombolytic
Infusion Catheter) Infusion Catheter) combines the use of a distal ultrasound transducer with combines the use of a distal ultrasound transducer with
infusion of a thrombolytic agent through the infusion of a thrombolytic agent through the microcathetermicrocatheter
Ultrasound changes the structure of the clot to Ultrasound changes the structure of the clot to temporarily increase its permeability while providing an temporarily increase its permeability while providing an acoustic pressure gradient to move the drug into the clot acoustic pressure gradient to move the drug into the clot to speed its dissolution to speed its dissolution
The EKOS catheter is placed in the proximal portion of the The EKOS catheter is placed in the proximal portion of the clot clot
After a 2-mg bolus of tPA was injected through the After a 2-mg bolus of tPA was injected through the catheter catheter
the patient received a continuous infusion of IA tPA 03 the patient received a continuous infusion of IA tPA 03 mgmin to a maximum of 20 mg and simultaneous mgmin to a maximum of 20 mg and simultaneous ultrasound transmission for as long as 60 minutes ultrasound transmission for as long as 60 minutes
One patient was treated with a total of 4 units of One patient was treated with a total of 4 units of recombinant reteplase (Retavase) hand-injected over 60 recombinant reteplase (Retavase) hand-injected over 60 minutes minutes
Penumbra system Penumbra system The Penumbra system (Penumbra Inc) provides a dual The Penumbra system (Penumbra Inc) provides a dual
approach to clot extraction using aspiration followed by approach to clot extraction using aspiration followed by clot retrieval with a ring device if needed clot retrieval with a ring device if needed
Mechanical Embolus Removal in Cerebral Ischemia Mechanical Embolus Removal in Cerebral Ischemia (MERCI)(MERCI)
a corkscrew-like apparatus to remove blood clots from a corkscrew-like apparatus to remove blood clots from the brain in patients experiencing an ischemic stroke the brain in patients experiencing an ischemic stroke
The corkscrew itself resides in the catheter tip which The corkscrew itself resides in the catheter tip which shields it from the wall of the vessel until it is ready to be shields it from the wall of the vessel until it is ready to be burrowed into the clot Once lodged in the clot the device burrowed into the clot Once lodged in the clot the device and clot are withdrawn from the vessel and clot are withdrawn from the vessel
Snarelike devicesSnarelike devices Snares such as the Neuronet snare (Guidant Snares such as the Neuronet snare (Guidant
Endovascular Santa Clara CA) have been developed Endovascular Santa Clara CA) have been developed specifically for use in the treatment of strokes specifically for use in the treatment of strokes
These devices are simple in design and do not require the These devices are simple in design and do not require the clot to be amenable to emulsification clot to be amenable to emulsification
X-Sizer deviceX-Sizer device a device with small moving blades at the a device with small moving blades at the
catheter tip catheter tip This device the X-Sizer device (EndiCor Medical This device the X-Sizer device (EndiCor Medical
San Clemente CA) can be used to excise the San Clemente CA) can be used to excise the thrombus and aspirate it thrombus and aspirate it
The device was being evaluated in randomized The device was being evaluated in randomized studies of coronary vessels and in a registry of studies of coronary vessels and in a registry of patients with acute myocardial infarctionpatients with acute myocardial infarction
Although the manufacturer had modified the Although the manufacturer had modified the device for use in cerebral vessels a safety and device for use in cerebral vessels a safety and feasibility study was indefinitely suspended after feasibility study was indefinitely suspended after only 1 patient was treated with the device in only 1 patient was treated with the device in Europe Europe
Suction thrombectomySuction thrombectomy This method of mechanical thrombolysis is one of the This method of mechanical thrombolysis is one of the
simplestsimplest In this readily available technique suction is applied with In this readily available technique suction is applied with
a syringe to remove thrombus in the ICA a syringe to remove thrombus in the ICA It requires no other devicesIt requires no other devices A catheter with a large inner diameter (Brite Tip Cordis A catheter with a large inner diameter (Brite Tip Cordis
Corporation Miami FL) was placed in the symptomatic Corporation Miami FL) was placed in the symptomatic vessel and navigated over a guidewire into the thrombusvessel and navigated over a guidewire into the thrombus
A 60-mL syringe was used to aspirate the thrombus A 60-mL syringe was used to aspirate the thrombus Each patient required angioplasty and stenting of carotid Each patient required angioplasty and stenting of carotid
bifurcation stenosis and received daily aspirin and bifurcation stenosis and received daily aspirin and ticlopidine after the procedure No complications ticlopidine after the procedure No complications occurred occurred
Summary Acute Stroke Summary Acute Stroke ImagingImaging
PhysiologyPhysiology importance collaterals importance collaterals
ndash ndashGrowing role for perfusion Growing role for perfusion assessmentassessment
tPAtPA guidelines amp limitations guidelines amp limitations Signs on CT amp MRSigns on CT amp MR follow physiology follow physiology Stroke trialsStroke trials PWI-DWI mismatch PWI-DWI mismatch
ndash ndashTreat based on physiology not timeTreat based on physiology not time ProtocolsProtocols should be fast and should be fast and
comprehensivecomprehensive
INTERNATIONAL NORMALISED RATIO (INR)INTERNATIONAL NORMALISED RATIO (INR)
International Normalized Ratio (INR) International Normalized Ratio (INR) a PT test with a a PT test with a formula based ratio to normalize the often variable source formula based ratio to normalize the often variable source of tissue factor (human rabbit recombinant)of tissue factor (human rabbit recombinant)
INR = [PTINR = [PTptpt] ] ISIISI
[PT[PTRefRef]]
PTPTpt pt ndash prothrombin time of patientndash prothrombin time of patient
PTPTRef Ref ndash prothrombin time of normal pooled samplendash prothrombin time of normal pooled sample
ISI ndash International Sensitivity IndexISI ndash International Sensitivity Index
Warfarin is given orally and titrated to achieve an INR of Warfarin is given orally and titrated to achieve an INR of typically 20 ndash 30typically 20 ndash 30
Heparin versus WarfarinHeparin versus Warfarin
Drug ActionMechan-ism
Moni-toring
Effective
HeparinDirect
Inhibition ofThrombin
ATIIIcofactor
APTTACT
Immediate
WarfarinDecreasesProductionof factors
Vitamin K PTDelay
3-5 days
INR
Recanalization or Antegrade Recanalization or Antegrade Reperfusion StrategiesReperfusion Strategies
Recanalization strategies focus on removing Recanalization strategies focus on removing andor dissolving the occlusive thrombus to re-andor dissolving the occlusive thrombus to re-establish antegrade flow Strategies may be establish antegrade flow Strategies may be classified into 7 different categories on the classified into 7 different categories on the basis of their primary mechanism of action basis of their primary mechanism of action 1) 1) IV andor intraarterial thrombolysis (IAT) IV andor intraarterial thrombolysis (IAT) 2) endovascular thrombectomy2) endovascular thrombectomy3) endovascular thromboaspiration 3) endovascular thromboaspiration 4) endovascular mechanical thrombus disruption or 4) endovascular mechanical thrombus disruption or
thromborrhexisthromborrhexis5) 5) transcranial or endovascular augmented transcranial or endovascular augmented
fibrinolysis fibrinolysis 6) endovascular thrombus entrapment and 6) endovascular thrombus entrapment and 7) temporary endovascular bypass7) temporary endovascular bypass
IAT in Acute Ischemic StrokeIAT in Acute Ischemic Stroke
IAT advantages over IV thrombolysisIAT advantages over IV thrombolysis Coaxial microcatheter techniques the occluded intracranial Coaxial microcatheter techniques the occluded intracranial
vessel is directly accessible and the fibrinolytic agent can be vessel is directly accessible and the fibrinolytic agent can be infused directly into the thrombusinfused directly into the thrombus
This permits a smaller dose of fibrinolytic agent to reach a This permits a smaller dose of fibrinolytic agent to reach a higher local concentration than that reached by systemic higher local concentration than that reached by systemic infusioninfusion
Allows more complete recanalization with lower total doses of Allows more complete recanalization with lower total doses of thrombolytic thrombolytic
With the smaller dose complications from systemic fibrinolytic With the smaller dose complications from systemic fibrinolytic effects including intracranial hemorrhage (ICH) can effects including intracranial hemorrhage (ICH) can theoretically be reduced theoretically be reduced
Treatment window for endovascular techniques can be Treatment window for endovascular techniques can be extended beyond the typical IV window of 3 hours extended beyond the typical IV window of 3 hours
IA techniques have led to higher recanalization rates than IV IA techniques have led to higher recanalization rates than IV thrombolysisthrombolysis
Major disadvantagesMajor disadvantages Relative complexity of the procedure the level Relative complexity of the procedure the level
of required technical expertise and its of required technical expertise and its relatively low availability relatively low availability
Delays in initiating treatmentDelays in initiating treatment InvasiveInvasive
ThrombolyticsThrombolytics
Plasminogen activators
Fibrinolytics
1 Plasminogen Activators 1 Plasminogen Activators drugs act by converting the inactive proenzyme drugs act by converting the inactive proenzyme plasminogen into the active enzyme plasmin Plasmin plasminogen into the active enzyme plasmin Plasmin digests fibrinogen fibrin monomers and cross-linked digests fibrinogen fibrin monomers and cross-linked fibrin (as found in a thrombus) into fibrin degradation fibrin (as found in a thrombus) into fibrin degradation productsproducts
First-Generation Agents First-Generation Agents StreptokinaseStreptokinase a protein derived from group C a protein derived from group C
szlig-hemolytic streptococci has a half-life of 16ndashszlig-hemolytic streptococci has a half-life of 16ndash90 minutes and low fibrin specificity This drug 90 minutes and low fibrin specificity This drug proved to have a very narrow therapeutic proved to have a very narrow therapeutic window and significant rates of ICH and window and significant rates of ICH and systemic hemorrhage18systemic hemorrhage18
UrokinaseUrokinase is a serine protease with a plasma is a serine protease with a plasma half life of 14 minutes and low fibrin specificity half life of 14 minutes and low fibrin specificity
The urokinase dose used in cerebral IAT has The urokinase dose used in cerebral IAT has ranged from 002 to 2 X106unitsranged from 002 to 2 X106units
Second-Generation Agents Second-Generation Agents Alteplase (rtPA) Alteplase (rtPA)
is a serine is a serine protease with a plasma half-life of 35 protease with a plasma half-life of 35 minutes and a high degree of fibrin affinity and minutes and a high degree of fibrin affinity and specificity specificity
Dose used in cerebral IAT has ranged between 20 Dose used in cerebral IAT has ranged between 20 and 60 mgand 60 mg
Disadvantages of alteplase include its relatively short Disadvantages of alteplase include its relatively short halflife and limited penetration into the clot matrix halflife and limited penetration into the clot matrix because of strong binding with surface fibrin which because of strong binding with surface fibrin which could delay recanalization and increase the risk of could delay recanalization and increase the risk of recurrent occlusion recurrent occlusion
Prourokinase (r-prourokinase) Prourokinase (r-prourokinase) is the proenzyme precursor of urokinase is the proenzyme precursor of urokinase T12 of 7 minutes and high fibrin specificity T12 of 7 minutes and high fibrin specificity
Third-Generation AgentsThird-Generation Agents
ReteplaseReteplase is a structurally modified is a structurally modified form of alteplase form of alteplase
with a longer half-life (15ndash18 minutes) In with a longer half-life (15ndash18 minutes) In addition it does not bind as highly to fibrin addition it does not bind as highly to fibrin unbound reteplase can thus theoretically better unbound reteplase can thus theoretically better penetrate the clot and potentially penetrate the clot and potentially improve in improve in vivo fibrinolytic activity vivo fibrinolytic activity
TenecteplaseTenecteplase is another modified form of rtPA with a longer is another modified form of rtPA with a longer
half-life (17 minutes)half-life (17 minutes) greater fibrin specificity and greater greater fibrin specificity and greater
resistance to plasminogen activator inhibitor-1 resistance to plasminogen activator inhibitor-1 IV tenecteplase in acute ischemic stroke IV tenecteplase in acute ischemic stroke
suggest that the drug is safe and promisingsuggest that the drug is safe and promising
Newer plasminogen activatorNewer plasminogen activator
DesmoteplaseDesmoteplase is a genetically engineered is a genetically engineered version of the clot-dissolving factor version of the clot-dissolving factor
found in the saliva found in the saliva of the vampire bat Desmodus rotundusof the vampire bat Desmodus rotundus moremore potent and more selective for fibrin-bound potent and more selective for fibrin-bound
plasminogen than any other known plasminogen plasminogen than any other known plasminogen activatoractivator
Unlike tissue plasminogen activator (tPA) desmoteplase Unlike tissue plasminogen activator (tPA) desmoteplase is not activated by fibrinogen or -amyloid proteins is not activated by fibrinogen or -amyloid proteins factors that may exacerbate the risk for ICH factors that may exacerbate the risk for ICH
The effect of IV administration of desmoteplase 3ndash9 The effect of IV administration of desmoteplase 3ndash9 hours after symptom onset in patients with stroke who hours after symptom onset in patients with stroke who present with mismatch on MR imaging or CT perfusion present with mismatch on MR imaging or CT perfusion
3 DefibrinogenatingFibrinogenolytic 3 DefibrinogenatingFibrinogenolytic Agents Agents
AncrodAncrod(Viprinex)(Viprinex) is is the purified fraction of the Malayan pit viper venomthe purified fraction of the Malayan pit viper venom It acts by directly cleaving and inactivating fibrinogen It acts by directly cleaving and inactivating fibrinogen
and thus indirectly promoting anticoagulation and thus indirectly promoting anticoagulation The reduction in the blood levels of fibrinogen also The reduction in the blood levels of fibrinogen also
leads to a reduced blood viscosity which may improve leads to a reduced blood viscosity which may improve blood flow to the affected areas of the brain blood flow to the affected areas of the brain
In the Stroke Treatment with Ancrod Trial 500 In the Stroke Treatment with Ancrod Trial 500 patients with stroke presenting within 3 hours of patients with stroke presenting within 3 hours of symptom onset were randomized to receive ancrod (symptom onset were randomized to receive ancrod (n n 248) or a placebo (n 252) Good outcome (Barthel 248) or a placebo (n 252) Good outcome (Barthel Index 95ndash100 at 3 months) was achieved in 4221 Index 95ndash100 at 3 months) was achieved in 4221 and 344 of the patients respectively and 344 of the patients respectively
2 Direct Fibrinolytics2 Direct Fibrinolytics
Microplasmin (Microplasmin (ThromboGenics Heverlee Belgium)ThromboGenics Heverlee Belgium) is a truncated form of plasmin that is more resistant to the effects is a truncated form of plasmin that is more resistant to the effects
of antiplasmin of antiplasmin microplasmin can be used upto 4ndash12 hours after stroke onset microplasmin can be used upto 4ndash12 hours after stroke onset There was no evidence of increased bleeding risk with There was no evidence of increased bleeding risk with
microplasminmicroplasmin
Alfimeprase (Nuvelo San Carlos Calif)Alfimeprase (Nuvelo San Carlos Calif) is a recombinant truncated form of fibrolase a fibrinolytic zinc metalloproteinase is a recombinant truncated form of fibrolase a fibrinolytic zinc metalloproteinase
isolated from the venom of the southern copperhead snake isolated from the venom of the southern copperhead snake It degrades fibrin directly and achieves thrombolysis independent It degrades fibrin directly and achieves thrombolysis independent
of plasmin formationof plasmin formation its thrombolytic activity appears to be localized to the site of its thrombolytic activity appears to be localized to the site of
delivery These properties should theoretically result in faster delivery These properties should theoretically result in faster recanalization and lower hemorrhagic conversion riskrecanalization and lower hemorrhagic conversion risk
Anti-fibrinolyticsAnti-fibrinolytics
to limit fibrinolytic activityto limit fibrinolytic activity -aminocaproic acid (EACA) -aminocaproic acid (EACA) competitively inhibitscompetitively inhibits plasminogen and plasminogen activators from plasminogen and plasminogen activators from
binding to fibrinbinding to fibrin
alpha2-antiplasminalpha2-antiplasmin a serine protease inhibitor that a serine protease inhibitor that neutralizes any free circulating plasminneutralizes any free circulating plasmin
Plasminogen activator inhibitor-1Plasminogen activator inhibitor-1 a serine protease a serine protease inhibitor that inhibits tissue-type plasminogen inhibitor that inhibits tissue-type plasminogen activatoractivator
Glycoprotein (GP) IIbIIIa antagonistsGlycoprotein (GP) IIbIIIa antagonists
such as ReoPro (abciximab) Integrilin such as ReoPro (abciximab) Integrilin (eptifibatide) or Aggrastat (tirofiban) in (eptifibatide) or Aggrastat (tirofiban) in ischemic stroke remains investigational ischemic stroke remains investigational Deshmukh et al38 reported 21 patients with Deshmukh et al38 reported 21 patients with large-vessel occlusion refractory to IAT with large-vessel occlusion refractory to IAT with rtPA who were treated with IV andor IA rtPA who were treated with IV andor IA abciximab eptifibatide or tirofiban abciximab eptifibatide or tirofiban
IA Mechanical Approaches in Acute Ischemic Stroke IA Mechanical Approaches in Acute Ischemic Stroke Mechanical strategies have several advantagesMechanical strategies have several advantages First they lessen and may even preclude the use of chemical First they lessen and may even preclude the use of chemical
thrombolytics in this manner very likely reducing the risk of ICHthrombolytics in this manner very likely reducing the risk of ICH Second by avoiding the use of chemical thrombolytics it is Second by avoiding the use of chemical thrombolytics it is
possible to extend the treatment window beyond the limit of 6ndash8 possible to extend the treatment window beyond the limit of 6ndash8 hours hours
Third mechanically fragmenting a clot increases the surface area Third mechanically fragmenting a clot increases the surface area accessible to fibrinolytic agents and allows inflow of fresh accessible to fibrinolytic agents and allows inflow of fresh plasminogen which in turn may increase the speed of plasminogen which in turn may increase the speed of thrombolysis thrombolysis
Finally clot-retrieval devices may provide faster recanalization Finally clot-retrieval devices may provide faster recanalization
The disadvantages of the mechanical The disadvantages of the mechanical approaches approaches technical difficulty of navigating mechanical technical difficulty of navigating mechanical
devices into the intracranial circulation excessive devices into the intracranial circulation excessive trauma to the vasculature (potentially leading to trauma to the vasculature (potentially leading to vasospasm vessel dissection perforation or vasospasm vessel dissection perforation or rupture) rupture)
fragmented thrombus causing distal embolization fragmented thrombus causing distal embolization into previously unaffected territories into previously unaffected territories
Nevertheless the advantages of mechanical stroke Nevertheless the advantages of mechanical stroke therapy appear to significantly outweigh its therapy appear to significantly outweigh its disadvantages and risksdisadvantages and risks
Contraindications to Thrombolytic Contraindications to Thrombolytic agents agents
Recent thoracic abdominal or Recent thoracic abdominal or intracranial surgeryintracranial surgery
Recent haemorrhagic CVA Head injury Recent haemorrhagic CVA Head injury or neoplasmor neoplasm
Bleeding ulcerBleeding ulcer Anticipated invasive procedures (arterial Anticipated invasive procedures (arterial
punctures biopsies)punctures biopsies) Concurrent hemostatic dysfunctionConcurrent hemostatic dysfunction
Monitoring of thrombolytic Monitoring of thrombolytic therapytherapy
Thrombin time Measures the availability of functional
fibrinogen Normal thrombin time is 10-14 sec Prolonged when fibrinogen level is below
75-100 mgdl
Half Life of ThrombolyticsHalf Life of ThrombolyticsAgent Administration Half Life
Streptokinase IA 60-80min
Urokinase IAIV 9-12min
rTPA IAIV 6min
Abciximab(Reopro) IAIV 12hour
Aspirin POIV 15-20min
Heparin IVSC 60min
Coumadin PO 15-25 days
Anti Platelet DrugsAnti Platelet DrugsDrug Drug Mechanism Mechanism UsesUsesAspirinAspirin Permanently inhibits Permanently inhibits
COX-1 and COX-2COX-1 and COX-2CADCAD
Stroke-TIAsStroke-TIAs
NSAIDsNSAIDs Reversibly inhibits Reversibly inhibits COX-1COX-1
LimitedLimited
DipyridamoleDipyridamole Inhibits PDE increases Inhibits PDE increases cAMPcAMP
TIAsTIAs
ThenopyridinesThenopyridines
(Ticlopidine(Ticlopidine
ClopidrgrelClopidrgrel))
Inhibits ADP Inhibits ADP
PlatAg PlatAg
TIAsStrokeTIAsStroke
CAD PVDCAD PVD
Abciximab (ReoPro)Abciximab (ReoPro)
Eptifibatide (Integrilin)Eptifibatide (Integrilin)
TirofibanTirofiban
GP IIBIIIA InhibitorsGP IIBIIIA Inhibitors
Stroke- TIAs Stroke- TIAs
MonitoringMonitoring
Bleeding timeBleeding time
Optical aggregometryOptical aggregometry
Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay
Bleeding timeBleeding time
Requires a skin incision (usually made on the ear lobe or Requires a skin incision (usually made on the ear lobe or forearm offorearm of
a depth that results in disruption of capillary loops and a depth that results in disruption of capillary loops and small vessels)small vessels)
AdvantagesAdvantages Universally availableUniversally available Relatively simple techniquesRelatively simple techniques Can be performed bedsideCan be performed bedside
DisadvantagesDisadvantages Insensitive inaccurate non-specific techniqueInsensitive inaccurate non-specific technique
Poorly reproducible (as depends on multiple variables)Poorly reproducible (as depends on multiple variables)
Optical aggregometryOptical aggregometry
Gold standard assay for platelet functionGold standard assay for platelet function Agonist induced aggregation is measuredAgonist induced aggregation is measured Different agonist are available for different Different agonist are available for different
agentsagents However require unique expertise and are not However require unique expertise and are not
universally availableuniversally available Aspirin measured with ADP or AA(gt70 Aspirin measured with ADP or AA(gt70
aggregation so resistance)aggregation so resistance) Clopidogrel( ADP gt 90 aggregation means Clopidogrel( ADP gt 90 aggregation means
resistance) resistance)
Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay
Can be performed bed sideCan be performed bed side Different assay devices with different Different assay devices with different
agonist are used for each of different agonist are used for each of different antiplatelet agents antiplatelet agents
For Aspirin AA is used (result is reported as aspirin For Aspirin AA is used (result is reported as aspirin reaction units [ARU] ARUgt 550 indicates non-reaction units [ARU] ARUgt 550 indicates non-responsiveness)responsiveness)
Verify IIbIIIa assay device uses TRAP as agonist for Verify IIbIIIa assay device uses TRAP as agonist for Abciximab and TirofibanAbciximab and Tirofiban
Practical Applications Practical Applications related to specific related to specific
Neurovascular Neurovascular interventionsinterventions
Acute ischemic StrokeAcute ischemic Stroke When an artery occludes neurons are affected When an artery occludes neurons are affected
differently depending upon the amount of residual blood differently depending upon the amount of residual blood flowflow
Normal cerebral blood flow is greater than 50 mL100 Normal cerebral blood flow is greater than 50 mL100 mgminmgmin
Once blood flow decreases to less than 20 mL100 Once blood flow decreases to less than 20 mL100 mgmin infarction occursmgmin infarction occurs
If blood flow decreases to less than 10 mL100 mgmin If blood flow decreases to less than 10 mL100 mgmin irreversible neuronal death occurs rapidly irreversible neuronal death occurs rapidly
Blood flow between 11 and 20 mL100 mgmin is thought Blood flow between 11 and 20 mL100 mgmin is thought to represent the ischemic penumbra an area where the to represent the ischemic penumbra an area where the cells are functionally silent because of ischemia but are cells are functionally silent because of ischemia but are still able to recover if blood flow is restored still able to recover if blood flow is restored
Many acute stroke therapies are targeted toward Many acute stroke therapies are targeted toward restoring flow or function to the ischemic penumbrarestoring flow or function to the ischemic penumbra
Therapeutic window in Therapeutic window in management of acute Ischemic management of acute Ischemic
StrokeStrokeThe early diagnosis of ischemic stroke is critical to the The early diagnosis of ischemic stroke is critical to the
with only a narrow therapeutic window in the first few with only a narrow therapeutic window in the first few hours following stroke ictushours following stroke ictus
Diagnosis in the first 3 hours postictus provides the Diagnosis in the first 3 hours postictus provides the opportunity for intravenous or intraarterial thrombolysis opportunity for intravenous or intraarterial thrombolysis and intra-arterial clot mechanical treatment which and intra-arterial clot mechanical treatment which improve the outcome improve the outcome
Diagnosis in the time period between 3 and 6 hours Diagnosis in the time period between 3 and 6 hours provides an opportunity for intra-arterial thrombolysis provides an opportunity for intra-arterial thrombolysis and mechanical treatment and mechanical treatment
Involvement of the posterior circulation especially the Involvement of the posterior circulation especially the basilar artery is treated by some regardless of time of basilar artery is treated by some regardless of time of onset or up until 12 to 24 hours in some practices This is onset or up until 12 to 24 hours in some practices This is related to the potentially high mortality and morbidity related to the potentially high mortality and morbidity associated with basilar artery thrombosisassociated with basilar artery thrombosis
Infarct evaluation on angiographyInfarct evaluation on angiography(CT angiography and catheter (CT angiography and catheter
angiography)angiography)CTA is an excellent first-line examination for CTA is an excellent first-line examination for
evaluation of the head and neck arteries evaluation of the head and neck arteries In comparison with catheter angiography In comparison with catheter angiography
what it gives up in resolution and dynamic what it gives up in resolution and dynamic properties it makes up for with rapid properties it makes up for with rapid acquisition of a 3-D dataset and the potential acquisition of a 3-D dataset and the potential for assessment of whole-brain perfusion and for assessment of whole-brain perfusion and better parenchymal evaluationbetter parenchymal evaluation
Moreover CTA illustrates not only arterial Moreover CTA illustrates not only arterial stenosis or occlusion but also the vessel wall stenosis or occlusion but also the vessel wall This factor is most important for evaluation of This factor is most important for evaluation of intramural dissection and thrombosed intramural dissection and thrombosed aneurysms which may both complicate aneurysms which may both complicate evaluation of stroke patientsevaluation of stroke patients
Early angiographic signs of strokes Early angiographic signs of strokes both CTA both CTA and DSA and DSA
Vessel occlusion or cutoff related to Vessel occlusion or cutoff related to thromboembolithromboemboli
aneurysms aneurysms arterial dissection arterial dissection Meniscus or flattened shape to clot Meniscus or flattened shape to clot
(recent) versus reverse meniscus (older)(recent) versus reverse meniscus (older) tram track (nonocclusive or recanalized tram track (nonocclusive or recanalized
clot) clot) delayed (antegrade) flow (manifest as delayed (antegrade) flow (manifest as
decreased whole-brain perfusion on CTA)decreased whole-brain perfusion on CTA) retrograde collateral flowretrograde collateral flow
Non-occlusive left MCA thrombus on 3-D imaging performed from CTA source data and was confirmed at catheter angiography
Therapy to be started within a 6-hr Therapy to be started within a 6-hr time to treatment (TTT) window time to treatment (TTT) window (while in case of IV thrombolysis (while in case of IV thrombolysis therapy to be started with in 3hrs)therapy to be started with in 3hrs)
Exclusion criteria Exclusion criteria Rapidly improving neurologic deficit or Rapidly improving neurologic deficit or Sustained blood pressure of gt180100 Sustained blood pressure of gt180100 Hemorrhage is detected on CTHemorrhage is detected on CT Infarct involving gt more than 13 rd Infarct involving gt more than 13 rd
territory of MCAterritory of MCA MRADWI-Perfusion mismatchlt 20MRADWI-Perfusion mismatchlt 20 Definite hypodensity on CTDefinite hypodensity on CT
Intra-arterial Thrombolysis
Fibrinolytics + AntiplateletsFibrinolytics + Antiplatelets
PlasminogenPlasminogen activators through fibrinolysis exposes activators through fibrinolysis exposes free thrombin and paradoxically stimulatesfree thrombin and paradoxically stimulates platelet platelet aggregation which leads to formation of aaggregation which leads to formation of a platelet platelet thrombus (white clot) thrombus (white clot)
This new thrombus is relatively resistant to This new thrombus is relatively resistant to fibrinolyticsfibrinolytics
So new regimen in case of acute stroke isSo new regimen in case of acute stroke is fibrinolytics + antiplatelet drugsfibrinolytics + antiplatelet drugs
rtPA + IIbIIIa inhibitors( tirofiban rtPA + IIbIIIa inhibitors( tirofiban abciximab) orabciximab) or
Urokinase + IIbIIIa Urokinase + IIbIIIa inhibitors( tirofiban abciximab)inhibitors( tirofiban abciximab)
Intra-arterial Thrombolysis Tirofiban (04 microgkgmin bolus for 3 min followed by Tirofiban (04 microgkgmin bolus for 3 min followed by
0125 ugkgmin)0125 ugkgmin)
++
Heparin (2000ndash3000 IU bolus followed by Heparin (2000ndash3000 IU bolus followed by 1000 IUhour infusion 1000 IUhour infusion
with ACT maintained bw 200-300) throughout the with ACT maintained bw 200-300) throughout the interventional procedure and for 24ndash48 hours thereafter when interventional procedure and for 24ndash48 hours thereafter when there is neither intraprocedural bleeding nor suspicion of there is neither intraprocedural bleeding nor suspicion of increased risk of bleeding increased risk of bleeding
Maximum dose of Urokinase Maximum dose of Urokinase Anterior circulation stroke - 500000 IU (mean 400000 Anterior circulation stroke - 500000 IU (mean 400000
IU range 300000ndash500000 IU)IU range 300000ndash500000 IU) Posterior circulation stroke -1000000 IU (mean 837000 Posterior circulation stroke -1000000 IU (mean 837000
IU range 300000ndash1000000 IU)IU range 300000ndash1000000 IU)American Journal of NeuroradiologyAmerican Journal of Neuroradiology 262595-2601 2005262595-2601 2005
Intravenous ThrombolysisIntravenous Thrombolysis
The first method to restore cerebral The first method to restore cerebral perfusion is clot lysis with the goal perfusion is clot lysis with the goal of re-establishing blood flow to the of re-establishing blood flow to the affected tissue affected tissue
IV thrombolysis rt-PA is the only IV thrombolysis rt-PA is the only FDA- approved treatment for AIS FDA- approved treatment for AIS
Fibrinolysis is enhanced powerfully Fibrinolysis is enhanced powerfully by rt-PAby rt-PA
Intravenous rTPA Intravenous rTPA administration administration protocolprotocol
Total dose of rt-PA 09 mgkg (maximum dose Total dose of rt-PA 09 mgkg (maximum dose 90 mg)90 mg)
Give 10 as initial IV bolusGive 10 as initial IV bolus Infuse remainder over 1 hourInfuse remainder over 1 hour Admit patient to an ICU or stroke unit for Admit patient to an ICU or stroke unit for
monitoringmonitoring Neurologic assessments every 15 minutes Neurologic assessments every 15 minutes
during infusion then every 30 minutes for next during infusion then every 30 minutes for next 6 hours then every hour until 24hours after 6 hours then every hour until 24hours after treatmenttreatment
Favorable Outcome vs Treatment Time Favorable Outcome vs Treatment Time with IV rTPAwith IV rTPA
Protocol limit = 3 hrs
Benefit ~ 45 hrs
Thromboembolism During coilingThromboembolism During coiling Most feared and frequent complication Most feared and frequent complication Reported incidence - Approx 7 Reported incidence - Approx 7 SourcesSources of Thromboembolism are of Thromboembolism are
- Clots at the aneurysmal neck during or immediately- Clots at the aneurysmal neck during or immediately after after embolization embolization
- Thrombus forming on catheters during- Thrombus forming on catheters during proceduresprocedures
- Stenosis of an adjacent artery dt coil mass- Stenosis of an adjacent artery dt coil mass or herniationor herniation
- Migration of intraaneurysmal- Migration of intraaneurysmal thrombus during coil thrombus during coil placement placement
- Slow flow dt vasospasm - Slow flow dt vasospasm
- Rare and unlikely causes are hypercoagulable- Rare and unlikely causes are hypercoagulable state such state such as antiphospholipid antibody syndrome or due to HITas antiphospholipid antibody syndrome or due to HIT
Occur more often with wide-necked aneurysms (dt Occur more often with wide-necked aneurysms (dt increased exposed surface area of thrombogenic coil increased exposed surface area of thrombogenic coil material)material)
Current regimen of endovascular Current regimen of endovascular managementmanagement
The The glycoprotein IIbIIIa antagonist tirofiban glycoprotein IIbIIIa antagonist tirofiban (04 (04 microgkgmin bolus for 30 minutes followed by infusion of microgkgmin bolus for 30 minutes followed by infusion of 0125 ugkgmin until the thrombus dissolved) 0125 ugkgmin until the thrombus dissolved)
Intraarterial thrombolysis with Intraarterial thrombolysis with urokinase or r- TPA urokinase or r- TPA increase of intravenous (IV) heparin (measured by increase of intravenous (IV) heparin (measured by
ACT) ACT) Intravenous aspirin Intravenous aspirin
Coil-related platelet aggregation (white clot) is Coil-related platelet aggregation (white clot) is unlikely to respond to fibrinolytics but has a high risk unlikely to respond to fibrinolytics but has a high risk of hemorrhage (In ISAT) all 5 patients who had of hemorrhage (In ISAT) all 5 patients who had received thrombolytic therapy with tPA to treat a received thrombolytic therapy with tPA to treat a thromboembolic complication after endovascular thromboembolic complication after endovascular treatment rebleed and all of these patients died)treatment rebleed and all of these patients died)
IntracranialIntracranial Stenting Stenting Metallic foreign body such as stent will accumulate Metallic foreign body such as stent will accumulate
thrombus in the absence of platelet inhibitionthrombus in the absence of platelet inhibition Antiplatelet drugs are important to prevent peri or Antiplatelet drugs are important to prevent peri or
post-interventional thromboembolic eventspost-interventional thromboembolic events Optimal treatment regimens has not been determined Optimal treatment regimens has not been determined
but usually but usually Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-
procedureprocedureOrOr
Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on
morning of proceduremorning of procedure
If need to use stent is not pre-planned thanIf need to use stent is not pre-planned than
Abciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkgAbciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkg IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)
Glycoprotein IIbIIIa inhibitor are not used routinely during elective Glycoprotein IIbIIIa inhibitor are not used routinely during elective stenting procedure dt increased risk of ICH stenting procedure dt increased risk of ICH
Carotid StentingCarotid Stenting
Pre-procedurePre-procedure
Double Antiplatelet therapy is routinely given Double Antiplatelet therapy is routinely given beginning at least 3beginning at least 3
days before the proceduredays before the procedure
Aspirin 325mgd+Clopidogrel 75mgdAspirin 325mgd+Clopidogrel 75mgd During procedureDuring procedure
Heparin is given with target clotting time of 250-Heparin is given with target clotting time of 250-300sec300sec
Post-procedure Post-procedure
Aspirin 325mg is continued indefinitely and Aspirin 325mg is continued indefinitely and
Clopidogrel 75mgd for at least 6 weeks Clopidogrel 75mgd for at least 6 weeks
Inclusion criteria for Local ThrombolysisInclusion criteria for Local Thrombolysis a)a) Patients in severe clinical grade on admission Patients in severe clinical grade on admission
with evidence of dural venous sinus with evidence of dural venous sinus thrombosis and restrictive venous outflow on thrombosis and restrictive venous outflow on cerebral angiogramcerebral angiogram
b)b) Patients in clinical grade 3 worsening on Patients in clinical grade 3 worsening on heparin therapy Restriction to venous heparin therapy Restriction to venous outflow was defined as an increase in brain outflow was defined as an increase in brain circulation time gt 12 s delay in the drainage circulation time gt 12 s delay in the drainage of cortical veins with cortical veins hanging of cortical veins with cortical veins hanging in spacein space
Treatment Options for Venous Thrombosis
CT Grading for Venous ThrombosisCT Grading for Venous Thrombosis Grade I no parenchymal change Grade I no parenchymal change
(hyperdense (hyperdense sinuses cortical veins empty sinuses cortical veins empty delta sign)delta sign)
Grade II non hemorrhagic venous infarct Grade II non hemorrhagic venous infarct without mass effect without mass effect
Grade III non-hemorrhagic infarct with Grade III non-hemorrhagic infarct with mass effectmass effect
Grade IV hemorrhagic venous infarct (max Grade IV hemorrhagic venous infarct (max diameter lt 3 cm) with no mass effectdiameter lt 3 cm) with no mass effect
Grade V hemorrhagic venous infarct (max Grade V hemorrhagic venous infarct (max diameter gt 3 cm) with mass effect diameter gt 3 cm) with mass effect
Local ThrombolysisLocal Thrombolysis
Femoral Jugular access was secured and a guiding Femoral Jugular access was secured and a guiding catheter was placed in the jugular bulb catheter was placed in the jugular bulb Mechanical Mechanical clot maceration clot maceration was done with the guidewire was done with the guidewire following which a microcatheter (was navigated and following which a microcatheter (was navigated and placed in the thrombosed segment of sinus confirmed placed in the thrombosed segment of sinus confirmed on a selective venogram on a selective venogram
Urokinase infusion Bolus dose of 2-6 lacs followed Urokinase infusion Bolus dose of 2-6 lacs followed by 60000 to 100000 units per hour along with by 60000 to 100000 units per hour along with periodic check venogram Along with maintenance periodic check venogram Along with maintenance systemic infusion of Heparinsystemic infusion of Heparin Other agents such as Other agents such as streptokinase altepase or rTPAstreptokinase altepase or rTPA can be also used can be also used
After thrombolysis patient should subjected to oral After thrombolysis patient should subjected to oral anticoagulation for six monthsanticoagulation for six months
Low-molecular-weight Low-molecular-weight heparinheparin
PharmacologyPharmacologyLMWH as its name suggests is a glycosaminoglycan that is approximatelyLMWH as its name suggests is a glycosaminoglycan that is approximately
one third the molecular weight of UFH It is derived from UFH through one third the molecular weight of UFH It is derived from UFH through variousvarious
depolymerization processes LMWH binds to antithrombin which in turn depolymerization processes LMWH binds to antithrombin which in turn
Neutralizes actors Xa and IIa Because LMWH lacks many of the longer Neutralizes actors Xa and IIa Because LMWH lacks many of the longer chains chains
required for binding to thrombin it has less ability to neutralize thrombin required for binding to thrombin it has less ability to neutralize thrombin
relativeto its ability to neutralize factor Xa LMWH also has less relativeto its ability to neutralize factor Xa LMWH also has less nonspecific nonspecific
binding to other proteins There is greater bioavailability with more binding to other proteins There is greater bioavailability with more predictable predictable
pharmacokinetics that eliminates the need for monitoring The smaller pharmacokinetics that eliminates the need for monitoring The smaller size also size also
allows for enhanced subcutaneous absorption when compared with UFHallows for enhanced subcutaneous absorption when compared with UFH
Three LMWH preparations are Three LMWH preparations are currently approved for use in the currently approved for use in the United States (1) enoxaparin (2) United States (1) enoxaparin (2) dalteparin and (3) tinzaparin dalteparin and (3) tinzaparin
They are all administered They are all administered subcutaneously at intervals of either subcutaneously at intervals of either once or twice daily for both once or twice daily for both prophylaxis and treatment dosesprophylaxis and treatment doses
Few Experiences of Few Experiences of ThrombolysisThrombolysis
Vickey 25 Yrs male patient presented Vickey 25 Yrs male patient presented with 12with 12thth day HO severe headache with day HO severe headache with right sided hemiplegiaright sided hemiplegia
MRI shows thrombosis of the superior MRI shows thrombosis of the superior sagittal left transverse left sigmoid sagittal left transverse left sigmoid sinuses and cortical veins in the fronto-sinuses and cortical veins in the fronto-parietal regions with eo haemorrhagic parietal regions with eo haemorrhagic infarct in the left cerebral hemisphere infarct in the left cerebral hemisphere with mass effect( Grade ndashV)with mass effect( Grade ndashV)
Sashi Srivastava 64 yrs FSashi Srivastava 64 yrs F In a follow up case of MRD with infra-renal In a follow up case of MRD with infra-renal
aortic abdominal and bilateral renal artery aortic abdominal and bilateral renal artery thrombosis renal angiogram shows filling thrombosis renal angiogram shows filling defects in the right Renal artery defects in the right Renal artery
Initially Renal angioplasty was done Initially Renal angioplasty was done Following angioplasty few thrombi are seem Following angioplasty few thrombi are seem to extends into the segmental branches and to extends into the segmental branches and causing blockage So Thrombolysis was causing blockage So Thrombolysis was plane to dissolve the run-out thrombi with plane to dissolve the run-out thrombi with urokinase urokinase
Rakesh 34yrsMRakesh 34yrsM Left SFA pseudoaneurysm with Left SFA pseudoaneurysm with
Covered stent placementCovered stent placement Pre operative antiplatelets with post Pre operative antiplatelets with post
procedure heparin Tirofiban procedure heparin Tirofiban followed by aspirin and clopidogrel followed by aspirin and clopidogrel were usedwere used
IAT may be a treatment option for selected patients IAT may be a treatment option for selected patients Possible selection criteria include Possible selection criteria include
presentation between 3 and 6 hours from symptom onsetpresentation between 3 and 6 hours from symptom onset major cerebral artery occlusion major cerebral artery occlusion severe neurologic deficits severe neurologic deficits high risk of systemic hemorrhage with IV rt-PA (eg recent high risk of systemic hemorrhage with IV rt-PA (eg recent
surgery) surgery) The MERCI (Mechanical Embolus Removal in Cerebral The MERCI (Mechanical Embolus Removal in Cerebral
Ischemia) retrievalIschemia) retrieval system system
Has been FDA-approved for recanalizing acutely occluded Has been FDA-approved for recanalizing acutely occluded cerebral arteries cerebral arteries
In the Multi-MERCI study patients who did not improve In the Multi-MERCI study patients who did not improve immediately after IV rt-PA underwent mechanical immediately after IV rt-PA underwent mechanical embolectomy within 8 hours of symptom onset embolectomy within 8 hours of symptom onset
Partial or complete recanalization occurred in 74 of Partial or complete recanalization occurred in 74 of patientspatients
with a symptomatic intracerebral hemorrhage (sICH) rate of with a symptomatic intracerebral hemorrhage (sICH) rate of 67 67
Mechanical embolectomy with the MERCI retriever may be a Mechanical embolectomy with the MERCI retriever may be a feasible and safe option for patients after IV rt-PAfeasible and safe option for patients after IV rt-PA
Penumbra stroke systemPenumbra stroke system This device combines two methods of clot This device combines two methods of clot
extraction aspiration and mechanical extraction aspiration and mechanical extraction extraction
First the clot is aspirated then a thrombus First the clot is aspirated then a thrombus removal ring can be used if necessary to removal ring can be used if necessary to remove remaining clot remove remaining clot
successful recanalizing 82successful recanalizing 82 Bridging therapyBridging therapy
06 mgkg IV rt-PA followed by IAT with IA rt-06 mgkg IV rt-PA followed by IAT with IA rt-PA (up to 20 mg)PA (up to 20 mg)
achieved a higher recanalization rateachieved a higher recanalization rate
Criteria for thrombolysis with rTPACriteria for thrombolysis with rTPA
Inclusion criteriaInclusion criteria Clinical signs and symptoms consistent with ischemic Clinical signs and symptoms consistent with ischemic
strokestroke Patient last seen normal within 3 hoursPatient last seen normal within 3 hours Measurable neurologic deficitMeasurable neurologic deficit
Exclusion criteriaExclusion criteria Any hemorrhage on neuroimaging (CT or MRI)Any hemorrhage on neuroimaging (CT or MRI) Symptoms suggestive of subarachnoid hemorrhageSymptoms suggestive of subarachnoid hemorrhage Seizure at stroke onset that is thought to contribute to Seizure at stroke onset that is thought to contribute to
neurologic deficitneurologic deficit Hypodensity greater than one third cerebral hemisphere Hypodensity greater than one third cerebral hemisphere
on CTon CT SBP greater than 185 mm Hg or DBP greater than 110 SBP greater than 185 mm Hg or DBP greater than 110
mm Hgmm Hg International normalized ratio (INR) greater than 17International normalized ratio (INR) greater than 17
Ischemic Stroke Ischemic Stroke Treatment ndash 2006Treatment ndash 2006
IV tissue plasminogen activator (tPA)IV tissue plasminogen activator (tPA) ndash ndash Only FDA-approved acute stroke drugOnly FDA-approved acute stroke drug ndash ndash 3 hour treatment window3 hour treatment window
MERCI - Concentric clot retrieval MERCI - Concentric clot retrieval devicedevice ndash ndash Rescue therapy - approved 2004Rescue therapy - approved 2004 ndash ndash Device approval (not outcomes-based)Device approval (not outcomes-based)
Off label approachesOff label approaches ndash ndash IV tPA after 3 hoursIV tPA after 3 hours ndash ndash IV-IA tPA sequential strategiesIV-IA tPA sequential strategies ndash ndash IA tPA clot angioplasty fragmentationIA tPA clot angioplasty fragmentation ndash ndash Ultrasound-assisted tPA lysisUltrasound-assisted tPA lysis
rt-PA Trials NINDSrt-PA Trials NINDS
Acute stroke - 624 patientsAcute stroke - 624 patients Treat within 3 hrsTreat within 3 hrs Intravenous 09 mgkg rt-PA vs placeboIntravenous 09 mgkg rt-PA vs placebo Hemorrhage 64 tPA 06 placeboHemorrhage 64 tPA 06 placebo Neurologic recovery better with tPA 30 Neurologic recovery better with tPA 30
more like to have minimal or no disabilitymore like to have minimal or no disability
First proven approved treatment for First proven approved treatment for strokestroke
Limitations of tPALimitations of tPA Only 4 of acute strokes receive tPAOnly 4 of acute strokes receive tPA (Kleindorfer et al Stroke 2004 35 e27-e29)(Kleindorfer et al Stroke 2004 35 e27-e29)
Only 22 of patients present within 3 hoursOnly 22 of patients present within 3 hours1048707 1048707 51 of these ineligible due to51 of these ineligible due to
bull bull Mild severityMild severity bull bull Medical or surgical historyMedical or surgical history bull bull Blood testsBlood tests
Sustained recanalization only 13Sustained recanalization only 13 (Alexandrov et al NEJM 2004 351 2170-8)(Alexandrov et al NEJM 2004 351 2170-8)
Concern for hemorrhageConcern for hemorrhage tPA potentiates apoptotic injury tPA potentiates apoptotic injury (Liu et al Nature Med 2004 101379-83)(Liu et al Nature Med 2004 101379-83)
PROACT II IA Lysis TrialPROACT II IA Lysis Trial Baseline 24 hours 8 days
Baseline 60 minutes 120 minutes
9mg IAProurokinase
Desmoteplase Trials DEDAS Desmoteplase Trials DEDAS DIASDIAS
Trial OverviewTrial Overview Double blind randomized placebo Double blind randomized placebo
controlled trialscontrolled trials IV delivery 3-9 hour time windowIV delivery 3-9 hour time window Plasminogen activator ndash from Plasminogen activator ndash from vampire bat vampire bat
salivasaliva Selection based on PWI-DWI MismatchSelection based on PWI-DWI Mismatch
MRI InclusionMRI Inclusion PWI defect at least 2 cm AND ~20 larger PWI defect at least 2 cm AND ~20 larger
than DWIthan DWI PWI should be obvious even visible on PWI should be obvious even visible on
raw imagesraw imagesMRI ExclusionMRI Exclusion
DWI gt 13 MCADWI gt 13 MCA MRA ICA occlusionMRA ICA occlusion
Desmoteplase ndash DIAS Desmoteplase ndash DIAS ResultsResults
Mechanical Thrombolysis Mechanical Thrombolysis devicesdevices
mechanical thrombolysis potentially extends the treatment mechanical thrombolysis potentially extends the treatment window because they act promptly at the site of the thrombuswindow because they act promptly at the site of the thrombus
The devices can retrieve large clots that pharmaceutical agents The devices can retrieve large clots that pharmaceutical agents may not successfully lysemay not successfully lyse
Patients treated with IV tPA may be considered for treatment of Patients treated with IV tPA may be considered for treatment of residual clot with some of these devicesresidual clot with some of these devices
suction-creating saline jets suction-creating saline jets laser energy ultrasound laser energy ultrasound a corkscrew apparatus to treat strokesa corkscrew apparatus to treat strokes The AngioJet systemThe AngioJet system uses saline jets that are directed back into the catheter to uses saline jets that are directed back into the catheter to
create a low-pressure zone around the catheter tip inducing create a low-pressure zone around the catheter tip inducing suction suction
The clot is pulled into the exhaust lumen and removed from the The clot is pulled into the exhaust lumen and removed from the vessel Although US Food and Drug Administration (FDA) has vessel Although US Food and Drug Administration (FDA) has approved this device for use in arteriovenous dialysis grafts and approved this device for use in arteriovenous dialysis grafts and fistulae and for the treatment of coronary arteries saphenous fistulae and for the treatment of coronary arteries saphenous vein grafts and peripheral vessels clinical trials for the vein grafts and peripheral vessels clinical trials for the treatment of acute stroke are no longer in progress treatment of acute stroke are no longer in progress
Most devices are used in cerebral vessels that 2-5 mm
The Latis laser device The Latis laser device used laser energy to ablate clots used laser energy to ablate clots Arteries 2-5 mm in diameter could be Arteries 2-5 mm in diameter could be
treated including the ICA M1 or M2 treated including the ICA M1 or M2 branch of the MCA A1 branch of the branch of the MCA A1 branch of the anterior cerebral artery (ACA) basilar anterior cerebral artery (ACA) basilar artery posterior cerebral artery (PCA) artery posterior cerebral artery (PCA) and vertebral and vertebral
Patients could receive treatment as late Patients could receive treatment as late as 8 hours after symptom onset in the as 8 hours after symptom onset in the anterior circulation and within 24 hours in anterior circulation and within 24 hours in the posterior circulation the posterior circulation
Endovascular Photo Acoustic Endovascular Photo Acoustic Recanalization (EPAR) Recanalization (EPAR)
A laser power source generated energy for the A laser power source generated energy for the systemsystem
The energy was delivered by means of The energy was delivered by means of fiberoptics to the tip of the catheter at the fiberoptics to the tip of the catheter at the treatment sitetreatment site
Absorption of laser light by darkly pigmented Absorption of laser light by darkly pigmented materials (ie the clot) occurred inside the 1-mm materials (ie the clot) occurred inside the 1-mm catheter tipcatheter tip
the system was designed to minimize scattering the system was designed to minimize scattering of laser light of laser light
Absorption converted photo energy to acoustic Absorption converted photo energy to acoustic energy which then emulsified the clot inside the energy which then emulsified the clot inside the catheter tip catheter tip
EKOS ultrasound( the EKOS ultrasound( the Ultrasound Thrombolytic Ultrasound Thrombolytic
Infusion Catheter) Infusion Catheter) combines the use of a distal ultrasound transducer with combines the use of a distal ultrasound transducer with
infusion of a thrombolytic agent through the infusion of a thrombolytic agent through the microcathetermicrocatheter
Ultrasound changes the structure of the clot to Ultrasound changes the structure of the clot to temporarily increase its permeability while providing an temporarily increase its permeability while providing an acoustic pressure gradient to move the drug into the clot acoustic pressure gradient to move the drug into the clot to speed its dissolution to speed its dissolution
The EKOS catheter is placed in the proximal portion of the The EKOS catheter is placed in the proximal portion of the clot clot
After a 2-mg bolus of tPA was injected through the After a 2-mg bolus of tPA was injected through the catheter catheter
the patient received a continuous infusion of IA tPA 03 the patient received a continuous infusion of IA tPA 03 mgmin to a maximum of 20 mg and simultaneous mgmin to a maximum of 20 mg and simultaneous ultrasound transmission for as long as 60 minutes ultrasound transmission for as long as 60 minutes
One patient was treated with a total of 4 units of One patient was treated with a total of 4 units of recombinant reteplase (Retavase) hand-injected over 60 recombinant reteplase (Retavase) hand-injected over 60 minutes minutes
Penumbra system Penumbra system The Penumbra system (Penumbra Inc) provides a dual The Penumbra system (Penumbra Inc) provides a dual
approach to clot extraction using aspiration followed by approach to clot extraction using aspiration followed by clot retrieval with a ring device if needed clot retrieval with a ring device if needed
Mechanical Embolus Removal in Cerebral Ischemia Mechanical Embolus Removal in Cerebral Ischemia (MERCI)(MERCI)
a corkscrew-like apparatus to remove blood clots from a corkscrew-like apparatus to remove blood clots from the brain in patients experiencing an ischemic stroke the brain in patients experiencing an ischemic stroke
The corkscrew itself resides in the catheter tip which The corkscrew itself resides in the catheter tip which shields it from the wall of the vessel until it is ready to be shields it from the wall of the vessel until it is ready to be burrowed into the clot Once lodged in the clot the device burrowed into the clot Once lodged in the clot the device and clot are withdrawn from the vessel and clot are withdrawn from the vessel
Snarelike devicesSnarelike devices Snares such as the Neuronet snare (Guidant Snares such as the Neuronet snare (Guidant
Endovascular Santa Clara CA) have been developed Endovascular Santa Clara CA) have been developed specifically for use in the treatment of strokes specifically for use in the treatment of strokes
These devices are simple in design and do not require the These devices are simple in design and do not require the clot to be amenable to emulsification clot to be amenable to emulsification
X-Sizer deviceX-Sizer device a device with small moving blades at the a device with small moving blades at the
catheter tip catheter tip This device the X-Sizer device (EndiCor Medical This device the X-Sizer device (EndiCor Medical
San Clemente CA) can be used to excise the San Clemente CA) can be used to excise the thrombus and aspirate it thrombus and aspirate it
The device was being evaluated in randomized The device was being evaluated in randomized studies of coronary vessels and in a registry of studies of coronary vessels and in a registry of patients with acute myocardial infarctionpatients with acute myocardial infarction
Although the manufacturer had modified the Although the manufacturer had modified the device for use in cerebral vessels a safety and device for use in cerebral vessels a safety and feasibility study was indefinitely suspended after feasibility study was indefinitely suspended after only 1 patient was treated with the device in only 1 patient was treated with the device in Europe Europe
Suction thrombectomySuction thrombectomy This method of mechanical thrombolysis is one of the This method of mechanical thrombolysis is one of the
simplestsimplest In this readily available technique suction is applied with In this readily available technique suction is applied with
a syringe to remove thrombus in the ICA a syringe to remove thrombus in the ICA It requires no other devicesIt requires no other devices A catheter with a large inner diameter (Brite Tip Cordis A catheter with a large inner diameter (Brite Tip Cordis
Corporation Miami FL) was placed in the symptomatic Corporation Miami FL) was placed in the symptomatic vessel and navigated over a guidewire into the thrombusvessel and navigated over a guidewire into the thrombus
A 60-mL syringe was used to aspirate the thrombus A 60-mL syringe was used to aspirate the thrombus Each patient required angioplasty and stenting of carotid Each patient required angioplasty and stenting of carotid
bifurcation stenosis and received daily aspirin and bifurcation stenosis and received daily aspirin and ticlopidine after the procedure No complications ticlopidine after the procedure No complications occurred occurred
Summary Acute Stroke Summary Acute Stroke ImagingImaging
PhysiologyPhysiology importance collaterals importance collaterals
ndash ndashGrowing role for perfusion Growing role for perfusion assessmentassessment
tPAtPA guidelines amp limitations guidelines amp limitations Signs on CT amp MRSigns on CT amp MR follow physiology follow physiology Stroke trialsStroke trials PWI-DWI mismatch PWI-DWI mismatch
ndash ndashTreat based on physiology not timeTreat based on physiology not time ProtocolsProtocols should be fast and should be fast and
comprehensivecomprehensive
Heparin versus WarfarinHeparin versus Warfarin
Drug ActionMechan-ism
Moni-toring
Effective
HeparinDirect
Inhibition ofThrombin
ATIIIcofactor
APTTACT
Immediate
WarfarinDecreasesProductionof factors
Vitamin K PTDelay
3-5 days
INR
Recanalization or Antegrade Recanalization or Antegrade Reperfusion StrategiesReperfusion Strategies
Recanalization strategies focus on removing Recanalization strategies focus on removing andor dissolving the occlusive thrombus to re-andor dissolving the occlusive thrombus to re-establish antegrade flow Strategies may be establish antegrade flow Strategies may be classified into 7 different categories on the classified into 7 different categories on the basis of their primary mechanism of action basis of their primary mechanism of action 1) 1) IV andor intraarterial thrombolysis (IAT) IV andor intraarterial thrombolysis (IAT) 2) endovascular thrombectomy2) endovascular thrombectomy3) endovascular thromboaspiration 3) endovascular thromboaspiration 4) endovascular mechanical thrombus disruption or 4) endovascular mechanical thrombus disruption or
thromborrhexisthromborrhexis5) 5) transcranial or endovascular augmented transcranial or endovascular augmented
fibrinolysis fibrinolysis 6) endovascular thrombus entrapment and 6) endovascular thrombus entrapment and 7) temporary endovascular bypass7) temporary endovascular bypass
IAT in Acute Ischemic StrokeIAT in Acute Ischemic Stroke
IAT advantages over IV thrombolysisIAT advantages over IV thrombolysis Coaxial microcatheter techniques the occluded intracranial Coaxial microcatheter techniques the occluded intracranial
vessel is directly accessible and the fibrinolytic agent can be vessel is directly accessible and the fibrinolytic agent can be infused directly into the thrombusinfused directly into the thrombus
This permits a smaller dose of fibrinolytic agent to reach a This permits a smaller dose of fibrinolytic agent to reach a higher local concentration than that reached by systemic higher local concentration than that reached by systemic infusioninfusion
Allows more complete recanalization with lower total doses of Allows more complete recanalization with lower total doses of thrombolytic thrombolytic
With the smaller dose complications from systemic fibrinolytic With the smaller dose complications from systemic fibrinolytic effects including intracranial hemorrhage (ICH) can effects including intracranial hemorrhage (ICH) can theoretically be reduced theoretically be reduced
Treatment window for endovascular techniques can be Treatment window for endovascular techniques can be extended beyond the typical IV window of 3 hours extended beyond the typical IV window of 3 hours
IA techniques have led to higher recanalization rates than IV IA techniques have led to higher recanalization rates than IV thrombolysisthrombolysis
Major disadvantagesMajor disadvantages Relative complexity of the procedure the level Relative complexity of the procedure the level
of required technical expertise and its of required technical expertise and its relatively low availability relatively low availability
Delays in initiating treatmentDelays in initiating treatment InvasiveInvasive
ThrombolyticsThrombolytics
Plasminogen activators
Fibrinolytics
1 Plasminogen Activators 1 Plasminogen Activators drugs act by converting the inactive proenzyme drugs act by converting the inactive proenzyme plasminogen into the active enzyme plasmin Plasmin plasminogen into the active enzyme plasmin Plasmin digests fibrinogen fibrin monomers and cross-linked digests fibrinogen fibrin monomers and cross-linked fibrin (as found in a thrombus) into fibrin degradation fibrin (as found in a thrombus) into fibrin degradation productsproducts
First-Generation Agents First-Generation Agents StreptokinaseStreptokinase a protein derived from group C a protein derived from group C
szlig-hemolytic streptococci has a half-life of 16ndashszlig-hemolytic streptococci has a half-life of 16ndash90 minutes and low fibrin specificity This drug 90 minutes and low fibrin specificity This drug proved to have a very narrow therapeutic proved to have a very narrow therapeutic window and significant rates of ICH and window and significant rates of ICH and systemic hemorrhage18systemic hemorrhage18
UrokinaseUrokinase is a serine protease with a plasma is a serine protease with a plasma half life of 14 minutes and low fibrin specificity half life of 14 minutes and low fibrin specificity
The urokinase dose used in cerebral IAT has The urokinase dose used in cerebral IAT has ranged from 002 to 2 X106unitsranged from 002 to 2 X106units
Second-Generation Agents Second-Generation Agents Alteplase (rtPA) Alteplase (rtPA)
is a serine is a serine protease with a plasma half-life of 35 protease with a plasma half-life of 35 minutes and a high degree of fibrin affinity and minutes and a high degree of fibrin affinity and specificity specificity
Dose used in cerebral IAT has ranged between 20 Dose used in cerebral IAT has ranged between 20 and 60 mgand 60 mg
Disadvantages of alteplase include its relatively short Disadvantages of alteplase include its relatively short halflife and limited penetration into the clot matrix halflife and limited penetration into the clot matrix because of strong binding with surface fibrin which because of strong binding with surface fibrin which could delay recanalization and increase the risk of could delay recanalization and increase the risk of recurrent occlusion recurrent occlusion
Prourokinase (r-prourokinase) Prourokinase (r-prourokinase) is the proenzyme precursor of urokinase is the proenzyme precursor of urokinase T12 of 7 minutes and high fibrin specificity T12 of 7 minutes and high fibrin specificity
Third-Generation AgentsThird-Generation Agents
ReteplaseReteplase is a structurally modified is a structurally modified form of alteplase form of alteplase
with a longer half-life (15ndash18 minutes) In with a longer half-life (15ndash18 minutes) In addition it does not bind as highly to fibrin addition it does not bind as highly to fibrin unbound reteplase can thus theoretically better unbound reteplase can thus theoretically better penetrate the clot and potentially penetrate the clot and potentially improve in improve in vivo fibrinolytic activity vivo fibrinolytic activity
TenecteplaseTenecteplase is another modified form of rtPA with a longer is another modified form of rtPA with a longer
half-life (17 minutes)half-life (17 minutes) greater fibrin specificity and greater greater fibrin specificity and greater
resistance to plasminogen activator inhibitor-1 resistance to plasminogen activator inhibitor-1 IV tenecteplase in acute ischemic stroke IV tenecteplase in acute ischemic stroke
suggest that the drug is safe and promisingsuggest that the drug is safe and promising
Newer plasminogen activatorNewer plasminogen activator
DesmoteplaseDesmoteplase is a genetically engineered is a genetically engineered version of the clot-dissolving factor version of the clot-dissolving factor
found in the saliva found in the saliva of the vampire bat Desmodus rotundusof the vampire bat Desmodus rotundus moremore potent and more selective for fibrin-bound potent and more selective for fibrin-bound
plasminogen than any other known plasminogen plasminogen than any other known plasminogen activatoractivator
Unlike tissue plasminogen activator (tPA) desmoteplase Unlike tissue plasminogen activator (tPA) desmoteplase is not activated by fibrinogen or -amyloid proteins is not activated by fibrinogen or -amyloid proteins factors that may exacerbate the risk for ICH factors that may exacerbate the risk for ICH
The effect of IV administration of desmoteplase 3ndash9 The effect of IV administration of desmoteplase 3ndash9 hours after symptom onset in patients with stroke who hours after symptom onset in patients with stroke who present with mismatch on MR imaging or CT perfusion present with mismatch on MR imaging or CT perfusion
3 DefibrinogenatingFibrinogenolytic 3 DefibrinogenatingFibrinogenolytic Agents Agents
AncrodAncrod(Viprinex)(Viprinex) is is the purified fraction of the Malayan pit viper venomthe purified fraction of the Malayan pit viper venom It acts by directly cleaving and inactivating fibrinogen It acts by directly cleaving and inactivating fibrinogen
and thus indirectly promoting anticoagulation and thus indirectly promoting anticoagulation The reduction in the blood levels of fibrinogen also The reduction in the blood levels of fibrinogen also
leads to a reduced blood viscosity which may improve leads to a reduced blood viscosity which may improve blood flow to the affected areas of the brain blood flow to the affected areas of the brain
In the Stroke Treatment with Ancrod Trial 500 In the Stroke Treatment with Ancrod Trial 500 patients with stroke presenting within 3 hours of patients with stroke presenting within 3 hours of symptom onset were randomized to receive ancrod (symptom onset were randomized to receive ancrod (n n 248) or a placebo (n 252) Good outcome (Barthel 248) or a placebo (n 252) Good outcome (Barthel Index 95ndash100 at 3 months) was achieved in 4221 Index 95ndash100 at 3 months) was achieved in 4221 and 344 of the patients respectively and 344 of the patients respectively
2 Direct Fibrinolytics2 Direct Fibrinolytics
Microplasmin (Microplasmin (ThromboGenics Heverlee Belgium)ThromboGenics Heverlee Belgium) is a truncated form of plasmin that is more resistant to the effects is a truncated form of plasmin that is more resistant to the effects
of antiplasmin of antiplasmin microplasmin can be used upto 4ndash12 hours after stroke onset microplasmin can be used upto 4ndash12 hours after stroke onset There was no evidence of increased bleeding risk with There was no evidence of increased bleeding risk with
microplasminmicroplasmin
Alfimeprase (Nuvelo San Carlos Calif)Alfimeprase (Nuvelo San Carlos Calif) is a recombinant truncated form of fibrolase a fibrinolytic zinc metalloproteinase is a recombinant truncated form of fibrolase a fibrinolytic zinc metalloproteinase
isolated from the venom of the southern copperhead snake isolated from the venom of the southern copperhead snake It degrades fibrin directly and achieves thrombolysis independent It degrades fibrin directly and achieves thrombolysis independent
of plasmin formationof plasmin formation its thrombolytic activity appears to be localized to the site of its thrombolytic activity appears to be localized to the site of
delivery These properties should theoretically result in faster delivery These properties should theoretically result in faster recanalization and lower hemorrhagic conversion riskrecanalization and lower hemorrhagic conversion risk
Anti-fibrinolyticsAnti-fibrinolytics
to limit fibrinolytic activityto limit fibrinolytic activity -aminocaproic acid (EACA) -aminocaproic acid (EACA) competitively inhibitscompetitively inhibits plasminogen and plasminogen activators from plasminogen and plasminogen activators from
binding to fibrinbinding to fibrin
alpha2-antiplasminalpha2-antiplasmin a serine protease inhibitor that a serine protease inhibitor that neutralizes any free circulating plasminneutralizes any free circulating plasmin
Plasminogen activator inhibitor-1Plasminogen activator inhibitor-1 a serine protease a serine protease inhibitor that inhibits tissue-type plasminogen inhibitor that inhibits tissue-type plasminogen activatoractivator
Glycoprotein (GP) IIbIIIa antagonistsGlycoprotein (GP) IIbIIIa antagonists
such as ReoPro (abciximab) Integrilin such as ReoPro (abciximab) Integrilin (eptifibatide) or Aggrastat (tirofiban) in (eptifibatide) or Aggrastat (tirofiban) in ischemic stroke remains investigational ischemic stroke remains investigational Deshmukh et al38 reported 21 patients with Deshmukh et al38 reported 21 patients with large-vessel occlusion refractory to IAT with large-vessel occlusion refractory to IAT with rtPA who were treated with IV andor IA rtPA who were treated with IV andor IA abciximab eptifibatide or tirofiban abciximab eptifibatide or tirofiban
IA Mechanical Approaches in Acute Ischemic Stroke IA Mechanical Approaches in Acute Ischemic Stroke Mechanical strategies have several advantagesMechanical strategies have several advantages First they lessen and may even preclude the use of chemical First they lessen and may even preclude the use of chemical
thrombolytics in this manner very likely reducing the risk of ICHthrombolytics in this manner very likely reducing the risk of ICH Second by avoiding the use of chemical thrombolytics it is Second by avoiding the use of chemical thrombolytics it is
possible to extend the treatment window beyond the limit of 6ndash8 possible to extend the treatment window beyond the limit of 6ndash8 hours hours
Third mechanically fragmenting a clot increases the surface area Third mechanically fragmenting a clot increases the surface area accessible to fibrinolytic agents and allows inflow of fresh accessible to fibrinolytic agents and allows inflow of fresh plasminogen which in turn may increase the speed of plasminogen which in turn may increase the speed of thrombolysis thrombolysis
Finally clot-retrieval devices may provide faster recanalization Finally clot-retrieval devices may provide faster recanalization
The disadvantages of the mechanical The disadvantages of the mechanical approaches approaches technical difficulty of navigating mechanical technical difficulty of navigating mechanical
devices into the intracranial circulation excessive devices into the intracranial circulation excessive trauma to the vasculature (potentially leading to trauma to the vasculature (potentially leading to vasospasm vessel dissection perforation or vasospasm vessel dissection perforation or rupture) rupture)
fragmented thrombus causing distal embolization fragmented thrombus causing distal embolization into previously unaffected territories into previously unaffected territories
Nevertheless the advantages of mechanical stroke Nevertheless the advantages of mechanical stroke therapy appear to significantly outweigh its therapy appear to significantly outweigh its disadvantages and risksdisadvantages and risks
Contraindications to Thrombolytic Contraindications to Thrombolytic agents agents
Recent thoracic abdominal or Recent thoracic abdominal or intracranial surgeryintracranial surgery
Recent haemorrhagic CVA Head injury Recent haemorrhagic CVA Head injury or neoplasmor neoplasm
Bleeding ulcerBleeding ulcer Anticipated invasive procedures (arterial Anticipated invasive procedures (arterial
punctures biopsies)punctures biopsies) Concurrent hemostatic dysfunctionConcurrent hemostatic dysfunction
Monitoring of thrombolytic Monitoring of thrombolytic therapytherapy
Thrombin time Measures the availability of functional
fibrinogen Normal thrombin time is 10-14 sec Prolonged when fibrinogen level is below
75-100 mgdl
Half Life of ThrombolyticsHalf Life of ThrombolyticsAgent Administration Half Life
Streptokinase IA 60-80min
Urokinase IAIV 9-12min
rTPA IAIV 6min
Abciximab(Reopro) IAIV 12hour
Aspirin POIV 15-20min
Heparin IVSC 60min
Coumadin PO 15-25 days
Anti Platelet DrugsAnti Platelet DrugsDrug Drug Mechanism Mechanism UsesUsesAspirinAspirin Permanently inhibits Permanently inhibits
COX-1 and COX-2COX-1 and COX-2CADCAD
Stroke-TIAsStroke-TIAs
NSAIDsNSAIDs Reversibly inhibits Reversibly inhibits COX-1COX-1
LimitedLimited
DipyridamoleDipyridamole Inhibits PDE increases Inhibits PDE increases cAMPcAMP
TIAsTIAs
ThenopyridinesThenopyridines
(Ticlopidine(Ticlopidine
ClopidrgrelClopidrgrel))
Inhibits ADP Inhibits ADP
PlatAg PlatAg
TIAsStrokeTIAsStroke
CAD PVDCAD PVD
Abciximab (ReoPro)Abciximab (ReoPro)
Eptifibatide (Integrilin)Eptifibatide (Integrilin)
TirofibanTirofiban
GP IIBIIIA InhibitorsGP IIBIIIA Inhibitors
Stroke- TIAs Stroke- TIAs
MonitoringMonitoring
Bleeding timeBleeding time
Optical aggregometryOptical aggregometry
Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay
Bleeding timeBleeding time
Requires a skin incision (usually made on the ear lobe or Requires a skin incision (usually made on the ear lobe or forearm offorearm of
a depth that results in disruption of capillary loops and a depth that results in disruption of capillary loops and small vessels)small vessels)
AdvantagesAdvantages Universally availableUniversally available Relatively simple techniquesRelatively simple techniques Can be performed bedsideCan be performed bedside
DisadvantagesDisadvantages Insensitive inaccurate non-specific techniqueInsensitive inaccurate non-specific technique
Poorly reproducible (as depends on multiple variables)Poorly reproducible (as depends on multiple variables)
Optical aggregometryOptical aggregometry
Gold standard assay for platelet functionGold standard assay for platelet function Agonist induced aggregation is measuredAgonist induced aggregation is measured Different agonist are available for different Different agonist are available for different
agentsagents However require unique expertise and are not However require unique expertise and are not
universally availableuniversally available Aspirin measured with ADP or AA(gt70 Aspirin measured with ADP or AA(gt70
aggregation so resistance)aggregation so resistance) Clopidogrel( ADP gt 90 aggregation means Clopidogrel( ADP gt 90 aggregation means
resistance) resistance)
Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay
Can be performed bed sideCan be performed bed side Different assay devices with different Different assay devices with different
agonist are used for each of different agonist are used for each of different antiplatelet agents antiplatelet agents
For Aspirin AA is used (result is reported as aspirin For Aspirin AA is used (result is reported as aspirin reaction units [ARU] ARUgt 550 indicates non-reaction units [ARU] ARUgt 550 indicates non-responsiveness)responsiveness)
Verify IIbIIIa assay device uses TRAP as agonist for Verify IIbIIIa assay device uses TRAP as agonist for Abciximab and TirofibanAbciximab and Tirofiban
Practical Applications Practical Applications related to specific related to specific
Neurovascular Neurovascular interventionsinterventions
Acute ischemic StrokeAcute ischemic Stroke When an artery occludes neurons are affected When an artery occludes neurons are affected
differently depending upon the amount of residual blood differently depending upon the amount of residual blood flowflow
Normal cerebral blood flow is greater than 50 mL100 Normal cerebral blood flow is greater than 50 mL100 mgminmgmin
Once blood flow decreases to less than 20 mL100 Once blood flow decreases to less than 20 mL100 mgmin infarction occursmgmin infarction occurs
If blood flow decreases to less than 10 mL100 mgmin If blood flow decreases to less than 10 mL100 mgmin irreversible neuronal death occurs rapidly irreversible neuronal death occurs rapidly
Blood flow between 11 and 20 mL100 mgmin is thought Blood flow between 11 and 20 mL100 mgmin is thought to represent the ischemic penumbra an area where the to represent the ischemic penumbra an area where the cells are functionally silent because of ischemia but are cells are functionally silent because of ischemia but are still able to recover if blood flow is restored still able to recover if blood flow is restored
Many acute stroke therapies are targeted toward Many acute stroke therapies are targeted toward restoring flow or function to the ischemic penumbrarestoring flow or function to the ischemic penumbra
Therapeutic window in Therapeutic window in management of acute Ischemic management of acute Ischemic
StrokeStrokeThe early diagnosis of ischemic stroke is critical to the The early diagnosis of ischemic stroke is critical to the
with only a narrow therapeutic window in the first few with only a narrow therapeutic window in the first few hours following stroke ictushours following stroke ictus
Diagnosis in the first 3 hours postictus provides the Diagnosis in the first 3 hours postictus provides the opportunity for intravenous or intraarterial thrombolysis opportunity for intravenous or intraarterial thrombolysis and intra-arterial clot mechanical treatment which and intra-arterial clot mechanical treatment which improve the outcome improve the outcome
Diagnosis in the time period between 3 and 6 hours Diagnosis in the time period between 3 and 6 hours provides an opportunity for intra-arterial thrombolysis provides an opportunity for intra-arterial thrombolysis and mechanical treatment and mechanical treatment
Involvement of the posterior circulation especially the Involvement of the posterior circulation especially the basilar artery is treated by some regardless of time of basilar artery is treated by some regardless of time of onset or up until 12 to 24 hours in some practices This is onset or up until 12 to 24 hours in some practices This is related to the potentially high mortality and morbidity related to the potentially high mortality and morbidity associated with basilar artery thrombosisassociated with basilar artery thrombosis
Infarct evaluation on angiographyInfarct evaluation on angiography(CT angiography and catheter (CT angiography and catheter
angiography)angiography)CTA is an excellent first-line examination for CTA is an excellent first-line examination for
evaluation of the head and neck arteries evaluation of the head and neck arteries In comparison with catheter angiography In comparison with catheter angiography
what it gives up in resolution and dynamic what it gives up in resolution and dynamic properties it makes up for with rapid properties it makes up for with rapid acquisition of a 3-D dataset and the potential acquisition of a 3-D dataset and the potential for assessment of whole-brain perfusion and for assessment of whole-brain perfusion and better parenchymal evaluationbetter parenchymal evaluation
Moreover CTA illustrates not only arterial Moreover CTA illustrates not only arterial stenosis or occlusion but also the vessel wall stenosis or occlusion but also the vessel wall This factor is most important for evaluation of This factor is most important for evaluation of intramural dissection and thrombosed intramural dissection and thrombosed aneurysms which may both complicate aneurysms which may both complicate evaluation of stroke patientsevaluation of stroke patients
Early angiographic signs of strokes Early angiographic signs of strokes both CTA both CTA and DSA and DSA
Vessel occlusion or cutoff related to Vessel occlusion or cutoff related to thromboembolithromboemboli
aneurysms aneurysms arterial dissection arterial dissection Meniscus or flattened shape to clot Meniscus or flattened shape to clot
(recent) versus reverse meniscus (older)(recent) versus reverse meniscus (older) tram track (nonocclusive or recanalized tram track (nonocclusive or recanalized
clot) clot) delayed (antegrade) flow (manifest as delayed (antegrade) flow (manifest as
decreased whole-brain perfusion on CTA)decreased whole-brain perfusion on CTA) retrograde collateral flowretrograde collateral flow
Non-occlusive left MCA thrombus on 3-D imaging performed from CTA source data and was confirmed at catheter angiography
Therapy to be started within a 6-hr Therapy to be started within a 6-hr time to treatment (TTT) window time to treatment (TTT) window (while in case of IV thrombolysis (while in case of IV thrombolysis therapy to be started with in 3hrs)therapy to be started with in 3hrs)
Exclusion criteria Exclusion criteria Rapidly improving neurologic deficit or Rapidly improving neurologic deficit or Sustained blood pressure of gt180100 Sustained blood pressure of gt180100 Hemorrhage is detected on CTHemorrhage is detected on CT Infarct involving gt more than 13 rd Infarct involving gt more than 13 rd
territory of MCAterritory of MCA MRADWI-Perfusion mismatchlt 20MRADWI-Perfusion mismatchlt 20 Definite hypodensity on CTDefinite hypodensity on CT
Intra-arterial Thrombolysis
Fibrinolytics + AntiplateletsFibrinolytics + Antiplatelets
PlasminogenPlasminogen activators through fibrinolysis exposes activators through fibrinolysis exposes free thrombin and paradoxically stimulatesfree thrombin and paradoxically stimulates platelet platelet aggregation which leads to formation of aaggregation which leads to formation of a platelet platelet thrombus (white clot) thrombus (white clot)
This new thrombus is relatively resistant to This new thrombus is relatively resistant to fibrinolyticsfibrinolytics
So new regimen in case of acute stroke isSo new regimen in case of acute stroke is fibrinolytics + antiplatelet drugsfibrinolytics + antiplatelet drugs
rtPA + IIbIIIa inhibitors( tirofiban rtPA + IIbIIIa inhibitors( tirofiban abciximab) orabciximab) or
Urokinase + IIbIIIa Urokinase + IIbIIIa inhibitors( tirofiban abciximab)inhibitors( tirofiban abciximab)
Intra-arterial Thrombolysis Tirofiban (04 microgkgmin bolus for 3 min followed by Tirofiban (04 microgkgmin bolus for 3 min followed by
0125 ugkgmin)0125 ugkgmin)
++
Heparin (2000ndash3000 IU bolus followed by Heparin (2000ndash3000 IU bolus followed by 1000 IUhour infusion 1000 IUhour infusion
with ACT maintained bw 200-300) throughout the with ACT maintained bw 200-300) throughout the interventional procedure and for 24ndash48 hours thereafter when interventional procedure and for 24ndash48 hours thereafter when there is neither intraprocedural bleeding nor suspicion of there is neither intraprocedural bleeding nor suspicion of increased risk of bleeding increased risk of bleeding
Maximum dose of Urokinase Maximum dose of Urokinase Anterior circulation stroke - 500000 IU (mean 400000 Anterior circulation stroke - 500000 IU (mean 400000
IU range 300000ndash500000 IU)IU range 300000ndash500000 IU) Posterior circulation stroke -1000000 IU (mean 837000 Posterior circulation stroke -1000000 IU (mean 837000
IU range 300000ndash1000000 IU)IU range 300000ndash1000000 IU)American Journal of NeuroradiologyAmerican Journal of Neuroradiology 262595-2601 2005262595-2601 2005
Intravenous ThrombolysisIntravenous Thrombolysis
The first method to restore cerebral The first method to restore cerebral perfusion is clot lysis with the goal perfusion is clot lysis with the goal of re-establishing blood flow to the of re-establishing blood flow to the affected tissue affected tissue
IV thrombolysis rt-PA is the only IV thrombolysis rt-PA is the only FDA- approved treatment for AIS FDA- approved treatment for AIS
Fibrinolysis is enhanced powerfully Fibrinolysis is enhanced powerfully by rt-PAby rt-PA
Intravenous rTPA Intravenous rTPA administration administration protocolprotocol
Total dose of rt-PA 09 mgkg (maximum dose Total dose of rt-PA 09 mgkg (maximum dose 90 mg)90 mg)
Give 10 as initial IV bolusGive 10 as initial IV bolus Infuse remainder over 1 hourInfuse remainder over 1 hour Admit patient to an ICU or stroke unit for Admit patient to an ICU or stroke unit for
monitoringmonitoring Neurologic assessments every 15 minutes Neurologic assessments every 15 minutes
during infusion then every 30 minutes for next during infusion then every 30 minutes for next 6 hours then every hour until 24hours after 6 hours then every hour until 24hours after treatmenttreatment
Favorable Outcome vs Treatment Time Favorable Outcome vs Treatment Time with IV rTPAwith IV rTPA
Protocol limit = 3 hrs
Benefit ~ 45 hrs
Thromboembolism During coilingThromboembolism During coiling Most feared and frequent complication Most feared and frequent complication Reported incidence - Approx 7 Reported incidence - Approx 7 SourcesSources of Thromboembolism are of Thromboembolism are
- Clots at the aneurysmal neck during or immediately- Clots at the aneurysmal neck during or immediately after after embolization embolization
- Thrombus forming on catheters during- Thrombus forming on catheters during proceduresprocedures
- Stenosis of an adjacent artery dt coil mass- Stenosis of an adjacent artery dt coil mass or herniationor herniation
- Migration of intraaneurysmal- Migration of intraaneurysmal thrombus during coil thrombus during coil placement placement
- Slow flow dt vasospasm - Slow flow dt vasospasm
- Rare and unlikely causes are hypercoagulable- Rare and unlikely causes are hypercoagulable state such state such as antiphospholipid antibody syndrome or due to HITas antiphospholipid antibody syndrome or due to HIT
Occur more often with wide-necked aneurysms (dt Occur more often with wide-necked aneurysms (dt increased exposed surface area of thrombogenic coil increased exposed surface area of thrombogenic coil material)material)
Current regimen of endovascular Current regimen of endovascular managementmanagement
The The glycoprotein IIbIIIa antagonist tirofiban glycoprotein IIbIIIa antagonist tirofiban (04 (04 microgkgmin bolus for 30 minutes followed by infusion of microgkgmin bolus for 30 minutes followed by infusion of 0125 ugkgmin until the thrombus dissolved) 0125 ugkgmin until the thrombus dissolved)
Intraarterial thrombolysis with Intraarterial thrombolysis with urokinase or r- TPA urokinase or r- TPA increase of intravenous (IV) heparin (measured by increase of intravenous (IV) heparin (measured by
ACT) ACT) Intravenous aspirin Intravenous aspirin
Coil-related platelet aggregation (white clot) is Coil-related platelet aggregation (white clot) is unlikely to respond to fibrinolytics but has a high risk unlikely to respond to fibrinolytics but has a high risk of hemorrhage (In ISAT) all 5 patients who had of hemorrhage (In ISAT) all 5 patients who had received thrombolytic therapy with tPA to treat a received thrombolytic therapy with tPA to treat a thromboembolic complication after endovascular thromboembolic complication after endovascular treatment rebleed and all of these patients died)treatment rebleed and all of these patients died)
IntracranialIntracranial Stenting Stenting Metallic foreign body such as stent will accumulate Metallic foreign body such as stent will accumulate
thrombus in the absence of platelet inhibitionthrombus in the absence of platelet inhibition Antiplatelet drugs are important to prevent peri or Antiplatelet drugs are important to prevent peri or
post-interventional thromboembolic eventspost-interventional thromboembolic events Optimal treatment regimens has not been determined Optimal treatment regimens has not been determined
but usually but usually Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-
procedureprocedureOrOr
Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on
morning of proceduremorning of procedure
If need to use stent is not pre-planned thanIf need to use stent is not pre-planned than
Abciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkgAbciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkg IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)
Glycoprotein IIbIIIa inhibitor are not used routinely during elective Glycoprotein IIbIIIa inhibitor are not used routinely during elective stenting procedure dt increased risk of ICH stenting procedure dt increased risk of ICH
Carotid StentingCarotid Stenting
Pre-procedurePre-procedure
Double Antiplatelet therapy is routinely given Double Antiplatelet therapy is routinely given beginning at least 3beginning at least 3
days before the proceduredays before the procedure
Aspirin 325mgd+Clopidogrel 75mgdAspirin 325mgd+Clopidogrel 75mgd During procedureDuring procedure
Heparin is given with target clotting time of 250-Heparin is given with target clotting time of 250-300sec300sec
Post-procedure Post-procedure
Aspirin 325mg is continued indefinitely and Aspirin 325mg is continued indefinitely and
Clopidogrel 75mgd for at least 6 weeks Clopidogrel 75mgd for at least 6 weeks
Inclusion criteria for Local ThrombolysisInclusion criteria for Local Thrombolysis a)a) Patients in severe clinical grade on admission Patients in severe clinical grade on admission
with evidence of dural venous sinus with evidence of dural venous sinus thrombosis and restrictive venous outflow on thrombosis and restrictive venous outflow on cerebral angiogramcerebral angiogram
b)b) Patients in clinical grade 3 worsening on Patients in clinical grade 3 worsening on heparin therapy Restriction to venous heparin therapy Restriction to venous outflow was defined as an increase in brain outflow was defined as an increase in brain circulation time gt 12 s delay in the drainage circulation time gt 12 s delay in the drainage of cortical veins with cortical veins hanging of cortical veins with cortical veins hanging in spacein space
Treatment Options for Venous Thrombosis
CT Grading for Venous ThrombosisCT Grading for Venous Thrombosis Grade I no parenchymal change Grade I no parenchymal change
(hyperdense (hyperdense sinuses cortical veins empty sinuses cortical veins empty delta sign)delta sign)
Grade II non hemorrhagic venous infarct Grade II non hemorrhagic venous infarct without mass effect without mass effect
Grade III non-hemorrhagic infarct with Grade III non-hemorrhagic infarct with mass effectmass effect
Grade IV hemorrhagic venous infarct (max Grade IV hemorrhagic venous infarct (max diameter lt 3 cm) with no mass effectdiameter lt 3 cm) with no mass effect
Grade V hemorrhagic venous infarct (max Grade V hemorrhagic venous infarct (max diameter gt 3 cm) with mass effect diameter gt 3 cm) with mass effect
Local ThrombolysisLocal Thrombolysis
Femoral Jugular access was secured and a guiding Femoral Jugular access was secured and a guiding catheter was placed in the jugular bulb catheter was placed in the jugular bulb Mechanical Mechanical clot maceration clot maceration was done with the guidewire was done with the guidewire following which a microcatheter (was navigated and following which a microcatheter (was navigated and placed in the thrombosed segment of sinus confirmed placed in the thrombosed segment of sinus confirmed on a selective venogram on a selective venogram
Urokinase infusion Bolus dose of 2-6 lacs followed Urokinase infusion Bolus dose of 2-6 lacs followed by 60000 to 100000 units per hour along with by 60000 to 100000 units per hour along with periodic check venogram Along with maintenance periodic check venogram Along with maintenance systemic infusion of Heparinsystemic infusion of Heparin Other agents such as Other agents such as streptokinase altepase or rTPAstreptokinase altepase or rTPA can be also used can be also used
After thrombolysis patient should subjected to oral After thrombolysis patient should subjected to oral anticoagulation for six monthsanticoagulation for six months
Low-molecular-weight Low-molecular-weight heparinheparin
PharmacologyPharmacologyLMWH as its name suggests is a glycosaminoglycan that is approximatelyLMWH as its name suggests is a glycosaminoglycan that is approximately
one third the molecular weight of UFH It is derived from UFH through one third the molecular weight of UFH It is derived from UFH through variousvarious
depolymerization processes LMWH binds to antithrombin which in turn depolymerization processes LMWH binds to antithrombin which in turn
Neutralizes actors Xa and IIa Because LMWH lacks many of the longer Neutralizes actors Xa and IIa Because LMWH lacks many of the longer chains chains
required for binding to thrombin it has less ability to neutralize thrombin required for binding to thrombin it has less ability to neutralize thrombin
relativeto its ability to neutralize factor Xa LMWH also has less relativeto its ability to neutralize factor Xa LMWH also has less nonspecific nonspecific
binding to other proteins There is greater bioavailability with more binding to other proteins There is greater bioavailability with more predictable predictable
pharmacokinetics that eliminates the need for monitoring The smaller pharmacokinetics that eliminates the need for monitoring The smaller size also size also
allows for enhanced subcutaneous absorption when compared with UFHallows for enhanced subcutaneous absorption when compared with UFH
Three LMWH preparations are Three LMWH preparations are currently approved for use in the currently approved for use in the United States (1) enoxaparin (2) United States (1) enoxaparin (2) dalteparin and (3) tinzaparin dalteparin and (3) tinzaparin
They are all administered They are all administered subcutaneously at intervals of either subcutaneously at intervals of either once or twice daily for both once or twice daily for both prophylaxis and treatment dosesprophylaxis and treatment doses
Few Experiences of Few Experiences of ThrombolysisThrombolysis
Vickey 25 Yrs male patient presented Vickey 25 Yrs male patient presented with 12with 12thth day HO severe headache with day HO severe headache with right sided hemiplegiaright sided hemiplegia
MRI shows thrombosis of the superior MRI shows thrombosis of the superior sagittal left transverse left sigmoid sagittal left transverse left sigmoid sinuses and cortical veins in the fronto-sinuses and cortical veins in the fronto-parietal regions with eo haemorrhagic parietal regions with eo haemorrhagic infarct in the left cerebral hemisphere infarct in the left cerebral hemisphere with mass effect( Grade ndashV)with mass effect( Grade ndashV)
Sashi Srivastava 64 yrs FSashi Srivastava 64 yrs F In a follow up case of MRD with infra-renal In a follow up case of MRD with infra-renal
aortic abdominal and bilateral renal artery aortic abdominal and bilateral renal artery thrombosis renal angiogram shows filling thrombosis renal angiogram shows filling defects in the right Renal artery defects in the right Renal artery
Initially Renal angioplasty was done Initially Renal angioplasty was done Following angioplasty few thrombi are seem Following angioplasty few thrombi are seem to extends into the segmental branches and to extends into the segmental branches and causing blockage So Thrombolysis was causing blockage So Thrombolysis was plane to dissolve the run-out thrombi with plane to dissolve the run-out thrombi with urokinase urokinase
Rakesh 34yrsMRakesh 34yrsM Left SFA pseudoaneurysm with Left SFA pseudoaneurysm with
Covered stent placementCovered stent placement Pre operative antiplatelets with post Pre operative antiplatelets with post
procedure heparin Tirofiban procedure heparin Tirofiban followed by aspirin and clopidogrel followed by aspirin and clopidogrel were usedwere used
IAT may be a treatment option for selected patients IAT may be a treatment option for selected patients Possible selection criteria include Possible selection criteria include
presentation between 3 and 6 hours from symptom onsetpresentation between 3 and 6 hours from symptom onset major cerebral artery occlusion major cerebral artery occlusion severe neurologic deficits severe neurologic deficits high risk of systemic hemorrhage with IV rt-PA (eg recent high risk of systemic hemorrhage with IV rt-PA (eg recent
surgery) surgery) The MERCI (Mechanical Embolus Removal in Cerebral The MERCI (Mechanical Embolus Removal in Cerebral
Ischemia) retrievalIschemia) retrieval system system
Has been FDA-approved for recanalizing acutely occluded Has been FDA-approved for recanalizing acutely occluded cerebral arteries cerebral arteries
In the Multi-MERCI study patients who did not improve In the Multi-MERCI study patients who did not improve immediately after IV rt-PA underwent mechanical immediately after IV rt-PA underwent mechanical embolectomy within 8 hours of symptom onset embolectomy within 8 hours of symptom onset
Partial or complete recanalization occurred in 74 of Partial or complete recanalization occurred in 74 of patientspatients
with a symptomatic intracerebral hemorrhage (sICH) rate of with a symptomatic intracerebral hemorrhage (sICH) rate of 67 67
Mechanical embolectomy with the MERCI retriever may be a Mechanical embolectomy with the MERCI retriever may be a feasible and safe option for patients after IV rt-PAfeasible and safe option for patients after IV rt-PA
Penumbra stroke systemPenumbra stroke system This device combines two methods of clot This device combines two methods of clot
extraction aspiration and mechanical extraction aspiration and mechanical extraction extraction
First the clot is aspirated then a thrombus First the clot is aspirated then a thrombus removal ring can be used if necessary to removal ring can be used if necessary to remove remaining clot remove remaining clot
successful recanalizing 82successful recanalizing 82 Bridging therapyBridging therapy
06 mgkg IV rt-PA followed by IAT with IA rt-06 mgkg IV rt-PA followed by IAT with IA rt-PA (up to 20 mg)PA (up to 20 mg)
achieved a higher recanalization rateachieved a higher recanalization rate
Criteria for thrombolysis with rTPACriteria for thrombolysis with rTPA
Inclusion criteriaInclusion criteria Clinical signs and symptoms consistent with ischemic Clinical signs and symptoms consistent with ischemic
strokestroke Patient last seen normal within 3 hoursPatient last seen normal within 3 hours Measurable neurologic deficitMeasurable neurologic deficit
Exclusion criteriaExclusion criteria Any hemorrhage on neuroimaging (CT or MRI)Any hemorrhage on neuroimaging (CT or MRI) Symptoms suggestive of subarachnoid hemorrhageSymptoms suggestive of subarachnoid hemorrhage Seizure at stroke onset that is thought to contribute to Seizure at stroke onset that is thought to contribute to
neurologic deficitneurologic deficit Hypodensity greater than one third cerebral hemisphere Hypodensity greater than one third cerebral hemisphere
on CTon CT SBP greater than 185 mm Hg or DBP greater than 110 SBP greater than 185 mm Hg or DBP greater than 110
mm Hgmm Hg International normalized ratio (INR) greater than 17International normalized ratio (INR) greater than 17
Ischemic Stroke Ischemic Stroke Treatment ndash 2006Treatment ndash 2006
IV tissue plasminogen activator (tPA)IV tissue plasminogen activator (tPA) ndash ndash Only FDA-approved acute stroke drugOnly FDA-approved acute stroke drug ndash ndash 3 hour treatment window3 hour treatment window
MERCI - Concentric clot retrieval MERCI - Concentric clot retrieval devicedevice ndash ndash Rescue therapy - approved 2004Rescue therapy - approved 2004 ndash ndash Device approval (not outcomes-based)Device approval (not outcomes-based)
Off label approachesOff label approaches ndash ndash IV tPA after 3 hoursIV tPA after 3 hours ndash ndash IV-IA tPA sequential strategiesIV-IA tPA sequential strategies ndash ndash IA tPA clot angioplasty fragmentationIA tPA clot angioplasty fragmentation ndash ndash Ultrasound-assisted tPA lysisUltrasound-assisted tPA lysis
rt-PA Trials NINDSrt-PA Trials NINDS
Acute stroke - 624 patientsAcute stroke - 624 patients Treat within 3 hrsTreat within 3 hrs Intravenous 09 mgkg rt-PA vs placeboIntravenous 09 mgkg rt-PA vs placebo Hemorrhage 64 tPA 06 placeboHemorrhage 64 tPA 06 placebo Neurologic recovery better with tPA 30 Neurologic recovery better with tPA 30
more like to have minimal or no disabilitymore like to have minimal or no disability
First proven approved treatment for First proven approved treatment for strokestroke
Limitations of tPALimitations of tPA Only 4 of acute strokes receive tPAOnly 4 of acute strokes receive tPA (Kleindorfer et al Stroke 2004 35 e27-e29)(Kleindorfer et al Stroke 2004 35 e27-e29)
Only 22 of patients present within 3 hoursOnly 22 of patients present within 3 hours1048707 1048707 51 of these ineligible due to51 of these ineligible due to
bull bull Mild severityMild severity bull bull Medical or surgical historyMedical or surgical history bull bull Blood testsBlood tests
Sustained recanalization only 13Sustained recanalization only 13 (Alexandrov et al NEJM 2004 351 2170-8)(Alexandrov et al NEJM 2004 351 2170-8)
Concern for hemorrhageConcern for hemorrhage tPA potentiates apoptotic injury tPA potentiates apoptotic injury (Liu et al Nature Med 2004 101379-83)(Liu et al Nature Med 2004 101379-83)
PROACT II IA Lysis TrialPROACT II IA Lysis Trial Baseline 24 hours 8 days
Baseline 60 minutes 120 minutes
9mg IAProurokinase
Desmoteplase Trials DEDAS Desmoteplase Trials DEDAS DIASDIAS
Trial OverviewTrial Overview Double blind randomized placebo Double blind randomized placebo
controlled trialscontrolled trials IV delivery 3-9 hour time windowIV delivery 3-9 hour time window Plasminogen activator ndash from Plasminogen activator ndash from vampire bat vampire bat
salivasaliva Selection based on PWI-DWI MismatchSelection based on PWI-DWI Mismatch
MRI InclusionMRI Inclusion PWI defect at least 2 cm AND ~20 larger PWI defect at least 2 cm AND ~20 larger
than DWIthan DWI PWI should be obvious even visible on PWI should be obvious even visible on
raw imagesraw imagesMRI ExclusionMRI Exclusion
DWI gt 13 MCADWI gt 13 MCA MRA ICA occlusionMRA ICA occlusion
Desmoteplase ndash DIAS Desmoteplase ndash DIAS ResultsResults
Mechanical Thrombolysis Mechanical Thrombolysis devicesdevices
mechanical thrombolysis potentially extends the treatment mechanical thrombolysis potentially extends the treatment window because they act promptly at the site of the thrombuswindow because they act promptly at the site of the thrombus
The devices can retrieve large clots that pharmaceutical agents The devices can retrieve large clots that pharmaceutical agents may not successfully lysemay not successfully lyse
Patients treated with IV tPA may be considered for treatment of Patients treated with IV tPA may be considered for treatment of residual clot with some of these devicesresidual clot with some of these devices
suction-creating saline jets suction-creating saline jets laser energy ultrasound laser energy ultrasound a corkscrew apparatus to treat strokesa corkscrew apparatus to treat strokes The AngioJet systemThe AngioJet system uses saline jets that are directed back into the catheter to uses saline jets that are directed back into the catheter to
create a low-pressure zone around the catheter tip inducing create a low-pressure zone around the catheter tip inducing suction suction
The clot is pulled into the exhaust lumen and removed from the The clot is pulled into the exhaust lumen and removed from the vessel Although US Food and Drug Administration (FDA) has vessel Although US Food and Drug Administration (FDA) has approved this device for use in arteriovenous dialysis grafts and approved this device for use in arteriovenous dialysis grafts and fistulae and for the treatment of coronary arteries saphenous fistulae and for the treatment of coronary arteries saphenous vein grafts and peripheral vessels clinical trials for the vein grafts and peripheral vessels clinical trials for the treatment of acute stroke are no longer in progress treatment of acute stroke are no longer in progress
Most devices are used in cerebral vessels that 2-5 mm
The Latis laser device The Latis laser device used laser energy to ablate clots used laser energy to ablate clots Arteries 2-5 mm in diameter could be Arteries 2-5 mm in diameter could be
treated including the ICA M1 or M2 treated including the ICA M1 or M2 branch of the MCA A1 branch of the branch of the MCA A1 branch of the anterior cerebral artery (ACA) basilar anterior cerebral artery (ACA) basilar artery posterior cerebral artery (PCA) artery posterior cerebral artery (PCA) and vertebral and vertebral
Patients could receive treatment as late Patients could receive treatment as late as 8 hours after symptom onset in the as 8 hours after symptom onset in the anterior circulation and within 24 hours in anterior circulation and within 24 hours in the posterior circulation the posterior circulation
Endovascular Photo Acoustic Endovascular Photo Acoustic Recanalization (EPAR) Recanalization (EPAR)
A laser power source generated energy for the A laser power source generated energy for the systemsystem
The energy was delivered by means of The energy was delivered by means of fiberoptics to the tip of the catheter at the fiberoptics to the tip of the catheter at the treatment sitetreatment site
Absorption of laser light by darkly pigmented Absorption of laser light by darkly pigmented materials (ie the clot) occurred inside the 1-mm materials (ie the clot) occurred inside the 1-mm catheter tipcatheter tip
the system was designed to minimize scattering the system was designed to minimize scattering of laser light of laser light
Absorption converted photo energy to acoustic Absorption converted photo energy to acoustic energy which then emulsified the clot inside the energy which then emulsified the clot inside the catheter tip catheter tip
EKOS ultrasound( the EKOS ultrasound( the Ultrasound Thrombolytic Ultrasound Thrombolytic
Infusion Catheter) Infusion Catheter) combines the use of a distal ultrasound transducer with combines the use of a distal ultrasound transducer with
infusion of a thrombolytic agent through the infusion of a thrombolytic agent through the microcathetermicrocatheter
Ultrasound changes the structure of the clot to Ultrasound changes the structure of the clot to temporarily increase its permeability while providing an temporarily increase its permeability while providing an acoustic pressure gradient to move the drug into the clot acoustic pressure gradient to move the drug into the clot to speed its dissolution to speed its dissolution
The EKOS catheter is placed in the proximal portion of the The EKOS catheter is placed in the proximal portion of the clot clot
After a 2-mg bolus of tPA was injected through the After a 2-mg bolus of tPA was injected through the catheter catheter
the patient received a continuous infusion of IA tPA 03 the patient received a continuous infusion of IA tPA 03 mgmin to a maximum of 20 mg and simultaneous mgmin to a maximum of 20 mg and simultaneous ultrasound transmission for as long as 60 minutes ultrasound transmission for as long as 60 minutes
One patient was treated with a total of 4 units of One patient was treated with a total of 4 units of recombinant reteplase (Retavase) hand-injected over 60 recombinant reteplase (Retavase) hand-injected over 60 minutes minutes
Penumbra system Penumbra system The Penumbra system (Penumbra Inc) provides a dual The Penumbra system (Penumbra Inc) provides a dual
approach to clot extraction using aspiration followed by approach to clot extraction using aspiration followed by clot retrieval with a ring device if needed clot retrieval with a ring device if needed
Mechanical Embolus Removal in Cerebral Ischemia Mechanical Embolus Removal in Cerebral Ischemia (MERCI)(MERCI)
a corkscrew-like apparatus to remove blood clots from a corkscrew-like apparatus to remove blood clots from the brain in patients experiencing an ischemic stroke the brain in patients experiencing an ischemic stroke
The corkscrew itself resides in the catheter tip which The corkscrew itself resides in the catheter tip which shields it from the wall of the vessel until it is ready to be shields it from the wall of the vessel until it is ready to be burrowed into the clot Once lodged in the clot the device burrowed into the clot Once lodged in the clot the device and clot are withdrawn from the vessel and clot are withdrawn from the vessel
Snarelike devicesSnarelike devices Snares such as the Neuronet snare (Guidant Snares such as the Neuronet snare (Guidant
Endovascular Santa Clara CA) have been developed Endovascular Santa Clara CA) have been developed specifically for use in the treatment of strokes specifically for use in the treatment of strokes
These devices are simple in design and do not require the These devices are simple in design and do not require the clot to be amenable to emulsification clot to be amenable to emulsification
X-Sizer deviceX-Sizer device a device with small moving blades at the a device with small moving blades at the
catheter tip catheter tip This device the X-Sizer device (EndiCor Medical This device the X-Sizer device (EndiCor Medical
San Clemente CA) can be used to excise the San Clemente CA) can be used to excise the thrombus and aspirate it thrombus and aspirate it
The device was being evaluated in randomized The device was being evaluated in randomized studies of coronary vessels and in a registry of studies of coronary vessels and in a registry of patients with acute myocardial infarctionpatients with acute myocardial infarction
Although the manufacturer had modified the Although the manufacturer had modified the device for use in cerebral vessels a safety and device for use in cerebral vessels a safety and feasibility study was indefinitely suspended after feasibility study was indefinitely suspended after only 1 patient was treated with the device in only 1 patient was treated with the device in Europe Europe
Suction thrombectomySuction thrombectomy This method of mechanical thrombolysis is one of the This method of mechanical thrombolysis is one of the
simplestsimplest In this readily available technique suction is applied with In this readily available technique suction is applied with
a syringe to remove thrombus in the ICA a syringe to remove thrombus in the ICA It requires no other devicesIt requires no other devices A catheter with a large inner diameter (Brite Tip Cordis A catheter with a large inner diameter (Brite Tip Cordis
Corporation Miami FL) was placed in the symptomatic Corporation Miami FL) was placed in the symptomatic vessel and navigated over a guidewire into the thrombusvessel and navigated over a guidewire into the thrombus
A 60-mL syringe was used to aspirate the thrombus A 60-mL syringe was used to aspirate the thrombus Each patient required angioplasty and stenting of carotid Each patient required angioplasty and stenting of carotid
bifurcation stenosis and received daily aspirin and bifurcation stenosis and received daily aspirin and ticlopidine after the procedure No complications ticlopidine after the procedure No complications occurred occurred
Summary Acute Stroke Summary Acute Stroke ImagingImaging
PhysiologyPhysiology importance collaterals importance collaterals
ndash ndashGrowing role for perfusion Growing role for perfusion assessmentassessment
tPAtPA guidelines amp limitations guidelines amp limitations Signs on CT amp MRSigns on CT amp MR follow physiology follow physiology Stroke trialsStroke trials PWI-DWI mismatch PWI-DWI mismatch
ndash ndashTreat based on physiology not timeTreat based on physiology not time ProtocolsProtocols should be fast and should be fast and
comprehensivecomprehensive
Recanalization or Antegrade Recanalization or Antegrade Reperfusion StrategiesReperfusion Strategies
Recanalization strategies focus on removing Recanalization strategies focus on removing andor dissolving the occlusive thrombus to re-andor dissolving the occlusive thrombus to re-establish antegrade flow Strategies may be establish antegrade flow Strategies may be classified into 7 different categories on the classified into 7 different categories on the basis of their primary mechanism of action basis of their primary mechanism of action 1) 1) IV andor intraarterial thrombolysis (IAT) IV andor intraarterial thrombolysis (IAT) 2) endovascular thrombectomy2) endovascular thrombectomy3) endovascular thromboaspiration 3) endovascular thromboaspiration 4) endovascular mechanical thrombus disruption or 4) endovascular mechanical thrombus disruption or
thromborrhexisthromborrhexis5) 5) transcranial or endovascular augmented transcranial or endovascular augmented
fibrinolysis fibrinolysis 6) endovascular thrombus entrapment and 6) endovascular thrombus entrapment and 7) temporary endovascular bypass7) temporary endovascular bypass
IAT in Acute Ischemic StrokeIAT in Acute Ischemic Stroke
IAT advantages over IV thrombolysisIAT advantages over IV thrombolysis Coaxial microcatheter techniques the occluded intracranial Coaxial microcatheter techniques the occluded intracranial
vessel is directly accessible and the fibrinolytic agent can be vessel is directly accessible and the fibrinolytic agent can be infused directly into the thrombusinfused directly into the thrombus
This permits a smaller dose of fibrinolytic agent to reach a This permits a smaller dose of fibrinolytic agent to reach a higher local concentration than that reached by systemic higher local concentration than that reached by systemic infusioninfusion
Allows more complete recanalization with lower total doses of Allows more complete recanalization with lower total doses of thrombolytic thrombolytic
With the smaller dose complications from systemic fibrinolytic With the smaller dose complications from systemic fibrinolytic effects including intracranial hemorrhage (ICH) can effects including intracranial hemorrhage (ICH) can theoretically be reduced theoretically be reduced
Treatment window for endovascular techniques can be Treatment window for endovascular techniques can be extended beyond the typical IV window of 3 hours extended beyond the typical IV window of 3 hours
IA techniques have led to higher recanalization rates than IV IA techniques have led to higher recanalization rates than IV thrombolysisthrombolysis
Major disadvantagesMajor disadvantages Relative complexity of the procedure the level Relative complexity of the procedure the level
of required technical expertise and its of required technical expertise and its relatively low availability relatively low availability
Delays in initiating treatmentDelays in initiating treatment InvasiveInvasive
ThrombolyticsThrombolytics
Plasminogen activators
Fibrinolytics
1 Plasminogen Activators 1 Plasminogen Activators drugs act by converting the inactive proenzyme drugs act by converting the inactive proenzyme plasminogen into the active enzyme plasmin Plasmin plasminogen into the active enzyme plasmin Plasmin digests fibrinogen fibrin monomers and cross-linked digests fibrinogen fibrin monomers and cross-linked fibrin (as found in a thrombus) into fibrin degradation fibrin (as found in a thrombus) into fibrin degradation productsproducts
First-Generation Agents First-Generation Agents StreptokinaseStreptokinase a protein derived from group C a protein derived from group C
szlig-hemolytic streptococci has a half-life of 16ndashszlig-hemolytic streptococci has a half-life of 16ndash90 minutes and low fibrin specificity This drug 90 minutes and low fibrin specificity This drug proved to have a very narrow therapeutic proved to have a very narrow therapeutic window and significant rates of ICH and window and significant rates of ICH and systemic hemorrhage18systemic hemorrhage18
UrokinaseUrokinase is a serine protease with a plasma is a serine protease with a plasma half life of 14 minutes and low fibrin specificity half life of 14 minutes and low fibrin specificity
The urokinase dose used in cerebral IAT has The urokinase dose used in cerebral IAT has ranged from 002 to 2 X106unitsranged from 002 to 2 X106units
Second-Generation Agents Second-Generation Agents Alteplase (rtPA) Alteplase (rtPA)
is a serine is a serine protease with a plasma half-life of 35 protease with a plasma half-life of 35 minutes and a high degree of fibrin affinity and minutes and a high degree of fibrin affinity and specificity specificity
Dose used in cerebral IAT has ranged between 20 Dose used in cerebral IAT has ranged between 20 and 60 mgand 60 mg
Disadvantages of alteplase include its relatively short Disadvantages of alteplase include its relatively short halflife and limited penetration into the clot matrix halflife and limited penetration into the clot matrix because of strong binding with surface fibrin which because of strong binding with surface fibrin which could delay recanalization and increase the risk of could delay recanalization and increase the risk of recurrent occlusion recurrent occlusion
Prourokinase (r-prourokinase) Prourokinase (r-prourokinase) is the proenzyme precursor of urokinase is the proenzyme precursor of urokinase T12 of 7 minutes and high fibrin specificity T12 of 7 minutes and high fibrin specificity
Third-Generation AgentsThird-Generation Agents
ReteplaseReteplase is a structurally modified is a structurally modified form of alteplase form of alteplase
with a longer half-life (15ndash18 minutes) In with a longer half-life (15ndash18 minutes) In addition it does not bind as highly to fibrin addition it does not bind as highly to fibrin unbound reteplase can thus theoretically better unbound reteplase can thus theoretically better penetrate the clot and potentially penetrate the clot and potentially improve in improve in vivo fibrinolytic activity vivo fibrinolytic activity
TenecteplaseTenecteplase is another modified form of rtPA with a longer is another modified form of rtPA with a longer
half-life (17 minutes)half-life (17 minutes) greater fibrin specificity and greater greater fibrin specificity and greater
resistance to plasminogen activator inhibitor-1 resistance to plasminogen activator inhibitor-1 IV tenecteplase in acute ischemic stroke IV tenecteplase in acute ischemic stroke
suggest that the drug is safe and promisingsuggest that the drug is safe and promising
Newer plasminogen activatorNewer plasminogen activator
DesmoteplaseDesmoteplase is a genetically engineered is a genetically engineered version of the clot-dissolving factor version of the clot-dissolving factor
found in the saliva found in the saliva of the vampire bat Desmodus rotundusof the vampire bat Desmodus rotundus moremore potent and more selective for fibrin-bound potent and more selective for fibrin-bound
plasminogen than any other known plasminogen plasminogen than any other known plasminogen activatoractivator
Unlike tissue plasminogen activator (tPA) desmoteplase Unlike tissue plasminogen activator (tPA) desmoteplase is not activated by fibrinogen or -amyloid proteins is not activated by fibrinogen or -amyloid proteins factors that may exacerbate the risk for ICH factors that may exacerbate the risk for ICH
The effect of IV administration of desmoteplase 3ndash9 The effect of IV administration of desmoteplase 3ndash9 hours after symptom onset in patients with stroke who hours after symptom onset in patients with stroke who present with mismatch on MR imaging or CT perfusion present with mismatch on MR imaging or CT perfusion
3 DefibrinogenatingFibrinogenolytic 3 DefibrinogenatingFibrinogenolytic Agents Agents
AncrodAncrod(Viprinex)(Viprinex) is is the purified fraction of the Malayan pit viper venomthe purified fraction of the Malayan pit viper venom It acts by directly cleaving and inactivating fibrinogen It acts by directly cleaving and inactivating fibrinogen
and thus indirectly promoting anticoagulation and thus indirectly promoting anticoagulation The reduction in the blood levels of fibrinogen also The reduction in the blood levels of fibrinogen also
leads to a reduced blood viscosity which may improve leads to a reduced blood viscosity which may improve blood flow to the affected areas of the brain blood flow to the affected areas of the brain
In the Stroke Treatment with Ancrod Trial 500 In the Stroke Treatment with Ancrod Trial 500 patients with stroke presenting within 3 hours of patients with stroke presenting within 3 hours of symptom onset were randomized to receive ancrod (symptom onset were randomized to receive ancrod (n n 248) or a placebo (n 252) Good outcome (Barthel 248) or a placebo (n 252) Good outcome (Barthel Index 95ndash100 at 3 months) was achieved in 4221 Index 95ndash100 at 3 months) was achieved in 4221 and 344 of the patients respectively and 344 of the patients respectively
2 Direct Fibrinolytics2 Direct Fibrinolytics
Microplasmin (Microplasmin (ThromboGenics Heverlee Belgium)ThromboGenics Heverlee Belgium) is a truncated form of plasmin that is more resistant to the effects is a truncated form of plasmin that is more resistant to the effects
of antiplasmin of antiplasmin microplasmin can be used upto 4ndash12 hours after stroke onset microplasmin can be used upto 4ndash12 hours after stroke onset There was no evidence of increased bleeding risk with There was no evidence of increased bleeding risk with
microplasminmicroplasmin
Alfimeprase (Nuvelo San Carlos Calif)Alfimeprase (Nuvelo San Carlos Calif) is a recombinant truncated form of fibrolase a fibrinolytic zinc metalloproteinase is a recombinant truncated form of fibrolase a fibrinolytic zinc metalloproteinase
isolated from the venom of the southern copperhead snake isolated from the venom of the southern copperhead snake It degrades fibrin directly and achieves thrombolysis independent It degrades fibrin directly and achieves thrombolysis independent
of plasmin formationof plasmin formation its thrombolytic activity appears to be localized to the site of its thrombolytic activity appears to be localized to the site of
delivery These properties should theoretically result in faster delivery These properties should theoretically result in faster recanalization and lower hemorrhagic conversion riskrecanalization and lower hemorrhagic conversion risk
Anti-fibrinolyticsAnti-fibrinolytics
to limit fibrinolytic activityto limit fibrinolytic activity -aminocaproic acid (EACA) -aminocaproic acid (EACA) competitively inhibitscompetitively inhibits plasminogen and plasminogen activators from plasminogen and plasminogen activators from
binding to fibrinbinding to fibrin
alpha2-antiplasminalpha2-antiplasmin a serine protease inhibitor that a serine protease inhibitor that neutralizes any free circulating plasminneutralizes any free circulating plasmin
Plasminogen activator inhibitor-1Plasminogen activator inhibitor-1 a serine protease a serine protease inhibitor that inhibits tissue-type plasminogen inhibitor that inhibits tissue-type plasminogen activatoractivator
Glycoprotein (GP) IIbIIIa antagonistsGlycoprotein (GP) IIbIIIa antagonists
such as ReoPro (abciximab) Integrilin such as ReoPro (abciximab) Integrilin (eptifibatide) or Aggrastat (tirofiban) in (eptifibatide) or Aggrastat (tirofiban) in ischemic stroke remains investigational ischemic stroke remains investigational Deshmukh et al38 reported 21 patients with Deshmukh et al38 reported 21 patients with large-vessel occlusion refractory to IAT with large-vessel occlusion refractory to IAT with rtPA who were treated with IV andor IA rtPA who were treated with IV andor IA abciximab eptifibatide or tirofiban abciximab eptifibatide or tirofiban
IA Mechanical Approaches in Acute Ischemic Stroke IA Mechanical Approaches in Acute Ischemic Stroke Mechanical strategies have several advantagesMechanical strategies have several advantages First they lessen and may even preclude the use of chemical First they lessen and may even preclude the use of chemical
thrombolytics in this manner very likely reducing the risk of ICHthrombolytics in this manner very likely reducing the risk of ICH Second by avoiding the use of chemical thrombolytics it is Second by avoiding the use of chemical thrombolytics it is
possible to extend the treatment window beyond the limit of 6ndash8 possible to extend the treatment window beyond the limit of 6ndash8 hours hours
Third mechanically fragmenting a clot increases the surface area Third mechanically fragmenting a clot increases the surface area accessible to fibrinolytic agents and allows inflow of fresh accessible to fibrinolytic agents and allows inflow of fresh plasminogen which in turn may increase the speed of plasminogen which in turn may increase the speed of thrombolysis thrombolysis
Finally clot-retrieval devices may provide faster recanalization Finally clot-retrieval devices may provide faster recanalization
The disadvantages of the mechanical The disadvantages of the mechanical approaches approaches technical difficulty of navigating mechanical technical difficulty of navigating mechanical
devices into the intracranial circulation excessive devices into the intracranial circulation excessive trauma to the vasculature (potentially leading to trauma to the vasculature (potentially leading to vasospasm vessel dissection perforation or vasospasm vessel dissection perforation or rupture) rupture)
fragmented thrombus causing distal embolization fragmented thrombus causing distal embolization into previously unaffected territories into previously unaffected territories
Nevertheless the advantages of mechanical stroke Nevertheless the advantages of mechanical stroke therapy appear to significantly outweigh its therapy appear to significantly outweigh its disadvantages and risksdisadvantages and risks
Contraindications to Thrombolytic Contraindications to Thrombolytic agents agents
Recent thoracic abdominal or Recent thoracic abdominal or intracranial surgeryintracranial surgery
Recent haemorrhagic CVA Head injury Recent haemorrhagic CVA Head injury or neoplasmor neoplasm
Bleeding ulcerBleeding ulcer Anticipated invasive procedures (arterial Anticipated invasive procedures (arterial
punctures biopsies)punctures biopsies) Concurrent hemostatic dysfunctionConcurrent hemostatic dysfunction
Monitoring of thrombolytic Monitoring of thrombolytic therapytherapy
Thrombin time Measures the availability of functional
fibrinogen Normal thrombin time is 10-14 sec Prolonged when fibrinogen level is below
75-100 mgdl
Half Life of ThrombolyticsHalf Life of ThrombolyticsAgent Administration Half Life
Streptokinase IA 60-80min
Urokinase IAIV 9-12min
rTPA IAIV 6min
Abciximab(Reopro) IAIV 12hour
Aspirin POIV 15-20min
Heparin IVSC 60min
Coumadin PO 15-25 days
Anti Platelet DrugsAnti Platelet DrugsDrug Drug Mechanism Mechanism UsesUsesAspirinAspirin Permanently inhibits Permanently inhibits
COX-1 and COX-2COX-1 and COX-2CADCAD
Stroke-TIAsStroke-TIAs
NSAIDsNSAIDs Reversibly inhibits Reversibly inhibits COX-1COX-1
LimitedLimited
DipyridamoleDipyridamole Inhibits PDE increases Inhibits PDE increases cAMPcAMP
TIAsTIAs
ThenopyridinesThenopyridines
(Ticlopidine(Ticlopidine
ClopidrgrelClopidrgrel))
Inhibits ADP Inhibits ADP
PlatAg PlatAg
TIAsStrokeTIAsStroke
CAD PVDCAD PVD
Abciximab (ReoPro)Abciximab (ReoPro)
Eptifibatide (Integrilin)Eptifibatide (Integrilin)
TirofibanTirofiban
GP IIBIIIA InhibitorsGP IIBIIIA Inhibitors
Stroke- TIAs Stroke- TIAs
MonitoringMonitoring
Bleeding timeBleeding time
Optical aggregometryOptical aggregometry
Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay
Bleeding timeBleeding time
Requires a skin incision (usually made on the ear lobe or Requires a skin incision (usually made on the ear lobe or forearm offorearm of
a depth that results in disruption of capillary loops and a depth that results in disruption of capillary loops and small vessels)small vessels)
AdvantagesAdvantages Universally availableUniversally available Relatively simple techniquesRelatively simple techniques Can be performed bedsideCan be performed bedside
DisadvantagesDisadvantages Insensitive inaccurate non-specific techniqueInsensitive inaccurate non-specific technique
Poorly reproducible (as depends on multiple variables)Poorly reproducible (as depends on multiple variables)
Optical aggregometryOptical aggregometry
Gold standard assay for platelet functionGold standard assay for platelet function Agonist induced aggregation is measuredAgonist induced aggregation is measured Different agonist are available for different Different agonist are available for different
agentsagents However require unique expertise and are not However require unique expertise and are not
universally availableuniversally available Aspirin measured with ADP or AA(gt70 Aspirin measured with ADP or AA(gt70
aggregation so resistance)aggregation so resistance) Clopidogrel( ADP gt 90 aggregation means Clopidogrel( ADP gt 90 aggregation means
resistance) resistance)
Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay
Can be performed bed sideCan be performed bed side Different assay devices with different Different assay devices with different
agonist are used for each of different agonist are used for each of different antiplatelet agents antiplatelet agents
For Aspirin AA is used (result is reported as aspirin For Aspirin AA is used (result is reported as aspirin reaction units [ARU] ARUgt 550 indicates non-reaction units [ARU] ARUgt 550 indicates non-responsiveness)responsiveness)
Verify IIbIIIa assay device uses TRAP as agonist for Verify IIbIIIa assay device uses TRAP as agonist for Abciximab and TirofibanAbciximab and Tirofiban
Practical Applications Practical Applications related to specific related to specific
Neurovascular Neurovascular interventionsinterventions
Acute ischemic StrokeAcute ischemic Stroke When an artery occludes neurons are affected When an artery occludes neurons are affected
differently depending upon the amount of residual blood differently depending upon the amount of residual blood flowflow
Normal cerebral blood flow is greater than 50 mL100 Normal cerebral blood flow is greater than 50 mL100 mgminmgmin
Once blood flow decreases to less than 20 mL100 Once blood flow decreases to less than 20 mL100 mgmin infarction occursmgmin infarction occurs
If blood flow decreases to less than 10 mL100 mgmin If blood flow decreases to less than 10 mL100 mgmin irreversible neuronal death occurs rapidly irreversible neuronal death occurs rapidly
Blood flow between 11 and 20 mL100 mgmin is thought Blood flow between 11 and 20 mL100 mgmin is thought to represent the ischemic penumbra an area where the to represent the ischemic penumbra an area where the cells are functionally silent because of ischemia but are cells are functionally silent because of ischemia but are still able to recover if blood flow is restored still able to recover if blood flow is restored
Many acute stroke therapies are targeted toward Many acute stroke therapies are targeted toward restoring flow or function to the ischemic penumbrarestoring flow or function to the ischemic penumbra
Therapeutic window in Therapeutic window in management of acute Ischemic management of acute Ischemic
StrokeStrokeThe early diagnosis of ischemic stroke is critical to the The early diagnosis of ischemic stroke is critical to the
with only a narrow therapeutic window in the first few with only a narrow therapeutic window in the first few hours following stroke ictushours following stroke ictus
Diagnosis in the first 3 hours postictus provides the Diagnosis in the first 3 hours postictus provides the opportunity for intravenous or intraarterial thrombolysis opportunity for intravenous or intraarterial thrombolysis and intra-arterial clot mechanical treatment which and intra-arterial clot mechanical treatment which improve the outcome improve the outcome
Diagnosis in the time period between 3 and 6 hours Diagnosis in the time period between 3 and 6 hours provides an opportunity for intra-arterial thrombolysis provides an opportunity for intra-arterial thrombolysis and mechanical treatment and mechanical treatment
Involvement of the posterior circulation especially the Involvement of the posterior circulation especially the basilar artery is treated by some regardless of time of basilar artery is treated by some regardless of time of onset or up until 12 to 24 hours in some practices This is onset or up until 12 to 24 hours in some practices This is related to the potentially high mortality and morbidity related to the potentially high mortality and morbidity associated with basilar artery thrombosisassociated with basilar artery thrombosis
Infarct evaluation on angiographyInfarct evaluation on angiography(CT angiography and catheter (CT angiography and catheter
angiography)angiography)CTA is an excellent first-line examination for CTA is an excellent first-line examination for
evaluation of the head and neck arteries evaluation of the head and neck arteries In comparison with catheter angiography In comparison with catheter angiography
what it gives up in resolution and dynamic what it gives up in resolution and dynamic properties it makes up for with rapid properties it makes up for with rapid acquisition of a 3-D dataset and the potential acquisition of a 3-D dataset and the potential for assessment of whole-brain perfusion and for assessment of whole-brain perfusion and better parenchymal evaluationbetter parenchymal evaluation
Moreover CTA illustrates not only arterial Moreover CTA illustrates not only arterial stenosis or occlusion but also the vessel wall stenosis or occlusion but also the vessel wall This factor is most important for evaluation of This factor is most important for evaluation of intramural dissection and thrombosed intramural dissection and thrombosed aneurysms which may both complicate aneurysms which may both complicate evaluation of stroke patientsevaluation of stroke patients
Early angiographic signs of strokes Early angiographic signs of strokes both CTA both CTA and DSA and DSA
Vessel occlusion or cutoff related to Vessel occlusion or cutoff related to thromboembolithromboemboli
aneurysms aneurysms arterial dissection arterial dissection Meniscus or flattened shape to clot Meniscus or flattened shape to clot
(recent) versus reverse meniscus (older)(recent) versus reverse meniscus (older) tram track (nonocclusive or recanalized tram track (nonocclusive or recanalized
clot) clot) delayed (antegrade) flow (manifest as delayed (antegrade) flow (manifest as
decreased whole-brain perfusion on CTA)decreased whole-brain perfusion on CTA) retrograde collateral flowretrograde collateral flow
Non-occlusive left MCA thrombus on 3-D imaging performed from CTA source data and was confirmed at catheter angiography
Therapy to be started within a 6-hr Therapy to be started within a 6-hr time to treatment (TTT) window time to treatment (TTT) window (while in case of IV thrombolysis (while in case of IV thrombolysis therapy to be started with in 3hrs)therapy to be started with in 3hrs)
Exclusion criteria Exclusion criteria Rapidly improving neurologic deficit or Rapidly improving neurologic deficit or Sustained blood pressure of gt180100 Sustained blood pressure of gt180100 Hemorrhage is detected on CTHemorrhage is detected on CT Infarct involving gt more than 13 rd Infarct involving gt more than 13 rd
territory of MCAterritory of MCA MRADWI-Perfusion mismatchlt 20MRADWI-Perfusion mismatchlt 20 Definite hypodensity on CTDefinite hypodensity on CT
Intra-arterial Thrombolysis
Fibrinolytics + AntiplateletsFibrinolytics + Antiplatelets
PlasminogenPlasminogen activators through fibrinolysis exposes activators through fibrinolysis exposes free thrombin and paradoxically stimulatesfree thrombin and paradoxically stimulates platelet platelet aggregation which leads to formation of aaggregation which leads to formation of a platelet platelet thrombus (white clot) thrombus (white clot)
This new thrombus is relatively resistant to This new thrombus is relatively resistant to fibrinolyticsfibrinolytics
So new regimen in case of acute stroke isSo new regimen in case of acute stroke is fibrinolytics + antiplatelet drugsfibrinolytics + antiplatelet drugs
rtPA + IIbIIIa inhibitors( tirofiban rtPA + IIbIIIa inhibitors( tirofiban abciximab) orabciximab) or
Urokinase + IIbIIIa Urokinase + IIbIIIa inhibitors( tirofiban abciximab)inhibitors( tirofiban abciximab)
Intra-arterial Thrombolysis Tirofiban (04 microgkgmin bolus for 3 min followed by Tirofiban (04 microgkgmin bolus for 3 min followed by
0125 ugkgmin)0125 ugkgmin)
++
Heparin (2000ndash3000 IU bolus followed by Heparin (2000ndash3000 IU bolus followed by 1000 IUhour infusion 1000 IUhour infusion
with ACT maintained bw 200-300) throughout the with ACT maintained bw 200-300) throughout the interventional procedure and for 24ndash48 hours thereafter when interventional procedure and for 24ndash48 hours thereafter when there is neither intraprocedural bleeding nor suspicion of there is neither intraprocedural bleeding nor suspicion of increased risk of bleeding increased risk of bleeding
Maximum dose of Urokinase Maximum dose of Urokinase Anterior circulation stroke - 500000 IU (mean 400000 Anterior circulation stroke - 500000 IU (mean 400000
IU range 300000ndash500000 IU)IU range 300000ndash500000 IU) Posterior circulation stroke -1000000 IU (mean 837000 Posterior circulation stroke -1000000 IU (mean 837000
IU range 300000ndash1000000 IU)IU range 300000ndash1000000 IU)American Journal of NeuroradiologyAmerican Journal of Neuroradiology 262595-2601 2005262595-2601 2005
Intravenous ThrombolysisIntravenous Thrombolysis
The first method to restore cerebral The first method to restore cerebral perfusion is clot lysis with the goal perfusion is clot lysis with the goal of re-establishing blood flow to the of re-establishing blood flow to the affected tissue affected tissue
IV thrombolysis rt-PA is the only IV thrombolysis rt-PA is the only FDA- approved treatment for AIS FDA- approved treatment for AIS
Fibrinolysis is enhanced powerfully Fibrinolysis is enhanced powerfully by rt-PAby rt-PA
Intravenous rTPA Intravenous rTPA administration administration protocolprotocol
Total dose of rt-PA 09 mgkg (maximum dose Total dose of rt-PA 09 mgkg (maximum dose 90 mg)90 mg)
Give 10 as initial IV bolusGive 10 as initial IV bolus Infuse remainder over 1 hourInfuse remainder over 1 hour Admit patient to an ICU or stroke unit for Admit patient to an ICU or stroke unit for
monitoringmonitoring Neurologic assessments every 15 minutes Neurologic assessments every 15 minutes
during infusion then every 30 minutes for next during infusion then every 30 minutes for next 6 hours then every hour until 24hours after 6 hours then every hour until 24hours after treatmenttreatment
Favorable Outcome vs Treatment Time Favorable Outcome vs Treatment Time with IV rTPAwith IV rTPA
Protocol limit = 3 hrs
Benefit ~ 45 hrs
Thromboembolism During coilingThromboembolism During coiling Most feared and frequent complication Most feared and frequent complication Reported incidence - Approx 7 Reported incidence - Approx 7 SourcesSources of Thromboembolism are of Thromboembolism are
- Clots at the aneurysmal neck during or immediately- Clots at the aneurysmal neck during or immediately after after embolization embolization
- Thrombus forming on catheters during- Thrombus forming on catheters during proceduresprocedures
- Stenosis of an adjacent artery dt coil mass- Stenosis of an adjacent artery dt coil mass or herniationor herniation
- Migration of intraaneurysmal- Migration of intraaneurysmal thrombus during coil thrombus during coil placement placement
- Slow flow dt vasospasm - Slow flow dt vasospasm
- Rare and unlikely causes are hypercoagulable- Rare and unlikely causes are hypercoagulable state such state such as antiphospholipid antibody syndrome or due to HITas antiphospholipid antibody syndrome or due to HIT
Occur more often with wide-necked aneurysms (dt Occur more often with wide-necked aneurysms (dt increased exposed surface area of thrombogenic coil increased exposed surface area of thrombogenic coil material)material)
Current regimen of endovascular Current regimen of endovascular managementmanagement
The The glycoprotein IIbIIIa antagonist tirofiban glycoprotein IIbIIIa antagonist tirofiban (04 (04 microgkgmin bolus for 30 minutes followed by infusion of microgkgmin bolus for 30 minutes followed by infusion of 0125 ugkgmin until the thrombus dissolved) 0125 ugkgmin until the thrombus dissolved)
Intraarterial thrombolysis with Intraarterial thrombolysis with urokinase or r- TPA urokinase or r- TPA increase of intravenous (IV) heparin (measured by increase of intravenous (IV) heparin (measured by
ACT) ACT) Intravenous aspirin Intravenous aspirin
Coil-related platelet aggregation (white clot) is Coil-related platelet aggregation (white clot) is unlikely to respond to fibrinolytics but has a high risk unlikely to respond to fibrinolytics but has a high risk of hemorrhage (In ISAT) all 5 patients who had of hemorrhage (In ISAT) all 5 patients who had received thrombolytic therapy with tPA to treat a received thrombolytic therapy with tPA to treat a thromboembolic complication after endovascular thromboembolic complication after endovascular treatment rebleed and all of these patients died)treatment rebleed and all of these patients died)
IntracranialIntracranial Stenting Stenting Metallic foreign body such as stent will accumulate Metallic foreign body such as stent will accumulate
thrombus in the absence of platelet inhibitionthrombus in the absence of platelet inhibition Antiplatelet drugs are important to prevent peri or Antiplatelet drugs are important to prevent peri or
post-interventional thromboembolic eventspost-interventional thromboembolic events Optimal treatment regimens has not been determined Optimal treatment regimens has not been determined
but usually but usually Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-
procedureprocedureOrOr
Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on
morning of proceduremorning of procedure
If need to use stent is not pre-planned thanIf need to use stent is not pre-planned than
Abciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkgAbciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkg IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)
Glycoprotein IIbIIIa inhibitor are not used routinely during elective Glycoprotein IIbIIIa inhibitor are not used routinely during elective stenting procedure dt increased risk of ICH stenting procedure dt increased risk of ICH
Carotid StentingCarotid Stenting
Pre-procedurePre-procedure
Double Antiplatelet therapy is routinely given Double Antiplatelet therapy is routinely given beginning at least 3beginning at least 3
days before the proceduredays before the procedure
Aspirin 325mgd+Clopidogrel 75mgdAspirin 325mgd+Clopidogrel 75mgd During procedureDuring procedure
Heparin is given with target clotting time of 250-Heparin is given with target clotting time of 250-300sec300sec
Post-procedure Post-procedure
Aspirin 325mg is continued indefinitely and Aspirin 325mg is continued indefinitely and
Clopidogrel 75mgd for at least 6 weeks Clopidogrel 75mgd for at least 6 weeks
Inclusion criteria for Local ThrombolysisInclusion criteria for Local Thrombolysis a)a) Patients in severe clinical grade on admission Patients in severe clinical grade on admission
with evidence of dural venous sinus with evidence of dural venous sinus thrombosis and restrictive venous outflow on thrombosis and restrictive venous outflow on cerebral angiogramcerebral angiogram
b)b) Patients in clinical grade 3 worsening on Patients in clinical grade 3 worsening on heparin therapy Restriction to venous heparin therapy Restriction to venous outflow was defined as an increase in brain outflow was defined as an increase in brain circulation time gt 12 s delay in the drainage circulation time gt 12 s delay in the drainage of cortical veins with cortical veins hanging of cortical veins with cortical veins hanging in spacein space
Treatment Options for Venous Thrombosis
CT Grading for Venous ThrombosisCT Grading for Venous Thrombosis Grade I no parenchymal change Grade I no parenchymal change
(hyperdense (hyperdense sinuses cortical veins empty sinuses cortical veins empty delta sign)delta sign)
Grade II non hemorrhagic venous infarct Grade II non hemorrhagic venous infarct without mass effect without mass effect
Grade III non-hemorrhagic infarct with Grade III non-hemorrhagic infarct with mass effectmass effect
Grade IV hemorrhagic venous infarct (max Grade IV hemorrhagic venous infarct (max diameter lt 3 cm) with no mass effectdiameter lt 3 cm) with no mass effect
Grade V hemorrhagic venous infarct (max Grade V hemorrhagic venous infarct (max diameter gt 3 cm) with mass effect diameter gt 3 cm) with mass effect
Local ThrombolysisLocal Thrombolysis
Femoral Jugular access was secured and a guiding Femoral Jugular access was secured and a guiding catheter was placed in the jugular bulb catheter was placed in the jugular bulb Mechanical Mechanical clot maceration clot maceration was done with the guidewire was done with the guidewire following which a microcatheter (was navigated and following which a microcatheter (was navigated and placed in the thrombosed segment of sinus confirmed placed in the thrombosed segment of sinus confirmed on a selective venogram on a selective venogram
Urokinase infusion Bolus dose of 2-6 lacs followed Urokinase infusion Bolus dose of 2-6 lacs followed by 60000 to 100000 units per hour along with by 60000 to 100000 units per hour along with periodic check venogram Along with maintenance periodic check venogram Along with maintenance systemic infusion of Heparinsystemic infusion of Heparin Other agents such as Other agents such as streptokinase altepase or rTPAstreptokinase altepase or rTPA can be also used can be also used
After thrombolysis patient should subjected to oral After thrombolysis patient should subjected to oral anticoagulation for six monthsanticoagulation for six months
Low-molecular-weight Low-molecular-weight heparinheparin
PharmacologyPharmacologyLMWH as its name suggests is a glycosaminoglycan that is approximatelyLMWH as its name suggests is a glycosaminoglycan that is approximately
one third the molecular weight of UFH It is derived from UFH through one third the molecular weight of UFH It is derived from UFH through variousvarious
depolymerization processes LMWH binds to antithrombin which in turn depolymerization processes LMWH binds to antithrombin which in turn
Neutralizes actors Xa and IIa Because LMWH lacks many of the longer Neutralizes actors Xa and IIa Because LMWH lacks many of the longer chains chains
required for binding to thrombin it has less ability to neutralize thrombin required for binding to thrombin it has less ability to neutralize thrombin
relativeto its ability to neutralize factor Xa LMWH also has less relativeto its ability to neutralize factor Xa LMWH also has less nonspecific nonspecific
binding to other proteins There is greater bioavailability with more binding to other proteins There is greater bioavailability with more predictable predictable
pharmacokinetics that eliminates the need for monitoring The smaller pharmacokinetics that eliminates the need for monitoring The smaller size also size also
allows for enhanced subcutaneous absorption when compared with UFHallows for enhanced subcutaneous absorption when compared with UFH
Three LMWH preparations are Three LMWH preparations are currently approved for use in the currently approved for use in the United States (1) enoxaparin (2) United States (1) enoxaparin (2) dalteparin and (3) tinzaparin dalteparin and (3) tinzaparin
They are all administered They are all administered subcutaneously at intervals of either subcutaneously at intervals of either once or twice daily for both once or twice daily for both prophylaxis and treatment dosesprophylaxis and treatment doses
Few Experiences of Few Experiences of ThrombolysisThrombolysis
Vickey 25 Yrs male patient presented Vickey 25 Yrs male patient presented with 12with 12thth day HO severe headache with day HO severe headache with right sided hemiplegiaright sided hemiplegia
MRI shows thrombosis of the superior MRI shows thrombosis of the superior sagittal left transverse left sigmoid sagittal left transverse left sigmoid sinuses and cortical veins in the fronto-sinuses and cortical veins in the fronto-parietal regions with eo haemorrhagic parietal regions with eo haemorrhagic infarct in the left cerebral hemisphere infarct in the left cerebral hemisphere with mass effect( Grade ndashV)with mass effect( Grade ndashV)
Sashi Srivastava 64 yrs FSashi Srivastava 64 yrs F In a follow up case of MRD with infra-renal In a follow up case of MRD with infra-renal
aortic abdominal and bilateral renal artery aortic abdominal and bilateral renal artery thrombosis renal angiogram shows filling thrombosis renal angiogram shows filling defects in the right Renal artery defects in the right Renal artery
Initially Renal angioplasty was done Initially Renal angioplasty was done Following angioplasty few thrombi are seem Following angioplasty few thrombi are seem to extends into the segmental branches and to extends into the segmental branches and causing blockage So Thrombolysis was causing blockage So Thrombolysis was plane to dissolve the run-out thrombi with plane to dissolve the run-out thrombi with urokinase urokinase
Rakesh 34yrsMRakesh 34yrsM Left SFA pseudoaneurysm with Left SFA pseudoaneurysm with
Covered stent placementCovered stent placement Pre operative antiplatelets with post Pre operative antiplatelets with post
procedure heparin Tirofiban procedure heparin Tirofiban followed by aspirin and clopidogrel followed by aspirin and clopidogrel were usedwere used
IAT may be a treatment option for selected patients IAT may be a treatment option for selected patients Possible selection criteria include Possible selection criteria include
presentation between 3 and 6 hours from symptom onsetpresentation between 3 and 6 hours from symptom onset major cerebral artery occlusion major cerebral artery occlusion severe neurologic deficits severe neurologic deficits high risk of systemic hemorrhage with IV rt-PA (eg recent high risk of systemic hemorrhage with IV rt-PA (eg recent
surgery) surgery) The MERCI (Mechanical Embolus Removal in Cerebral The MERCI (Mechanical Embolus Removal in Cerebral
Ischemia) retrievalIschemia) retrieval system system
Has been FDA-approved for recanalizing acutely occluded Has been FDA-approved for recanalizing acutely occluded cerebral arteries cerebral arteries
In the Multi-MERCI study patients who did not improve In the Multi-MERCI study patients who did not improve immediately after IV rt-PA underwent mechanical immediately after IV rt-PA underwent mechanical embolectomy within 8 hours of symptom onset embolectomy within 8 hours of symptom onset
Partial or complete recanalization occurred in 74 of Partial or complete recanalization occurred in 74 of patientspatients
with a symptomatic intracerebral hemorrhage (sICH) rate of with a symptomatic intracerebral hemorrhage (sICH) rate of 67 67
Mechanical embolectomy with the MERCI retriever may be a Mechanical embolectomy with the MERCI retriever may be a feasible and safe option for patients after IV rt-PAfeasible and safe option for patients after IV rt-PA
Penumbra stroke systemPenumbra stroke system This device combines two methods of clot This device combines two methods of clot
extraction aspiration and mechanical extraction aspiration and mechanical extraction extraction
First the clot is aspirated then a thrombus First the clot is aspirated then a thrombus removal ring can be used if necessary to removal ring can be used if necessary to remove remaining clot remove remaining clot
successful recanalizing 82successful recanalizing 82 Bridging therapyBridging therapy
06 mgkg IV rt-PA followed by IAT with IA rt-06 mgkg IV rt-PA followed by IAT with IA rt-PA (up to 20 mg)PA (up to 20 mg)
achieved a higher recanalization rateachieved a higher recanalization rate
Criteria for thrombolysis with rTPACriteria for thrombolysis with rTPA
Inclusion criteriaInclusion criteria Clinical signs and symptoms consistent with ischemic Clinical signs and symptoms consistent with ischemic
strokestroke Patient last seen normal within 3 hoursPatient last seen normal within 3 hours Measurable neurologic deficitMeasurable neurologic deficit
Exclusion criteriaExclusion criteria Any hemorrhage on neuroimaging (CT or MRI)Any hemorrhage on neuroimaging (CT or MRI) Symptoms suggestive of subarachnoid hemorrhageSymptoms suggestive of subarachnoid hemorrhage Seizure at stroke onset that is thought to contribute to Seizure at stroke onset that is thought to contribute to
neurologic deficitneurologic deficit Hypodensity greater than one third cerebral hemisphere Hypodensity greater than one third cerebral hemisphere
on CTon CT SBP greater than 185 mm Hg or DBP greater than 110 SBP greater than 185 mm Hg or DBP greater than 110
mm Hgmm Hg International normalized ratio (INR) greater than 17International normalized ratio (INR) greater than 17
Ischemic Stroke Ischemic Stroke Treatment ndash 2006Treatment ndash 2006
IV tissue plasminogen activator (tPA)IV tissue plasminogen activator (tPA) ndash ndash Only FDA-approved acute stroke drugOnly FDA-approved acute stroke drug ndash ndash 3 hour treatment window3 hour treatment window
MERCI - Concentric clot retrieval MERCI - Concentric clot retrieval devicedevice ndash ndash Rescue therapy - approved 2004Rescue therapy - approved 2004 ndash ndash Device approval (not outcomes-based)Device approval (not outcomes-based)
Off label approachesOff label approaches ndash ndash IV tPA after 3 hoursIV tPA after 3 hours ndash ndash IV-IA tPA sequential strategiesIV-IA tPA sequential strategies ndash ndash IA tPA clot angioplasty fragmentationIA tPA clot angioplasty fragmentation ndash ndash Ultrasound-assisted tPA lysisUltrasound-assisted tPA lysis
rt-PA Trials NINDSrt-PA Trials NINDS
Acute stroke - 624 patientsAcute stroke - 624 patients Treat within 3 hrsTreat within 3 hrs Intravenous 09 mgkg rt-PA vs placeboIntravenous 09 mgkg rt-PA vs placebo Hemorrhage 64 tPA 06 placeboHemorrhage 64 tPA 06 placebo Neurologic recovery better with tPA 30 Neurologic recovery better with tPA 30
more like to have minimal or no disabilitymore like to have minimal or no disability
First proven approved treatment for First proven approved treatment for strokestroke
Limitations of tPALimitations of tPA Only 4 of acute strokes receive tPAOnly 4 of acute strokes receive tPA (Kleindorfer et al Stroke 2004 35 e27-e29)(Kleindorfer et al Stroke 2004 35 e27-e29)
Only 22 of patients present within 3 hoursOnly 22 of patients present within 3 hours1048707 1048707 51 of these ineligible due to51 of these ineligible due to
bull bull Mild severityMild severity bull bull Medical or surgical historyMedical or surgical history bull bull Blood testsBlood tests
Sustained recanalization only 13Sustained recanalization only 13 (Alexandrov et al NEJM 2004 351 2170-8)(Alexandrov et al NEJM 2004 351 2170-8)
Concern for hemorrhageConcern for hemorrhage tPA potentiates apoptotic injury tPA potentiates apoptotic injury (Liu et al Nature Med 2004 101379-83)(Liu et al Nature Med 2004 101379-83)
PROACT II IA Lysis TrialPROACT II IA Lysis Trial Baseline 24 hours 8 days
Baseline 60 minutes 120 minutes
9mg IAProurokinase
Desmoteplase Trials DEDAS Desmoteplase Trials DEDAS DIASDIAS
Trial OverviewTrial Overview Double blind randomized placebo Double blind randomized placebo
controlled trialscontrolled trials IV delivery 3-9 hour time windowIV delivery 3-9 hour time window Plasminogen activator ndash from Plasminogen activator ndash from vampire bat vampire bat
salivasaliva Selection based on PWI-DWI MismatchSelection based on PWI-DWI Mismatch
MRI InclusionMRI Inclusion PWI defect at least 2 cm AND ~20 larger PWI defect at least 2 cm AND ~20 larger
than DWIthan DWI PWI should be obvious even visible on PWI should be obvious even visible on
raw imagesraw imagesMRI ExclusionMRI Exclusion
DWI gt 13 MCADWI gt 13 MCA MRA ICA occlusionMRA ICA occlusion
Desmoteplase ndash DIAS Desmoteplase ndash DIAS ResultsResults
Mechanical Thrombolysis Mechanical Thrombolysis devicesdevices
mechanical thrombolysis potentially extends the treatment mechanical thrombolysis potentially extends the treatment window because they act promptly at the site of the thrombuswindow because they act promptly at the site of the thrombus
The devices can retrieve large clots that pharmaceutical agents The devices can retrieve large clots that pharmaceutical agents may not successfully lysemay not successfully lyse
Patients treated with IV tPA may be considered for treatment of Patients treated with IV tPA may be considered for treatment of residual clot with some of these devicesresidual clot with some of these devices
suction-creating saline jets suction-creating saline jets laser energy ultrasound laser energy ultrasound a corkscrew apparatus to treat strokesa corkscrew apparatus to treat strokes The AngioJet systemThe AngioJet system uses saline jets that are directed back into the catheter to uses saline jets that are directed back into the catheter to
create a low-pressure zone around the catheter tip inducing create a low-pressure zone around the catheter tip inducing suction suction
The clot is pulled into the exhaust lumen and removed from the The clot is pulled into the exhaust lumen and removed from the vessel Although US Food and Drug Administration (FDA) has vessel Although US Food and Drug Administration (FDA) has approved this device for use in arteriovenous dialysis grafts and approved this device for use in arteriovenous dialysis grafts and fistulae and for the treatment of coronary arteries saphenous fistulae and for the treatment of coronary arteries saphenous vein grafts and peripheral vessels clinical trials for the vein grafts and peripheral vessels clinical trials for the treatment of acute stroke are no longer in progress treatment of acute stroke are no longer in progress
Most devices are used in cerebral vessels that 2-5 mm
The Latis laser device The Latis laser device used laser energy to ablate clots used laser energy to ablate clots Arteries 2-5 mm in diameter could be Arteries 2-5 mm in diameter could be
treated including the ICA M1 or M2 treated including the ICA M1 or M2 branch of the MCA A1 branch of the branch of the MCA A1 branch of the anterior cerebral artery (ACA) basilar anterior cerebral artery (ACA) basilar artery posterior cerebral artery (PCA) artery posterior cerebral artery (PCA) and vertebral and vertebral
Patients could receive treatment as late Patients could receive treatment as late as 8 hours after symptom onset in the as 8 hours after symptom onset in the anterior circulation and within 24 hours in anterior circulation and within 24 hours in the posterior circulation the posterior circulation
Endovascular Photo Acoustic Endovascular Photo Acoustic Recanalization (EPAR) Recanalization (EPAR)
A laser power source generated energy for the A laser power source generated energy for the systemsystem
The energy was delivered by means of The energy was delivered by means of fiberoptics to the tip of the catheter at the fiberoptics to the tip of the catheter at the treatment sitetreatment site
Absorption of laser light by darkly pigmented Absorption of laser light by darkly pigmented materials (ie the clot) occurred inside the 1-mm materials (ie the clot) occurred inside the 1-mm catheter tipcatheter tip
the system was designed to minimize scattering the system was designed to minimize scattering of laser light of laser light
Absorption converted photo energy to acoustic Absorption converted photo energy to acoustic energy which then emulsified the clot inside the energy which then emulsified the clot inside the catheter tip catheter tip
EKOS ultrasound( the EKOS ultrasound( the Ultrasound Thrombolytic Ultrasound Thrombolytic
Infusion Catheter) Infusion Catheter) combines the use of a distal ultrasound transducer with combines the use of a distal ultrasound transducer with
infusion of a thrombolytic agent through the infusion of a thrombolytic agent through the microcathetermicrocatheter
Ultrasound changes the structure of the clot to Ultrasound changes the structure of the clot to temporarily increase its permeability while providing an temporarily increase its permeability while providing an acoustic pressure gradient to move the drug into the clot acoustic pressure gradient to move the drug into the clot to speed its dissolution to speed its dissolution
The EKOS catheter is placed in the proximal portion of the The EKOS catheter is placed in the proximal portion of the clot clot
After a 2-mg bolus of tPA was injected through the After a 2-mg bolus of tPA was injected through the catheter catheter
the patient received a continuous infusion of IA tPA 03 the patient received a continuous infusion of IA tPA 03 mgmin to a maximum of 20 mg and simultaneous mgmin to a maximum of 20 mg and simultaneous ultrasound transmission for as long as 60 minutes ultrasound transmission for as long as 60 minutes
One patient was treated with a total of 4 units of One patient was treated with a total of 4 units of recombinant reteplase (Retavase) hand-injected over 60 recombinant reteplase (Retavase) hand-injected over 60 minutes minutes
Penumbra system Penumbra system The Penumbra system (Penumbra Inc) provides a dual The Penumbra system (Penumbra Inc) provides a dual
approach to clot extraction using aspiration followed by approach to clot extraction using aspiration followed by clot retrieval with a ring device if needed clot retrieval with a ring device if needed
Mechanical Embolus Removal in Cerebral Ischemia Mechanical Embolus Removal in Cerebral Ischemia (MERCI)(MERCI)
a corkscrew-like apparatus to remove blood clots from a corkscrew-like apparatus to remove blood clots from the brain in patients experiencing an ischemic stroke the brain in patients experiencing an ischemic stroke
The corkscrew itself resides in the catheter tip which The corkscrew itself resides in the catheter tip which shields it from the wall of the vessel until it is ready to be shields it from the wall of the vessel until it is ready to be burrowed into the clot Once lodged in the clot the device burrowed into the clot Once lodged in the clot the device and clot are withdrawn from the vessel and clot are withdrawn from the vessel
Snarelike devicesSnarelike devices Snares such as the Neuronet snare (Guidant Snares such as the Neuronet snare (Guidant
Endovascular Santa Clara CA) have been developed Endovascular Santa Clara CA) have been developed specifically for use in the treatment of strokes specifically for use in the treatment of strokes
These devices are simple in design and do not require the These devices are simple in design and do not require the clot to be amenable to emulsification clot to be amenable to emulsification
X-Sizer deviceX-Sizer device a device with small moving blades at the a device with small moving blades at the
catheter tip catheter tip This device the X-Sizer device (EndiCor Medical This device the X-Sizer device (EndiCor Medical
San Clemente CA) can be used to excise the San Clemente CA) can be used to excise the thrombus and aspirate it thrombus and aspirate it
The device was being evaluated in randomized The device was being evaluated in randomized studies of coronary vessels and in a registry of studies of coronary vessels and in a registry of patients with acute myocardial infarctionpatients with acute myocardial infarction
Although the manufacturer had modified the Although the manufacturer had modified the device for use in cerebral vessels a safety and device for use in cerebral vessels a safety and feasibility study was indefinitely suspended after feasibility study was indefinitely suspended after only 1 patient was treated with the device in only 1 patient was treated with the device in Europe Europe
Suction thrombectomySuction thrombectomy This method of mechanical thrombolysis is one of the This method of mechanical thrombolysis is one of the
simplestsimplest In this readily available technique suction is applied with In this readily available technique suction is applied with
a syringe to remove thrombus in the ICA a syringe to remove thrombus in the ICA It requires no other devicesIt requires no other devices A catheter with a large inner diameter (Brite Tip Cordis A catheter with a large inner diameter (Brite Tip Cordis
Corporation Miami FL) was placed in the symptomatic Corporation Miami FL) was placed in the symptomatic vessel and navigated over a guidewire into the thrombusvessel and navigated over a guidewire into the thrombus
A 60-mL syringe was used to aspirate the thrombus A 60-mL syringe was used to aspirate the thrombus Each patient required angioplasty and stenting of carotid Each patient required angioplasty and stenting of carotid
bifurcation stenosis and received daily aspirin and bifurcation stenosis and received daily aspirin and ticlopidine after the procedure No complications ticlopidine after the procedure No complications occurred occurred
Summary Acute Stroke Summary Acute Stroke ImagingImaging
PhysiologyPhysiology importance collaterals importance collaterals
ndash ndashGrowing role for perfusion Growing role for perfusion assessmentassessment
tPAtPA guidelines amp limitations guidelines amp limitations Signs on CT amp MRSigns on CT amp MR follow physiology follow physiology Stroke trialsStroke trials PWI-DWI mismatch PWI-DWI mismatch
ndash ndashTreat based on physiology not timeTreat based on physiology not time ProtocolsProtocols should be fast and should be fast and
comprehensivecomprehensive
IAT in Acute Ischemic StrokeIAT in Acute Ischemic Stroke
IAT advantages over IV thrombolysisIAT advantages over IV thrombolysis Coaxial microcatheter techniques the occluded intracranial Coaxial microcatheter techniques the occluded intracranial
vessel is directly accessible and the fibrinolytic agent can be vessel is directly accessible and the fibrinolytic agent can be infused directly into the thrombusinfused directly into the thrombus
This permits a smaller dose of fibrinolytic agent to reach a This permits a smaller dose of fibrinolytic agent to reach a higher local concentration than that reached by systemic higher local concentration than that reached by systemic infusioninfusion
Allows more complete recanalization with lower total doses of Allows more complete recanalization with lower total doses of thrombolytic thrombolytic
With the smaller dose complications from systemic fibrinolytic With the smaller dose complications from systemic fibrinolytic effects including intracranial hemorrhage (ICH) can effects including intracranial hemorrhage (ICH) can theoretically be reduced theoretically be reduced
Treatment window for endovascular techniques can be Treatment window for endovascular techniques can be extended beyond the typical IV window of 3 hours extended beyond the typical IV window of 3 hours
IA techniques have led to higher recanalization rates than IV IA techniques have led to higher recanalization rates than IV thrombolysisthrombolysis
Major disadvantagesMajor disadvantages Relative complexity of the procedure the level Relative complexity of the procedure the level
of required technical expertise and its of required technical expertise and its relatively low availability relatively low availability
Delays in initiating treatmentDelays in initiating treatment InvasiveInvasive
ThrombolyticsThrombolytics
Plasminogen activators
Fibrinolytics
1 Plasminogen Activators 1 Plasminogen Activators drugs act by converting the inactive proenzyme drugs act by converting the inactive proenzyme plasminogen into the active enzyme plasmin Plasmin plasminogen into the active enzyme plasmin Plasmin digests fibrinogen fibrin monomers and cross-linked digests fibrinogen fibrin monomers and cross-linked fibrin (as found in a thrombus) into fibrin degradation fibrin (as found in a thrombus) into fibrin degradation productsproducts
First-Generation Agents First-Generation Agents StreptokinaseStreptokinase a protein derived from group C a protein derived from group C
szlig-hemolytic streptococci has a half-life of 16ndashszlig-hemolytic streptococci has a half-life of 16ndash90 minutes and low fibrin specificity This drug 90 minutes and low fibrin specificity This drug proved to have a very narrow therapeutic proved to have a very narrow therapeutic window and significant rates of ICH and window and significant rates of ICH and systemic hemorrhage18systemic hemorrhage18
UrokinaseUrokinase is a serine protease with a plasma is a serine protease with a plasma half life of 14 minutes and low fibrin specificity half life of 14 minutes and low fibrin specificity
The urokinase dose used in cerebral IAT has The urokinase dose used in cerebral IAT has ranged from 002 to 2 X106unitsranged from 002 to 2 X106units
Second-Generation Agents Second-Generation Agents Alteplase (rtPA) Alteplase (rtPA)
is a serine is a serine protease with a plasma half-life of 35 protease with a plasma half-life of 35 minutes and a high degree of fibrin affinity and minutes and a high degree of fibrin affinity and specificity specificity
Dose used in cerebral IAT has ranged between 20 Dose used in cerebral IAT has ranged between 20 and 60 mgand 60 mg
Disadvantages of alteplase include its relatively short Disadvantages of alteplase include its relatively short halflife and limited penetration into the clot matrix halflife and limited penetration into the clot matrix because of strong binding with surface fibrin which because of strong binding with surface fibrin which could delay recanalization and increase the risk of could delay recanalization and increase the risk of recurrent occlusion recurrent occlusion
Prourokinase (r-prourokinase) Prourokinase (r-prourokinase) is the proenzyme precursor of urokinase is the proenzyme precursor of urokinase T12 of 7 minutes and high fibrin specificity T12 of 7 minutes and high fibrin specificity
Third-Generation AgentsThird-Generation Agents
ReteplaseReteplase is a structurally modified is a structurally modified form of alteplase form of alteplase
with a longer half-life (15ndash18 minutes) In with a longer half-life (15ndash18 minutes) In addition it does not bind as highly to fibrin addition it does not bind as highly to fibrin unbound reteplase can thus theoretically better unbound reteplase can thus theoretically better penetrate the clot and potentially penetrate the clot and potentially improve in improve in vivo fibrinolytic activity vivo fibrinolytic activity
TenecteplaseTenecteplase is another modified form of rtPA with a longer is another modified form of rtPA with a longer
half-life (17 minutes)half-life (17 minutes) greater fibrin specificity and greater greater fibrin specificity and greater
resistance to plasminogen activator inhibitor-1 resistance to plasminogen activator inhibitor-1 IV tenecteplase in acute ischemic stroke IV tenecteplase in acute ischemic stroke
suggest that the drug is safe and promisingsuggest that the drug is safe and promising
Newer plasminogen activatorNewer plasminogen activator
DesmoteplaseDesmoteplase is a genetically engineered is a genetically engineered version of the clot-dissolving factor version of the clot-dissolving factor
found in the saliva found in the saliva of the vampire bat Desmodus rotundusof the vampire bat Desmodus rotundus moremore potent and more selective for fibrin-bound potent and more selective for fibrin-bound
plasminogen than any other known plasminogen plasminogen than any other known plasminogen activatoractivator
Unlike tissue plasminogen activator (tPA) desmoteplase Unlike tissue plasminogen activator (tPA) desmoteplase is not activated by fibrinogen or -amyloid proteins is not activated by fibrinogen or -amyloid proteins factors that may exacerbate the risk for ICH factors that may exacerbate the risk for ICH
The effect of IV administration of desmoteplase 3ndash9 The effect of IV administration of desmoteplase 3ndash9 hours after symptom onset in patients with stroke who hours after symptom onset in patients with stroke who present with mismatch on MR imaging or CT perfusion present with mismatch on MR imaging or CT perfusion
3 DefibrinogenatingFibrinogenolytic 3 DefibrinogenatingFibrinogenolytic Agents Agents
AncrodAncrod(Viprinex)(Viprinex) is is the purified fraction of the Malayan pit viper venomthe purified fraction of the Malayan pit viper venom It acts by directly cleaving and inactivating fibrinogen It acts by directly cleaving and inactivating fibrinogen
and thus indirectly promoting anticoagulation and thus indirectly promoting anticoagulation The reduction in the blood levels of fibrinogen also The reduction in the blood levels of fibrinogen also
leads to a reduced blood viscosity which may improve leads to a reduced blood viscosity which may improve blood flow to the affected areas of the brain blood flow to the affected areas of the brain
In the Stroke Treatment with Ancrod Trial 500 In the Stroke Treatment with Ancrod Trial 500 patients with stroke presenting within 3 hours of patients with stroke presenting within 3 hours of symptom onset were randomized to receive ancrod (symptom onset were randomized to receive ancrod (n n 248) or a placebo (n 252) Good outcome (Barthel 248) or a placebo (n 252) Good outcome (Barthel Index 95ndash100 at 3 months) was achieved in 4221 Index 95ndash100 at 3 months) was achieved in 4221 and 344 of the patients respectively and 344 of the patients respectively
2 Direct Fibrinolytics2 Direct Fibrinolytics
Microplasmin (Microplasmin (ThromboGenics Heverlee Belgium)ThromboGenics Heverlee Belgium) is a truncated form of plasmin that is more resistant to the effects is a truncated form of plasmin that is more resistant to the effects
of antiplasmin of antiplasmin microplasmin can be used upto 4ndash12 hours after stroke onset microplasmin can be used upto 4ndash12 hours after stroke onset There was no evidence of increased bleeding risk with There was no evidence of increased bleeding risk with
microplasminmicroplasmin
Alfimeprase (Nuvelo San Carlos Calif)Alfimeprase (Nuvelo San Carlos Calif) is a recombinant truncated form of fibrolase a fibrinolytic zinc metalloproteinase is a recombinant truncated form of fibrolase a fibrinolytic zinc metalloproteinase
isolated from the venom of the southern copperhead snake isolated from the venom of the southern copperhead snake It degrades fibrin directly and achieves thrombolysis independent It degrades fibrin directly and achieves thrombolysis independent
of plasmin formationof plasmin formation its thrombolytic activity appears to be localized to the site of its thrombolytic activity appears to be localized to the site of
delivery These properties should theoretically result in faster delivery These properties should theoretically result in faster recanalization and lower hemorrhagic conversion riskrecanalization and lower hemorrhagic conversion risk
Anti-fibrinolyticsAnti-fibrinolytics
to limit fibrinolytic activityto limit fibrinolytic activity -aminocaproic acid (EACA) -aminocaproic acid (EACA) competitively inhibitscompetitively inhibits plasminogen and plasminogen activators from plasminogen and plasminogen activators from
binding to fibrinbinding to fibrin
alpha2-antiplasminalpha2-antiplasmin a serine protease inhibitor that a serine protease inhibitor that neutralizes any free circulating plasminneutralizes any free circulating plasmin
Plasminogen activator inhibitor-1Plasminogen activator inhibitor-1 a serine protease a serine protease inhibitor that inhibits tissue-type plasminogen inhibitor that inhibits tissue-type plasminogen activatoractivator
Glycoprotein (GP) IIbIIIa antagonistsGlycoprotein (GP) IIbIIIa antagonists
such as ReoPro (abciximab) Integrilin such as ReoPro (abciximab) Integrilin (eptifibatide) or Aggrastat (tirofiban) in (eptifibatide) or Aggrastat (tirofiban) in ischemic stroke remains investigational ischemic stroke remains investigational Deshmukh et al38 reported 21 patients with Deshmukh et al38 reported 21 patients with large-vessel occlusion refractory to IAT with large-vessel occlusion refractory to IAT with rtPA who were treated with IV andor IA rtPA who were treated with IV andor IA abciximab eptifibatide or tirofiban abciximab eptifibatide or tirofiban
IA Mechanical Approaches in Acute Ischemic Stroke IA Mechanical Approaches in Acute Ischemic Stroke Mechanical strategies have several advantagesMechanical strategies have several advantages First they lessen and may even preclude the use of chemical First they lessen and may even preclude the use of chemical
thrombolytics in this manner very likely reducing the risk of ICHthrombolytics in this manner very likely reducing the risk of ICH Second by avoiding the use of chemical thrombolytics it is Second by avoiding the use of chemical thrombolytics it is
possible to extend the treatment window beyond the limit of 6ndash8 possible to extend the treatment window beyond the limit of 6ndash8 hours hours
Third mechanically fragmenting a clot increases the surface area Third mechanically fragmenting a clot increases the surface area accessible to fibrinolytic agents and allows inflow of fresh accessible to fibrinolytic agents and allows inflow of fresh plasminogen which in turn may increase the speed of plasminogen which in turn may increase the speed of thrombolysis thrombolysis
Finally clot-retrieval devices may provide faster recanalization Finally clot-retrieval devices may provide faster recanalization
The disadvantages of the mechanical The disadvantages of the mechanical approaches approaches technical difficulty of navigating mechanical technical difficulty of navigating mechanical
devices into the intracranial circulation excessive devices into the intracranial circulation excessive trauma to the vasculature (potentially leading to trauma to the vasculature (potentially leading to vasospasm vessel dissection perforation or vasospasm vessel dissection perforation or rupture) rupture)
fragmented thrombus causing distal embolization fragmented thrombus causing distal embolization into previously unaffected territories into previously unaffected territories
Nevertheless the advantages of mechanical stroke Nevertheless the advantages of mechanical stroke therapy appear to significantly outweigh its therapy appear to significantly outweigh its disadvantages and risksdisadvantages and risks
Contraindications to Thrombolytic Contraindications to Thrombolytic agents agents
Recent thoracic abdominal or Recent thoracic abdominal or intracranial surgeryintracranial surgery
Recent haemorrhagic CVA Head injury Recent haemorrhagic CVA Head injury or neoplasmor neoplasm
Bleeding ulcerBleeding ulcer Anticipated invasive procedures (arterial Anticipated invasive procedures (arterial
punctures biopsies)punctures biopsies) Concurrent hemostatic dysfunctionConcurrent hemostatic dysfunction
Monitoring of thrombolytic Monitoring of thrombolytic therapytherapy
Thrombin time Measures the availability of functional
fibrinogen Normal thrombin time is 10-14 sec Prolonged when fibrinogen level is below
75-100 mgdl
Half Life of ThrombolyticsHalf Life of ThrombolyticsAgent Administration Half Life
Streptokinase IA 60-80min
Urokinase IAIV 9-12min
rTPA IAIV 6min
Abciximab(Reopro) IAIV 12hour
Aspirin POIV 15-20min
Heparin IVSC 60min
Coumadin PO 15-25 days
Anti Platelet DrugsAnti Platelet DrugsDrug Drug Mechanism Mechanism UsesUsesAspirinAspirin Permanently inhibits Permanently inhibits
COX-1 and COX-2COX-1 and COX-2CADCAD
Stroke-TIAsStroke-TIAs
NSAIDsNSAIDs Reversibly inhibits Reversibly inhibits COX-1COX-1
LimitedLimited
DipyridamoleDipyridamole Inhibits PDE increases Inhibits PDE increases cAMPcAMP
TIAsTIAs
ThenopyridinesThenopyridines
(Ticlopidine(Ticlopidine
ClopidrgrelClopidrgrel))
Inhibits ADP Inhibits ADP
PlatAg PlatAg
TIAsStrokeTIAsStroke
CAD PVDCAD PVD
Abciximab (ReoPro)Abciximab (ReoPro)
Eptifibatide (Integrilin)Eptifibatide (Integrilin)
TirofibanTirofiban
GP IIBIIIA InhibitorsGP IIBIIIA Inhibitors
Stroke- TIAs Stroke- TIAs
MonitoringMonitoring
Bleeding timeBleeding time
Optical aggregometryOptical aggregometry
Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay
Bleeding timeBleeding time
Requires a skin incision (usually made on the ear lobe or Requires a skin incision (usually made on the ear lobe or forearm offorearm of
a depth that results in disruption of capillary loops and a depth that results in disruption of capillary loops and small vessels)small vessels)
AdvantagesAdvantages Universally availableUniversally available Relatively simple techniquesRelatively simple techniques Can be performed bedsideCan be performed bedside
DisadvantagesDisadvantages Insensitive inaccurate non-specific techniqueInsensitive inaccurate non-specific technique
Poorly reproducible (as depends on multiple variables)Poorly reproducible (as depends on multiple variables)
Optical aggregometryOptical aggregometry
Gold standard assay for platelet functionGold standard assay for platelet function Agonist induced aggregation is measuredAgonist induced aggregation is measured Different agonist are available for different Different agonist are available for different
agentsagents However require unique expertise and are not However require unique expertise and are not
universally availableuniversally available Aspirin measured with ADP or AA(gt70 Aspirin measured with ADP or AA(gt70
aggregation so resistance)aggregation so resistance) Clopidogrel( ADP gt 90 aggregation means Clopidogrel( ADP gt 90 aggregation means
resistance) resistance)
Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay
Can be performed bed sideCan be performed bed side Different assay devices with different Different assay devices with different
agonist are used for each of different agonist are used for each of different antiplatelet agents antiplatelet agents
For Aspirin AA is used (result is reported as aspirin For Aspirin AA is used (result is reported as aspirin reaction units [ARU] ARUgt 550 indicates non-reaction units [ARU] ARUgt 550 indicates non-responsiveness)responsiveness)
Verify IIbIIIa assay device uses TRAP as agonist for Verify IIbIIIa assay device uses TRAP as agonist for Abciximab and TirofibanAbciximab and Tirofiban
Practical Applications Practical Applications related to specific related to specific
Neurovascular Neurovascular interventionsinterventions
Acute ischemic StrokeAcute ischemic Stroke When an artery occludes neurons are affected When an artery occludes neurons are affected
differently depending upon the amount of residual blood differently depending upon the amount of residual blood flowflow
Normal cerebral blood flow is greater than 50 mL100 Normal cerebral blood flow is greater than 50 mL100 mgminmgmin
Once blood flow decreases to less than 20 mL100 Once blood flow decreases to less than 20 mL100 mgmin infarction occursmgmin infarction occurs
If blood flow decreases to less than 10 mL100 mgmin If blood flow decreases to less than 10 mL100 mgmin irreversible neuronal death occurs rapidly irreversible neuronal death occurs rapidly
Blood flow between 11 and 20 mL100 mgmin is thought Blood flow between 11 and 20 mL100 mgmin is thought to represent the ischemic penumbra an area where the to represent the ischemic penumbra an area where the cells are functionally silent because of ischemia but are cells are functionally silent because of ischemia but are still able to recover if blood flow is restored still able to recover if blood flow is restored
Many acute stroke therapies are targeted toward Many acute stroke therapies are targeted toward restoring flow or function to the ischemic penumbrarestoring flow or function to the ischemic penumbra
Therapeutic window in Therapeutic window in management of acute Ischemic management of acute Ischemic
StrokeStrokeThe early diagnosis of ischemic stroke is critical to the The early diagnosis of ischemic stroke is critical to the
with only a narrow therapeutic window in the first few with only a narrow therapeutic window in the first few hours following stroke ictushours following stroke ictus
Diagnosis in the first 3 hours postictus provides the Diagnosis in the first 3 hours postictus provides the opportunity for intravenous or intraarterial thrombolysis opportunity for intravenous or intraarterial thrombolysis and intra-arterial clot mechanical treatment which and intra-arterial clot mechanical treatment which improve the outcome improve the outcome
Diagnosis in the time period between 3 and 6 hours Diagnosis in the time period between 3 and 6 hours provides an opportunity for intra-arterial thrombolysis provides an opportunity for intra-arterial thrombolysis and mechanical treatment and mechanical treatment
Involvement of the posterior circulation especially the Involvement of the posterior circulation especially the basilar artery is treated by some regardless of time of basilar artery is treated by some regardless of time of onset or up until 12 to 24 hours in some practices This is onset or up until 12 to 24 hours in some practices This is related to the potentially high mortality and morbidity related to the potentially high mortality and morbidity associated with basilar artery thrombosisassociated with basilar artery thrombosis
Infarct evaluation on angiographyInfarct evaluation on angiography(CT angiography and catheter (CT angiography and catheter
angiography)angiography)CTA is an excellent first-line examination for CTA is an excellent first-line examination for
evaluation of the head and neck arteries evaluation of the head and neck arteries In comparison with catheter angiography In comparison with catheter angiography
what it gives up in resolution and dynamic what it gives up in resolution and dynamic properties it makes up for with rapid properties it makes up for with rapid acquisition of a 3-D dataset and the potential acquisition of a 3-D dataset and the potential for assessment of whole-brain perfusion and for assessment of whole-brain perfusion and better parenchymal evaluationbetter parenchymal evaluation
Moreover CTA illustrates not only arterial Moreover CTA illustrates not only arterial stenosis or occlusion but also the vessel wall stenosis or occlusion but also the vessel wall This factor is most important for evaluation of This factor is most important for evaluation of intramural dissection and thrombosed intramural dissection and thrombosed aneurysms which may both complicate aneurysms which may both complicate evaluation of stroke patientsevaluation of stroke patients
Early angiographic signs of strokes Early angiographic signs of strokes both CTA both CTA and DSA and DSA
Vessel occlusion or cutoff related to Vessel occlusion or cutoff related to thromboembolithromboemboli
aneurysms aneurysms arterial dissection arterial dissection Meniscus or flattened shape to clot Meniscus or flattened shape to clot
(recent) versus reverse meniscus (older)(recent) versus reverse meniscus (older) tram track (nonocclusive or recanalized tram track (nonocclusive or recanalized
clot) clot) delayed (antegrade) flow (manifest as delayed (antegrade) flow (manifest as
decreased whole-brain perfusion on CTA)decreased whole-brain perfusion on CTA) retrograde collateral flowretrograde collateral flow
Non-occlusive left MCA thrombus on 3-D imaging performed from CTA source data and was confirmed at catheter angiography
Therapy to be started within a 6-hr Therapy to be started within a 6-hr time to treatment (TTT) window time to treatment (TTT) window (while in case of IV thrombolysis (while in case of IV thrombolysis therapy to be started with in 3hrs)therapy to be started with in 3hrs)
Exclusion criteria Exclusion criteria Rapidly improving neurologic deficit or Rapidly improving neurologic deficit or Sustained blood pressure of gt180100 Sustained blood pressure of gt180100 Hemorrhage is detected on CTHemorrhage is detected on CT Infarct involving gt more than 13 rd Infarct involving gt more than 13 rd
territory of MCAterritory of MCA MRADWI-Perfusion mismatchlt 20MRADWI-Perfusion mismatchlt 20 Definite hypodensity on CTDefinite hypodensity on CT
Intra-arterial Thrombolysis
Fibrinolytics + AntiplateletsFibrinolytics + Antiplatelets
PlasminogenPlasminogen activators through fibrinolysis exposes activators through fibrinolysis exposes free thrombin and paradoxically stimulatesfree thrombin and paradoxically stimulates platelet platelet aggregation which leads to formation of aaggregation which leads to formation of a platelet platelet thrombus (white clot) thrombus (white clot)
This new thrombus is relatively resistant to This new thrombus is relatively resistant to fibrinolyticsfibrinolytics
So new regimen in case of acute stroke isSo new regimen in case of acute stroke is fibrinolytics + antiplatelet drugsfibrinolytics + antiplatelet drugs
rtPA + IIbIIIa inhibitors( tirofiban rtPA + IIbIIIa inhibitors( tirofiban abciximab) orabciximab) or
Urokinase + IIbIIIa Urokinase + IIbIIIa inhibitors( tirofiban abciximab)inhibitors( tirofiban abciximab)
Intra-arterial Thrombolysis Tirofiban (04 microgkgmin bolus for 3 min followed by Tirofiban (04 microgkgmin bolus for 3 min followed by
0125 ugkgmin)0125 ugkgmin)
++
Heparin (2000ndash3000 IU bolus followed by Heparin (2000ndash3000 IU bolus followed by 1000 IUhour infusion 1000 IUhour infusion
with ACT maintained bw 200-300) throughout the with ACT maintained bw 200-300) throughout the interventional procedure and for 24ndash48 hours thereafter when interventional procedure and for 24ndash48 hours thereafter when there is neither intraprocedural bleeding nor suspicion of there is neither intraprocedural bleeding nor suspicion of increased risk of bleeding increased risk of bleeding
Maximum dose of Urokinase Maximum dose of Urokinase Anterior circulation stroke - 500000 IU (mean 400000 Anterior circulation stroke - 500000 IU (mean 400000
IU range 300000ndash500000 IU)IU range 300000ndash500000 IU) Posterior circulation stroke -1000000 IU (mean 837000 Posterior circulation stroke -1000000 IU (mean 837000
IU range 300000ndash1000000 IU)IU range 300000ndash1000000 IU)American Journal of NeuroradiologyAmerican Journal of Neuroradiology 262595-2601 2005262595-2601 2005
Intravenous ThrombolysisIntravenous Thrombolysis
The first method to restore cerebral The first method to restore cerebral perfusion is clot lysis with the goal perfusion is clot lysis with the goal of re-establishing blood flow to the of re-establishing blood flow to the affected tissue affected tissue
IV thrombolysis rt-PA is the only IV thrombolysis rt-PA is the only FDA- approved treatment for AIS FDA- approved treatment for AIS
Fibrinolysis is enhanced powerfully Fibrinolysis is enhanced powerfully by rt-PAby rt-PA
Intravenous rTPA Intravenous rTPA administration administration protocolprotocol
Total dose of rt-PA 09 mgkg (maximum dose Total dose of rt-PA 09 mgkg (maximum dose 90 mg)90 mg)
Give 10 as initial IV bolusGive 10 as initial IV bolus Infuse remainder over 1 hourInfuse remainder over 1 hour Admit patient to an ICU or stroke unit for Admit patient to an ICU or stroke unit for
monitoringmonitoring Neurologic assessments every 15 minutes Neurologic assessments every 15 minutes
during infusion then every 30 minutes for next during infusion then every 30 minutes for next 6 hours then every hour until 24hours after 6 hours then every hour until 24hours after treatmenttreatment
Favorable Outcome vs Treatment Time Favorable Outcome vs Treatment Time with IV rTPAwith IV rTPA
Protocol limit = 3 hrs
Benefit ~ 45 hrs
Thromboembolism During coilingThromboembolism During coiling Most feared and frequent complication Most feared and frequent complication Reported incidence - Approx 7 Reported incidence - Approx 7 SourcesSources of Thromboembolism are of Thromboembolism are
- Clots at the aneurysmal neck during or immediately- Clots at the aneurysmal neck during or immediately after after embolization embolization
- Thrombus forming on catheters during- Thrombus forming on catheters during proceduresprocedures
- Stenosis of an adjacent artery dt coil mass- Stenosis of an adjacent artery dt coil mass or herniationor herniation
- Migration of intraaneurysmal- Migration of intraaneurysmal thrombus during coil thrombus during coil placement placement
- Slow flow dt vasospasm - Slow flow dt vasospasm
- Rare and unlikely causes are hypercoagulable- Rare and unlikely causes are hypercoagulable state such state such as antiphospholipid antibody syndrome or due to HITas antiphospholipid antibody syndrome or due to HIT
Occur more often with wide-necked aneurysms (dt Occur more often with wide-necked aneurysms (dt increased exposed surface area of thrombogenic coil increased exposed surface area of thrombogenic coil material)material)
Current regimen of endovascular Current regimen of endovascular managementmanagement
The The glycoprotein IIbIIIa antagonist tirofiban glycoprotein IIbIIIa antagonist tirofiban (04 (04 microgkgmin bolus for 30 minutes followed by infusion of microgkgmin bolus for 30 minutes followed by infusion of 0125 ugkgmin until the thrombus dissolved) 0125 ugkgmin until the thrombus dissolved)
Intraarterial thrombolysis with Intraarterial thrombolysis with urokinase or r- TPA urokinase or r- TPA increase of intravenous (IV) heparin (measured by increase of intravenous (IV) heparin (measured by
ACT) ACT) Intravenous aspirin Intravenous aspirin
Coil-related platelet aggregation (white clot) is Coil-related platelet aggregation (white clot) is unlikely to respond to fibrinolytics but has a high risk unlikely to respond to fibrinolytics but has a high risk of hemorrhage (In ISAT) all 5 patients who had of hemorrhage (In ISAT) all 5 patients who had received thrombolytic therapy with tPA to treat a received thrombolytic therapy with tPA to treat a thromboembolic complication after endovascular thromboembolic complication after endovascular treatment rebleed and all of these patients died)treatment rebleed and all of these patients died)
IntracranialIntracranial Stenting Stenting Metallic foreign body such as stent will accumulate Metallic foreign body such as stent will accumulate
thrombus in the absence of platelet inhibitionthrombus in the absence of platelet inhibition Antiplatelet drugs are important to prevent peri or Antiplatelet drugs are important to prevent peri or
post-interventional thromboembolic eventspost-interventional thromboembolic events Optimal treatment regimens has not been determined Optimal treatment regimens has not been determined
but usually but usually Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-
procedureprocedureOrOr
Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on
morning of proceduremorning of procedure
If need to use stent is not pre-planned thanIf need to use stent is not pre-planned than
Abciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkgAbciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkg IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)
Glycoprotein IIbIIIa inhibitor are not used routinely during elective Glycoprotein IIbIIIa inhibitor are not used routinely during elective stenting procedure dt increased risk of ICH stenting procedure dt increased risk of ICH
Carotid StentingCarotid Stenting
Pre-procedurePre-procedure
Double Antiplatelet therapy is routinely given Double Antiplatelet therapy is routinely given beginning at least 3beginning at least 3
days before the proceduredays before the procedure
Aspirin 325mgd+Clopidogrel 75mgdAspirin 325mgd+Clopidogrel 75mgd During procedureDuring procedure
Heparin is given with target clotting time of 250-Heparin is given with target clotting time of 250-300sec300sec
Post-procedure Post-procedure
Aspirin 325mg is continued indefinitely and Aspirin 325mg is continued indefinitely and
Clopidogrel 75mgd for at least 6 weeks Clopidogrel 75mgd for at least 6 weeks
Inclusion criteria for Local ThrombolysisInclusion criteria for Local Thrombolysis a)a) Patients in severe clinical grade on admission Patients in severe clinical grade on admission
with evidence of dural venous sinus with evidence of dural venous sinus thrombosis and restrictive venous outflow on thrombosis and restrictive venous outflow on cerebral angiogramcerebral angiogram
b)b) Patients in clinical grade 3 worsening on Patients in clinical grade 3 worsening on heparin therapy Restriction to venous heparin therapy Restriction to venous outflow was defined as an increase in brain outflow was defined as an increase in brain circulation time gt 12 s delay in the drainage circulation time gt 12 s delay in the drainage of cortical veins with cortical veins hanging of cortical veins with cortical veins hanging in spacein space
Treatment Options for Venous Thrombosis
CT Grading for Venous ThrombosisCT Grading for Venous Thrombosis Grade I no parenchymal change Grade I no parenchymal change
(hyperdense (hyperdense sinuses cortical veins empty sinuses cortical veins empty delta sign)delta sign)
Grade II non hemorrhagic venous infarct Grade II non hemorrhagic venous infarct without mass effect without mass effect
Grade III non-hemorrhagic infarct with Grade III non-hemorrhagic infarct with mass effectmass effect
Grade IV hemorrhagic venous infarct (max Grade IV hemorrhagic venous infarct (max diameter lt 3 cm) with no mass effectdiameter lt 3 cm) with no mass effect
Grade V hemorrhagic venous infarct (max Grade V hemorrhagic venous infarct (max diameter gt 3 cm) with mass effect diameter gt 3 cm) with mass effect
Local ThrombolysisLocal Thrombolysis
Femoral Jugular access was secured and a guiding Femoral Jugular access was secured and a guiding catheter was placed in the jugular bulb catheter was placed in the jugular bulb Mechanical Mechanical clot maceration clot maceration was done with the guidewire was done with the guidewire following which a microcatheter (was navigated and following which a microcatheter (was navigated and placed in the thrombosed segment of sinus confirmed placed in the thrombosed segment of sinus confirmed on a selective venogram on a selective venogram
Urokinase infusion Bolus dose of 2-6 lacs followed Urokinase infusion Bolus dose of 2-6 lacs followed by 60000 to 100000 units per hour along with by 60000 to 100000 units per hour along with periodic check venogram Along with maintenance periodic check venogram Along with maintenance systemic infusion of Heparinsystemic infusion of Heparin Other agents such as Other agents such as streptokinase altepase or rTPAstreptokinase altepase or rTPA can be also used can be also used
After thrombolysis patient should subjected to oral After thrombolysis patient should subjected to oral anticoagulation for six monthsanticoagulation for six months
Low-molecular-weight Low-molecular-weight heparinheparin
PharmacologyPharmacologyLMWH as its name suggests is a glycosaminoglycan that is approximatelyLMWH as its name suggests is a glycosaminoglycan that is approximately
one third the molecular weight of UFH It is derived from UFH through one third the molecular weight of UFH It is derived from UFH through variousvarious
depolymerization processes LMWH binds to antithrombin which in turn depolymerization processes LMWH binds to antithrombin which in turn
Neutralizes actors Xa and IIa Because LMWH lacks many of the longer Neutralizes actors Xa and IIa Because LMWH lacks many of the longer chains chains
required for binding to thrombin it has less ability to neutralize thrombin required for binding to thrombin it has less ability to neutralize thrombin
relativeto its ability to neutralize factor Xa LMWH also has less relativeto its ability to neutralize factor Xa LMWH also has less nonspecific nonspecific
binding to other proteins There is greater bioavailability with more binding to other proteins There is greater bioavailability with more predictable predictable
pharmacokinetics that eliminates the need for monitoring The smaller pharmacokinetics that eliminates the need for monitoring The smaller size also size also
allows for enhanced subcutaneous absorption when compared with UFHallows for enhanced subcutaneous absorption when compared with UFH
Three LMWH preparations are Three LMWH preparations are currently approved for use in the currently approved for use in the United States (1) enoxaparin (2) United States (1) enoxaparin (2) dalteparin and (3) tinzaparin dalteparin and (3) tinzaparin
They are all administered They are all administered subcutaneously at intervals of either subcutaneously at intervals of either once or twice daily for both once or twice daily for both prophylaxis and treatment dosesprophylaxis and treatment doses
Few Experiences of Few Experiences of ThrombolysisThrombolysis
Vickey 25 Yrs male patient presented Vickey 25 Yrs male patient presented with 12with 12thth day HO severe headache with day HO severe headache with right sided hemiplegiaright sided hemiplegia
MRI shows thrombosis of the superior MRI shows thrombosis of the superior sagittal left transverse left sigmoid sagittal left transverse left sigmoid sinuses and cortical veins in the fronto-sinuses and cortical veins in the fronto-parietal regions with eo haemorrhagic parietal regions with eo haemorrhagic infarct in the left cerebral hemisphere infarct in the left cerebral hemisphere with mass effect( Grade ndashV)with mass effect( Grade ndashV)
Sashi Srivastava 64 yrs FSashi Srivastava 64 yrs F In a follow up case of MRD with infra-renal In a follow up case of MRD with infra-renal
aortic abdominal and bilateral renal artery aortic abdominal and bilateral renal artery thrombosis renal angiogram shows filling thrombosis renal angiogram shows filling defects in the right Renal artery defects in the right Renal artery
Initially Renal angioplasty was done Initially Renal angioplasty was done Following angioplasty few thrombi are seem Following angioplasty few thrombi are seem to extends into the segmental branches and to extends into the segmental branches and causing blockage So Thrombolysis was causing blockage So Thrombolysis was plane to dissolve the run-out thrombi with plane to dissolve the run-out thrombi with urokinase urokinase
Rakesh 34yrsMRakesh 34yrsM Left SFA pseudoaneurysm with Left SFA pseudoaneurysm with
Covered stent placementCovered stent placement Pre operative antiplatelets with post Pre operative antiplatelets with post
procedure heparin Tirofiban procedure heparin Tirofiban followed by aspirin and clopidogrel followed by aspirin and clopidogrel were usedwere used
IAT may be a treatment option for selected patients IAT may be a treatment option for selected patients Possible selection criteria include Possible selection criteria include
presentation between 3 and 6 hours from symptom onsetpresentation between 3 and 6 hours from symptom onset major cerebral artery occlusion major cerebral artery occlusion severe neurologic deficits severe neurologic deficits high risk of systemic hemorrhage with IV rt-PA (eg recent high risk of systemic hemorrhage with IV rt-PA (eg recent
surgery) surgery) The MERCI (Mechanical Embolus Removal in Cerebral The MERCI (Mechanical Embolus Removal in Cerebral
Ischemia) retrievalIschemia) retrieval system system
Has been FDA-approved for recanalizing acutely occluded Has been FDA-approved for recanalizing acutely occluded cerebral arteries cerebral arteries
In the Multi-MERCI study patients who did not improve In the Multi-MERCI study patients who did not improve immediately after IV rt-PA underwent mechanical immediately after IV rt-PA underwent mechanical embolectomy within 8 hours of symptom onset embolectomy within 8 hours of symptom onset
Partial or complete recanalization occurred in 74 of Partial or complete recanalization occurred in 74 of patientspatients
with a symptomatic intracerebral hemorrhage (sICH) rate of with a symptomatic intracerebral hemorrhage (sICH) rate of 67 67
Mechanical embolectomy with the MERCI retriever may be a Mechanical embolectomy with the MERCI retriever may be a feasible and safe option for patients after IV rt-PAfeasible and safe option for patients after IV rt-PA
Penumbra stroke systemPenumbra stroke system This device combines two methods of clot This device combines two methods of clot
extraction aspiration and mechanical extraction aspiration and mechanical extraction extraction
First the clot is aspirated then a thrombus First the clot is aspirated then a thrombus removal ring can be used if necessary to removal ring can be used if necessary to remove remaining clot remove remaining clot
successful recanalizing 82successful recanalizing 82 Bridging therapyBridging therapy
06 mgkg IV rt-PA followed by IAT with IA rt-06 mgkg IV rt-PA followed by IAT with IA rt-PA (up to 20 mg)PA (up to 20 mg)
achieved a higher recanalization rateachieved a higher recanalization rate
Criteria for thrombolysis with rTPACriteria for thrombolysis with rTPA
Inclusion criteriaInclusion criteria Clinical signs and symptoms consistent with ischemic Clinical signs and symptoms consistent with ischemic
strokestroke Patient last seen normal within 3 hoursPatient last seen normal within 3 hours Measurable neurologic deficitMeasurable neurologic deficit
Exclusion criteriaExclusion criteria Any hemorrhage on neuroimaging (CT or MRI)Any hemorrhage on neuroimaging (CT or MRI) Symptoms suggestive of subarachnoid hemorrhageSymptoms suggestive of subarachnoid hemorrhage Seizure at stroke onset that is thought to contribute to Seizure at stroke onset that is thought to contribute to
neurologic deficitneurologic deficit Hypodensity greater than one third cerebral hemisphere Hypodensity greater than one third cerebral hemisphere
on CTon CT SBP greater than 185 mm Hg or DBP greater than 110 SBP greater than 185 mm Hg or DBP greater than 110
mm Hgmm Hg International normalized ratio (INR) greater than 17International normalized ratio (INR) greater than 17
Ischemic Stroke Ischemic Stroke Treatment ndash 2006Treatment ndash 2006
IV tissue plasminogen activator (tPA)IV tissue plasminogen activator (tPA) ndash ndash Only FDA-approved acute stroke drugOnly FDA-approved acute stroke drug ndash ndash 3 hour treatment window3 hour treatment window
MERCI - Concentric clot retrieval MERCI - Concentric clot retrieval devicedevice ndash ndash Rescue therapy - approved 2004Rescue therapy - approved 2004 ndash ndash Device approval (not outcomes-based)Device approval (not outcomes-based)
Off label approachesOff label approaches ndash ndash IV tPA after 3 hoursIV tPA after 3 hours ndash ndash IV-IA tPA sequential strategiesIV-IA tPA sequential strategies ndash ndash IA tPA clot angioplasty fragmentationIA tPA clot angioplasty fragmentation ndash ndash Ultrasound-assisted tPA lysisUltrasound-assisted tPA lysis
rt-PA Trials NINDSrt-PA Trials NINDS
Acute stroke - 624 patientsAcute stroke - 624 patients Treat within 3 hrsTreat within 3 hrs Intravenous 09 mgkg rt-PA vs placeboIntravenous 09 mgkg rt-PA vs placebo Hemorrhage 64 tPA 06 placeboHemorrhage 64 tPA 06 placebo Neurologic recovery better with tPA 30 Neurologic recovery better with tPA 30
more like to have minimal or no disabilitymore like to have minimal or no disability
First proven approved treatment for First proven approved treatment for strokestroke
Limitations of tPALimitations of tPA Only 4 of acute strokes receive tPAOnly 4 of acute strokes receive tPA (Kleindorfer et al Stroke 2004 35 e27-e29)(Kleindorfer et al Stroke 2004 35 e27-e29)
Only 22 of patients present within 3 hoursOnly 22 of patients present within 3 hours1048707 1048707 51 of these ineligible due to51 of these ineligible due to
bull bull Mild severityMild severity bull bull Medical or surgical historyMedical or surgical history bull bull Blood testsBlood tests
Sustained recanalization only 13Sustained recanalization only 13 (Alexandrov et al NEJM 2004 351 2170-8)(Alexandrov et al NEJM 2004 351 2170-8)
Concern for hemorrhageConcern for hemorrhage tPA potentiates apoptotic injury tPA potentiates apoptotic injury (Liu et al Nature Med 2004 101379-83)(Liu et al Nature Med 2004 101379-83)
PROACT II IA Lysis TrialPROACT II IA Lysis Trial Baseline 24 hours 8 days
Baseline 60 minutes 120 minutes
9mg IAProurokinase
Desmoteplase Trials DEDAS Desmoteplase Trials DEDAS DIASDIAS
Trial OverviewTrial Overview Double blind randomized placebo Double blind randomized placebo
controlled trialscontrolled trials IV delivery 3-9 hour time windowIV delivery 3-9 hour time window Plasminogen activator ndash from Plasminogen activator ndash from vampire bat vampire bat
salivasaliva Selection based on PWI-DWI MismatchSelection based on PWI-DWI Mismatch
MRI InclusionMRI Inclusion PWI defect at least 2 cm AND ~20 larger PWI defect at least 2 cm AND ~20 larger
than DWIthan DWI PWI should be obvious even visible on PWI should be obvious even visible on
raw imagesraw imagesMRI ExclusionMRI Exclusion
DWI gt 13 MCADWI gt 13 MCA MRA ICA occlusionMRA ICA occlusion
Desmoteplase ndash DIAS Desmoteplase ndash DIAS ResultsResults
Mechanical Thrombolysis Mechanical Thrombolysis devicesdevices
mechanical thrombolysis potentially extends the treatment mechanical thrombolysis potentially extends the treatment window because they act promptly at the site of the thrombuswindow because they act promptly at the site of the thrombus
The devices can retrieve large clots that pharmaceutical agents The devices can retrieve large clots that pharmaceutical agents may not successfully lysemay not successfully lyse
Patients treated with IV tPA may be considered for treatment of Patients treated with IV tPA may be considered for treatment of residual clot with some of these devicesresidual clot with some of these devices
suction-creating saline jets suction-creating saline jets laser energy ultrasound laser energy ultrasound a corkscrew apparatus to treat strokesa corkscrew apparatus to treat strokes The AngioJet systemThe AngioJet system uses saline jets that are directed back into the catheter to uses saline jets that are directed back into the catheter to
create a low-pressure zone around the catheter tip inducing create a low-pressure zone around the catheter tip inducing suction suction
The clot is pulled into the exhaust lumen and removed from the The clot is pulled into the exhaust lumen and removed from the vessel Although US Food and Drug Administration (FDA) has vessel Although US Food and Drug Administration (FDA) has approved this device for use in arteriovenous dialysis grafts and approved this device for use in arteriovenous dialysis grafts and fistulae and for the treatment of coronary arteries saphenous fistulae and for the treatment of coronary arteries saphenous vein grafts and peripheral vessels clinical trials for the vein grafts and peripheral vessels clinical trials for the treatment of acute stroke are no longer in progress treatment of acute stroke are no longer in progress
Most devices are used in cerebral vessels that 2-5 mm
The Latis laser device The Latis laser device used laser energy to ablate clots used laser energy to ablate clots Arteries 2-5 mm in diameter could be Arteries 2-5 mm in diameter could be
treated including the ICA M1 or M2 treated including the ICA M1 or M2 branch of the MCA A1 branch of the branch of the MCA A1 branch of the anterior cerebral artery (ACA) basilar anterior cerebral artery (ACA) basilar artery posterior cerebral artery (PCA) artery posterior cerebral artery (PCA) and vertebral and vertebral
Patients could receive treatment as late Patients could receive treatment as late as 8 hours after symptom onset in the as 8 hours after symptom onset in the anterior circulation and within 24 hours in anterior circulation and within 24 hours in the posterior circulation the posterior circulation
Endovascular Photo Acoustic Endovascular Photo Acoustic Recanalization (EPAR) Recanalization (EPAR)
A laser power source generated energy for the A laser power source generated energy for the systemsystem
The energy was delivered by means of The energy was delivered by means of fiberoptics to the tip of the catheter at the fiberoptics to the tip of the catheter at the treatment sitetreatment site
Absorption of laser light by darkly pigmented Absorption of laser light by darkly pigmented materials (ie the clot) occurred inside the 1-mm materials (ie the clot) occurred inside the 1-mm catheter tipcatheter tip
the system was designed to minimize scattering the system was designed to minimize scattering of laser light of laser light
Absorption converted photo energy to acoustic Absorption converted photo energy to acoustic energy which then emulsified the clot inside the energy which then emulsified the clot inside the catheter tip catheter tip
EKOS ultrasound( the EKOS ultrasound( the Ultrasound Thrombolytic Ultrasound Thrombolytic
Infusion Catheter) Infusion Catheter) combines the use of a distal ultrasound transducer with combines the use of a distal ultrasound transducer with
infusion of a thrombolytic agent through the infusion of a thrombolytic agent through the microcathetermicrocatheter
Ultrasound changes the structure of the clot to Ultrasound changes the structure of the clot to temporarily increase its permeability while providing an temporarily increase its permeability while providing an acoustic pressure gradient to move the drug into the clot acoustic pressure gradient to move the drug into the clot to speed its dissolution to speed its dissolution
The EKOS catheter is placed in the proximal portion of the The EKOS catheter is placed in the proximal portion of the clot clot
After a 2-mg bolus of tPA was injected through the After a 2-mg bolus of tPA was injected through the catheter catheter
the patient received a continuous infusion of IA tPA 03 the patient received a continuous infusion of IA tPA 03 mgmin to a maximum of 20 mg and simultaneous mgmin to a maximum of 20 mg and simultaneous ultrasound transmission for as long as 60 minutes ultrasound transmission for as long as 60 minutes
One patient was treated with a total of 4 units of One patient was treated with a total of 4 units of recombinant reteplase (Retavase) hand-injected over 60 recombinant reteplase (Retavase) hand-injected over 60 minutes minutes
Penumbra system Penumbra system The Penumbra system (Penumbra Inc) provides a dual The Penumbra system (Penumbra Inc) provides a dual
approach to clot extraction using aspiration followed by approach to clot extraction using aspiration followed by clot retrieval with a ring device if needed clot retrieval with a ring device if needed
Mechanical Embolus Removal in Cerebral Ischemia Mechanical Embolus Removal in Cerebral Ischemia (MERCI)(MERCI)
a corkscrew-like apparatus to remove blood clots from a corkscrew-like apparatus to remove blood clots from the brain in patients experiencing an ischemic stroke the brain in patients experiencing an ischemic stroke
The corkscrew itself resides in the catheter tip which The corkscrew itself resides in the catheter tip which shields it from the wall of the vessel until it is ready to be shields it from the wall of the vessel until it is ready to be burrowed into the clot Once lodged in the clot the device burrowed into the clot Once lodged in the clot the device and clot are withdrawn from the vessel and clot are withdrawn from the vessel
Snarelike devicesSnarelike devices Snares such as the Neuronet snare (Guidant Snares such as the Neuronet snare (Guidant
Endovascular Santa Clara CA) have been developed Endovascular Santa Clara CA) have been developed specifically for use in the treatment of strokes specifically for use in the treatment of strokes
These devices are simple in design and do not require the These devices are simple in design and do not require the clot to be amenable to emulsification clot to be amenable to emulsification
X-Sizer deviceX-Sizer device a device with small moving blades at the a device with small moving blades at the
catheter tip catheter tip This device the X-Sizer device (EndiCor Medical This device the X-Sizer device (EndiCor Medical
San Clemente CA) can be used to excise the San Clemente CA) can be used to excise the thrombus and aspirate it thrombus and aspirate it
The device was being evaluated in randomized The device was being evaluated in randomized studies of coronary vessels and in a registry of studies of coronary vessels and in a registry of patients with acute myocardial infarctionpatients with acute myocardial infarction
Although the manufacturer had modified the Although the manufacturer had modified the device for use in cerebral vessels a safety and device for use in cerebral vessels a safety and feasibility study was indefinitely suspended after feasibility study was indefinitely suspended after only 1 patient was treated with the device in only 1 patient was treated with the device in Europe Europe
Suction thrombectomySuction thrombectomy This method of mechanical thrombolysis is one of the This method of mechanical thrombolysis is one of the
simplestsimplest In this readily available technique suction is applied with In this readily available technique suction is applied with
a syringe to remove thrombus in the ICA a syringe to remove thrombus in the ICA It requires no other devicesIt requires no other devices A catheter with a large inner diameter (Brite Tip Cordis A catheter with a large inner diameter (Brite Tip Cordis
Corporation Miami FL) was placed in the symptomatic Corporation Miami FL) was placed in the symptomatic vessel and navigated over a guidewire into the thrombusvessel and navigated over a guidewire into the thrombus
A 60-mL syringe was used to aspirate the thrombus A 60-mL syringe was used to aspirate the thrombus Each patient required angioplasty and stenting of carotid Each patient required angioplasty and stenting of carotid
bifurcation stenosis and received daily aspirin and bifurcation stenosis and received daily aspirin and ticlopidine after the procedure No complications ticlopidine after the procedure No complications occurred occurred
Summary Acute Stroke Summary Acute Stroke ImagingImaging
PhysiologyPhysiology importance collaterals importance collaterals
ndash ndashGrowing role for perfusion Growing role for perfusion assessmentassessment
tPAtPA guidelines amp limitations guidelines amp limitations Signs on CT amp MRSigns on CT amp MR follow physiology follow physiology Stroke trialsStroke trials PWI-DWI mismatch PWI-DWI mismatch
ndash ndashTreat based on physiology not timeTreat based on physiology not time ProtocolsProtocols should be fast and should be fast and
comprehensivecomprehensive
Major disadvantagesMajor disadvantages Relative complexity of the procedure the level Relative complexity of the procedure the level
of required technical expertise and its of required technical expertise and its relatively low availability relatively low availability
Delays in initiating treatmentDelays in initiating treatment InvasiveInvasive
ThrombolyticsThrombolytics
Plasminogen activators
Fibrinolytics
1 Plasminogen Activators 1 Plasminogen Activators drugs act by converting the inactive proenzyme drugs act by converting the inactive proenzyme plasminogen into the active enzyme plasmin Plasmin plasminogen into the active enzyme plasmin Plasmin digests fibrinogen fibrin monomers and cross-linked digests fibrinogen fibrin monomers and cross-linked fibrin (as found in a thrombus) into fibrin degradation fibrin (as found in a thrombus) into fibrin degradation productsproducts
First-Generation Agents First-Generation Agents StreptokinaseStreptokinase a protein derived from group C a protein derived from group C
szlig-hemolytic streptococci has a half-life of 16ndashszlig-hemolytic streptococci has a half-life of 16ndash90 minutes and low fibrin specificity This drug 90 minutes and low fibrin specificity This drug proved to have a very narrow therapeutic proved to have a very narrow therapeutic window and significant rates of ICH and window and significant rates of ICH and systemic hemorrhage18systemic hemorrhage18
UrokinaseUrokinase is a serine protease with a plasma is a serine protease with a plasma half life of 14 minutes and low fibrin specificity half life of 14 minutes and low fibrin specificity
The urokinase dose used in cerebral IAT has The urokinase dose used in cerebral IAT has ranged from 002 to 2 X106unitsranged from 002 to 2 X106units
Second-Generation Agents Second-Generation Agents Alteplase (rtPA) Alteplase (rtPA)
is a serine is a serine protease with a plasma half-life of 35 protease with a plasma half-life of 35 minutes and a high degree of fibrin affinity and minutes and a high degree of fibrin affinity and specificity specificity
Dose used in cerebral IAT has ranged between 20 Dose used in cerebral IAT has ranged between 20 and 60 mgand 60 mg
Disadvantages of alteplase include its relatively short Disadvantages of alteplase include its relatively short halflife and limited penetration into the clot matrix halflife and limited penetration into the clot matrix because of strong binding with surface fibrin which because of strong binding with surface fibrin which could delay recanalization and increase the risk of could delay recanalization and increase the risk of recurrent occlusion recurrent occlusion
Prourokinase (r-prourokinase) Prourokinase (r-prourokinase) is the proenzyme precursor of urokinase is the proenzyme precursor of urokinase T12 of 7 minutes and high fibrin specificity T12 of 7 minutes and high fibrin specificity
Third-Generation AgentsThird-Generation Agents
ReteplaseReteplase is a structurally modified is a structurally modified form of alteplase form of alteplase
with a longer half-life (15ndash18 minutes) In with a longer half-life (15ndash18 minutes) In addition it does not bind as highly to fibrin addition it does not bind as highly to fibrin unbound reteplase can thus theoretically better unbound reteplase can thus theoretically better penetrate the clot and potentially penetrate the clot and potentially improve in improve in vivo fibrinolytic activity vivo fibrinolytic activity
TenecteplaseTenecteplase is another modified form of rtPA with a longer is another modified form of rtPA with a longer
half-life (17 minutes)half-life (17 minutes) greater fibrin specificity and greater greater fibrin specificity and greater
resistance to plasminogen activator inhibitor-1 resistance to plasminogen activator inhibitor-1 IV tenecteplase in acute ischemic stroke IV tenecteplase in acute ischemic stroke
suggest that the drug is safe and promisingsuggest that the drug is safe and promising
Newer plasminogen activatorNewer plasminogen activator
DesmoteplaseDesmoteplase is a genetically engineered is a genetically engineered version of the clot-dissolving factor version of the clot-dissolving factor
found in the saliva found in the saliva of the vampire bat Desmodus rotundusof the vampire bat Desmodus rotundus moremore potent and more selective for fibrin-bound potent and more selective for fibrin-bound
plasminogen than any other known plasminogen plasminogen than any other known plasminogen activatoractivator
Unlike tissue plasminogen activator (tPA) desmoteplase Unlike tissue plasminogen activator (tPA) desmoteplase is not activated by fibrinogen or -amyloid proteins is not activated by fibrinogen or -amyloid proteins factors that may exacerbate the risk for ICH factors that may exacerbate the risk for ICH
The effect of IV administration of desmoteplase 3ndash9 The effect of IV administration of desmoteplase 3ndash9 hours after symptom onset in patients with stroke who hours after symptom onset in patients with stroke who present with mismatch on MR imaging or CT perfusion present with mismatch on MR imaging or CT perfusion
3 DefibrinogenatingFibrinogenolytic 3 DefibrinogenatingFibrinogenolytic Agents Agents
AncrodAncrod(Viprinex)(Viprinex) is is the purified fraction of the Malayan pit viper venomthe purified fraction of the Malayan pit viper venom It acts by directly cleaving and inactivating fibrinogen It acts by directly cleaving and inactivating fibrinogen
and thus indirectly promoting anticoagulation and thus indirectly promoting anticoagulation The reduction in the blood levels of fibrinogen also The reduction in the blood levels of fibrinogen also
leads to a reduced blood viscosity which may improve leads to a reduced blood viscosity which may improve blood flow to the affected areas of the brain blood flow to the affected areas of the brain
In the Stroke Treatment with Ancrod Trial 500 In the Stroke Treatment with Ancrod Trial 500 patients with stroke presenting within 3 hours of patients with stroke presenting within 3 hours of symptom onset were randomized to receive ancrod (symptom onset were randomized to receive ancrod (n n 248) or a placebo (n 252) Good outcome (Barthel 248) or a placebo (n 252) Good outcome (Barthel Index 95ndash100 at 3 months) was achieved in 4221 Index 95ndash100 at 3 months) was achieved in 4221 and 344 of the patients respectively and 344 of the patients respectively
2 Direct Fibrinolytics2 Direct Fibrinolytics
Microplasmin (Microplasmin (ThromboGenics Heverlee Belgium)ThromboGenics Heverlee Belgium) is a truncated form of plasmin that is more resistant to the effects is a truncated form of plasmin that is more resistant to the effects
of antiplasmin of antiplasmin microplasmin can be used upto 4ndash12 hours after stroke onset microplasmin can be used upto 4ndash12 hours after stroke onset There was no evidence of increased bleeding risk with There was no evidence of increased bleeding risk with
microplasminmicroplasmin
Alfimeprase (Nuvelo San Carlos Calif)Alfimeprase (Nuvelo San Carlos Calif) is a recombinant truncated form of fibrolase a fibrinolytic zinc metalloproteinase is a recombinant truncated form of fibrolase a fibrinolytic zinc metalloproteinase
isolated from the venom of the southern copperhead snake isolated from the venom of the southern copperhead snake It degrades fibrin directly and achieves thrombolysis independent It degrades fibrin directly and achieves thrombolysis independent
of plasmin formationof plasmin formation its thrombolytic activity appears to be localized to the site of its thrombolytic activity appears to be localized to the site of
delivery These properties should theoretically result in faster delivery These properties should theoretically result in faster recanalization and lower hemorrhagic conversion riskrecanalization and lower hemorrhagic conversion risk
Anti-fibrinolyticsAnti-fibrinolytics
to limit fibrinolytic activityto limit fibrinolytic activity -aminocaproic acid (EACA) -aminocaproic acid (EACA) competitively inhibitscompetitively inhibits plasminogen and plasminogen activators from plasminogen and plasminogen activators from
binding to fibrinbinding to fibrin
alpha2-antiplasminalpha2-antiplasmin a serine protease inhibitor that a serine protease inhibitor that neutralizes any free circulating plasminneutralizes any free circulating plasmin
Plasminogen activator inhibitor-1Plasminogen activator inhibitor-1 a serine protease a serine protease inhibitor that inhibits tissue-type plasminogen inhibitor that inhibits tissue-type plasminogen activatoractivator
Glycoprotein (GP) IIbIIIa antagonistsGlycoprotein (GP) IIbIIIa antagonists
such as ReoPro (abciximab) Integrilin such as ReoPro (abciximab) Integrilin (eptifibatide) or Aggrastat (tirofiban) in (eptifibatide) or Aggrastat (tirofiban) in ischemic stroke remains investigational ischemic stroke remains investigational Deshmukh et al38 reported 21 patients with Deshmukh et al38 reported 21 patients with large-vessel occlusion refractory to IAT with large-vessel occlusion refractory to IAT with rtPA who were treated with IV andor IA rtPA who were treated with IV andor IA abciximab eptifibatide or tirofiban abciximab eptifibatide or tirofiban
IA Mechanical Approaches in Acute Ischemic Stroke IA Mechanical Approaches in Acute Ischemic Stroke Mechanical strategies have several advantagesMechanical strategies have several advantages First they lessen and may even preclude the use of chemical First they lessen and may even preclude the use of chemical
thrombolytics in this manner very likely reducing the risk of ICHthrombolytics in this manner very likely reducing the risk of ICH Second by avoiding the use of chemical thrombolytics it is Second by avoiding the use of chemical thrombolytics it is
possible to extend the treatment window beyond the limit of 6ndash8 possible to extend the treatment window beyond the limit of 6ndash8 hours hours
Third mechanically fragmenting a clot increases the surface area Third mechanically fragmenting a clot increases the surface area accessible to fibrinolytic agents and allows inflow of fresh accessible to fibrinolytic agents and allows inflow of fresh plasminogen which in turn may increase the speed of plasminogen which in turn may increase the speed of thrombolysis thrombolysis
Finally clot-retrieval devices may provide faster recanalization Finally clot-retrieval devices may provide faster recanalization
The disadvantages of the mechanical The disadvantages of the mechanical approaches approaches technical difficulty of navigating mechanical technical difficulty of navigating mechanical
devices into the intracranial circulation excessive devices into the intracranial circulation excessive trauma to the vasculature (potentially leading to trauma to the vasculature (potentially leading to vasospasm vessel dissection perforation or vasospasm vessel dissection perforation or rupture) rupture)
fragmented thrombus causing distal embolization fragmented thrombus causing distal embolization into previously unaffected territories into previously unaffected territories
Nevertheless the advantages of mechanical stroke Nevertheless the advantages of mechanical stroke therapy appear to significantly outweigh its therapy appear to significantly outweigh its disadvantages and risksdisadvantages and risks
Contraindications to Thrombolytic Contraindications to Thrombolytic agents agents
Recent thoracic abdominal or Recent thoracic abdominal or intracranial surgeryintracranial surgery
Recent haemorrhagic CVA Head injury Recent haemorrhagic CVA Head injury or neoplasmor neoplasm
Bleeding ulcerBleeding ulcer Anticipated invasive procedures (arterial Anticipated invasive procedures (arterial
punctures biopsies)punctures biopsies) Concurrent hemostatic dysfunctionConcurrent hemostatic dysfunction
Monitoring of thrombolytic Monitoring of thrombolytic therapytherapy
Thrombin time Measures the availability of functional
fibrinogen Normal thrombin time is 10-14 sec Prolonged when fibrinogen level is below
75-100 mgdl
Half Life of ThrombolyticsHalf Life of ThrombolyticsAgent Administration Half Life
Streptokinase IA 60-80min
Urokinase IAIV 9-12min
rTPA IAIV 6min
Abciximab(Reopro) IAIV 12hour
Aspirin POIV 15-20min
Heparin IVSC 60min
Coumadin PO 15-25 days
Anti Platelet DrugsAnti Platelet DrugsDrug Drug Mechanism Mechanism UsesUsesAspirinAspirin Permanently inhibits Permanently inhibits
COX-1 and COX-2COX-1 and COX-2CADCAD
Stroke-TIAsStroke-TIAs
NSAIDsNSAIDs Reversibly inhibits Reversibly inhibits COX-1COX-1
LimitedLimited
DipyridamoleDipyridamole Inhibits PDE increases Inhibits PDE increases cAMPcAMP
TIAsTIAs
ThenopyridinesThenopyridines
(Ticlopidine(Ticlopidine
ClopidrgrelClopidrgrel))
Inhibits ADP Inhibits ADP
PlatAg PlatAg
TIAsStrokeTIAsStroke
CAD PVDCAD PVD
Abciximab (ReoPro)Abciximab (ReoPro)
Eptifibatide (Integrilin)Eptifibatide (Integrilin)
TirofibanTirofiban
GP IIBIIIA InhibitorsGP IIBIIIA Inhibitors
Stroke- TIAs Stroke- TIAs
MonitoringMonitoring
Bleeding timeBleeding time
Optical aggregometryOptical aggregometry
Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay
Bleeding timeBleeding time
Requires a skin incision (usually made on the ear lobe or Requires a skin incision (usually made on the ear lobe or forearm offorearm of
a depth that results in disruption of capillary loops and a depth that results in disruption of capillary loops and small vessels)small vessels)
AdvantagesAdvantages Universally availableUniversally available Relatively simple techniquesRelatively simple techniques Can be performed bedsideCan be performed bedside
DisadvantagesDisadvantages Insensitive inaccurate non-specific techniqueInsensitive inaccurate non-specific technique
Poorly reproducible (as depends on multiple variables)Poorly reproducible (as depends on multiple variables)
Optical aggregometryOptical aggregometry
Gold standard assay for platelet functionGold standard assay for platelet function Agonist induced aggregation is measuredAgonist induced aggregation is measured Different agonist are available for different Different agonist are available for different
agentsagents However require unique expertise and are not However require unique expertise and are not
universally availableuniversally available Aspirin measured with ADP or AA(gt70 Aspirin measured with ADP or AA(gt70
aggregation so resistance)aggregation so resistance) Clopidogrel( ADP gt 90 aggregation means Clopidogrel( ADP gt 90 aggregation means
resistance) resistance)
Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay
Can be performed bed sideCan be performed bed side Different assay devices with different Different assay devices with different
agonist are used for each of different agonist are used for each of different antiplatelet agents antiplatelet agents
For Aspirin AA is used (result is reported as aspirin For Aspirin AA is used (result is reported as aspirin reaction units [ARU] ARUgt 550 indicates non-reaction units [ARU] ARUgt 550 indicates non-responsiveness)responsiveness)
Verify IIbIIIa assay device uses TRAP as agonist for Verify IIbIIIa assay device uses TRAP as agonist for Abciximab and TirofibanAbciximab and Tirofiban
Practical Applications Practical Applications related to specific related to specific
Neurovascular Neurovascular interventionsinterventions
Acute ischemic StrokeAcute ischemic Stroke When an artery occludes neurons are affected When an artery occludes neurons are affected
differently depending upon the amount of residual blood differently depending upon the amount of residual blood flowflow
Normal cerebral blood flow is greater than 50 mL100 Normal cerebral blood flow is greater than 50 mL100 mgminmgmin
Once blood flow decreases to less than 20 mL100 Once blood flow decreases to less than 20 mL100 mgmin infarction occursmgmin infarction occurs
If blood flow decreases to less than 10 mL100 mgmin If blood flow decreases to less than 10 mL100 mgmin irreversible neuronal death occurs rapidly irreversible neuronal death occurs rapidly
Blood flow between 11 and 20 mL100 mgmin is thought Blood flow between 11 and 20 mL100 mgmin is thought to represent the ischemic penumbra an area where the to represent the ischemic penumbra an area where the cells are functionally silent because of ischemia but are cells are functionally silent because of ischemia but are still able to recover if blood flow is restored still able to recover if blood flow is restored
Many acute stroke therapies are targeted toward Many acute stroke therapies are targeted toward restoring flow or function to the ischemic penumbrarestoring flow or function to the ischemic penumbra
Therapeutic window in Therapeutic window in management of acute Ischemic management of acute Ischemic
StrokeStrokeThe early diagnosis of ischemic stroke is critical to the The early diagnosis of ischemic stroke is critical to the
with only a narrow therapeutic window in the first few with only a narrow therapeutic window in the first few hours following stroke ictushours following stroke ictus
Diagnosis in the first 3 hours postictus provides the Diagnosis in the first 3 hours postictus provides the opportunity for intravenous or intraarterial thrombolysis opportunity for intravenous or intraarterial thrombolysis and intra-arterial clot mechanical treatment which and intra-arterial clot mechanical treatment which improve the outcome improve the outcome
Diagnosis in the time period between 3 and 6 hours Diagnosis in the time period between 3 and 6 hours provides an opportunity for intra-arterial thrombolysis provides an opportunity for intra-arterial thrombolysis and mechanical treatment and mechanical treatment
Involvement of the posterior circulation especially the Involvement of the posterior circulation especially the basilar artery is treated by some regardless of time of basilar artery is treated by some regardless of time of onset or up until 12 to 24 hours in some practices This is onset or up until 12 to 24 hours in some practices This is related to the potentially high mortality and morbidity related to the potentially high mortality and morbidity associated with basilar artery thrombosisassociated with basilar artery thrombosis
Infarct evaluation on angiographyInfarct evaluation on angiography(CT angiography and catheter (CT angiography and catheter
angiography)angiography)CTA is an excellent first-line examination for CTA is an excellent first-line examination for
evaluation of the head and neck arteries evaluation of the head and neck arteries In comparison with catheter angiography In comparison with catheter angiography
what it gives up in resolution and dynamic what it gives up in resolution and dynamic properties it makes up for with rapid properties it makes up for with rapid acquisition of a 3-D dataset and the potential acquisition of a 3-D dataset and the potential for assessment of whole-brain perfusion and for assessment of whole-brain perfusion and better parenchymal evaluationbetter parenchymal evaluation
Moreover CTA illustrates not only arterial Moreover CTA illustrates not only arterial stenosis or occlusion but also the vessel wall stenosis or occlusion but also the vessel wall This factor is most important for evaluation of This factor is most important for evaluation of intramural dissection and thrombosed intramural dissection and thrombosed aneurysms which may both complicate aneurysms which may both complicate evaluation of stroke patientsevaluation of stroke patients
Early angiographic signs of strokes Early angiographic signs of strokes both CTA both CTA and DSA and DSA
Vessel occlusion or cutoff related to Vessel occlusion or cutoff related to thromboembolithromboemboli
aneurysms aneurysms arterial dissection arterial dissection Meniscus or flattened shape to clot Meniscus or flattened shape to clot
(recent) versus reverse meniscus (older)(recent) versus reverse meniscus (older) tram track (nonocclusive or recanalized tram track (nonocclusive or recanalized
clot) clot) delayed (antegrade) flow (manifest as delayed (antegrade) flow (manifest as
decreased whole-brain perfusion on CTA)decreased whole-brain perfusion on CTA) retrograde collateral flowretrograde collateral flow
Non-occlusive left MCA thrombus on 3-D imaging performed from CTA source data and was confirmed at catheter angiography
Therapy to be started within a 6-hr Therapy to be started within a 6-hr time to treatment (TTT) window time to treatment (TTT) window (while in case of IV thrombolysis (while in case of IV thrombolysis therapy to be started with in 3hrs)therapy to be started with in 3hrs)
Exclusion criteria Exclusion criteria Rapidly improving neurologic deficit or Rapidly improving neurologic deficit or Sustained blood pressure of gt180100 Sustained blood pressure of gt180100 Hemorrhage is detected on CTHemorrhage is detected on CT Infarct involving gt more than 13 rd Infarct involving gt more than 13 rd
territory of MCAterritory of MCA MRADWI-Perfusion mismatchlt 20MRADWI-Perfusion mismatchlt 20 Definite hypodensity on CTDefinite hypodensity on CT
Intra-arterial Thrombolysis
Fibrinolytics + AntiplateletsFibrinolytics + Antiplatelets
PlasminogenPlasminogen activators through fibrinolysis exposes activators through fibrinolysis exposes free thrombin and paradoxically stimulatesfree thrombin and paradoxically stimulates platelet platelet aggregation which leads to formation of aaggregation which leads to formation of a platelet platelet thrombus (white clot) thrombus (white clot)
This new thrombus is relatively resistant to This new thrombus is relatively resistant to fibrinolyticsfibrinolytics
So new regimen in case of acute stroke isSo new regimen in case of acute stroke is fibrinolytics + antiplatelet drugsfibrinolytics + antiplatelet drugs
rtPA + IIbIIIa inhibitors( tirofiban rtPA + IIbIIIa inhibitors( tirofiban abciximab) orabciximab) or
Urokinase + IIbIIIa Urokinase + IIbIIIa inhibitors( tirofiban abciximab)inhibitors( tirofiban abciximab)
Intra-arterial Thrombolysis Tirofiban (04 microgkgmin bolus for 3 min followed by Tirofiban (04 microgkgmin bolus for 3 min followed by
0125 ugkgmin)0125 ugkgmin)
++
Heparin (2000ndash3000 IU bolus followed by Heparin (2000ndash3000 IU bolus followed by 1000 IUhour infusion 1000 IUhour infusion
with ACT maintained bw 200-300) throughout the with ACT maintained bw 200-300) throughout the interventional procedure and for 24ndash48 hours thereafter when interventional procedure and for 24ndash48 hours thereafter when there is neither intraprocedural bleeding nor suspicion of there is neither intraprocedural bleeding nor suspicion of increased risk of bleeding increased risk of bleeding
Maximum dose of Urokinase Maximum dose of Urokinase Anterior circulation stroke - 500000 IU (mean 400000 Anterior circulation stroke - 500000 IU (mean 400000
IU range 300000ndash500000 IU)IU range 300000ndash500000 IU) Posterior circulation stroke -1000000 IU (mean 837000 Posterior circulation stroke -1000000 IU (mean 837000
IU range 300000ndash1000000 IU)IU range 300000ndash1000000 IU)American Journal of NeuroradiologyAmerican Journal of Neuroradiology 262595-2601 2005262595-2601 2005
Intravenous ThrombolysisIntravenous Thrombolysis
The first method to restore cerebral The first method to restore cerebral perfusion is clot lysis with the goal perfusion is clot lysis with the goal of re-establishing blood flow to the of re-establishing blood flow to the affected tissue affected tissue
IV thrombolysis rt-PA is the only IV thrombolysis rt-PA is the only FDA- approved treatment for AIS FDA- approved treatment for AIS
Fibrinolysis is enhanced powerfully Fibrinolysis is enhanced powerfully by rt-PAby rt-PA
Intravenous rTPA Intravenous rTPA administration administration protocolprotocol
Total dose of rt-PA 09 mgkg (maximum dose Total dose of rt-PA 09 mgkg (maximum dose 90 mg)90 mg)
Give 10 as initial IV bolusGive 10 as initial IV bolus Infuse remainder over 1 hourInfuse remainder over 1 hour Admit patient to an ICU or stroke unit for Admit patient to an ICU or stroke unit for
monitoringmonitoring Neurologic assessments every 15 minutes Neurologic assessments every 15 minutes
during infusion then every 30 minutes for next during infusion then every 30 minutes for next 6 hours then every hour until 24hours after 6 hours then every hour until 24hours after treatmenttreatment
Favorable Outcome vs Treatment Time Favorable Outcome vs Treatment Time with IV rTPAwith IV rTPA
Protocol limit = 3 hrs
Benefit ~ 45 hrs
Thromboembolism During coilingThromboembolism During coiling Most feared and frequent complication Most feared and frequent complication Reported incidence - Approx 7 Reported incidence - Approx 7 SourcesSources of Thromboembolism are of Thromboembolism are
- Clots at the aneurysmal neck during or immediately- Clots at the aneurysmal neck during or immediately after after embolization embolization
- Thrombus forming on catheters during- Thrombus forming on catheters during proceduresprocedures
- Stenosis of an adjacent artery dt coil mass- Stenosis of an adjacent artery dt coil mass or herniationor herniation
- Migration of intraaneurysmal- Migration of intraaneurysmal thrombus during coil thrombus during coil placement placement
- Slow flow dt vasospasm - Slow flow dt vasospasm
- Rare and unlikely causes are hypercoagulable- Rare and unlikely causes are hypercoagulable state such state such as antiphospholipid antibody syndrome or due to HITas antiphospholipid antibody syndrome or due to HIT
Occur more often with wide-necked aneurysms (dt Occur more often with wide-necked aneurysms (dt increased exposed surface area of thrombogenic coil increased exposed surface area of thrombogenic coil material)material)
Current regimen of endovascular Current regimen of endovascular managementmanagement
The The glycoprotein IIbIIIa antagonist tirofiban glycoprotein IIbIIIa antagonist tirofiban (04 (04 microgkgmin bolus for 30 minutes followed by infusion of microgkgmin bolus for 30 minutes followed by infusion of 0125 ugkgmin until the thrombus dissolved) 0125 ugkgmin until the thrombus dissolved)
Intraarterial thrombolysis with Intraarterial thrombolysis with urokinase or r- TPA urokinase or r- TPA increase of intravenous (IV) heparin (measured by increase of intravenous (IV) heparin (measured by
ACT) ACT) Intravenous aspirin Intravenous aspirin
Coil-related platelet aggregation (white clot) is Coil-related platelet aggregation (white clot) is unlikely to respond to fibrinolytics but has a high risk unlikely to respond to fibrinolytics but has a high risk of hemorrhage (In ISAT) all 5 patients who had of hemorrhage (In ISAT) all 5 patients who had received thrombolytic therapy with tPA to treat a received thrombolytic therapy with tPA to treat a thromboembolic complication after endovascular thromboembolic complication after endovascular treatment rebleed and all of these patients died)treatment rebleed and all of these patients died)
IntracranialIntracranial Stenting Stenting Metallic foreign body such as stent will accumulate Metallic foreign body such as stent will accumulate
thrombus in the absence of platelet inhibitionthrombus in the absence of platelet inhibition Antiplatelet drugs are important to prevent peri or Antiplatelet drugs are important to prevent peri or
post-interventional thromboembolic eventspost-interventional thromboembolic events Optimal treatment regimens has not been determined Optimal treatment regimens has not been determined
but usually but usually Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-
procedureprocedureOrOr
Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on
morning of proceduremorning of procedure
If need to use stent is not pre-planned thanIf need to use stent is not pre-planned than
Abciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkgAbciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkg IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)
Glycoprotein IIbIIIa inhibitor are not used routinely during elective Glycoprotein IIbIIIa inhibitor are not used routinely during elective stenting procedure dt increased risk of ICH stenting procedure dt increased risk of ICH
Carotid StentingCarotid Stenting
Pre-procedurePre-procedure
Double Antiplatelet therapy is routinely given Double Antiplatelet therapy is routinely given beginning at least 3beginning at least 3
days before the proceduredays before the procedure
Aspirin 325mgd+Clopidogrel 75mgdAspirin 325mgd+Clopidogrel 75mgd During procedureDuring procedure
Heparin is given with target clotting time of 250-Heparin is given with target clotting time of 250-300sec300sec
Post-procedure Post-procedure
Aspirin 325mg is continued indefinitely and Aspirin 325mg is continued indefinitely and
Clopidogrel 75mgd for at least 6 weeks Clopidogrel 75mgd for at least 6 weeks
Inclusion criteria for Local ThrombolysisInclusion criteria for Local Thrombolysis a)a) Patients in severe clinical grade on admission Patients in severe clinical grade on admission
with evidence of dural venous sinus with evidence of dural venous sinus thrombosis and restrictive venous outflow on thrombosis and restrictive venous outflow on cerebral angiogramcerebral angiogram
b)b) Patients in clinical grade 3 worsening on Patients in clinical grade 3 worsening on heparin therapy Restriction to venous heparin therapy Restriction to venous outflow was defined as an increase in brain outflow was defined as an increase in brain circulation time gt 12 s delay in the drainage circulation time gt 12 s delay in the drainage of cortical veins with cortical veins hanging of cortical veins with cortical veins hanging in spacein space
Treatment Options for Venous Thrombosis
CT Grading for Venous ThrombosisCT Grading for Venous Thrombosis Grade I no parenchymal change Grade I no parenchymal change
(hyperdense (hyperdense sinuses cortical veins empty sinuses cortical veins empty delta sign)delta sign)
Grade II non hemorrhagic venous infarct Grade II non hemorrhagic venous infarct without mass effect without mass effect
Grade III non-hemorrhagic infarct with Grade III non-hemorrhagic infarct with mass effectmass effect
Grade IV hemorrhagic venous infarct (max Grade IV hemorrhagic venous infarct (max diameter lt 3 cm) with no mass effectdiameter lt 3 cm) with no mass effect
Grade V hemorrhagic venous infarct (max Grade V hemorrhagic venous infarct (max diameter gt 3 cm) with mass effect diameter gt 3 cm) with mass effect
Local ThrombolysisLocal Thrombolysis
Femoral Jugular access was secured and a guiding Femoral Jugular access was secured and a guiding catheter was placed in the jugular bulb catheter was placed in the jugular bulb Mechanical Mechanical clot maceration clot maceration was done with the guidewire was done with the guidewire following which a microcatheter (was navigated and following which a microcatheter (was navigated and placed in the thrombosed segment of sinus confirmed placed in the thrombosed segment of sinus confirmed on a selective venogram on a selective venogram
Urokinase infusion Bolus dose of 2-6 lacs followed Urokinase infusion Bolus dose of 2-6 lacs followed by 60000 to 100000 units per hour along with by 60000 to 100000 units per hour along with periodic check venogram Along with maintenance periodic check venogram Along with maintenance systemic infusion of Heparinsystemic infusion of Heparin Other agents such as Other agents such as streptokinase altepase or rTPAstreptokinase altepase or rTPA can be also used can be also used
After thrombolysis patient should subjected to oral After thrombolysis patient should subjected to oral anticoagulation for six monthsanticoagulation for six months
Low-molecular-weight Low-molecular-weight heparinheparin
PharmacologyPharmacologyLMWH as its name suggests is a glycosaminoglycan that is approximatelyLMWH as its name suggests is a glycosaminoglycan that is approximately
one third the molecular weight of UFH It is derived from UFH through one third the molecular weight of UFH It is derived from UFH through variousvarious
depolymerization processes LMWH binds to antithrombin which in turn depolymerization processes LMWH binds to antithrombin which in turn
Neutralizes actors Xa and IIa Because LMWH lacks many of the longer Neutralizes actors Xa and IIa Because LMWH lacks many of the longer chains chains
required for binding to thrombin it has less ability to neutralize thrombin required for binding to thrombin it has less ability to neutralize thrombin
relativeto its ability to neutralize factor Xa LMWH also has less relativeto its ability to neutralize factor Xa LMWH also has less nonspecific nonspecific
binding to other proteins There is greater bioavailability with more binding to other proteins There is greater bioavailability with more predictable predictable
pharmacokinetics that eliminates the need for monitoring The smaller pharmacokinetics that eliminates the need for monitoring The smaller size also size also
allows for enhanced subcutaneous absorption when compared with UFHallows for enhanced subcutaneous absorption when compared with UFH
Three LMWH preparations are Three LMWH preparations are currently approved for use in the currently approved for use in the United States (1) enoxaparin (2) United States (1) enoxaparin (2) dalteparin and (3) tinzaparin dalteparin and (3) tinzaparin
They are all administered They are all administered subcutaneously at intervals of either subcutaneously at intervals of either once or twice daily for both once or twice daily for both prophylaxis and treatment dosesprophylaxis and treatment doses
Few Experiences of Few Experiences of ThrombolysisThrombolysis
Vickey 25 Yrs male patient presented Vickey 25 Yrs male patient presented with 12with 12thth day HO severe headache with day HO severe headache with right sided hemiplegiaright sided hemiplegia
MRI shows thrombosis of the superior MRI shows thrombosis of the superior sagittal left transverse left sigmoid sagittal left transverse left sigmoid sinuses and cortical veins in the fronto-sinuses and cortical veins in the fronto-parietal regions with eo haemorrhagic parietal regions with eo haemorrhagic infarct in the left cerebral hemisphere infarct in the left cerebral hemisphere with mass effect( Grade ndashV)with mass effect( Grade ndashV)
Sashi Srivastava 64 yrs FSashi Srivastava 64 yrs F In a follow up case of MRD with infra-renal In a follow up case of MRD with infra-renal
aortic abdominal and bilateral renal artery aortic abdominal and bilateral renal artery thrombosis renal angiogram shows filling thrombosis renal angiogram shows filling defects in the right Renal artery defects in the right Renal artery
Initially Renal angioplasty was done Initially Renal angioplasty was done Following angioplasty few thrombi are seem Following angioplasty few thrombi are seem to extends into the segmental branches and to extends into the segmental branches and causing blockage So Thrombolysis was causing blockage So Thrombolysis was plane to dissolve the run-out thrombi with plane to dissolve the run-out thrombi with urokinase urokinase
Rakesh 34yrsMRakesh 34yrsM Left SFA pseudoaneurysm with Left SFA pseudoaneurysm with
Covered stent placementCovered stent placement Pre operative antiplatelets with post Pre operative antiplatelets with post
procedure heparin Tirofiban procedure heparin Tirofiban followed by aspirin and clopidogrel followed by aspirin and clopidogrel were usedwere used
IAT may be a treatment option for selected patients IAT may be a treatment option for selected patients Possible selection criteria include Possible selection criteria include
presentation between 3 and 6 hours from symptom onsetpresentation between 3 and 6 hours from symptom onset major cerebral artery occlusion major cerebral artery occlusion severe neurologic deficits severe neurologic deficits high risk of systemic hemorrhage with IV rt-PA (eg recent high risk of systemic hemorrhage with IV rt-PA (eg recent
surgery) surgery) The MERCI (Mechanical Embolus Removal in Cerebral The MERCI (Mechanical Embolus Removal in Cerebral
Ischemia) retrievalIschemia) retrieval system system
Has been FDA-approved for recanalizing acutely occluded Has been FDA-approved for recanalizing acutely occluded cerebral arteries cerebral arteries
In the Multi-MERCI study patients who did not improve In the Multi-MERCI study patients who did not improve immediately after IV rt-PA underwent mechanical immediately after IV rt-PA underwent mechanical embolectomy within 8 hours of symptom onset embolectomy within 8 hours of symptom onset
Partial or complete recanalization occurred in 74 of Partial or complete recanalization occurred in 74 of patientspatients
with a symptomatic intracerebral hemorrhage (sICH) rate of with a symptomatic intracerebral hemorrhage (sICH) rate of 67 67
Mechanical embolectomy with the MERCI retriever may be a Mechanical embolectomy with the MERCI retriever may be a feasible and safe option for patients after IV rt-PAfeasible and safe option for patients after IV rt-PA
Penumbra stroke systemPenumbra stroke system This device combines two methods of clot This device combines two methods of clot
extraction aspiration and mechanical extraction aspiration and mechanical extraction extraction
First the clot is aspirated then a thrombus First the clot is aspirated then a thrombus removal ring can be used if necessary to removal ring can be used if necessary to remove remaining clot remove remaining clot
successful recanalizing 82successful recanalizing 82 Bridging therapyBridging therapy
06 mgkg IV rt-PA followed by IAT with IA rt-06 mgkg IV rt-PA followed by IAT with IA rt-PA (up to 20 mg)PA (up to 20 mg)
achieved a higher recanalization rateachieved a higher recanalization rate
Criteria for thrombolysis with rTPACriteria for thrombolysis with rTPA
Inclusion criteriaInclusion criteria Clinical signs and symptoms consistent with ischemic Clinical signs and symptoms consistent with ischemic
strokestroke Patient last seen normal within 3 hoursPatient last seen normal within 3 hours Measurable neurologic deficitMeasurable neurologic deficit
Exclusion criteriaExclusion criteria Any hemorrhage on neuroimaging (CT or MRI)Any hemorrhage on neuroimaging (CT or MRI) Symptoms suggestive of subarachnoid hemorrhageSymptoms suggestive of subarachnoid hemorrhage Seizure at stroke onset that is thought to contribute to Seizure at stroke onset that is thought to contribute to
neurologic deficitneurologic deficit Hypodensity greater than one third cerebral hemisphere Hypodensity greater than one third cerebral hemisphere
on CTon CT SBP greater than 185 mm Hg or DBP greater than 110 SBP greater than 185 mm Hg or DBP greater than 110
mm Hgmm Hg International normalized ratio (INR) greater than 17International normalized ratio (INR) greater than 17
Ischemic Stroke Ischemic Stroke Treatment ndash 2006Treatment ndash 2006
IV tissue plasminogen activator (tPA)IV tissue plasminogen activator (tPA) ndash ndash Only FDA-approved acute stroke drugOnly FDA-approved acute stroke drug ndash ndash 3 hour treatment window3 hour treatment window
MERCI - Concentric clot retrieval MERCI - Concentric clot retrieval devicedevice ndash ndash Rescue therapy - approved 2004Rescue therapy - approved 2004 ndash ndash Device approval (not outcomes-based)Device approval (not outcomes-based)
Off label approachesOff label approaches ndash ndash IV tPA after 3 hoursIV tPA after 3 hours ndash ndash IV-IA tPA sequential strategiesIV-IA tPA sequential strategies ndash ndash IA tPA clot angioplasty fragmentationIA tPA clot angioplasty fragmentation ndash ndash Ultrasound-assisted tPA lysisUltrasound-assisted tPA lysis
rt-PA Trials NINDSrt-PA Trials NINDS
Acute stroke - 624 patientsAcute stroke - 624 patients Treat within 3 hrsTreat within 3 hrs Intravenous 09 mgkg rt-PA vs placeboIntravenous 09 mgkg rt-PA vs placebo Hemorrhage 64 tPA 06 placeboHemorrhage 64 tPA 06 placebo Neurologic recovery better with tPA 30 Neurologic recovery better with tPA 30
more like to have minimal or no disabilitymore like to have minimal or no disability
First proven approved treatment for First proven approved treatment for strokestroke
Limitations of tPALimitations of tPA Only 4 of acute strokes receive tPAOnly 4 of acute strokes receive tPA (Kleindorfer et al Stroke 2004 35 e27-e29)(Kleindorfer et al Stroke 2004 35 e27-e29)
Only 22 of patients present within 3 hoursOnly 22 of patients present within 3 hours1048707 1048707 51 of these ineligible due to51 of these ineligible due to
bull bull Mild severityMild severity bull bull Medical or surgical historyMedical or surgical history bull bull Blood testsBlood tests
Sustained recanalization only 13Sustained recanalization only 13 (Alexandrov et al NEJM 2004 351 2170-8)(Alexandrov et al NEJM 2004 351 2170-8)
Concern for hemorrhageConcern for hemorrhage tPA potentiates apoptotic injury tPA potentiates apoptotic injury (Liu et al Nature Med 2004 101379-83)(Liu et al Nature Med 2004 101379-83)
PROACT II IA Lysis TrialPROACT II IA Lysis Trial Baseline 24 hours 8 days
Baseline 60 minutes 120 minutes
9mg IAProurokinase
Desmoteplase Trials DEDAS Desmoteplase Trials DEDAS DIASDIAS
Trial OverviewTrial Overview Double blind randomized placebo Double blind randomized placebo
controlled trialscontrolled trials IV delivery 3-9 hour time windowIV delivery 3-9 hour time window Plasminogen activator ndash from Plasminogen activator ndash from vampire bat vampire bat
salivasaliva Selection based on PWI-DWI MismatchSelection based on PWI-DWI Mismatch
MRI InclusionMRI Inclusion PWI defect at least 2 cm AND ~20 larger PWI defect at least 2 cm AND ~20 larger
than DWIthan DWI PWI should be obvious even visible on PWI should be obvious even visible on
raw imagesraw imagesMRI ExclusionMRI Exclusion
DWI gt 13 MCADWI gt 13 MCA MRA ICA occlusionMRA ICA occlusion
Desmoteplase ndash DIAS Desmoteplase ndash DIAS ResultsResults
Mechanical Thrombolysis Mechanical Thrombolysis devicesdevices
mechanical thrombolysis potentially extends the treatment mechanical thrombolysis potentially extends the treatment window because they act promptly at the site of the thrombuswindow because they act promptly at the site of the thrombus
The devices can retrieve large clots that pharmaceutical agents The devices can retrieve large clots that pharmaceutical agents may not successfully lysemay not successfully lyse
Patients treated with IV tPA may be considered for treatment of Patients treated with IV tPA may be considered for treatment of residual clot with some of these devicesresidual clot with some of these devices
suction-creating saline jets suction-creating saline jets laser energy ultrasound laser energy ultrasound a corkscrew apparatus to treat strokesa corkscrew apparatus to treat strokes The AngioJet systemThe AngioJet system uses saline jets that are directed back into the catheter to uses saline jets that are directed back into the catheter to
create a low-pressure zone around the catheter tip inducing create a low-pressure zone around the catheter tip inducing suction suction
The clot is pulled into the exhaust lumen and removed from the The clot is pulled into the exhaust lumen and removed from the vessel Although US Food and Drug Administration (FDA) has vessel Although US Food and Drug Administration (FDA) has approved this device for use in arteriovenous dialysis grafts and approved this device for use in arteriovenous dialysis grafts and fistulae and for the treatment of coronary arteries saphenous fistulae and for the treatment of coronary arteries saphenous vein grafts and peripheral vessels clinical trials for the vein grafts and peripheral vessels clinical trials for the treatment of acute stroke are no longer in progress treatment of acute stroke are no longer in progress
Most devices are used in cerebral vessels that 2-5 mm
The Latis laser device The Latis laser device used laser energy to ablate clots used laser energy to ablate clots Arteries 2-5 mm in diameter could be Arteries 2-5 mm in diameter could be
treated including the ICA M1 or M2 treated including the ICA M1 or M2 branch of the MCA A1 branch of the branch of the MCA A1 branch of the anterior cerebral artery (ACA) basilar anterior cerebral artery (ACA) basilar artery posterior cerebral artery (PCA) artery posterior cerebral artery (PCA) and vertebral and vertebral
Patients could receive treatment as late Patients could receive treatment as late as 8 hours after symptom onset in the as 8 hours after symptom onset in the anterior circulation and within 24 hours in anterior circulation and within 24 hours in the posterior circulation the posterior circulation
Endovascular Photo Acoustic Endovascular Photo Acoustic Recanalization (EPAR) Recanalization (EPAR)
A laser power source generated energy for the A laser power source generated energy for the systemsystem
The energy was delivered by means of The energy was delivered by means of fiberoptics to the tip of the catheter at the fiberoptics to the tip of the catheter at the treatment sitetreatment site
Absorption of laser light by darkly pigmented Absorption of laser light by darkly pigmented materials (ie the clot) occurred inside the 1-mm materials (ie the clot) occurred inside the 1-mm catheter tipcatheter tip
the system was designed to minimize scattering the system was designed to minimize scattering of laser light of laser light
Absorption converted photo energy to acoustic Absorption converted photo energy to acoustic energy which then emulsified the clot inside the energy which then emulsified the clot inside the catheter tip catheter tip
EKOS ultrasound( the EKOS ultrasound( the Ultrasound Thrombolytic Ultrasound Thrombolytic
Infusion Catheter) Infusion Catheter) combines the use of a distal ultrasound transducer with combines the use of a distal ultrasound transducer with
infusion of a thrombolytic agent through the infusion of a thrombolytic agent through the microcathetermicrocatheter
Ultrasound changes the structure of the clot to Ultrasound changes the structure of the clot to temporarily increase its permeability while providing an temporarily increase its permeability while providing an acoustic pressure gradient to move the drug into the clot acoustic pressure gradient to move the drug into the clot to speed its dissolution to speed its dissolution
The EKOS catheter is placed in the proximal portion of the The EKOS catheter is placed in the proximal portion of the clot clot
After a 2-mg bolus of tPA was injected through the After a 2-mg bolus of tPA was injected through the catheter catheter
the patient received a continuous infusion of IA tPA 03 the patient received a continuous infusion of IA tPA 03 mgmin to a maximum of 20 mg and simultaneous mgmin to a maximum of 20 mg and simultaneous ultrasound transmission for as long as 60 minutes ultrasound transmission for as long as 60 minutes
One patient was treated with a total of 4 units of One patient was treated with a total of 4 units of recombinant reteplase (Retavase) hand-injected over 60 recombinant reteplase (Retavase) hand-injected over 60 minutes minutes
Penumbra system Penumbra system The Penumbra system (Penumbra Inc) provides a dual The Penumbra system (Penumbra Inc) provides a dual
approach to clot extraction using aspiration followed by approach to clot extraction using aspiration followed by clot retrieval with a ring device if needed clot retrieval with a ring device if needed
Mechanical Embolus Removal in Cerebral Ischemia Mechanical Embolus Removal in Cerebral Ischemia (MERCI)(MERCI)
a corkscrew-like apparatus to remove blood clots from a corkscrew-like apparatus to remove blood clots from the brain in patients experiencing an ischemic stroke the brain in patients experiencing an ischemic stroke
The corkscrew itself resides in the catheter tip which The corkscrew itself resides in the catheter tip which shields it from the wall of the vessel until it is ready to be shields it from the wall of the vessel until it is ready to be burrowed into the clot Once lodged in the clot the device burrowed into the clot Once lodged in the clot the device and clot are withdrawn from the vessel and clot are withdrawn from the vessel
Snarelike devicesSnarelike devices Snares such as the Neuronet snare (Guidant Snares such as the Neuronet snare (Guidant
Endovascular Santa Clara CA) have been developed Endovascular Santa Clara CA) have been developed specifically for use in the treatment of strokes specifically for use in the treatment of strokes
These devices are simple in design and do not require the These devices are simple in design and do not require the clot to be amenable to emulsification clot to be amenable to emulsification
X-Sizer deviceX-Sizer device a device with small moving blades at the a device with small moving blades at the
catheter tip catheter tip This device the X-Sizer device (EndiCor Medical This device the X-Sizer device (EndiCor Medical
San Clemente CA) can be used to excise the San Clemente CA) can be used to excise the thrombus and aspirate it thrombus and aspirate it
The device was being evaluated in randomized The device was being evaluated in randomized studies of coronary vessels and in a registry of studies of coronary vessels and in a registry of patients with acute myocardial infarctionpatients with acute myocardial infarction
Although the manufacturer had modified the Although the manufacturer had modified the device for use in cerebral vessels a safety and device for use in cerebral vessels a safety and feasibility study was indefinitely suspended after feasibility study was indefinitely suspended after only 1 patient was treated with the device in only 1 patient was treated with the device in Europe Europe
Suction thrombectomySuction thrombectomy This method of mechanical thrombolysis is one of the This method of mechanical thrombolysis is one of the
simplestsimplest In this readily available technique suction is applied with In this readily available technique suction is applied with
a syringe to remove thrombus in the ICA a syringe to remove thrombus in the ICA It requires no other devicesIt requires no other devices A catheter with a large inner diameter (Brite Tip Cordis A catheter with a large inner diameter (Brite Tip Cordis
Corporation Miami FL) was placed in the symptomatic Corporation Miami FL) was placed in the symptomatic vessel and navigated over a guidewire into the thrombusvessel and navigated over a guidewire into the thrombus
A 60-mL syringe was used to aspirate the thrombus A 60-mL syringe was used to aspirate the thrombus Each patient required angioplasty and stenting of carotid Each patient required angioplasty and stenting of carotid
bifurcation stenosis and received daily aspirin and bifurcation stenosis and received daily aspirin and ticlopidine after the procedure No complications ticlopidine after the procedure No complications occurred occurred
Summary Acute Stroke Summary Acute Stroke ImagingImaging
PhysiologyPhysiology importance collaterals importance collaterals
ndash ndashGrowing role for perfusion Growing role for perfusion assessmentassessment
tPAtPA guidelines amp limitations guidelines amp limitations Signs on CT amp MRSigns on CT amp MR follow physiology follow physiology Stroke trialsStroke trials PWI-DWI mismatch PWI-DWI mismatch
ndash ndashTreat based on physiology not timeTreat based on physiology not time ProtocolsProtocols should be fast and should be fast and
comprehensivecomprehensive
ThrombolyticsThrombolytics
Plasminogen activators
Fibrinolytics
1 Plasminogen Activators 1 Plasminogen Activators drugs act by converting the inactive proenzyme drugs act by converting the inactive proenzyme plasminogen into the active enzyme plasmin Plasmin plasminogen into the active enzyme plasmin Plasmin digests fibrinogen fibrin monomers and cross-linked digests fibrinogen fibrin monomers and cross-linked fibrin (as found in a thrombus) into fibrin degradation fibrin (as found in a thrombus) into fibrin degradation productsproducts
First-Generation Agents First-Generation Agents StreptokinaseStreptokinase a protein derived from group C a protein derived from group C
szlig-hemolytic streptococci has a half-life of 16ndashszlig-hemolytic streptococci has a half-life of 16ndash90 minutes and low fibrin specificity This drug 90 minutes and low fibrin specificity This drug proved to have a very narrow therapeutic proved to have a very narrow therapeutic window and significant rates of ICH and window and significant rates of ICH and systemic hemorrhage18systemic hemorrhage18
UrokinaseUrokinase is a serine protease with a plasma is a serine protease with a plasma half life of 14 minutes and low fibrin specificity half life of 14 minutes and low fibrin specificity
The urokinase dose used in cerebral IAT has The urokinase dose used in cerebral IAT has ranged from 002 to 2 X106unitsranged from 002 to 2 X106units
Second-Generation Agents Second-Generation Agents Alteplase (rtPA) Alteplase (rtPA)
is a serine is a serine protease with a plasma half-life of 35 protease with a plasma half-life of 35 minutes and a high degree of fibrin affinity and minutes and a high degree of fibrin affinity and specificity specificity
Dose used in cerebral IAT has ranged between 20 Dose used in cerebral IAT has ranged between 20 and 60 mgand 60 mg
Disadvantages of alteplase include its relatively short Disadvantages of alteplase include its relatively short halflife and limited penetration into the clot matrix halflife and limited penetration into the clot matrix because of strong binding with surface fibrin which because of strong binding with surface fibrin which could delay recanalization and increase the risk of could delay recanalization and increase the risk of recurrent occlusion recurrent occlusion
Prourokinase (r-prourokinase) Prourokinase (r-prourokinase) is the proenzyme precursor of urokinase is the proenzyme precursor of urokinase T12 of 7 minutes and high fibrin specificity T12 of 7 minutes and high fibrin specificity
Third-Generation AgentsThird-Generation Agents
ReteplaseReteplase is a structurally modified is a structurally modified form of alteplase form of alteplase
with a longer half-life (15ndash18 minutes) In with a longer half-life (15ndash18 minutes) In addition it does not bind as highly to fibrin addition it does not bind as highly to fibrin unbound reteplase can thus theoretically better unbound reteplase can thus theoretically better penetrate the clot and potentially penetrate the clot and potentially improve in improve in vivo fibrinolytic activity vivo fibrinolytic activity
TenecteplaseTenecteplase is another modified form of rtPA with a longer is another modified form of rtPA with a longer
half-life (17 minutes)half-life (17 minutes) greater fibrin specificity and greater greater fibrin specificity and greater
resistance to plasminogen activator inhibitor-1 resistance to plasminogen activator inhibitor-1 IV tenecteplase in acute ischemic stroke IV tenecteplase in acute ischemic stroke
suggest that the drug is safe and promisingsuggest that the drug is safe and promising
Newer plasminogen activatorNewer plasminogen activator
DesmoteplaseDesmoteplase is a genetically engineered is a genetically engineered version of the clot-dissolving factor version of the clot-dissolving factor
found in the saliva found in the saliva of the vampire bat Desmodus rotundusof the vampire bat Desmodus rotundus moremore potent and more selective for fibrin-bound potent and more selective for fibrin-bound
plasminogen than any other known plasminogen plasminogen than any other known plasminogen activatoractivator
Unlike tissue plasminogen activator (tPA) desmoteplase Unlike tissue plasminogen activator (tPA) desmoteplase is not activated by fibrinogen or -amyloid proteins is not activated by fibrinogen or -amyloid proteins factors that may exacerbate the risk for ICH factors that may exacerbate the risk for ICH
The effect of IV administration of desmoteplase 3ndash9 The effect of IV administration of desmoteplase 3ndash9 hours after symptom onset in patients with stroke who hours after symptom onset in patients with stroke who present with mismatch on MR imaging or CT perfusion present with mismatch on MR imaging or CT perfusion
3 DefibrinogenatingFibrinogenolytic 3 DefibrinogenatingFibrinogenolytic Agents Agents
AncrodAncrod(Viprinex)(Viprinex) is is the purified fraction of the Malayan pit viper venomthe purified fraction of the Malayan pit viper venom It acts by directly cleaving and inactivating fibrinogen It acts by directly cleaving and inactivating fibrinogen
and thus indirectly promoting anticoagulation and thus indirectly promoting anticoagulation The reduction in the blood levels of fibrinogen also The reduction in the blood levels of fibrinogen also
leads to a reduced blood viscosity which may improve leads to a reduced blood viscosity which may improve blood flow to the affected areas of the brain blood flow to the affected areas of the brain
In the Stroke Treatment with Ancrod Trial 500 In the Stroke Treatment with Ancrod Trial 500 patients with stroke presenting within 3 hours of patients with stroke presenting within 3 hours of symptom onset were randomized to receive ancrod (symptom onset were randomized to receive ancrod (n n 248) or a placebo (n 252) Good outcome (Barthel 248) or a placebo (n 252) Good outcome (Barthel Index 95ndash100 at 3 months) was achieved in 4221 Index 95ndash100 at 3 months) was achieved in 4221 and 344 of the patients respectively and 344 of the patients respectively
2 Direct Fibrinolytics2 Direct Fibrinolytics
Microplasmin (Microplasmin (ThromboGenics Heverlee Belgium)ThromboGenics Heverlee Belgium) is a truncated form of plasmin that is more resistant to the effects is a truncated form of plasmin that is more resistant to the effects
of antiplasmin of antiplasmin microplasmin can be used upto 4ndash12 hours after stroke onset microplasmin can be used upto 4ndash12 hours after stroke onset There was no evidence of increased bleeding risk with There was no evidence of increased bleeding risk with
microplasminmicroplasmin
Alfimeprase (Nuvelo San Carlos Calif)Alfimeprase (Nuvelo San Carlos Calif) is a recombinant truncated form of fibrolase a fibrinolytic zinc metalloproteinase is a recombinant truncated form of fibrolase a fibrinolytic zinc metalloproteinase
isolated from the venom of the southern copperhead snake isolated from the venom of the southern copperhead snake It degrades fibrin directly and achieves thrombolysis independent It degrades fibrin directly and achieves thrombolysis independent
of plasmin formationof plasmin formation its thrombolytic activity appears to be localized to the site of its thrombolytic activity appears to be localized to the site of
delivery These properties should theoretically result in faster delivery These properties should theoretically result in faster recanalization and lower hemorrhagic conversion riskrecanalization and lower hemorrhagic conversion risk
Anti-fibrinolyticsAnti-fibrinolytics
to limit fibrinolytic activityto limit fibrinolytic activity -aminocaproic acid (EACA) -aminocaproic acid (EACA) competitively inhibitscompetitively inhibits plasminogen and plasminogen activators from plasminogen and plasminogen activators from
binding to fibrinbinding to fibrin
alpha2-antiplasminalpha2-antiplasmin a serine protease inhibitor that a serine protease inhibitor that neutralizes any free circulating plasminneutralizes any free circulating plasmin
Plasminogen activator inhibitor-1Plasminogen activator inhibitor-1 a serine protease a serine protease inhibitor that inhibits tissue-type plasminogen inhibitor that inhibits tissue-type plasminogen activatoractivator
Glycoprotein (GP) IIbIIIa antagonistsGlycoprotein (GP) IIbIIIa antagonists
such as ReoPro (abciximab) Integrilin such as ReoPro (abciximab) Integrilin (eptifibatide) or Aggrastat (tirofiban) in (eptifibatide) or Aggrastat (tirofiban) in ischemic stroke remains investigational ischemic stroke remains investigational Deshmukh et al38 reported 21 patients with Deshmukh et al38 reported 21 patients with large-vessel occlusion refractory to IAT with large-vessel occlusion refractory to IAT with rtPA who were treated with IV andor IA rtPA who were treated with IV andor IA abciximab eptifibatide or tirofiban abciximab eptifibatide or tirofiban
IA Mechanical Approaches in Acute Ischemic Stroke IA Mechanical Approaches in Acute Ischemic Stroke Mechanical strategies have several advantagesMechanical strategies have several advantages First they lessen and may even preclude the use of chemical First they lessen and may even preclude the use of chemical
thrombolytics in this manner very likely reducing the risk of ICHthrombolytics in this manner very likely reducing the risk of ICH Second by avoiding the use of chemical thrombolytics it is Second by avoiding the use of chemical thrombolytics it is
possible to extend the treatment window beyond the limit of 6ndash8 possible to extend the treatment window beyond the limit of 6ndash8 hours hours
Third mechanically fragmenting a clot increases the surface area Third mechanically fragmenting a clot increases the surface area accessible to fibrinolytic agents and allows inflow of fresh accessible to fibrinolytic agents and allows inflow of fresh plasminogen which in turn may increase the speed of plasminogen which in turn may increase the speed of thrombolysis thrombolysis
Finally clot-retrieval devices may provide faster recanalization Finally clot-retrieval devices may provide faster recanalization
The disadvantages of the mechanical The disadvantages of the mechanical approaches approaches technical difficulty of navigating mechanical technical difficulty of navigating mechanical
devices into the intracranial circulation excessive devices into the intracranial circulation excessive trauma to the vasculature (potentially leading to trauma to the vasculature (potentially leading to vasospasm vessel dissection perforation or vasospasm vessel dissection perforation or rupture) rupture)
fragmented thrombus causing distal embolization fragmented thrombus causing distal embolization into previously unaffected territories into previously unaffected territories
Nevertheless the advantages of mechanical stroke Nevertheless the advantages of mechanical stroke therapy appear to significantly outweigh its therapy appear to significantly outweigh its disadvantages and risksdisadvantages and risks
Contraindications to Thrombolytic Contraindications to Thrombolytic agents agents
Recent thoracic abdominal or Recent thoracic abdominal or intracranial surgeryintracranial surgery
Recent haemorrhagic CVA Head injury Recent haemorrhagic CVA Head injury or neoplasmor neoplasm
Bleeding ulcerBleeding ulcer Anticipated invasive procedures (arterial Anticipated invasive procedures (arterial
punctures biopsies)punctures biopsies) Concurrent hemostatic dysfunctionConcurrent hemostatic dysfunction
Monitoring of thrombolytic Monitoring of thrombolytic therapytherapy
Thrombin time Measures the availability of functional
fibrinogen Normal thrombin time is 10-14 sec Prolonged when fibrinogen level is below
75-100 mgdl
Half Life of ThrombolyticsHalf Life of ThrombolyticsAgent Administration Half Life
Streptokinase IA 60-80min
Urokinase IAIV 9-12min
rTPA IAIV 6min
Abciximab(Reopro) IAIV 12hour
Aspirin POIV 15-20min
Heparin IVSC 60min
Coumadin PO 15-25 days
Anti Platelet DrugsAnti Platelet DrugsDrug Drug Mechanism Mechanism UsesUsesAspirinAspirin Permanently inhibits Permanently inhibits
COX-1 and COX-2COX-1 and COX-2CADCAD
Stroke-TIAsStroke-TIAs
NSAIDsNSAIDs Reversibly inhibits Reversibly inhibits COX-1COX-1
LimitedLimited
DipyridamoleDipyridamole Inhibits PDE increases Inhibits PDE increases cAMPcAMP
TIAsTIAs
ThenopyridinesThenopyridines
(Ticlopidine(Ticlopidine
ClopidrgrelClopidrgrel))
Inhibits ADP Inhibits ADP
PlatAg PlatAg
TIAsStrokeTIAsStroke
CAD PVDCAD PVD
Abciximab (ReoPro)Abciximab (ReoPro)
Eptifibatide (Integrilin)Eptifibatide (Integrilin)
TirofibanTirofiban
GP IIBIIIA InhibitorsGP IIBIIIA Inhibitors
Stroke- TIAs Stroke- TIAs
MonitoringMonitoring
Bleeding timeBleeding time
Optical aggregometryOptical aggregometry
Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay
Bleeding timeBleeding time
Requires a skin incision (usually made on the ear lobe or Requires a skin incision (usually made on the ear lobe or forearm offorearm of
a depth that results in disruption of capillary loops and a depth that results in disruption of capillary loops and small vessels)small vessels)
AdvantagesAdvantages Universally availableUniversally available Relatively simple techniquesRelatively simple techniques Can be performed bedsideCan be performed bedside
DisadvantagesDisadvantages Insensitive inaccurate non-specific techniqueInsensitive inaccurate non-specific technique
Poorly reproducible (as depends on multiple variables)Poorly reproducible (as depends on multiple variables)
Optical aggregometryOptical aggregometry
Gold standard assay for platelet functionGold standard assay for platelet function Agonist induced aggregation is measuredAgonist induced aggregation is measured Different agonist are available for different Different agonist are available for different
agentsagents However require unique expertise and are not However require unique expertise and are not
universally availableuniversally available Aspirin measured with ADP or AA(gt70 Aspirin measured with ADP or AA(gt70
aggregation so resistance)aggregation so resistance) Clopidogrel( ADP gt 90 aggregation means Clopidogrel( ADP gt 90 aggregation means
resistance) resistance)
Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay
Can be performed bed sideCan be performed bed side Different assay devices with different Different assay devices with different
agonist are used for each of different agonist are used for each of different antiplatelet agents antiplatelet agents
For Aspirin AA is used (result is reported as aspirin For Aspirin AA is used (result is reported as aspirin reaction units [ARU] ARUgt 550 indicates non-reaction units [ARU] ARUgt 550 indicates non-responsiveness)responsiveness)
Verify IIbIIIa assay device uses TRAP as agonist for Verify IIbIIIa assay device uses TRAP as agonist for Abciximab and TirofibanAbciximab and Tirofiban
Practical Applications Practical Applications related to specific related to specific
Neurovascular Neurovascular interventionsinterventions
Acute ischemic StrokeAcute ischemic Stroke When an artery occludes neurons are affected When an artery occludes neurons are affected
differently depending upon the amount of residual blood differently depending upon the amount of residual blood flowflow
Normal cerebral blood flow is greater than 50 mL100 Normal cerebral blood flow is greater than 50 mL100 mgminmgmin
Once blood flow decreases to less than 20 mL100 Once blood flow decreases to less than 20 mL100 mgmin infarction occursmgmin infarction occurs
If blood flow decreases to less than 10 mL100 mgmin If blood flow decreases to less than 10 mL100 mgmin irreversible neuronal death occurs rapidly irreversible neuronal death occurs rapidly
Blood flow between 11 and 20 mL100 mgmin is thought Blood flow between 11 and 20 mL100 mgmin is thought to represent the ischemic penumbra an area where the to represent the ischemic penumbra an area where the cells are functionally silent because of ischemia but are cells are functionally silent because of ischemia but are still able to recover if blood flow is restored still able to recover if blood flow is restored
Many acute stroke therapies are targeted toward Many acute stroke therapies are targeted toward restoring flow or function to the ischemic penumbrarestoring flow or function to the ischemic penumbra
Therapeutic window in Therapeutic window in management of acute Ischemic management of acute Ischemic
StrokeStrokeThe early diagnosis of ischemic stroke is critical to the The early diagnosis of ischemic stroke is critical to the
with only a narrow therapeutic window in the first few with only a narrow therapeutic window in the first few hours following stroke ictushours following stroke ictus
Diagnosis in the first 3 hours postictus provides the Diagnosis in the first 3 hours postictus provides the opportunity for intravenous or intraarterial thrombolysis opportunity for intravenous or intraarterial thrombolysis and intra-arterial clot mechanical treatment which and intra-arterial clot mechanical treatment which improve the outcome improve the outcome
Diagnosis in the time period between 3 and 6 hours Diagnosis in the time period between 3 and 6 hours provides an opportunity for intra-arterial thrombolysis provides an opportunity for intra-arterial thrombolysis and mechanical treatment and mechanical treatment
Involvement of the posterior circulation especially the Involvement of the posterior circulation especially the basilar artery is treated by some regardless of time of basilar artery is treated by some regardless of time of onset or up until 12 to 24 hours in some practices This is onset or up until 12 to 24 hours in some practices This is related to the potentially high mortality and morbidity related to the potentially high mortality and morbidity associated with basilar artery thrombosisassociated with basilar artery thrombosis
Infarct evaluation on angiographyInfarct evaluation on angiography(CT angiography and catheter (CT angiography and catheter
angiography)angiography)CTA is an excellent first-line examination for CTA is an excellent first-line examination for
evaluation of the head and neck arteries evaluation of the head and neck arteries In comparison with catheter angiography In comparison with catheter angiography
what it gives up in resolution and dynamic what it gives up in resolution and dynamic properties it makes up for with rapid properties it makes up for with rapid acquisition of a 3-D dataset and the potential acquisition of a 3-D dataset and the potential for assessment of whole-brain perfusion and for assessment of whole-brain perfusion and better parenchymal evaluationbetter parenchymal evaluation
Moreover CTA illustrates not only arterial Moreover CTA illustrates not only arterial stenosis or occlusion but also the vessel wall stenosis or occlusion but also the vessel wall This factor is most important for evaluation of This factor is most important for evaluation of intramural dissection and thrombosed intramural dissection and thrombosed aneurysms which may both complicate aneurysms which may both complicate evaluation of stroke patientsevaluation of stroke patients
Early angiographic signs of strokes Early angiographic signs of strokes both CTA both CTA and DSA and DSA
Vessel occlusion or cutoff related to Vessel occlusion or cutoff related to thromboembolithromboemboli
aneurysms aneurysms arterial dissection arterial dissection Meniscus or flattened shape to clot Meniscus or flattened shape to clot
(recent) versus reverse meniscus (older)(recent) versus reverse meniscus (older) tram track (nonocclusive or recanalized tram track (nonocclusive or recanalized
clot) clot) delayed (antegrade) flow (manifest as delayed (antegrade) flow (manifest as
decreased whole-brain perfusion on CTA)decreased whole-brain perfusion on CTA) retrograde collateral flowretrograde collateral flow
Non-occlusive left MCA thrombus on 3-D imaging performed from CTA source data and was confirmed at catheter angiography
Therapy to be started within a 6-hr Therapy to be started within a 6-hr time to treatment (TTT) window time to treatment (TTT) window (while in case of IV thrombolysis (while in case of IV thrombolysis therapy to be started with in 3hrs)therapy to be started with in 3hrs)
Exclusion criteria Exclusion criteria Rapidly improving neurologic deficit or Rapidly improving neurologic deficit or Sustained blood pressure of gt180100 Sustained blood pressure of gt180100 Hemorrhage is detected on CTHemorrhage is detected on CT Infarct involving gt more than 13 rd Infarct involving gt more than 13 rd
territory of MCAterritory of MCA MRADWI-Perfusion mismatchlt 20MRADWI-Perfusion mismatchlt 20 Definite hypodensity on CTDefinite hypodensity on CT
Intra-arterial Thrombolysis
Fibrinolytics + AntiplateletsFibrinolytics + Antiplatelets
PlasminogenPlasminogen activators through fibrinolysis exposes activators through fibrinolysis exposes free thrombin and paradoxically stimulatesfree thrombin and paradoxically stimulates platelet platelet aggregation which leads to formation of aaggregation which leads to formation of a platelet platelet thrombus (white clot) thrombus (white clot)
This new thrombus is relatively resistant to This new thrombus is relatively resistant to fibrinolyticsfibrinolytics
So new regimen in case of acute stroke isSo new regimen in case of acute stroke is fibrinolytics + antiplatelet drugsfibrinolytics + antiplatelet drugs
rtPA + IIbIIIa inhibitors( tirofiban rtPA + IIbIIIa inhibitors( tirofiban abciximab) orabciximab) or
Urokinase + IIbIIIa Urokinase + IIbIIIa inhibitors( tirofiban abciximab)inhibitors( tirofiban abciximab)
Intra-arterial Thrombolysis Tirofiban (04 microgkgmin bolus for 3 min followed by Tirofiban (04 microgkgmin bolus for 3 min followed by
0125 ugkgmin)0125 ugkgmin)
++
Heparin (2000ndash3000 IU bolus followed by Heparin (2000ndash3000 IU bolus followed by 1000 IUhour infusion 1000 IUhour infusion
with ACT maintained bw 200-300) throughout the with ACT maintained bw 200-300) throughout the interventional procedure and for 24ndash48 hours thereafter when interventional procedure and for 24ndash48 hours thereafter when there is neither intraprocedural bleeding nor suspicion of there is neither intraprocedural bleeding nor suspicion of increased risk of bleeding increased risk of bleeding
Maximum dose of Urokinase Maximum dose of Urokinase Anterior circulation stroke - 500000 IU (mean 400000 Anterior circulation stroke - 500000 IU (mean 400000
IU range 300000ndash500000 IU)IU range 300000ndash500000 IU) Posterior circulation stroke -1000000 IU (mean 837000 Posterior circulation stroke -1000000 IU (mean 837000
IU range 300000ndash1000000 IU)IU range 300000ndash1000000 IU)American Journal of NeuroradiologyAmerican Journal of Neuroradiology 262595-2601 2005262595-2601 2005
Intravenous ThrombolysisIntravenous Thrombolysis
The first method to restore cerebral The first method to restore cerebral perfusion is clot lysis with the goal perfusion is clot lysis with the goal of re-establishing blood flow to the of re-establishing blood flow to the affected tissue affected tissue
IV thrombolysis rt-PA is the only IV thrombolysis rt-PA is the only FDA- approved treatment for AIS FDA- approved treatment for AIS
Fibrinolysis is enhanced powerfully Fibrinolysis is enhanced powerfully by rt-PAby rt-PA
Intravenous rTPA Intravenous rTPA administration administration protocolprotocol
Total dose of rt-PA 09 mgkg (maximum dose Total dose of rt-PA 09 mgkg (maximum dose 90 mg)90 mg)
Give 10 as initial IV bolusGive 10 as initial IV bolus Infuse remainder over 1 hourInfuse remainder over 1 hour Admit patient to an ICU or stroke unit for Admit patient to an ICU or stroke unit for
monitoringmonitoring Neurologic assessments every 15 minutes Neurologic assessments every 15 minutes
during infusion then every 30 minutes for next during infusion then every 30 minutes for next 6 hours then every hour until 24hours after 6 hours then every hour until 24hours after treatmenttreatment
Favorable Outcome vs Treatment Time Favorable Outcome vs Treatment Time with IV rTPAwith IV rTPA
Protocol limit = 3 hrs
Benefit ~ 45 hrs
Thromboembolism During coilingThromboembolism During coiling Most feared and frequent complication Most feared and frequent complication Reported incidence - Approx 7 Reported incidence - Approx 7 SourcesSources of Thromboembolism are of Thromboembolism are
- Clots at the aneurysmal neck during or immediately- Clots at the aneurysmal neck during or immediately after after embolization embolization
- Thrombus forming on catheters during- Thrombus forming on catheters during proceduresprocedures
- Stenosis of an adjacent artery dt coil mass- Stenosis of an adjacent artery dt coil mass or herniationor herniation
- Migration of intraaneurysmal- Migration of intraaneurysmal thrombus during coil thrombus during coil placement placement
- Slow flow dt vasospasm - Slow flow dt vasospasm
- Rare and unlikely causes are hypercoagulable- Rare and unlikely causes are hypercoagulable state such state such as antiphospholipid antibody syndrome or due to HITas antiphospholipid antibody syndrome or due to HIT
Occur more often with wide-necked aneurysms (dt Occur more often with wide-necked aneurysms (dt increased exposed surface area of thrombogenic coil increased exposed surface area of thrombogenic coil material)material)
Current regimen of endovascular Current regimen of endovascular managementmanagement
The The glycoprotein IIbIIIa antagonist tirofiban glycoprotein IIbIIIa antagonist tirofiban (04 (04 microgkgmin bolus for 30 minutes followed by infusion of microgkgmin bolus for 30 minutes followed by infusion of 0125 ugkgmin until the thrombus dissolved) 0125 ugkgmin until the thrombus dissolved)
Intraarterial thrombolysis with Intraarterial thrombolysis with urokinase or r- TPA urokinase or r- TPA increase of intravenous (IV) heparin (measured by increase of intravenous (IV) heparin (measured by
ACT) ACT) Intravenous aspirin Intravenous aspirin
Coil-related platelet aggregation (white clot) is Coil-related platelet aggregation (white clot) is unlikely to respond to fibrinolytics but has a high risk unlikely to respond to fibrinolytics but has a high risk of hemorrhage (In ISAT) all 5 patients who had of hemorrhage (In ISAT) all 5 patients who had received thrombolytic therapy with tPA to treat a received thrombolytic therapy with tPA to treat a thromboembolic complication after endovascular thromboembolic complication after endovascular treatment rebleed and all of these patients died)treatment rebleed and all of these patients died)
IntracranialIntracranial Stenting Stenting Metallic foreign body such as stent will accumulate Metallic foreign body such as stent will accumulate
thrombus in the absence of platelet inhibitionthrombus in the absence of platelet inhibition Antiplatelet drugs are important to prevent peri or Antiplatelet drugs are important to prevent peri or
post-interventional thromboembolic eventspost-interventional thromboembolic events Optimal treatment regimens has not been determined Optimal treatment regimens has not been determined
but usually but usually Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-
procedureprocedureOrOr
Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on
morning of proceduremorning of procedure
If need to use stent is not pre-planned thanIf need to use stent is not pre-planned than
Abciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkgAbciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkg IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)
Glycoprotein IIbIIIa inhibitor are not used routinely during elective Glycoprotein IIbIIIa inhibitor are not used routinely during elective stenting procedure dt increased risk of ICH stenting procedure dt increased risk of ICH
Carotid StentingCarotid Stenting
Pre-procedurePre-procedure
Double Antiplatelet therapy is routinely given Double Antiplatelet therapy is routinely given beginning at least 3beginning at least 3
days before the proceduredays before the procedure
Aspirin 325mgd+Clopidogrel 75mgdAspirin 325mgd+Clopidogrel 75mgd During procedureDuring procedure
Heparin is given with target clotting time of 250-Heparin is given with target clotting time of 250-300sec300sec
Post-procedure Post-procedure
Aspirin 325mg is continued indefinitely and Aspirin 325mg is continued indefinitely and
Clopidogrel 75mgd for at least 6 weeks Clopidogrel 75mgd for at least 6 weeks
Inclusion criteria for Local ThrombolysisInclusion criteria for Local Thrombolysis a)a) Patients in severe clinical grade on admission Patients in severe clinical grade on admission
with evidence of dural venous sinus with evidence of dural venous sinus thrombosis and restrictive venous outflow on thrombosis and restrictive venous outflow on cerebral angiogramcerebral angiogram
b)b) Patients in clinical grade 3 worsening on Patients in clinical grade 3 worsening on heparin therapy Restriction to venous heparin therapy Restriction to venous outflow was defined as an increase in brain outflow was defined as an increase in brain circulation time gt 12 s delay in the drainage circulation time gt 12 s delay in the drainage of cortical veins with cortical veins hanging of cortical veins with cortical veins hanging in spacein space
Treatment Options for Venous Thrombosis
CT Grading for Venous ThrombosisCT Grading for Venous Thrombosis Grade I no parenchymal change Grade I no parenchymal change
(hyperdense (hyperdense sinuses cortical veins empty sinuses cortical veins empty delta sign)delta sign)
Grade II non hemorrhagic venous infarct Grade II non hemorrhagic venous infarct without mass effect without mass effect
Grade III non-hemorrhagic infarct with Grade III non-hemorrhagic infarct with mass effectmass effect
Grade IV hemorrhagic venous infarct (max Grade IV hemorrhagic venous infarct (max diameter lt 3 cm) with no mass effectdiameter lt 3 cm) with no mass effect
Grade V hemorrhagic venous infarct (max Grade V hemorrhagic venous infarct (max diameter gt 3 cm) with mass effect diameter gt 3 cm) with mass effect
Local ThrombolysisLocal Thrombolysis
Femoral Jugular access was secured and a guiding Femoral Jugular access was secured and a guiding catheter was placed in the jugular bulb catheter was placed in the jugular bulb Mechanical Mechanical clot maceration clot maceration was done with the guidewire was done with the guidewire following which a microcatheter (was navigated and following which a microcatheter (was navigated and placed in the thrombosed segment of sinus confirmed placed in the thrombosed segment of sinus confirmed on a selective venogram on a selective venogram
Urokinase infusion Bolus dose of 2-6 lacs followed Urokinase infusion Bolus dose of 2-6 lacs followed by 60000 to 100000 units per hour along with by 60000 to 100000 units per hour along with periodic check venogram Along with maintenance periodic check venogram Along with maintenance systemic infusion of Heparinsystemic infusion of Heparin Other agents such as Other agents such as streptokinase altepase or rTPAstreptokinase altepase or rTPA can be also used can be also used
After thrombolysis patient should subjected to oral After thrombolysis patient should subjected to oral anticoagulation for six monthsanticoagulation for six months
Low-molecular-weight Low-molecular-weight heparinheparin
PharmacologyPharmacologyLMWH as its name suggests is a glycosaminoglycan that is approximatelyLMWH as its name suggests is a glycosaminoglycan that is approximately
one third the molecular weight of UFH It is derived from UFH through one third the molecular weight of UFH It is derived from UFH through variousvarious
depolymerization processes LMWH binds to antithrombin which in turn depolymerization processes LMWH binds to antithrombin which in turn
Neutralizes actors Xa and IIa Because LMWH lacks many of the longer Neutralizes actors Xa and IIa Because LMWH lacks many of the longer chains chains
required for binding to thrombin it has less ability to neutralize thrombin required for binding to thrombin it has less ability to neutralize thrombin
relativeto its ability to neutralize factor Xa LMWH also has less relativeto its ability to neutralize factor Xa LMWH also has less nonspecific nonspecific
binding to other proteins There is greater bioavailability with more binding to other proteins There is greater bioavailability with more predictable predictable
pharmacokinetics that eliminates the need for monitoring The smaller pharmacokinetics that eliminates the need for monitoring The smaller size also size also
allows for enhanced subcutaneous absorption when compared with UFHallows for enhanced subcutaneous absorption when compared with UFH
Three LMWH preparations are Three LMWH preparations are currently approved for use in the currently approved for use in the United States (1) enoxaparin (2) United States (1) enoxaparin (2) dalteparin and (3) tinzaparin dalteparin and (3) tinzaparin
They are all administered They are all administered subcutaneously at intervals of either subcutaneously at intervals of either once or twice daily for both once or twice daily for both prophylaxis and treatment dosesprophylaxis and treatment doses
Few Experiences of Few Experiences of ThrombolysisThrombolysis
Vickey 25 Yrs male patient presented Vickey 25 Yrs male patient presented with 12with 12thth day HO severe headache with day HO severe headache with right sided hemiplegiaright sided hemiplegia
MRI shows thrombosis of the superior MRI shows thrombosis of the superior sagittal left transverse left sigmoid sagittal left transverse left sigmoid sinuses and cortical veins in the fronto-sinuses and cortical veins in the fronto-parietal regions with eo haemorrhagic parietal regions with eo haemorrhagic infarct in the left cerebral hemisphere infarct in the left cerebral hemisphere with mass effect( Grade ndashV)with mass effect( Grade ndashV)
Sashi Srivastava 64 yrs FSashi Srivastava 64 yrs F In a follow up case of MRD with infra-renal In a follow up case of MRD with infra-renal
aortic abdominal and bilateral renal artery aortic abdominal and bilateral renal artery thrombosis renal angiogram shows filling thrombosis renal angiogram shows filling defects in the right Renal artery defects in the right Renal artery
Initially Renal angioplasty was done Initially Renal angioplasty was done Following angioplasty few thrombi are seem Following angioplasty few thrombi are seem to extends into the segmental branches and to extends into the segmental branches and causing blockage So Thrombolysis was causing blockage So Thrombolysis was plane to dissolve the run-out thrombi with plane to dissolve the run-out thrombi with urokinase urokinase
Rakesh 34yrsMRakesh 34yrsM Left SFA pseudoaneurysm with Left SFA pseudoaneurysm with
Covered stent placementCovered stent placement Pre operative antiplatelets with post Pre operative antiplatelets with post
procedure heparin Tirofiban procedure heparin Tirofiban followed by aspirin and clopidogrel followed by aspirin and clopidogrel were usedwere used
IAT may be a treatment option for selected patients IAT may be a treatment option for selected patients Possible selection criteria include Possible selection criteria include
presentation between 3 and 6 hours from symptom onsetpresentation between 3 and 6 hours from symptom onset major cerebral artery occlusion major cerebral artery occlusion severe neurologic deficits severe neurologic deficits high risk of systemic hemorrhage with IV rt-PA (eg recent high risk of systemic hemorrhage with IV rt-PA (eg recent
surgery) surgery) The MERCI (Mechanical Embolus Removal in Cerebral The MERCI (Mechanical Embolus Removal in Cerebral
Ischemia) retrievalIschemia) retrieval system system
Has been FDA-approved for recanalizing acutely occluded Has been FDA-approved for recanalizing acutely occluded cerebral arteries cerebral arteries
In the Multi-MERCI study patients who did not improve In the Multi-MERCI study patients who did not improve immediately after IV rt-PA underwent mechanical immediately after IV rt-PA underwent mechanical embolectomy within 8 hours of symptom onset embolectomy within 8 hours of symptom onset
Partial or complete recanalization occurred in 74 of Partial or complete recanalization occurred in 74 of patientspatients
with a symptomatic intracerebral hemorrhage (sICH) rate of with a symptomatic intracerebral hemorrhage (sICH) rate of 67 67
Mechanical embolectomy with the MERCI retriever may be a Mechanical embolectomy with the MERCI retriever may be a feasible and safe option for patients after IV rt-PAfeasible and safe option for patients after IV rt-PA
Penumbra stroke systemPenumbra stroke system This device combines two methods of clot This device combines two methods of clot
extraction aspiration and mechanical extraction aspiration and mechanical extraction extraction
First the clot is aspirated then a thrombus First the clot is aspirated then a thrombus removal ring can be used if necessary to removal ring can be used if necessary to remove remaining clot remove remaining clot
successful recanalizing 82successful recanalizing 82 Bridging therapyBridging therapy
06 mgkg IV rt-PA followed by IAT with IA rt-06 mgkg IV rt-PA followed by IAT with IA rt-PA (up to 20 mg)PA (up to 20 mg)
achieved a higher recanalization rateachieved a higher recanalization rate
Criteria for thrombolysis with rTPACriteria for thrombolysis with rTPA
Inclusion criteriaInclusion criteria Clinical signs and symptoms consistent with ischemic Clinical signs and symptoms consistent with ischemic
strokestroke Patient last seen normal within 3 hoursPatient last seen normal within 3 hours Measurable neurologic deficitMeasurable neurologic deficit
Exclusion criteriaExclusion criteria Any hemorrhage on neuroimaging (CT or MRI)Any hemorrhage on neuroimaging (CT or MRI) Symptoms suggestive of subarachnoid hemorrhageSymptoms suggestive of subarachnoid hemorrhage Seizure at stroke onset that is thought to contribute to Seizure at stroke onset that is thought to contribute to
neurologic deficitneurologic deficit Hypodensity greater than one third cerebral hemisphere Hypodensity greater than one third cerebral hemisphere
on CTon CT SBP greater than 185 mm Hg or DBP greater than 110 SBP greater than 185 mm Hg or DBP greater than 110
mm Hgmm Hg International normalized ratio (INR) greater than 17International normalized ratio (INR) greater than 17
Ischemic Stroke Ischemic Stroke Treatment ndash 2006Treatment ndash 2006
IV tissue plasminogen activator (tPA)IV tissue plasminogen activator (tPA) ndash ndash Only FDA-approved acute stroke drugOnly FDA-approved acute stroke drug ndash ndash 3 hour treatment window3 hour treatment window
MERCI - Concentric clot retrieval MERCI - Concentric clot retrieval devicedevice ndash ndash Rescue therapy - approved 2004Rescue therapy - approved 2004 ndash ndash Device approval (not outcomes-based)Device approval (not outcomes-based)
Off label approachesOff label approaches ndash ndash IV tPA after 3 hoursIV tPA after 3 hours ndash ndash IV-IA tPA sequential strategiesIV-IA tPA sequential strategies ndash ndash IA tPA clot angioplasty fragmentationIA tPA clot angioplasty fragmentation ndash ndash Ultrasound-assisted tPA lysisUltrasound-assisted tPA lysis
rt-PA Trials NINDSrt-PA Trials NINDS
Acute stroke - 624 patientsAcute stroke - 624 patients Treat within 3 hrsTreat within 3 hrs Intravenous 09 mgkg rt-PA vs placeboIntravenous 09 mgkg rt-PA vs placebo Hemorrhage 64 tPA 06 placeboHemorrhage 64 tPA 06 placebo Neurologic recovery better with tPA 30 Neurologic recovery better with tPA 30
more like to have minimal or no disabilitymore like to have minimal or no disability
First proven approved treatment for First proven approved treatment for strokestroke
Limitations of tPALimitations of tPA Only 4 of acute strokes receive tPAOnly 4 of acute strokes receive tPA (Kleindorfer et al Stroke 2004 35 e27-e29)(Kleindorfer et al Stroke 2004 35 e27-e29)
Only 22 of patients present within 3 hoursOnly 22 of patients present within 3 hours1048707 1048707 51 of these ineligible due to51 of these ineligible due to
bull bull Mild severityMild severity bull bull Medical or surgical historyMedical or surgical history bull bull Blood testsBlood tests
Sustained recanalization only 13Sustained recanalization only 13 (Alexandrov et al NEJM 2004 351 2170-8)(Alexandrov et al NEJM 2004 351 2170-8)
Concern for hemorrhageConcern for hemorrhage tPA potentiates apoptotic injury tPA potentiates apoptotic injury (Liu et al Nature Med 2004 101379-83)(Liu et al Nature Med 2004 101379-83)
PROACT II IA Lysis TrialPROACT II IA Lysis Trial Baseline 24 hours 8 days
Baseline 60 minutes 120 minutes
9mg IAProurokinase
Desmoteplase Trials DEDAS Desmoteplase Trials DEDAS DIASDIAS
Trial OverviewTrial Overview Double blind randomized placebo Double blind randomized placebo
controlled trialscontrolled trials IV delivery 3-9 hour time windowIV delivery 3-9 hour time window Plasminogen activator ndash from Plasminogen activator ndash from vampire bat vampire bat
salivasaliva Selection based on PWI-DWI MismatchSelection based on PWI-DWI Mismatch
MRI InclusionMRI Inclusion PWI defect at least 2 cm AND ~20 larger PWI defect at least 2 cm AND ~20 larger
than DWIthan DWI PWI should be obvious even visible on PWI should be obvious even visible on
raw imagesraw imagesMRI ExclusionMRI Exclusion
DWI gt 13 MCADWI gt 13 MCA MRA ICA occlusionMRA ICA occlusion
Desmoteplase ndash DIAS Desmoteplase ndash DIAS ResultsResults
Mechanical Thrombolysis Mechanical Thrombolysis devicesdevices
mechanical thrombolysis potentially extends the treatment mechanical thrombolysis potentially extends the treatment window because they act promptly at the site of the thrombuswindow because they act promptly at the site of the thrombus
The devices can retrieve large clots that pharmaceutical agents The devices can retrieve large clots that pharmaceutical agents may not successfully lysemay not successfully lyse
Patients treated with IV tPA may be considered for treatment of Patients treated with IV tPA may be considered for treatment of residual clot with some of these devicesresidual clot with some of these devices
suction-creating saline jets suction-creating saline jets laser energy ultrasound laser energy ultrasound a corkscrew apparatus to treat strokesa corkscrew apparatus to treat strokes The AngioJet systemThe AngioJet system uses saline jets that are directed back into the catheter to uses saline jets that are directed back into the catheter to
create a low-pressure zone around the catheter tip inducing create a low-pressure zone around the catheter tip inducing suction suction
The clot is pulled into the exhaust lumen and removed from the The clot is pulled into the exhaust lumen and removed from the vessel Although US Food and Drug Administration (FDA) has vessel Although US Food and Drug Administration (FDA) has approved this device for use in arteriovenous dialysis grafts and approved this device for use in arteriovenous dialysis grafts and fistulae and for the treatment of coronary arteries saphenous fistulae and for the treatment of coronary arteries saphenous vein grafts and peripheral vessels clinical trials for the vein grafts and peripheral vessels clinical trials for the treatment of acute stroke are no longer in progress treatment of acute stroke are no longer in progress
Most devices are used in cerebral vessels that 2-5 mm
The Latis laser device The Latis laser device used laser energy to ablate clots used laser energy to ablate clots Arteries 2-5 mm in diameter could be Arteries 2-5 mm in diameter could be
treated including the ICA M1 or M2 treated including the ICA M1 or M2 branch of the MCA A1 branch of the branch of the MCA A1 branch of the anterior cerebral artery (ACA) basilar anterior cerebral artery (ACA) basilar artery posterior cerebral artery (PCA) artery posterior cerebral artery (PCA) and vertebral and vertebral
Patients could receive treatment as late Patients could receive treatment as late as 8 hours after symptom onset in the as 8 hours after symptom onset in the anterior circulation and within 24 hours in anterior circulation and within 24 hours in the posterior circulation the posterior circulation
Endovascular Photo Acoustic Endovascular Photo Acoustic Recanalization (EPAR) Recanalization (EPAR)
A laser power source generated energy for the A laser power source generated energy for the systemsystem
The energy was delivered by means of The energy was delivered by means of fiberoptics to the tip of the catheter at the fiberoptics to the tip of the catheter at the treatment sitetreatment site
Absorption of laser light by darkly pigmented Absorption of laser light by darkly pigmented materials (ie the clot) occurred inside the 1-mm materials (ie the clot) occurred inside the 1-mm catheter tipcatheter tip
the system was designed to minimize scattering the system was designed to minimize scattering of laser light of laser light
Absorption converted photo energy to acoustic Absorption converted photo energy to acoustic energy which then emulsified the clot inside the energy which then emulsified the clot inside the catheter tip catheter tip
EKOS ultrasound( the EKOS ultrasound( the Ultrasound Thrombolytic Ultrasound Thrombolytic
Infusion Catheter) Infusion Catheter) combines the use of a distal ultrasound transducer with combines the use of a distal ultrasound transducer with
infusion of a thrombolytic agent through the infusion of a thrombolytic agent through the microcathetermicrocatheter
Ultrasound changes the structure of the clot to Ultrasound changes the structure of the clot to temporarily increase its permeability while providing an temporarily increase its permeability while providing an acoustic pressure gradient to move the drug into the clot acoustic pressure gradient to move the drug into the clot to speed its dissolution to speed its dissolution
The EKOS catheter is placed in the proximal portion of the The EKOS catheter is placed in the proximal portion of the clot clot
After a 2-mg bolus of tPA was injected through the After a 2-mg bolus of tPA was injected through the catheter catheter
the patient received a continuous infusion of IA tPA 03 the patient received a continuous infusion of IA tPA 03 mgmin to a maximum of 20 mg and simultaneous mgmin to a maximum of 20 mg and simultaneous ultrasound transmission for as long as 60 minutes ultrasound transmission for as long as 60 minutes
One patient was treated with a total of 4 units of One patient was treated with a total of 4 units of recombinant reteplase (Retavase) hand-injected over 60 recombinant reteplase (Retavase) hand-injected over 60 minutes minutes
Penumbra system Penumbra system The Penumbra system (Penumbra Inc) provides a dual The Penumbra system (Penumbra Inc) provides a dual
approach to clot extraction using aspiration followed by approach to clot extraction using aspiration followed by clot retrieval with a ring device if needed clot retrieval with a ring device if needed
Mechanical Embolus Removal in Cerebral Ischemia Mechanical Embolus Removal in Cerebral Ischemia (MERCI)(MERCI)
a corkscrew-like apparatus to remove blood clots from a corkscrew-like apparatus to remove blood clots from the brain in patients experiencing an ischemic stroke the brain in patients experiencing an ischemic stroke
The corkscrew itself resides in the catheter tip which The corkscrew itself resides in the catheter tip which shields it from the wall of the vessel until it is ready to be shields it from the wall of the vessel until it is ready to be burrowed into the clot Once lodged in the clot the device burrowed into the clot Once lodged in the clot the device and clot are withdrawn from the vessel and clot are withdrawn from the vessel
Snarelike devicesSnarelike devices Snares such as the Neuronet snare (Guidant Snares such as the Neuronet snare (Guidant
Endovascular Santa Clara CA) have been developed Endovascular Santa Clara CA) have been developed specifically for use in the treatment of strokes specifically for use in the treatment of strokes
These devices are simple in design and do not require the These devices are simple in design and do not require the clot to be amenable to emulsification clot to be amenable to emulsification
X-Sizer deviceX-Sizer device a device with small moving blades at the a device with small moving blades at the
catheter tip catheter tip This device the X-Sizer device (EndiCor Medical This device the X-Sizer device (EndiCor Medical
San Clemente CA) can be used to excise the San Clemente CA) can be used to excise the thrombus and aspirate it thrombus and aspirate it
The device was being evaluated in randomized The device was being evaluated in randomized studies of coronary vessels and in a registry of studies of coronary vessels and in a registry of patients with acute myocardial infarctionpatients with acute myocardial infarction
Although the manufacturer had modified the Although the manufacturer had modified the device for use in cerebral vessels a safety and device for use in cerebral vessels a safety and feasibility study was indefinitely suspended after feasibility study was indefinitely suspended after only 1 patient was treated with the device in only 1 patient was treated with the device in Europe Europe
Suction thrombectomySuction thrombectomy This method of mechanical thrombolysis is one of the This method of mechanical thrombolysis is one of the
simplestsimplest In this readily available technique suction is applied with In this readily available technique suction is applied with
a syringe to remove thrombus in the ICA a syringe to remove thrombus in the ICA It requires no other devicesIt requires no other devices A catheter with a large inner diameter (Brite Tip Cordis A catheter with a large inner diameter (Brite Tip Cordis
Corporation Miami FL) was placed in the symptomatic Corporation Miami FL) was placed in the symptomatic vessel and navigated over a guidewire into the thrombusvessel and navigated over a guidewire into the thrombus
A 60-mL syringe was used to aspirate the thrombus A 60-mL syringe was used to aspirate the thrombus Each patient required angioplasty and stenting of carotid Each patient required angioplasty and stenting of carotid
bifurcation stenosis and received daily aspirin and bifurcation stenosis and received daily aspirin and ticlopidine after the procedure No complications ticlopidine after the procedure No complications occurred occurred
Summary Acute Stroke Summary Acute Stroke ImagingImaging
PhysiologyPhysiology importance collaterals importance collaterals
ndash ndashGrowing role for perfusion Growing role for perfusion assessmentassessment
tPAtPA guidelines amp limitations guidelines amp limitations Signs on CT amp MRSigns on CT amp MR follow physiology follow physiology Stroke trialsStroke trials PWI-DWI mismatch PWI-DWI mismatch
ndash ndashTreat based on physiology not timeTreat based on physiology not time ProtocolsProtocols should be fast and should be fast and
comprehensivecomprehensive
1 Plasminogen Activators 1 Plasminogen Activators drugs act by converting the inactive proenzyme drugs act by converting the inactive proenzyme plasminogen into the active enzyme plasmin Plasmin plasminogen into the active enzyme plasmin Plasmin digests fibrinogen fibrin monomers and cross-linked digests fibrinogen fibrin monomers and cross-linked fibrin (as found in a thrombus) into fibrin degradation fibrin (as found in a thrombus) into fibrin degradation productsproducts
First-Generation Agents First-Generation Agents StreptokinaseStreptokinase a protein derived from group C a protein derived from group C
szlig-hemolytic streptococci has a half-life of 16ndashszlig-hemolytic streptococci has a half-life of 16ndash90 minutes and low fibrin specificity This drug 90 minutes and low fibrin specificity This drug proved to have a very narrow therapeutic proved to have a very narrow therapeutic window and significant rates of ICH and window and significant rates of ICH and systemic hemorrhage18systemic hemorrhage18
UrokinaseUrokinase is a serine protease with a plasma is a serine protease with a plasma half life of 14 minutes and low fibrin specificity half life of 14 minutes and low fibrin specificity
The urokinase dose used in cerebral IAT has The urokinase dose used in cerebral IAT has ranged from 002 to 2 X106unitsranged from 002 to 2 X106units
Second-Generation Agents Second-Generation Agents Alteplase (rtPA) Alteplase (rtPA)
is a serine is a serine protease with a plasma half-life of 35 protease with a plasma half-life of 35 minutes and a high degree of fibrin affinity and minutes and a high degree of fibrin affinity and specificity specificity
Dose used in cerebral IAT has ranged between 20 Dose used in cerebral IAT has ranged between 20 and 60 mgand 60 mg
Disadvantages of alteplase include its relatively short Disadvantages of alteplase include its relatively short halflife and limited penetration into the clot matrix halflife and limited penetration into the clot matrix because of strong binding with surface fibrin which because of strong binding with surface fibrin which could delay recanalization and increase the risk of could delay recanalization and increase the risk of recurrent occlusion recurrent occlusion
Prourokinase (r-prourokinase) Prourokinase (r-prourokinase) is the proenzyme precursor of urokinase is the proenzyme precursor of urokinase T12 of 7 minutes and high fibrin specificity T12 of 7 minutes and high fibrin specificity
Third-Generation AgentsThird-Generation Agents
ReteplaseReteplase is a structurally modified is a structurally modified form of alteplase form of alteplase
with a longer half-life (15ndash18 minutes) In with a longer half-life (15ndash18 minutes) In addition it does not bind as highly to fibrin addition it does not bind as highly to fibrin unbound reteplase can thus theoretically better unbound reteplase can thus theoretically better penetrate the clot and potentially penetrate the clot and potentially improve in improve in vivo fibrinolytic activity vivo fibrinolytic activity
TenecteplaseTenecteplase is another modified form of rtPA with a longer is another modified form of rtPA with a longer
half-life (17 minutes)half-life (17 minutes) greater fibrin specificity and greater greater fibrin specificity and greater
resistance to plasminogen activator inhibitor-1 resistance to plasminogen activator inhibitor-1 IV tenecteplase in acute ischemic stroke IV tenecteplase in acute ischemic stroke
suggest that the drug is safe and promisingsuggest that the drug is safe and promising
Newer plasminogen activatorNewer plasminogen activator
DesmoteplaseDesmoteplase is a genetically engineered is a genetically engineered version of the clot-dissolving factor version of the clot-dissolving factor
found in the saliva found in the saliva of the vampire bat Desmodus rotundusof the vampire bat Desmodus rotundus moremore potent and more selective for fibrin-bound potent and more selective for fibrin-bound
plasminogen than any other known plasminogen plasminogen than any other known plasminogen activatoractivator
Unlike tissue plasminogen activator (tPA) desmoteplase Unlike tissue plasminogen activator (tPA) desmoteplase is not activated by fibrinogen or -amyloid proteins is not activated by fibrinogen or -amyloid proteins factors that may exacerbate the risk for ICH factors that may exacerbate the risk for ICH
The effect of IV administration of desmoteplase 3ndash9 The effect of IV administration of desmoteplase 3ndash9 hours after symptom onset in patients with stroke who hours after symptom onset in patients with stroke who present with mismatch on MR imaging or CT perfusion present with mismatch on MR imaging or CT perfusion
3 DefibrinogenatingFibrinogenolytic 3 DefibrinogenatingFibrinogenolytic Agents Agents
AncrodAncrod(Viprinex)(Viprinex) is is the purified fraction of the Malayan pit viper venomthe purified fraction of the Malayan pit viper venom It acts by directly cleaving and inactivating fibrinogen It acts by directly cleaving and inactivating fibrinogen
and thus indirectly promoting anticoagulation and thus indirectly promoting anticoagulation The reduction in the blood levels of fibrinogen also The reduction in the blood levels of fibrinogen also
leads to a reduced blood viscosity which may improve leads to a reduced blood viscosity which may improve blood flow to the affected areas of the brain blood flow to the affected areas of the brain
In the Stroke Treatment with Ancrod Trial 500 In the Stroke Treatment with Ancrod Trial 500 patients with stroke presenting within 3 hours of patients with stroke presenting within 3 hours of symptom onset were randomized to receive ancrod (symptom onset were randomized to receive ancrod (n n 248) or a placebo (n 252) Good outcome (Barthel 248) or a placebo (n 252) Good outcome (Barthel Index 95ndash100 at 3 months) was achieved in 4221 Index 95ndash100 at 3 months) was achieved in 4221 and 344 of the patients respectively and 344 of the patients respectively
2 Direct Fibrinolytics2 Direct Fibrinolytics
Microplasmin (Microplasmin (ThromboGenics Heverlee Belgium)ThromboGenics Heverlee Belgium) is a truncated form of plasmin that is more resistant to the effects is a truncated form of plasmin that is more resistant to the effects
of antiplasmin of antiplasmin microplasmin can be used upto 4ndash12 hours after stroke onset microplasmin can be used upto 4ndash12 hours after stroke onset There was no evidence of increased bleeding risk with There was no evidence of increased bleeding risk with
microplasminmicroplasmin
Alfimeprase (Nuvelo San Carlos Calif)Alfimeprase (Nuvelo San Carlos Calif) is a recombinant truncated form of fibrolase a fibrinolytic zinc metalloproteinase is a recombinant truncated form of fibrolase a fibrinolytic zinc metalloproteinase
isolated from the venom of the southern copperhead snake isolated from the venom of the southern copperhead snake It degrades fibrin directly and achieves thrombolysis independent It degrades fibrin directly and achieves thrombolysis independent
of plasmin formationof plasmin formation its thrombolytic activity appears to be localized to the site of its thrombolytic activity appears to be localized to the site of
delivery These properties should theoretically result in faster delivery These properties should theoretically result in faster recanalization and lower hemorrhagic conversion riskrecanalization and lower hemorrhagic conversion risk
Anti-fibrinolyticsAnti-fibrinolytics
to limit fibrinolytic activityto limit fibrinolytic activity -aminocaproic acid (EACA) -aminocaproic acid (EACA) competitively inhibitscompetitively inhibits plasminogen and plasminogen activators from plasminogen and plasminogen activators from
binding to fibrinbinding to fibrin
alpha2-antiplasminalpha2-antiplasmin a serine protease inhibitor that a serine protease inhibitor that neutralizes any free circulating plasminneutralizes any free circulating plasmin
Plasminogen activator inhibitor-1Plasminogen activator inhibitor-1 a serine protease a serine protease inhibitor that inhibits tissue-type plasminogen inhibitor that inhibits tissue-type plasminogen activatoractivator
Glycoprotein (GP) IIbIIIa antagonistsGlycoprotein (GP) IIbIIIa antagonists
such as ReoPro (abciximab) Integrilin such as ReoPro (abciximab) Integrilin (eptifibatide) or Aggrastat (tirofiban) in (eptifibatide) or Aggrastat (tirofiban) in ischemic stroke remains investigational ischemic stroke remains investigational Deshmukh et al38 reported 21 patients with Deshmukh et al38 reported 21 patients with large-vessel occlusion refractory to IAT with large-vessel occlusion refractory to IAT with rtPA who were treated with IV andor IA rtPA who were treated with IV andor IA abciximab eptifibatide or tirofiban abciximab eptifibatide or tirofiban
IA Mechanical Approaches in Acute Ischemic Stroke IA Mechanical Approaches in Acute Ischemic Stroke Mechanical strategies have several advantagesMechanical strategies have several advantages First they lessen and may even preclude the use of chemical First they lessen and may even preclude the use of chemical
thrombolytics in this manner very likely reducing the risk of ICHthrombolytics in this manner very likely reducing the risk of ICH Second by avoiding the use of chemical thrombolytics it is Second by avoiding the use of chemical thrombolytics it is
possible to extend the treatment window beyond the limit of 6ndash8 possible to extend the treatment window beyond the limit of 6ndash8 hours hours
Third mechanically fragmenting a clot increases the surface area Third mechanically fragmenting a clot increases the surface area accessible to fibrinolytic agents and allows inflow of fresh accessible to fibrinolytic agents and allows inflow of fresh plasminogen which in turn may increase the speed of plasminogen which in turn may increase the speed of thrombolysis thrombolysis
Finally clot-retrieval devices may provide faster recanalization Finally clot-retrieval devices may provide faster recanalization
The disadvantages of the mechanical The disadvantages of the mechanical approaches approaches technical difficulty of navigating mechanical technical difficulty of navigating mechanical
devices into the intracranial circulation excessive devices into the intracranial circulation excessive trauma to the vasculature (potentially leading to trauma to the vasculature (potentially leading to vasospasm vessel dissection perforation or vasospasm vessel dissection perforation or rupture) rupture)
fragmented thrombus causing distal embolization fragmented thrombus causing distal embolization into previously unaffected territories into previously unaffected territories
Nevertheless the advantages of mechanical stroke Nevertheless the advantages of mechanical stroke therapy appear to significantly outweigh its therapy appear to significantly outweigh its disadvantages and risksdisadvantages and risks
Contraindications to Thrombolytic Contraindications to Thrombolytic agents agents
Recent thoracic abdominal or Recent thoracic abdominal or intracranial surgeryintracranial surgery
Recent haemorrhagic CVA Head injury Recent haemorrhagic CVA Head injury or neoplasmor neoplasm
Bleeding ulcerBleeding ulcer Anticipated invasive procedures (arterial Anticipated invasive procedures (arterial
punctures biopsies)punctures biopsies) Concurrent hemostatic dysfunctionConcurrent hemostatic dysfunction
Monitoring of thrombolytic Monitoring of thrombolytic therapytherapy
Thrombin time Measures the availability of functional
fibrinogen Normal thrombin time is 10-14 sec Prolonged when fibrinogen level is below
75-100 mgdl
Half Life of ThrombolyticsHalf Life of ThrombolyticsAgent Administration Half Life
Streptokinase IA 60-80min
Urokinase IAIV 9-12min
rTPA IAIV 6min
Abciximab(Reopro) IAIV 12hour
Aspirin POIV 15-20min
Heparin IVSC 60min
Coumadin PO 15-25 days
Anti Platelet DrugsAnti Platelet DrugsDrug Drug Mechanism Mechanism UsesUsesAspirinAspirin Permanently inhibits Permanently inhibits
COX-1 and COX-2COX-1 and COX-2CADCAD
Stroke-TIAsStroke-TIAs
NSAIDsNSAIDs Reversibly inhibits Reversibly inhibits COX-1COX-1
LimitedLimited
DipyridamoleDipyridamole Inhibits PDE increases Inhibits PDE increases cAMPcAMP
TIAsTIAs
ThenopyridinesThenopyridines
(Ticlopidine(Ticlopidine
ClopidrgrelClopidrgrel))
Inhibits ADP Inhibits ADP
PlatAg PlatAg
TIAsStrokeTIAsStroke
CAD PVDCAD PVD
Abciximab (ReoPro)Abciximab (ReoPro)
Eptifibatide (Integrilin)Eptifibatide (Integrilin)
TirofibanTirofiban
GP IIBIIIA InhibitorsGP IIBIIIA Inhibitors
Stroke- TIAs Stroke- TIAs
MonitoringMonitoring
Bleeding timeBleeding time
Optical aggregometryOptical aggregometry
Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay
Bleeding timeBleeding time
Requires a skin incision (usually made on the ear lobe or Requires a skin incision (usually made on the ear lobe or forearm offorearm of
a depth that results in disruption of capillary loops and a depth that results in disruption of capillary loops and small vessels)small vessels)
AdvantagesAdvantages Universally availableUniversally available Relatively simple techniquesRelatively simple techniques Can be performed bedsideCan be performed bedside
DisadvantagesDisadvantages Insensitive inaccurate non-specific techniqueInsensitive inaccurate non-specific technique
Poorly reproducible (as depends on multiple variables)Poorly reproducible (as depends on multiple variables)
Optical aggregometryOptical aggregometry
Gold standard assay for platelet functionGold standard assay for platelet function Agonist induced aggregation is measuredAgonist induced aggregation is measured Different agonist are available for different Different agonist are available for different
agentsagents However require unique expertise and are not However require unique expertise and are not
universally availableuniversally available Aspirin measured with ADP or AA(gt70 Aspirin measured with ADP or AA(gt70
aggregation so resistance)aggregation so resistance) Clopidogrel( ADP gt 90 aggregation means Clopidogrel( ADP gt 90 aggregation means
resistance) resistance)
Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay
Can be performed bed sideCan be performed bed side Different assay devices with different Different assay devices with different
agonist are used for each of different agonist are used for each of different antiplatelet agents antiplatelet agents
For Aspirin AA is used (result is reported as aspirin For Aspirin AA is used (result is reported as aspirin reaction units [ARU] ARUgt 550 indicates non-reaction units [ARU] ARUgt 550 indicates non-responsiveness)responsiveness)
Verify IIbIIIa assay device uses TRAP as agonist for Verify IIbIIIa assay device uses TRAP as agonist for Abciximab and TirofibanAbciximab and Tirofiban
Practical Applications Practical Applications related to specific related to specific
Neurovascular Neurovascular interventionsinterventions
Acute ischemic StrokeAcute ischemic Stroke When an artery occludes neurons are affected When an artery occludes neurons are affected
differently depending upon the amount of residual blood differently depending upon the amount of residual blood flowflow
Normal cerebral blood flow is greater than 50 mL100 Normal cerebral blood flow is greater than 50 mL100 mgminmgmin
Once blood flow decreases to less than 20 mL100 Once blood flow decreases to less than 20 mL100 mgmin infarction occursmgmin infarction occurs
If blood flow decreases to less than 10 mL100 mgmin If blood flow decreases to less than 10 mL100 mgmin irreversible neuronal death occurs rapidly irreversible neuronal death occurs rapidly
Blood flow between 11 and 20 mL100 mgmin is thought Blood flow between 11 and 20 mL100 mgmin is thought to represent the ischemic penumbra an area where the to represent the ischemic penumbra an area where the cells are functionally silent because of ischemia but are cells are functionally silent because of ischemia but are still able to recover if blood flow is restored still able to recover if blood flow is restored
Many acute stroke therapies are targeted toward Many acute stroke therapies are targeted toward restoring flow or function to the ischemic penumbrarestoring flow or function to the ischemic penumbra
Therapeutic window in Therapeutic window in management of acute Ischemic management of acute Ischemic
StrokeStrokeThe early diagnosis of ischemic stroke is critical to the The early diagnosis of ischemic stroke is critical to the
with only a narrow therapeutic window in the first few with only a narrow therapeutic window in the first few hours following stroke ictushours following stroke ictus
Diagnosis in the first 3 hours postictus provides the Diagnosis in the first 3 hours postictus provides the opportunity for intravenous or intraarterial thrombolysis opportunity for intravenous or intraarterial thrombolysis and intra-arterial clot mechanical treatment which and intra-arterial clot mechanical treatment which improve the outcome improve the outcome
Diagnosis in the time period between 3 and 6 hours Diagnosis in the time period between 3 and 6 hours provides an opportunity for intra-arterial thrombolysis provides an opportunity for intra-arterial thrombolysis and mechanical treatment and mechanical treatment
Involvement of the posterior circulation especially the Involvement of the posterior circulation especially the basilar artery is treated by some regardless of time of basilar artery is treated by some regardless of time of onset or up until 12 to 24 hours in some practices This is onset or up until 12 to 24 hours in some practices This is related to the potentially high mortality and morbidity related to the potentially high mortality and morbidity associated with basilar artery thrombosisassociated with basilar artery thrombosis
Infarct evaluation on angiographyInfarct evaluation on angiography(CT angiography and catheter (CT angiography and catheter
angiography)angiography)CTA is an excellent first-line examination for CTA is an excellent first-line examination for
evaluation of the head and neck arteries evaluation of the head and neck arteries In comparison with catheter angiography In comparison with catheter angiography
what it gives up in resolution and dynamic what it gives up in resolution and dynamic properties it makes up for with rapid properties it makes up for with rapid acquisition of a 3-D dataset and the potential acquisition of a 3-D dataset and the potential for assessment of whole-brain perfusion and for assessment of whole-brain perfusion and better parenchymal evaluationbetter parenchymal evaluation
Moreover CTA illustrates not only arterial Moreover CTA illustrates not only arterial stenosis or occlusion but also the vessel wall stenosis or occlusion but also the vessel wall This factor is most important for evaluation of This factor is most important for evaluation of intramural dissection and thrombosed intramural dissection and thrombosed aneurysms which may both complicate aneurysms which may both complicate evaluation of stroke patientsevaluation of stroke patients
Early angiographic signs of strokes Early angiographic signs of strokes both CTA both CTA and DSA and DSA
Vessel occlusion or cutoff related to Vessel occlusion or cutoff related to thromboembolithromboemboli
aneurysms aneurysms arterial dissection arterial dissection Meniscus or flattened shape to clot Meniscus or flattened shape to clot
(recent) versus reverse meniscus (older)(recent) versus reverse meniscus (older) tram track (nonocclusive or recanalized tram track (nonocclusive or recanalized
clot) clot) delayed (antegrade) flow (manifest as delayed (antegrade) flow (manifest as
decreased whole-brain perfusion on CTA)decreased whole-brain perfusion on CTA) retrograde collateral flowretrograde collateral flow
Non-occlusive left MCA thrombus on 3-D imaging performed from CTA source data and was confirmed at catheter angiography
Therapy to be started within a 6-hr Therapy to be started within a 6-hr time to treatment (TTT) window time to treatment (TTT) window (while in case of IV thrombolysis (while in case of IV thrombolysis therapy to be started with in 3hrs)therapy to be started with in 3hrs)
Exclusion criteria Exclusion criteria Rapidly improving neurologic deficit or Rapidly improving neurologic deficit or Sustained blood pressure of gt180100 Sustained blood pressure of gt180100 Hemorrhage is detected on CTHemorrhage is detected on CT Infarct involving gt more than 13 rd Infarct involving gt more than 13 rd
territory of MCAterritory of MCA MRADWI-Perfusion mismatchlt 20MRADWI-Perfusion mismatchlt 20 Definite hypodensity on CTDefinite hypodensity on CT
Intra-arterial Thrombolysis
Fibrinolytics + AntiplateletsFibrinolytics + Antiplatelets
PlasminogenPlasminogen activators through fibrinolysis exposes activators through fibrinolysis exposes free thrombin and paradoxically stimulatesfree thrombin and paradoxically stimulates platelet platelet aggregation which leads to formation of aaggregation which leads to formation of a platelet platelet thrombus (white clot) thrombus (white clot)
This new thrombus is relatively resistant to This new thrombus is relatively resistant to fibrinolyticsfibrinolytics
So new regimen in case of acute stroke isSo new regimen in case of acute stroke is fibrinolytics + antiplatelet drugsfibrinolytics + antiplatelet drugs
rtPA + IIbIIIa inhibitors( tirofiban rtPA + IIbIIIa inhibitors( tirofiban abciximab) orabciximab) or
Urokinase + IIbIIIa Urokinase + IIbIIIa inhibitors( tirofiban abciximab)inhibitors( tirofiban abciximab)
Intra-arterial Thrombolysis Tirofiban (04 microgkgmin bolus for 3 min followed by Tirofiban (04 microgkgmin bolus for 3 min followed by
0125 ugkgmin)0125 ugkgmin)
++
Heparin (2000ndash3000 IU bolus followed by Heparin (2000ndash3000 IU bolus followed by 1000 IUhour infusion 1000 IUhour infusion
with ACT maintained bw 200-300) throughout the with ACT maintained bw 200-300) throughout the interventional procedure and for 24ndash48 hours thereafter when interventional procedure and for 24ndash48 hours thereafter when there is neither intraprocedural bleeding nor suspicion of there is neither intraprocedural bleeding nor suspicion of increased risk of bleeding increased risk of bleeding
Maximum dose of Urokinase Maximum dose of Urokinase Anterior circulation stroke - 500000 IU (mean 400000 Anterior circulation stroke - 500000 IU (mean 400000
IU range 300000ndash500000 IU)IU range 300000ndash500000 IU) Posterior circulation stroke -1000000 IU (mean 837000 Posterior circulation stroke -1000000 IU (mean 837000
IU range 300000ndash1000000 IU)IU range 300000ndash1000000 IU)American Journal of NeuroradiologyAmerican Journal of Neuroradiology 262595-2601 2005262595-2601 2005
Intravenous ThrombolysisIntravenous Thrombolysis
The first method to restore cerebral The first method to restore cerebral perfusion is clot lysis with the goal perfusion is clot lysis with the goal of re-establishing blood flow to the of re-establishing blood flow to the affected tissue affected tissue
IV thrombolysis rt-PA is the only IV thrombolysis rt-PA is the only FDA- approved treatment for AIS FDA- approved treatment for AIS
Fibrinolysis is enhanced powerfully Fibrinolysis is enhanced powerfully by rt-PAby rt-PA
Intravenous rTPA Intravenous rTPA administration administration protocolprotocol
Total dose of rt-PA 09 mgkg (maximum dose Total dose of rt-PA 09 mgkg (maximum dose 90 mg)90 mg)
Give 10 as initial IV bolusGive 10 as initial IV bolus Infuse remainder over 1 hourInfuse remainder over 1 hour Admit patient to an ICU or stroke unit for Admit patient to an ICU or stroke unit for
monitoringmonitoring Neurologic assessments every 15 minutes Neurologic assessments every 15 minutes
during infusion then every 30 minutes for next during infusion then every 30 minutes for next 6 hours then every hour until 24hours after 6 hours then every hour until 24hours after treatmenttreatment
Favorable Outcome vs Treatment Time Favorable Outcome vs Treatment Time with IV rTPAwith IV rTPA
Protocol limit = 3 hrs
Benefit ~ 45 hrs
Thromboembolism During coilingThromboembolism During coiling Most feared and frequent complication Most feared and frequent complication Reported incidence - Approx 7 Reported incidence - Approx 7 SourcesSources of Thromboembolism are of Thromboembolism are
- Clots at the aneurysmal neck during or immediately- Clots at the aneurysmal neck during or immediately after after embolization embolization
- Thrombus forming on catheters during- Thrombus forming on catheters during proceduresprocedures
- Stenosis of an adjacent artery dt coil mass- Stenosis of an adjacent artery dt coil mass or herniationor herniation
- Migration of intraaneurysmal- Migration of intraaneurysmal thrombus during coil thrombus during coil placement placement
- Slow flow dt vasospasm - Slow flow dt vasospasm
- Rare and unlikely causes are hypercoagulable- Rare and unlikely causes are hypercoagulable state such state such as antiphospholipid antibody syndrome or due to HITas antiphospholipid antibody syndrome or due to HIT
Occur more often with wide-necked aneurysms (dt Occur more often with wide-necked aneurysms (dt increased exposed surface area of thrombogenic coil increased exposed surface area of thrombogenic coil material)material)
Current regimen of endovascular Current regimen of endovascular managementmanagement
The The glycoprotein IIbIIIa antagonist tirofiban glycoprotein IIbIIIa antagonist tirofiban (04 (04 microgkgmin bolus for 30 minutes followed by infusion of microgkgmin bolus for 30 minutes followed by infusion of 0125 ugkgmin until the thrombus dissolved) 0125 ugkgmin until the thrombus dissolved)
Intraarterial thrombolysis with Intraarterial thrombolysis with urokinase or r- TPA urokinase or r- TPA increase of intravenous (IV) heparin (measured by increase of intravenous (IV) heparin (measured by
ACT) ACT) Intravenous aspirin Intravenous aspirin
Coil-related platelet aggregation (white clot) is Coil-related platelet aggregation (white clot) is unlikely to respond to fibrinolytics but has a high risk unlikely to respond to fibrinolytics but has a high risk of hemorrhage (In ISAT) all 5 patients who had of hemorrhage (In ISAT) all 5 patients who had received thrombolytic therapy with tPA to treat a received thrombolytic therapy with tPA to treat a thromboembolic complication after endovascular thromboembolic complication after endovascular treatment rebleed and all of these patients died)treatment rebleed and all of these patients died)
IntracranialIntracranial Stenting Stenting Metallic foreign body such as stent will accumulate Metallic foreign body such as stent will accumulate
thrombus in the absence of platelet inhibitionthrombus in the absence of platelet inhibition Antiplatelet drugs are important to prevent peri or Antiplatelet drugs are important to prevent peri or
post-interventional thromboembolic eventspost-interventional thromboembolic events Optimal treatment regimens has not been determined Optimal treatment regimens has not been determined
but usually but usually Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-
procedureprocedureOrOr
Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on
morning of proceduremorning of procedure
If need to use stent is not pre-planned thanIf need to use stent is not pre-planned than
Abciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkgAbciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkg IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)
Glycoprotein IIbIIIa inhibitor are not used routinely during elective Glycoprotein IIbIIIa inhibitor are not used routinely during elective stenting procedure dt increased risk of ICH stenting procedure dt increased risk of ICH
Carotid StentingCarotid Stenting
Pre-procedurePre-procedure
Double Antiplatelet therapy is routinely given Double Antiplatelet therapy is routinely given beginning at least 3beginning at least 3
days before the proceduredays before the procedure
Aspirin 325mgd+Clopidogrel 75mgdAspirin 325mgd+Clopidogrel 75mgd During procedureDuring procedure
Heparin is given with target clotting time of 250-Heparin is given with target clotting time of 250-300sec300sec
Post-procedure Post-procedure
Aspirin 325mg is continued indefinitely and Aspirin 325mg is continued indefinitely and
Clopidogrel 75mgd for at least 6 weeks Clopidogrel 75mgd for at least 6 weeks
Inclusion criteria for Local ThrombolysisInclusion criteria for Local Thrombolysis a)a) Patients in severe clinical grade on admission Patients in severe clinical grade on admission
with evidence of dural venous sinus with evidence of dural venous sinus thrombosis and restrictive venous outflow on thrombosis and restrictive venous outflow on cerebral angiogramcerebral angiogram
b)b) Patients in clinical grade 3 worsening on Patients in clinical grade 3 worsening on heparin therapy Restriction to venous heparin therapy Restriction to venous outflow was defined as an increase in brain outflow was defined as an increase in brain circulation time gt 12 s delay in the drainage circulation time gt 12 s delay in the drainage of cortical veins with cortical veins hanging of cortical veins with cortical veins hanging in spacein space
Treatment Options for Venous Thrombosis
CT Grading for Venous ThrombosisCT Grading for Venous Thrombosis Grade I no parenchymal change Grade I no parenchymal change
(hyperdense (hyperdense sinuses cortical veins empty sinuses cortical veins empty delta sign)delta sign)
Grade II non hemorrhagic venous infarct Grade II non hemorrhagic venous infarct without mass effect without mass effect
Grade III non-hemorrhagic infarct with Grade III non-hemorrhagic infarct with mass effectmass effect
Grade IV hemorrhagic venous infarct (max Grade IV hemorrhagic venous infarct (max diameter lt 3 cm) with no mass effectdiameter lt 3 cm) with no mass effect
Grade V hemorrhagic venous infarct (max Grade V hemorrhagic venous infarct (max diameter gt 3 cm) with mass effect diameter gt 3 cm) with mass effect
Local ThrombolysisLocal Thrombolysis
Femoral Jugular access was secured and a guiding Femoral Jugular access was secured and a guiding catheter was placed in the jugular bulb catheter was placed in the jugular bulb Mechanical Mechanical clot maceration clot maceration was done with the guidewire was done with the guidewire following which a microcatheter (was navigated and following which a microcatheter (was navigated and placed in the thrombosed segment of sinus confirmed placed in the thrombosed segment of sinus confirmed on a selective venogram on a selective venogram
Urokinase infusion Bolus dose of 2-6 lacs followed Urokinase infusion Bolus dose of 2-6 lacs followed by 60000 to 100000 units per hour along with by 60000 to 100000 units per hour along with periodic check venogram Along with maintenance periodic check venogram Along with maintenance systemic infusion of Heparinsystemic infusion of Heparin Other agents such as Other agents such as streptokinase altepase or rTPAstreptokinase altepase or rTPA can be also used can be also used
After thrombolysis patient should subjected to oral After thrombolysis patient should subjected to oral anticoagulation for six monthsanticoagulation for six months
Low-molecular-weight Low-molecular-weight heparinheparin
PharmacologyPharmacologyLMWH as its name suggests is a glycosaminoglycan that is approximatelyLMWH as its name suggests is a glycosaminoglycan that is approximately
one third the molecular weight of UFH It is derived from UFH through one third the molecular weight of UFH It is derived from UFH through variousvarious
depolymerization processes LMWH binds to antithrombin which in turn depolymerization processes LMWH binds to antithrombin which in turn
Neutralizes actors Xa and IIa Because LMWH lacks many of the longer Neutralizes actors Xa and IIa Because LMWH lacks many of the longer chains chains
required for binding to thrombin it has less ability to neutralize thrombin required for binding to thrombin it has less ability to neutralize thrombin
relativeto its ability to neutralize factor Xa LMWH also has less relativeto its ability to neutralize factor Xa LMWH also has less nonspecific nonspecific
binding to other proteins There is greater bioavailability with more binding to other proteins There is greater bioavailability with more predictable predictable
pharmacokinetics that eliminates the need for monitoring The smaller pharmacokinetics that eliminates the need for monitoring The smaller size also size also
allows for enhanced subcutaneous absorption when compared with UFHallows for enhanced subcutaneous absorption when compared with UFH
Three LMWH preparations are Three LMWH preparations are currently approved for use in the currently approved for use in the United States (1) enoxaparin (2) United States (1) enoxaparin (2) dalteparin and (3) tinzaparin dalteparin and (3) tinzaparin
They are all administered They are all administered subcutaneously at intervals of either subcutaneously at intervals of either once or twice daily for both once or twice daily for both prophylaxis and treatment dosesprophylaxis and treatment doses
Few Experiences of Few Experiences of ThrombolysisThrombolysis
Vickey 25 Yrs male patient presented Vickey 25 Yrs male patient presented with 12with 12thth day HO severe headache with day HO severe headache with right sided hemiplegiaright sided hemiplegia
MRI shows thrombosis of the superior MRI shows thrombosis of the superior sagittal left transverse left sigmoid sagittal left transverse left sigmoid sinuses and cortical veins in the fronto-sinuses and cortical veins in the fronto-parietal regions with eo haemorrhagic parietal regions with eo haemorrhagic infarct in the left cerebral hemisphere infarct in the left cerebral hemisphere with mass effect( Grade ndashV)with mass effect( Grade ndashV)
Sashi Srivastava 64 yrs FSashi Srivastava 64 yrs F In a follow up case of MRD with infra-renal In a follow up case of MRD with infra-renal
aortic abdominal and bilateral renal artery aortic abdominal and bilateral renal artery thrombosis renal angiogram shows filling thrombosis renal angiogram shows filling defects in the right Renal artery defects in the right Renal artery
Initially Renal angioplasty was done Initially Renal angioplasty was done Following angioplasty few thrombi are seem Following angioplasty few thrombi are seem to extends into the segmental branches and to extends into the segmental branches and causing blockage So Thrombolysis was causing blockage So Thrombolysis was plane to dissolve the run-out thrombi with plane to dissolve the run-out thrombi with urokinase urokinase
Rakesh 34yrsMRakesh 34yrsM Left SFA pseudoaneurysm with Left SFA pseudoaneurysm with
Covered stent placementCovered stent placement Pre operative antiplatelets with post Pre operative antiplatelets with post
procedure heparin Tirofiban procedure heparin Tirofiban followed by aspirin and clopidogrel followed by aspirin and clopidogrel were usedwere used
IAT may be a treatment option for selected patients IAT may be a treatment option for selected patients Possible selection criteria include Possible selection criteria include
presentation between 3 and 6 hours from symptom onsetpresentation between 3 and 6 hours from symptom onset major cerebral artery occlusion major cerebral artery occlusion severe neurologic deficits severe neurologic deficits high risk of systemic hemorrhage with IV rt-PA (eg recent high risk of systemic hemorrhage with IV rt-PA (eg recent
surgery) surgery) The MERCI (Mechanical Embolus Removal in Cerebral The MERCI (Mechanical Embolus Removal in Cerebral
Ischemia) retrievalIschemia) retrieval system system
Has been FDA-approved for recanalizing acutely occluded Has been FDA-approved for recanalizing acutely occluded cerebral arteries cerebral arteries
In the Multi-MERCI study patients who did not improve In the Multi-MERCI study patients who did not improve immediately after IV rt-PA underwent mechanical immediately after IV rt-PA underwent mechanical embolectomy within 8 hours of symptom onset embolectomy within 8 hours of symptom onset
Partial or complete recanalization occurred in 74 of Partial or complete recanalization occurred in 74 of patientspatients
with a symptomatic intracerebral hemorrhage (sICH) rate of with a symptomatic intracerebral hemorrhage (sICH) rate of 67 67
Mechanical embolectomy with the MERCI retriever may be a Mechanical embolectomy with the MERCI retriever may be a feasible and safe option for patients after IV rt-PAfeasible and safe option for patients after IV rt-PA
Penumbra stroke systemPenumbra stroke system This device combines two methods of clot This device combines two methods of clot
extraction aspiration and mechanical extraction aspiration and mechanical extraction extraction
First the clot is aspirated then a thrombus First the clot is aspirated then a thrombus removal ring can be used if necessary to removal ring can be used if necessary to remove remaining clot remove remaining clot
successful recanalizing 82successful recanalizing 82 Bridging therapyBridging therapy
06 mgkg IV rt-PA followed by IAT with IA rt-06 mgkg IV rt-PA followed by IAT with IA rt-PA (up to 20 mg)PA (up to 20 mg)
achieved a higher recanalization rateachieved a higher recanalization rate
Criteria for thrombolysis with rTPACriteria for thrombolysis with rTPA
Inclusion criteriaInclusion criteria Clinical signs and symptoms consistent with ischemic Clinical signs and symptoms consistent with ischemic
strokestroke Patient last seen normal within 3 hoursPatient last seen normal within 3 hours Measurable neurologic deficitMeasurable neurologic deficit
Exclusion criteriaExclusion criteria Any hemorrhage on neuroimaging (CT or MRI)Any hemorrhage on neuroimaging (CT or MRI) Symptoms suggestive of subarachnoid hemorrhageSymptoms suggestive of subarachnoid hemorrhage Seizure at stroke onset that is thought to contribute to Seizure at stroke onset that is thought to contribute to
neurologic deficitneurologic deficit Hypodensity greater than one third cerebral hemisphere Hypodensity greater than one third cerebral hemisphere
on CTon CT SBP greater than 185 mm Hg or DBP greater than 110 SBP greater than 185 mm Hg or DBP greater than 110
mm Hgmm Hg International normalized ratio (INR) greater than 17International normalized ratio (INR) greater than 17
Ischemic Stroke Ischemic Stroke Treatment ndash 2006Treatment ndash 2006
IV tissue plasminogen activator (tPA)IV tissue plasminogen activator (tPA) ndash ndash Only FDA-approved acute stroke drugOnly FDA-approved acute stroke drug ndash ndash 3 hour treatment window3 hour treatment window
MERCI - Concentric clot retrieval MERCI - Concentric clot retrieval devicedevice ndash ndash Rescue therapy - approved 2004Rescue therapy - approved 2004 ndash ndash Device approval (not outcomes-based)Device approval (not outcomes-based)
Off label approachesOff label approaches ndash ndash IV tPA after 3 hoursIV tPA after 3 hours ndash ndash IV-IA tPA sequential strategiesIV-IA tPA sequential strategies ndash ndash IA tPA clot angioplasty fragmentationIA tPA clot angioplasty fragmentation ndash ndash Ultrasound-assisted tPA lysisUltrasound-assisted tPA lysis
rt-PA Trials NINDSrt-PA Trials NINDS
Acute stroke - 624 patientsAcute stroke - 624 patients Treat within 3 hrsTreat within 3 hrs Intravenous 09 mgkg rt-PA vs placeboIntravenous 09 mgkg rt-PA vs placebo Hemorrhage 64 tPA 06 placeboHemorrhage 64 tPA 06 placebo Neurologic recovery better with tPA 30 Neurologic recovery better with tPA 30
more like to have minimal or no disabilitymore like to have minimal or no disability
First proven approved treatment for First proven approved treatment for strokestroke
Limitations of tPALimitations of tPA Only 4 of acute strokes receive tPAOnly 4 of acute strokes receive tPA (Kleindorfer et al Stroke 2004 35 e27-e29)(Kleindorfer et al Stroke 2004 35 e27-e29)
Only 22 of patients present within 3 hoursOnly 22 of patients present within 3 hours1048707 1048707 51 of these ineligible due to51 of these ineligible due to
bull bull Mild severityMild severity bull bull Medical or surgical historyMedical or surgical history bull bull Blood testsBlood tests
Sustained recanalization only 13Sustained recanalization only 13 (Alexandrov et al NEJM 2004 351 2170-8)(Alexandrov et al NEJM 2004 351 2170-8)
Concern for hemorrhageConcern for hemorrhage tPA potentiates apoptotic injury tPA potentiates apoptotic injury (Liu et al Nature Med 2004 101379-83)(Liu et al Nature Med 2004 101379-83)
PROACT II IA Lysis TrialPROACT II IA Lysis Trial Baseline 24 hours 8 days
Baseline 60 minutes 120 minutes
9mg IAProurokinase
Desmoteplase Trials DEDAS Desmoteplase Trials DEDAS DIASDIAS
Trial OverviewTrial Overview Double blind randomized placebo Double blind randomized placebo
controlled trialscontrolled trials IV delivery 3-9 hour time windowIV delivery 3-9 hour time window Plasminogen activator ndash from Plasminogen activator ndash from vampire bat vampire bat
salivasaliva Selection based on PWI-DWI MismatchSelection based on PWI-DWI Mismatch
MRI InclusionMRI Inclusion PWI defect at least 2 cm AND ~20 larger PWI defect at least 2 cm AND ~20 larger
than DWIthan DWI PWI should be obvious even visible on PWI should be obvious even visible on
raw imagesraw imagesMRI ExclusionMRI Exclusion
DWI gt 13 MCADWI gt 13 MCA MRA ICA occlusionMRA ICA occlusion
Desmoteplase ndash DIAS Desmoteplase ndash DIAS ResultsResults
Mechanical Thrombolysis Mechanical Thrombolysis devicesdevices
mechanical thrombolysis potentially extends the treatment mechanical thrombolysis potentially extends the treatment window because they act promptly at the site of the thrombuswindow because they act promptly at the site of the thrombus
The devices can retrieve large clots that pharmaceutical agents The devices can retrieve large clots that pharmaceutical agents may not successfully lysemay not successfully lyse
Patients treated with IV tPA may be considered for treatment of Patients treated with IV tPA may be considered for treatment of residual clot with some of these devicesresidual clot with some of these devices
suction-creating saline jets suction-creating saline jets laser energy ultrasound laser energy ultrasound a corkscrew apparatus to treat strokesa corkscrew apparatus to treat strokes The AngioJet systemThe AngioJet system uses saline jets that are directed back into the catheter to uses saline jets that are directed back into the catheter to
create a low-pressure zone around the catheter tip inducing create a low-pressure zone around the catheter tip inducing suction suction
The clot is pulled into the exhaust lumen and removed from the The clot is pulled into the exhaust lumen and removed from the vessel Although US Food and Drug Administration (FDA) has vessel Although US Food and Drug Administration (FDA) has approved this device for use in arteriovenous dialysis grafts and approved this device for use in arteriovenous dialysis grafts and fistulae and for the treatment of coronary arteries saphenous fistulae and for the treatment of coronary arteries saphenous vein grafts and peripheral vessels clinical trials for the vein grafts and peripheral vessels clinical trials for the treatment of acute stroke are no longer in progress treatment of acute stroke are no longer in progress
Most devices are used in cerebral vessels that 2-5 mm
The Latis laser device The Latis laser device used laser energy to ablate clots used laser energy to ablate clots Arteries 2-5 mm in diameter could be Arteries 2-5 mm in diameter could be
treated including the ICA M1 or M2 treated including the ICA M1 or M2 branch of the MCA A1 branch of the branch of the MCA A1 branch of the anterior cerebral artery (ACA) basilar anterior cerebral artery (ACA) basilar artery posterior cerebral artery (PCA) artery posterior cerebral artery (PCA) and vertebral and vertebral
Patients could receive treatment as late Patients could receive treatment as late as 8 hours after symptom onset in the as 8 hours after symptom onset in the anterior circulation and within 24 hours in anterior circulation and within 24 hours in the posterior circulation the posterior circulation
Endovascular Photo Acoustic Endovascular Photo Acoustic Recanalization (EPAR) Recanalization (EPAR)
A laser power source generated energy for the A laser power source generated energy for the systemsystem
The energy was delivered by means of The energy was delivered by means of fiberoptics to the tip of the catheter at the fiberoptics to the tip of the catheter at the treatment sitetreatment site
Absorption of laser light by darkly pigmented Absorption of laser light by darkly pigmented materials (ie the clot) occurred inside the 1-mm materials (ie the clot) occurred inside the 1-mm catheter tipcatheter tip
the system was designed to minimize scattering the system was designed to minimize scattering of laser light of laser light
Absorption converted photo energy to acoustic Absorption converted photo energy to acoustic energy which then emulsified the clot inside the energy which then emulsified the clot inside the catheter tip catheter tip
EKOS ultrasound( the EKOS ultrasound( the Ultrasound Thrombolytic Ultrasound Thrombolytic
Infusion Catheter) Infusion Catheter) combines the use of a distal ultrasound transducer with combines the use of a distal ultrasound transducer with
infusion of a thrombolytic agent through the infusion of a thrombolytic agent through the microcathetermicrocatheter
Ultrasound changes the structure of the clot to Ultrasound changes the structure of the clot to temporarily increase its permeability while providing an temporarily increase its permeability while providing an acoustic pressure gradient to move the drug into the clot acoustic pressure gradient to move the drug into the clot to speed its dissolution to speed its dissolution
The EKOS catheter is placed in the proximal portion of the The EKOS catheter is placed in the proximal portion of the clot clot
After a 2-mg bolus of tPA was injected through the After a 2-mg bolus of tPA was injected through the catheter catheter
the patient received a continuous infusion of IA tPA 03 the patient received a continuous infusion of IA tPA 03 mgmin to a maximum of 20 mg and simultaneous mgmin to a maximum of 20 mg and simultaneous ultrasound transmission for as long as 60 minutes ultrasound transmission for as long as 60 minutes
One patient was treated with a total of 4 units of One patient was treated with a total of 4 units of recombinant reteplase (Retavase) hand-injected over 60 recombinant reteplase (Retavase) hand-injected over 60 minutes minutes
Penumbra system Penumbra system The Penumbra system (Penumbra Inc) provides a dual The Penumbra system (Penumbra Inc) provides a dual
approach to clot extraction using aspiration followed by approach to clot extraction using aspiration followed by clot retrieval with a ring device if needed clot retrieval with a ring device if needed
Mechanical Embolus Removal in Cerebral Ischemia Mechanical Embolus Removal in Cerebral Ischemia (MERCI)(MERCI)
a corkscrew-like apparatus to remove blood clots from a corkscrew-like apparatus to remove blood clots from the brain in patients experiencing an ischemic stroke the brain in patients experiencing an ischemic stroke
The corkscrew itself resides in the catheter tip which The corkscrew itself resides in the catheter tip which shields it from the wall of the vessel until it is ready to be shields it from the wall of the vessel until it is ready to be burrowed into the clot Once lodged in the clot the device burrowed into the clot Once lodged in the clot the device and clot are withdrawn from the vessel and clot are withdrawn from the vessel
Snarelike devicesSnarelike devices Snares such as the Neuronet snare (Guidant Snares such as the Neuronet snare (Guidant
Endovascular Santa Clara CA) have been developed Endovascular Santa Clara CA) have been developed specifically for use in the treatment of strokes specifically for use in the treatment of strokes
These devices are simple in design and do not require the These devices are simple in design and do not require the clot to be amenable to emulsification clot to be amenable to emulsification
X-Sizer deviceX-Sizer device a device with small moving blades at the a device with small moving blades at the
catheter tip catheter tip This device the X-Sizer device (EndiCor Medical This device the X-Sizer device (EndiCor Medical
San Clemente CA) can be used to excise the San Clemente CA) can be used to excise the thrombus and aspirate it thrombus and aspirate it
The device was being evaluated in randomized The device was being evaluated in randomized studies of coronary vessels and in a registry of studies of coronary vessels and in a registry of patients with acute myocardial infarctionpatients with acute myocardial infarction
Although the manufacturer had modified the Although the manufacturer had modified the device for use in cerebral vessels a safety and device for use in cerebral vessels a safety and feasibility study was indefinitely suspended after feasibility study was indefinitely suspended after only 1 patient was treated with the device in only 1 patient was treated with the device in Europe Europe
Suction thrombectomySuction thrombectomy This method of mechanical thrombolysis is one of the This method of mechanical thrombolysis is one of the
simplestsimplest In this readily available technique suction is applied with In this readily available technique suction is applied with
a syringe to remove thrombus in the ICA a syringe to remove thrombus in the ICA It requires no other devicesIt requires no other devices A catheter with a large inner diameter (Brite Tip Cordis A catheter with a large inner diameter (Brite Tip Cordis
Corporation Miami FL) was placed in the symptomatic Corporation Miami FL) was placed in the symptomatic vessel and navigated over a guidewire into the thrombusvessel and navigated over a guidewire into the thrombus
A 60-mL syringe was used to aspirate the thrombus A 60-mL syringe was used to aspirate the thrombus Each patient required angioplasty and stenting of carotid Each patient required angioplasty and stenting of carotid
bifurcation stenosis and received daily aspirin and bifurcation stenosis and received daily aspirin and ticlopidine after the procedure No complications ticlopidine after the procedure No complications occurred occurred
Summary Acute Stroke Summary Acute Stroke ImagingImaging
PhysiologyPhysiology importance collaterals importance collaterals
ndash ndashGrowing role for perfusion Growing role for perfusion assessmentassessment
tPAtPA guidelines amp limitations guidelines amp limitations Signs on CT amp MRSigns on CT amp MR follow physiology follow physiology Stroke trialsStroke trials PWI-DWI mismatch PWI-DWI mismatch
ndash ndashTreat based on physiology not timeTreat based on physiology not time ProtocolsProtocols should be fast and should be fast and
comprehensivecomprehensive
Second-Generation Agents Second-Generation Agents Alteplase (rtPA) Alteplase (rtPA)
is a serine is a serine protease with a plasma half-life of 35 protease with a plasma half-life of 35 minutes and a high degree of fibrin affinity and minutes and a high degree of fibrin affinity and specificity specificity
Dose used in cerebral IAT has ranged between 20 Dose used in cerebral IAT has ranged between 20 and 60 mgand 60 mg
Disadvantages of alteplase include its relatively short Disadvantages of alteplase include its relatively short halflife and limited penetration into the clot matrix halflife and limited penetration into the clot matrix because of strong binding with surface fibrin which because of strong binding with surface fibrin which could delay recanalization and increase the risk of could delay recanalization and increase the risk of recurrent occlusion recurrent occlusion
Prourokinase (r-prourokinase) Prourokinase (r-prourokinase) is the proenzyme precursor of urokinase is the proenzyme precursor of urokinase T12 of 7 minutes and high fibrin specificity T12 of 7 minutes and high fibrin specificity
Third-Generation AgentsThird-Generation Agents
ReteplaseReteplase is a structurally modified is a structurally modified form of alteplase form of alteplase
with a longer half-life (15ndash18 minutes) In with a longer half-life (15ndash18 minutes) In addition it does not bind as highly to fibrin addition it does not bind as highly to fibrin unbound reteplase can thus theoretically better unbound reteplase can thus theoretically better penetrate the clot and potentially penetrate the clot and potentially improve in improve in vivo fibrinolytic activity vivo fibrinolytic activity
TenecteplaseTenecteplase is another modified form of rtPA with a longer is another modified form of rtPA with a longer
half-life (17 minutes)half-life (17 minutes) greater fibrin specificity and greater greater fibrin specificity and greater
resistance to plasminogen activator inhibitor-1 resistance to plasminogen activator inhibitor-1 IV tenecteplase in acute ischemic stroke IV tenecteplase in acute ischemic stroke
suggest that the drug is safe and promisingsuggest that the drug is safe and promising
Newer plasminogen activatorNewer plasminogen activator
DesmoteplaseDesmoteplase is a genetically engineered is a genetically engineered version of the clot-dissolving factor version of the clot-dissolving factor
found in the saliva found in the saliva of the vampire bat Desmodus rotundusof the vampire bat Desmodus rotundus moremore potent and more selective for fibrin-bound potent and more selective for fibrin-bound
plasminogen than any other known plasminogen plasminogen than any other known plasminogen activatoractivator
Unlike tissue plasminogen activator (tPA) desmoteplase Unlike tissue plasminogen activator (tPA) desmoteplase is not activated by fibrinogen or -amyloid proteins is not activated by fibrinogen or -amyloid proteins factors that may exacerbate the risk for ICH factors that may exacerbate the risk for ICH
The effect of IV administration of desmoteplase 3ndash9 The effect of IV administration of desmoteplase 3ndash9 hours after symptom onset in patients with stroke who hours after symptom onset in patients with stroke who present with mismatch on MR imaging or CT perfusion present with mismatch on MR imaging or CT perfusion
3 DefibrinogenatingFibrinogenolytic 3 DefibrinogenatingFibrinogenolytic Agents Agents
AncrodAncrod(Viprinex)(Viprinex) is is the purified fraction of the Malayan pit viper venomthe purified fraction of the Malayan pit viper venom It acts by directly cleaving and inactivating fibrinogen It acts by directly cleaving and inactivating fibrinogen
and thus indirectly promoting anticoagulation and thus indirectly promoting anticoagulation The reduction in the blood levels of fibrinogen also The reduction in the blood levels of fibrinogen also
leads to a reduced blood viscosity which may improve leads to a reduced blood viscosity which may improve blood flow to the affected areas of the brain blood flow to the affected areas of the brain
In the Stroke Treatment with Ancrod Trial 500 In the Stroke Treatment with Ancrod Trial 500 patients with stroke presenting within 3 hours of patients with stroke presenting within 3 hours of symptom onset were randomized to receive ancrod (symptom onset were randomized to receive ancrod (n n 248) or a placebo (n 252) Good outcome (Barthel 248) or a placebo (n 252) Good outcome (Barthel Index 95ndash100 at 3 months) was achieved in 4221 Index 95ndash100 at 3 months) was achieved in 4221 and 344 of the patients respectively and 344 of the patients respectively
2 Direct Fibrinolytics2 Direct Fibrinolytics
Microplasmin (Microplasmin (ThromboGenics Heverlee Belgium)ThromboGenics Heverlee Belgium) is a truncated form of plasmin that is more resistant to the effects is a truncated form of plasmin that is more resistant to the effects
of antiplasmin of antiplasmin microplasmin can be used upto 4ndash12 hours after stroke onset microplasmin can be used upto 4ndash12 hours after stroke onset There was no evidence of increased bleeding risk with There was no evidence of increased bleeding risk with
microplasminmicroplasmin
Alfimeprase (Nuvelo San Carlos Calif)Alfimeprase (Nuvelo San Carlos Calif) is a recombinant truncated form of fibrolase a fibrinolytic zinc metalloproteinase is a recombinant truncated form of fibrolase a fibrinolytic zinc metalloproteinase
isolated from the venom of the southern copperhead snake isolated from the venom of the southern copperhead snake It degrades fibrin directly and achieves thrombolysis independent It degrades fibrin directly and achieves thrombolysis independent
of plasmin formationof plasmin formation its thrombolytic activity appears to be localized to the site of its thrombolytic activity appears to be localized to the site of
delivery These properties should theoretically result in faster delivery These properties should theoretically result in faster recanalization and lower hemorrhagic conversion riskrecanalization and lower hemorrhagic conversion risk
Anti-fibrinolyticsAnti-fibrinolytics
to limit fibrinolytic activityto limit fibrinolytic activity -aminocaproic acid (EACA) -aminocaproic acid (EACA) competitively inhibitscompetitively inhibits plasminogen and plasminogen activators from plasminogen and plasminogen activators from
binding to fibrinbinding to fibrin
alpha2-antiplasminalpha2-antiplasmin a serine protease inhibitor that a serine protease inhibitor that neutralizes any free circulating plasminneutralizes any free circulating plasmin
Plasminogen activator inhibitor-1Plasminogen activator inhibitor-1 a serine protease a serine protease inhibitor that inhibits tissue-type plasminogen inhibitor that inhibits tissue-type plasminogen activatoractivator
Glycoprotein (GP) IIbIIIa antagonistsGlycoprotein (GP) IIbIIIa antagonists
such as ReoPro (abciximab) Integrilin such as ReoPro (abciximab) Integrilin (eptifibatide) or Aggrastat (tirofiban) in (eptifibatide) or Aggrastat (tirofiban) in ischemic stroke remains investigational ischemic stroke remains investigational Deshmukh et al38 reported 21 patients with Deshmukh et al38 reported 21 patients with large-vessel occlusion refractory to IAT with large-vessel occlusion refractory to IAT with rtPA who were treated with IV andor IA rtPA who were treated with IV andor IA abciximab eptifibatide or tirofiban abciximab eptifibatide or tirofiban
IA Mechanical Approaches in Acute Ischemic Stroke IA Mechanical Approaches in Acute Ischemic Stroke Mechanical strategies have several advantagesMechanical strategies have several advantages First they lessen and may even preclude the use of chemical First they lessen and may even preclude the use of chemical
thrombolytics in this manner very likely reducing the risk of ICHthrombolytics in this manner very likely reducing the risk of ICH Second by avoiding the use of chemical thrombolytics it is Second by avoiding the use of chemical thrombolytics it is
possible to extend the treatment window beyond the limit of 6ndash8 possible to extend the treatment window beyond the limit of 6ndash8 hours hours
Third mechanically fragmenting a clot increases the surface area Third mechanically fragmenting a clot increases the surface area accessible to fibrinolytic agents and allows inflow of fresh accessible to fibrinolytic agents and allows inflow of fresh plasminogen which in turn may increase the speed of plasminogen which in turn may increase the speed of thrombolysis thrombolysis
Finally clot-retrieval devices may provide faster recanalization Finally clot-retrieval devices may provide faster recanalization
The disadvantages of the mechanical The disadvantages of the mechanical approaches approaches technical difficulty of navigating mechanical technical difficulty of navigating mechanical
devices into the intracranial circulation excessive devices into the intracranial circulation excessive trauma to the vasculature (potentially leading to trauma to the vasculature (potentially leading to vasospasm vessel dissection perforation or vasospasm vessel dissection perforation or rupture) rupture)
fragmented thrombus causing distal embolization fragmented thrombus causing distal embolization into previously unaffected territories into previously unaffected territories
Nevertheless the advantages of mechanical stroke Nevertheless the advantages of mechanical stroke therapy appear to significantly outweigh its therapy appear to significantly outweigh its disadvantages and risksdisadvantages and risks
Contraindications to Thrombolytic Contraindications to Thrombolytic agents agents
Recent thoracic abdominal or Recent thoracic abdominal or intracranial surgeryintracranial surgery
Recent haemorrhagic CVA Head injury Recent haemorrhagic CVA Head injury or neoplasmor neoplasm
Bleeding ulcerBleeding ulcer Anticipated invasive procedures (arterial Anticipated invasive procedures (arterial
punctures biopsies)punctures biopsies) Concurrent hemostatic dysfunctionConcurrent hemostatic dysfunction
Monitoring of thrombolytic Monitoring of thrombolytic therapytherapy
Thrombin time Measures the availability of functional
fibrinogen Normal thrombin time is 10-14 sec Prolonged when fibrinogen level is below
75-100 mgdl
Half Life of ThrombolyticsHalf Life of ThrombolyticsAgent Administration Half Life
Streptokinase IA 60-80min
Urokinase IAIV 9-12min
rTPA IAIV 6min
Abciximab(Reopro) IAIV 12hour
Aspirin POIV 15-20min
Heparin IVSC 60min
Coumadin PO 15-25 days
Anti Platelet DrugsAnti Platelet DrugsDrug Drug Mechanism Mechanism UsesUsesAspirinAspirin Permanently inhibits Permanently inhibits
COX-1 and COX-2COX-1 and COX-2CADCAD
Stroke-TIAsStroke-TIAs
NSAIDsNSAIDs Reversibly inhibits Reversibly inhibits COX-1COX-1
LimitedLimited
DipyridamoleDipyridamole Inhibits PDE increases Inhibits PDE increases cAMPcAMP
TIAsTIAs
ThenopyridinesThenopyridines
(Ticlopidine(Ticlopidine
ClopidrgrelClopidrgrel))
Inhibits ADP Inhibits ADP
PlatAg PlatAg
TIAsStrokeTIAsStroke
CAD PVDCAD PVD
Abciximab (ReoPro)Abciximab (ReoPro)
Eptifibatide (Integrilin)Eptifibatide (Integrilin)
TirofibanTirofiban
GP IIBIIIA InhibitorsGP IIBIIIA Inhibitors
Stroke- TIAs Stroke- TIAs
MonitoringMonitoring
Bleeding timeBleeding time
Optical aggregometryOptical aggregometry
Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay
Bleeding timeBleeding time
Requires a skin incision (usually made on the ear lobe or Requires a skin incision (usually made on the ear lobe or forearm offorearm of
a depth that results in disruption of capillary loops and a depth that results in disruption of capillary loops and small vessels)small vessels)
AdvantagesAdvantages Universally availableUniversally available Relatively simple techniquesRelatively simple techniques Can be performed bedsideCan be performed bedside
DisadvantagesDisadvantages Insensitive inaccurate non-specific techniqueInsensitive inaccurate non-specific technique
Poorly reproducible (as depends on multiple variables)Poorly reproducible (as depends on multiple variables)
Optical aggregometryOptical aggregometry
Gold standard assay for platelet functionGold standard assay for platelet function Agonist induced aggregation is measuredAgonist induced aggregation is measured Different agonist are available for different Different agonist are available for different
agentsagents However require unique expertise and are not However require unique expertise and are not
universally availableuniversally available Aspirin measured with ADP or AA(gt70 Aspirin measured with ADP or AA(gt70
aggregation so resistance)aggregation so resistance) Clopidogrel( ADP gt 90 aggregation means Clopidogrel( ADP gt 90 aggregation means
resistance) resistance)
Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay
Can be performed bed sideCan be performed bed side Different assay devices with different Different assay devices with different
agonist are used for each of different agonist are used for each of different antiplatelet agents antiplatelet agents
For Aspirin AA is used (result is reported as aspirin For Aspirin AA is used (result is reported as aspirin reaction units [ARU] ARUgt 550 indicates non-reaction units [ARU] ARUgt 550 indicates non-responsiveness)responsiveness)
Verify IIbIIIa assay device uses TRAP as agonist for Verify IIbIIIa assay device uses TRAP as agonist for Abciximab and TirofibanAbciximab and Tirofiban
Practical Applications Practical Applications related to specific related to specific
Neurovascular Neurovascular interventionsinterventions
Acute ischemic StrokeAcute ischemic Stroke When an artery occludes neurons are affected When an artery occludes neurons are affected
differently depending upon the amount of residual blood differently depending upon the amount of residual blood flowflow
Normal cerebral blood flow is greater than 50 mL100 Normal cerebral blood flow is greater than 50 mL100 mgminmgmin
Once blood flow decreases to less than 20 mL100 Once blood flow decreases to less than 20 mL100 mgmin infarction occursmgmin infarction occurs
If blood flow decreases to less than 10 mL100 mgmin If blood flow decreases to less than 10 mL100 mgmin irreversible neuronal death occurs rapidly irreversible neuronal death occurs rapidly
Blood flow between 11 and 20 mL100 mgmin is thought Blood flow between 11 and 20 mL100 mgmin is thought to represent the ischemic penumbra an area where the to represent the ischemic penumbra an area where the cells are functionally silent because of ischemia but are cells are functionally silent because of ischemia but are still able to recover if blood flow is restored still able to recover if blood flow is restored
Many acute stroke therapies are targeted toward Many acute stroke therapies are targeted toward restoring flow or function to the ischemic penumbrarestoring flow or function to the ischemic penumbra
Therapeutic window in Therapeutic window in management of acute Ischemic management of acute Ischemic
StrokeStrokeThe early diagnosis of ischemic stroke is critical to the The early diagnosis of ischemic stroke is critical to the
with only a narrow therapeutic window in the first few with only a narrow therapeutic window in the first few hours following stroke ictushours following stroke ictus
Diagnosis in the first 3 hours postictus provides the Diagnosis in the first 3 hours postictus provides the opportunity for intravenous or intraarterial thrombolysis opportunity for intravenous or intraarterial thrombolysis and intra-arterial clot mechanical treatment which and intra-arterial clot mechanical treatment which improve the outcome improve the outcome
Diagnosis in the time period between 3 and 6 hours Diagnosis in the time period between 3 and 6 hours provides an opportunity for intra-arterial thrombolysis provides an opportunity for intra-arterial thrombolysis and mechanical treatment and mechanical treatment
Involvement of the posterior circulation especially the Involvement of the posterior circulation especially the basilar artery is treated by some regardless of time of basilar artery is treated by some regardless of time of onset or up until 12 to 24 hours in some practices This is onset or up until 12 to 24 hours in some practices This is related to the potentially high mortality and morbidity related to the potentially high mortality and morbidity associated with basilar artery thrombosisassociated with basilar artery thrombosis
Infarct evaluation on angiographyInfarct evaluation on angiography(CT angiography and catheter (CT angiography and catheter
angiography)angiography)CTA is an excellent first-line examination for CTA is an excellent first-line examination for
evaluation of the head and neck arteries evaluation of the head and neck arteries In comparison with catheter angiography In comparison with catheter angiography
what it gives up in resolution and dynamic what it gives up in resolution and dynamic properties it makes up for with rapid properties it makes up for with rapid acquisition of a 3-D dataset and the potential acquisition of a 3-D dataset and the potential for assessment of whole-brain perfusion and for assessment of whole-brain perfusion and better parenchymal evaluationbetter parenchymal evaluation
Moreover CTA illustrates not only arterial Moreover CTA illustrates not only arterial stenosis or occlusion but also the vessel wall stenosis or occlusion but also the vessel wall This factor is most important for evaluation of This factor is most important for evaluation of intramural dissection and thrombosed intramural dissection and thrombosed aneurysms which may both complicate aneurysms which may both complicate evaluation of stroke patientsevaluation of stroke patients
Early angiographic signs of strokes Early angiographic signs of strokes both CTA both CTA and DSA and DSA
Vessel occlusion or cutoff related to Vessel occlusion or cutoff related to thromboembolithromboemboli
aneurysms aneurysms arterial dissection arterial dissection Meniscus or flattened shape to clot Meniscus or flattened shape to clot
(recent) versus reverse meniscus (older)(recent) versus reverse meniscus (older) tram track (nonocclusive or recanalized tram track (nonocclusive or recanalized
clot) clot) delayed (antegrade) flow (manifest as delayed (antegrade) flow (manifest as
decreased whole-brain perfusion on CTA)decreased whole-brain perfusion on CTA) retrograde collateral flowretrograde collateral flow
Non-occlusive left MCA thrombus on 3-D imaging performed from CTA source data and was confirmed at catheter angiography
Therapy to be started within a 6-hr Therapy to be started within a 6-hr time to treatment (TTT) window time to treatment (TTT) window (while in case of IV thrombolysis (while in case of IV thrombolysis therapy to be started with in 3hrs)therapy to be started with in 3hrs)
Exclusion criteria Exclusion criteria Rapidly improving neurologic deficit or Rapidly improving neurologic deficit or Sustained blood pressure of gt180100 Sustained blood pressure of gt180100 Hemorrhage is detected on CTHemorrhage is detected on CT Infarct involving gt more than 13 rd Infarct involving gt more than 13 rd
territory of MCAterritory of MCA MRADWI-Perfusion mismatchlt 20MRADWI-Perfusion mismatchlt 20 Definite hypodensity on CTDefinite hypodensity on CT
Intra-arterial Thrombolysis
Fibrinolytics + AntiplateletsFibrinolytics + Antiplatelets
PlasminogenPlasminogen activators through fibrinolysis exposes activators through fibrinolysis exposes free thrombin and paradoxically stimulatesfree thrombin and paradoxically stimulates platelet platelet aggregation which leads to formation of aaggregation which leads to formation of a platelet platelet thrombus (white clot) thrombus (white clot)
This new thrombus is relatively resistant to This new thrombus is relatively resistant to fibrinolyticsfibrinolytics
So new regimen in case of acute stroke isSo new regimen in case of acute stroke is fibrinolytics + antiplatelet drugsfibrinolytics + antiplatelet drugs
rtPA + IIbIIIa inhibitors( tirofiban rtPA + IIbIIIa inhibitors( tirofiban abciximab) orabciximab) or
Urokinase + IIbIIIa Urokinase + IIbIIIa inhibitors( tirofiban abciximab)inhibitors( tirofiban abciximab)
Intra-arterial Thrombolysis Tirofiban (04 microgkgmin bolus for 3 min followed by Tirofiban (04 microgkgmin bolus for 3 min followed by
0125 ugkgmin)0125 ugkgmin)
++
Heparin (2000ndash3000 IU bolus followed by Heparin (2000ndash3000 IU bolus followed by 1000 IUhour infusion 1000 IUhour infusion
with ACT maintained bw 200-300) throughout the with ACT maintained bw 200-300) throughout the interventional procedure and for 24ndash48 hours thereafter when interventional procedure and for 24ndash48 hours thereafter when there is neither intraprocedural bleeding nor suspicion of there is neither intraprocedural bleeding nor suspicion of increased risk of bleeding increased risk of bleeding
Maximum dose of Urokinase Maximum dose of Urokinase Anterior circulation stroke - 500000 IU (mean 400000 Anterior circulation stroke - 500000 IU (mean 400000
IU range 300000ndash500000 IU)IU range 300000ndash500000 IU) Posterior circulation stroke -1000000 IU (mean 837000 Posterior circulation stroke -1000000 IU (mean 837000
IU range 300000ndash1000000 IU)IU range 300000ndash1000000 IU)American Journal of NeuroradiologyAmerican Journal of Neuroradiology 262595-2601 2005262595-2601 2005
Intravenous ThrombolysisIntravenous Thrombolysis
The first method to restore cerebral The first method to restore cerebral perfusion is clot lysis with the goal perfusion is clot lysis with the goal of re-establishing blood flow to the of re-establishing blood flow to the affected tissue affected tissue
IV thrombolysis rt-PA is the only IV thrombolysis rt-PA is the only FDA- approved treatment for AIS FDA- approved treatment for AIS
Fibrinolysis is enhanced powerfully Fibrinolysis is enhanced powerfully by rt-PAby rt-PA
Intravenous rTPA Intravenous rTPA administration administration protocolprotocol
Total dose of rt-PA 09 mgkg (maximum dose Total dose of rt-PA 09 mgkg (maximum dose 90 mg)90 mg)
Give 10 as initial IV bolusGive 10 as initial IV bolus Infuse remainder over 1 hourInfuse remainder over 1 hour Admit patient to an ICU or stroke unit for Admit patient to an ICU or stroke unit for
monitoringmonitoring Neurologic assessments every 15 minutes Neurologic assessments every 15 minutes
during infusion then every 30 minutes for next during infusion then every 30 minutes for next 6 hours then every hour until 24hours after 6 hours then every hour until 24hours after treatmenttreatment
Favorable Outcome vs Treatment Time Favorable Outcome vs Treatment Time with IV rTPAwith IV rTPA
Protocol limit = 3 hrs
Benefit ~ 45 hrs
Thromboembolism During coilingThromboembolism During coiling Most feared and frequent complication Most feared and frequent complication Reported incidence - Approx 7 Reported incidence - Approx 7 SourcesSources of Thromboembolism are of Thromboembolism are
- Clots at the aneurysmal neck during or immediately- Clots at the aneurysmal neck during or immediately after after embolization embolization
- Thrombus forming on catheters during- Thrombus forming on catheters during proceduresprocedures
- Stenosis of an adjacent artery dt coil mass- Stenosis of an adjacent artery dt coil mass or herniationor herniation
- Migration of intraaneurysmal- Migration of intraaneurysmal thrombus during coil thrombus during coil placement placement
- Slow flow dt vasospasm - Slow flow dt vasospasm
- Rare and unlikely causes are hypercoagulable- Rare and unlikely causes are hypercoagulable state such state such as antiphospholipid antibody syndrome or due to HITas antiphospholipid antibody syndrome or due to HIT
Occur more often with wide-necked aneurysms (dt Occur more often with wide-necked aneurysms (dt increased exposed surface area of thrombogenic coil increased exposed surface area of thrombogenic coil material)material)
Current regimen of endovascular Current regimen of endovascular managementmanagement
The The glycoprotein IIbIIIa antagonist tirofiban glycoprotein IIbIIIa antagonist tirofiban (04 (04 microgkgmin bolus for 30 minutes followed by infusion of microgkgmin bolus for 30 minutes followed by infusion of 0125 ugkgmin until the thrombus dissolved) 0125 ugkgmin until the thrombus dissolved)
Intraarterial thrombolysis with Intraarterial thrombolysis with urokinase or r- TPA urokinase or r- TPA increase of intravenous (IV) heparin (measured by increase of intravenous (IV) heparin (measured by
ACT) ACT) Intravenous aspirin Intravenous aspirin
Coil-related platelet aggregation (white clot) is Coil-related platelet aggregation (white clot) is unlikely to respond to fibrinolytics but has a high risk unlikely to respond to fibrinolytics but has a high risk of hemorrhage (In ISAT) all 5 patients who had of hemorrhage (In ISAT) all 5 patients who had received thrombolytic therapy with tPA to treat a received thrombolytic therapy with tPA to treat a thromboembolic complication after endovascular thromboembolic complication after endovascular treatment rebleed and all of these patients died)treatment rebleed and all of these patients died)
IntracranialIntracranial Stenting Stenting Metallic foreign body such as stent will accumulate Metallic foreign body such as stent will accumulate
thrombus in the absence of platelet inhibitionthrombus in the absence of platelet inhibition Antiplatelet drugs are important to prevent peri or Antiplatelet drugs are important to prevent peri or
post-interventional thromboembolic eventspost-interventional thromboembolic events Optimal treatment regimens has not been determined Optimal treatment regimens has not been determined
but usually but usually Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-
procedureprocedureOrOr
Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on
morning of proceduremorning of procedure
If need to use stent is not pre-planned thanIf need to use stent is not pre-planned than
Abciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkgAbciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkg IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)
Glycoprotein IIbIIIa inhibitor are not used routinely during elective Glycoprotein IIbIIIa inhibitor are not used routinely during elective stenting procedure dt increased risk of ICH stenting procedure dt increased risk of ICH
Carotid StentingCarotid Stenting
Pre-procedurePre-procedure
Double Antiplatelet therapy is routinely given Double Antiplatelet therapy is routinely given beginning at least 3beginning at least 3
days before the proceduredays before the procedure
Aspirin 325mgd+Clopidogrel 75mgdAspirin 325mgd+Clopidogrel 75mgd During procedureDuring procedure
Heparin is given with target clotting time of 250-Heparin is given with target clotting time of 250-300sec300sec
Post-procedure Post-procedure
Aspirin 325mg is continued indefinitely and Aspirin 325mg is continued indefinitely and
Clopidogrel 75mgd for at least 6 weeks Clopidogrel 75mgd for at least 6 weeks
Inclusion criteria for Local ThrombolysisInclusion criteria for Local Thrombolysis a)a) Patients in severe clinical grade on admission Patients in severe clinical grade on admission
with evidence of dural venous sinus with evidence of dural venous sinus thrombosis and restrictive venous outflow on thrombosis and restrictive venous outflow on cerebral angiogramcerebral angiogram
b)b) Patients in clinical grade 3 worsening on Patients in clinical grade 3 worsening on heparin therapy Restriction to venous heparin therapy Restriction to venous outflow was defined as an increase in brain outflow was defined as an increase in brain circulation time gt 12 s delay in the drainage circulation time gt 12 s delay in the drainage of cortical veins with cortical veins hanging of cortical veins with cortical veins hanging in spacein space
Treatment Options for Venous Thrombosis
CT Grading for Venous ThrombosisCT Grading for Venous Thrombosis Grade I no parenchymal change Grade I no parenchymal change
(hyperdense (hyperdense sinuses cortical veins empty sinuses cortical veins empty delta sign)delta sign)
Grade II non hemorrhagic venous infarct Grade II non hemorrhagic venous infarct without mass effect without mass effect
Grade III non-hemorrhagic infarct with Grade III non-hemorrhagic infarct with mass effectmass effect
Grade IV hemorrhagic venous infarct (max Grade IV hemorrhagic venous infarct (max diameter lt 3 cm) with no mass effectdiameter lt 3 cm) with no mass effect
Grade V hemorrhagic venous infarct (max Grade V hemorrhagic venous infarct (max diameter gt 3 cm) with mass effect diameter gt 3 cm) with mass effect
Local ThrombolysisLocal Thrombolysis
Femoral Jugular access was secured and a guiding Femoral Jugular access was secured and a guiding catheter was placed in the jugular bulb catheter was placed in the jugular bulb Mechanical Mechanical clot maceration clot maceration was done with the guidewire was done with the guidewire following which a microcatheter (was navigated and following which a microcatheter (was navigated and placed in the thrombosed segment of sinus confirmed placed in the thrombosed segment of sinus confirmed on a selective venogram on a selective venogram
Urokinase infusion Bolus dose of 2-6 lacs followed Urokinase infusion Bolus dose of 2-6 lacs followed by 60000 to 100000 units per hour along with by 60000 to 100000 units per hour along with periodic check venogram Along with maintenance periodic check venogram Along with maintenance systemic infusion of Heparinsystemic infusion of Heparin Other agents such as Other agents such as streptokinase altepase or rTPAstreptokinase altepase or rTPA can be also used can be also used
After thrombolysis patient should subjected to oral After thrombolysis patient should subjected to oral anticoagulation for six monthsanticoagulation for six months
Low-molecular-weight Low-molecular-weight heparinheparin
PharmacologyPharmacologyLMWH as its name suggests is a glycosaminoglycan that is approximatelyLMWH as its name suggests is a glycosaminoglycan that is approximately
one third the molecular weight of UFH It is derived from UFH through one third the molecular weight of UFH It is derived from UFH through variousvarious
depolymerization processes LMWH binds to antithrombin which in turn depolymerization processes LMWH binds to antithrombin which in turn
Neutralizes actors Xa and IIa Because LMWH lacks many of the longer Neutralizes actors Xa and IIa Because LMWH lacks many of the longer chains chains
required for binding to thrombin it has less ability to neutralize thrombin required for binding to thrombin it has less ability to neutralize thrombin
relativeto its ability to neutralize factor Xa LMWH also has less relativeto its ability to neutralize factor Xa LMWH also has less nonspecific nonspecific
binding to other proteins There is greater bioavailability with more binding to other proteins There is greater bioavailability with more predictable predictable
pharmacokinetics that eliminates the need for monitoring The smaller pharmacokinetics that eliminates the need for monitoring The smaller size also size also
allows for enhanced subcutaneous absorption when compared with UFHallows for enhanced subcutaneous absorption when compared with UFH
Three LMWH preparations are Three LMWH preparations are currently approved for use in the currently approved for use in the United States (1) enoxaparin (2) United States (1) enoxaparin (2) dalteparin and (3) tinzaparin dalteparin and (3) tinzaparin
They are all administered They are all administered subcutaneously at intervals of either subcutaneously at intervals of either once or twice daily for both once or twice daily for both prophylaxis and treatment dosesprophylaxis and treatment doses
Few Experiences of Few Experiences of ThrombolysisThrombolysis
Vickey 25 Yrs male patient presented Vickey 25 Yrs male patient presented with 12with 12thth day HO severe headache with day HO severe headache with right sided hemiplegiaright sided hemiplegia
MRI shows thrombosis of the superior MRI shows thrombosis of the superior sagittal left transverse left sigmoid sagittal left transverse left sigmoid sinuses and cortical veins in the fronto-sinuses and cortical veins in the fronto-parietal regions with eo haemorrhagic parietal regions with eo haemorrhagic infarct in the left cerebral hemisphere infarct in the left cerebral hemisphere with mass effect( Grade ndashV)with mass effect( Grade ndashV)
Sashi Srivastava 64 yrs FSashi Srivastava 64 yrs F In a follow up case of MRD with infra-renal In a follow up case of MRD with infra-renal
aortic abdominal and bilateral renal artery aortic abdominal and bilateral renal artery thrombosis renal angiogram shows filling thrombosis renal angiogram shows filling defects in the right Renal artery defects in the right Renal artery
Initially Renal angioplasty was done Initially Renal angioplasty was done Following angioplasty few thrombi are seem Following angioplasty few thrombi are seem to extends into the segmental branches and to extends into the segmental branches and causing blockage So Thrombolysis was causing blockage So Thrombolysis was plane to dissolve the run-out thrombi with plane to dissolve the run-out thrombi with urokinase urokinase
Rakesh 34yrsMRakesh 34yrsM Left SFA pseudoaneurysm with Left SFA pseudoaneurysm with
Covered stent placementCovered stent placement Pre operative antiplatelets with post Pre operative antiplatelets with post
procedure heparin Tirofiban procedure heparin Tirofiban followed by aspirin and clopidogrel followed by aspirin and clopidogrel were usedwere used
IAT may be a treatment option for selected patients IAT may be a treatment option for selected patients Possible selection criteria include Possible selection criteria include
presentation between 3 and 6 hours from symptom onsetpresentation between 3 and 6 hours from symptom onset major cerebral artery occlusion major cerebral artery occlusion severe neurologic deficits severe neurologic deficits high risk of systemic hemorrhage with IV rt-PA (eg recent high risk of systemic hemorrhage with IV rt-PA (eg recent
surgery) surgery) The MERCI (Mechanical Embolus Removal in Cerebral The MERCI (Mechanical Embolus Removal in Cerebral
Ischemia) retrievalIschemia) retrieval system system
Has been FDA-approved for recanalizing acutely occluded Has been FDA-approved for recanalizing acutely occluded cerebral arteries cerebral arteries
In the Multi-MERCI study patients who did not improve In the Multi-MERCI study patients who did not improve immediately after IV rt-PA underwent mechanical immediately after IV rt-PA underwent mechanical embolectomy within 8 hours of symptom onset embolectomy within 8 hours of symptom onset
Partial or complete recanalization occurred in 74 of Partial or complete recanalization occurred in 74 of patientspatients
with a symptomatic intracerebral hemorrhage (sICH) rate of with a symptomatic intracerebral hemorrhage (sICH) rate of 67 67
Mechanical embolectomy with the MERCI retriever may be a Mechanical embolectomy with the MERCI retriever may be a feasible and safe option for patients after IV rt-PAfeasible and safe option for patients after IV rt-PA
Penumbra stroke systemPenumbra stroke system This device combines two methods of clot This device combines two methods of clot
extraction aspiration and mechanical extraction aspiration and mechanical extraction extraction
First the clot is aspirated then a thrombus First the clot is aspirated then a thrombus removal ring can be used if necessary to removal ring can be used if necessary to remove remaining clot remove remaining clot
successful recanalizing 82successful recanalizing 82 Bridging therapyBridging therapy
06 mgkg IV rt-PA followed by IAT with IA rt-06 mgkg IV rt-PA followed by IAT with IA rt-PA (up to 20 mg)PA (up to 20 mg)
achieved a higher recanalization rateachieved a higher recanalization rate
Criteria for thrombolysis with rTPACriteria for thrombolysis with rTPA
Inclusion criteriaInclusion criteria Clinical signs and symptoms consistent with ischemic Clinical signs and symptoms consistent with ischemic
strokestroke Patient last seen normal within 3 hoursPatient last seen normal within 3 hours Measurable neurologic deficitMeasurable neurologic deficit
Exclusion criteriaExclusion criteria Any hemorrhage on neuroimaging (CT or MRI)Any hemorrhage on neuroimaging (CT or MRI) Symptoms suggestive of subarachnoid hemorrhageSymptoms suggestive of subarachnoid hemorrhage Seizure at stroke onset that is thought to contribute to Seizure at stroke onset that is thought to contribute to
neurologic deficitneurologic deficit Hypodensity greater than one third cerebral hemisphere Hypodensity greater than one third cerebral hemisphere
on CTon CT SBP greater than 185 mm Hg or DBP greater than 110 SBP greater than 185 mm Hg or DBP greater than 110
mm Hgmm Hg International normalized ratio (INR) greater than 17International normalized ratio (INR) greater than 17
Ischemic Stroke Ischemic Stroke Treatment ndash 2006Treatment ndash 2006
IV tissue plasminogen activator (tPA)IV tissue plasminogen activator (tPA) ndash ndash Only FDA-approved acute stroke drugOnly FDA-approved acute stroke drug ndash ndash 3 hour treatment window3 hour treatment window
MERCI - Concentric clot retrieval MERCI - Concentric clot retrieval devicedevice ndash ndash Rescue therapy - approved 2004Rescue therapy - approved 2004 ndash ndash Device approval (not outcomes-based)Device approval (not outcomes-based)
Off label approachesOff label approaches ndash ndash IV tPA after 3 hoursIV tPA after 3 hours ndash ndash IV-IA tPA sequential strategiesIV-IA tPA sequential strategies ndash ndash IA tPA clot angioplasty fragmentationIA tPA clot angioplasty fragmentation ndash ndash Ultrasound-assisted tPA lysisUltrasound-assisted tPA lysis
rt-PA Trials NINDSrt-PA Trials NINDS
Acute stroke - 624 patientsAcute stroke - 624 patients Treat within 3 hrsTreat within 3 hrs Intravenous 09 mgkg rt-PA vs placeboIntravenous 09 mgkg rt-PA vs placebo Hemorrhage 64 tPA 06 placeboHemorrhage 64 tPA 06 placebo Neurologic recovery better with tPA 30 Neurologic recovery better with tPA 30
more like to have minimal or no disabilitymore like to have minimal or no disability
First proven approved treatment for First proven approved treatment for strokestroke
Limitations of tPALimitations of tPA Only 4 of acute strokes receive tPAOnly 4 of acute strokes receive tPA (Kleindorfer et al Stroke 2004 35 e27-e29)(Kleindorfer et al Stroke 2004 35 e27-e29)
Only 22 of patients present within 3 hoursOnly 22 of patients present within 3 hours1048707 1048707 51 of these ineligible due to51 of these ineligible due to
bull bull Mild severityMild severity bull bull Medical or surgical historyMedical or surgical history bull bull Blood testsBlood tests
Sustained recanalization only 13Sustained recanalization only 13 (Alexandrov et al NEJM 2004 351 2170-8)(Alexandrov et al NEJM 2004 351 2170-8)
Concern for hemorrhageConcern for hemorrhage tPA potentiates apoptotic injury tPA potentiates apoptotic injury (Liu et al Nature Med 2004 101379-83)(Liu et al Nature Med 2004 101379-83)
PROACT II IA Lysis TrialPROACT II IA Lysis Trial Baseline 24 hours 8 days
Baseline 60 minutes 120 minutes
9mg IAProurokinase
Desmoteplase Trials DEDAS Desmoteplase Trials DEDAS DIASDIAS
Trial OverviewTrial Overview Double blind randomized placebo Double blind randomized placebo
controlled trialscontrolled trials IV delivery 3-9 hour time windowIV delivery 3-9 hour time window Plasminogen activator ndash from Plasminogen activator ndash from vampire bat vampire bat
salivasaliva Selection based on PWI-DWI MismatchSelection based on PWI-DWI Mismatch
MRI InclusionMRI Inclusion PWI defect at least 2 cm AND ~20 larger PWI defect at least 2 cm AND ~20 larger
than DWIthan DWI PWI should be obvious even visible on PWI should be obvious even visible on
raw imagesraw imagesMRI ExclusionMRI Exclusion
DWI gt 13 MCADWI gt 13 MCA MRA ICA occlusionMRA ICA occlusion
Desmoteplase ndash DIAS Desmoteplase ndash DIAS ResultsResults
Mechanical Thrombolysis Mechanical Thrombolysis devicesdevices
mechanical thrombolysis potentially extends the treatment mechanical thrombolysis potentially extends the treatment window because they act promptly at the site of the thrombuswindow because they act promptly at the site of the thrombus
The devices can retrieve large clots that pharmaceutical agents The devices can retrieve large clots that pharmaceutical agents may not successfully lysemay not successfully lyse
Patients treated with IV tPA may be considered for treatment of Patients treated with IV tPA may be considered for treatment of residual clot with some of these devicesresidual clot with some of these devices
suction-creating saline jets suction-creating saline jets laser energy ultrasound laser energy ultrasound a corkscrew apparatus to treat strokesa corkscrew apparatus to treat strokes The AngioJet systemThe AngioJet system uses saline jets that are directed back into the catheter to uses saline jets that are directed back into the catheter to
create a low-pressure zone around the catheter tip inducing create a low-pressure zone around the catheter tip inducing suction suction
The clot is pulled into the exhaust lumen and removed from the The clot is pulled into the exhaust lumen and removed from the vessel Although US Food and Drug Administration (FDA) has vessel Although US Food and Drug Administration (FDA) has approved this device for use in arteriovenous dialysis grafts and approved this device for use in arteriovenous dialysis grafts and fistulae and for the treatment of coronary arteries saphenous fistulae and for the treatment of coronary arteries saphenous vein grafts and peripheral vessels clinical trials for the vein grafts and peripheral vessels clinical trials for the treatment of acute stroke are no longer in progress treatment of acute stroke are no longer in progress
Most devices are used in cerebral vessels that 2-5 mm
The Latis laser device The Latis laser device used laser energy to ablate clots used laser energy to ablate clots Arteries 2-5 mm in diameter could be Arteries 2-5 mm in diameter could be
treated including the ICA M1 or M2 treated including the ICA M1 or M2 branch of the MCA A1 branch of the branch of the MCA A1 branch of the anterior cerebral artery (ACA) basilar anterior cerebral artery (ACA) basilar artery posterior cerebral artery (PCA) artery posterior cerebral artery (PCA) and vertebral and vertebral
Patients could receive treatment as late Patients could receive treatment as late as 8 hours after symptom onset in the as 8 hours after symptom onset in the anterior circulation and within 24 hours in anterior circulation and within 24 hours in the posterior circulation the posterior circulation
Endovascular Photo Acoustic Endovascular Photo Acoustic Recanalization (EPAR) Recanalization (EPAR)
A laser power source generated energy for the A laser power source generated energy for the systemsystem
The energy was delivered by means of The energy was delivered by means of fiberoptics to the tip of the catheter at the fiberoptics to the tip of the catheter at the treatment sitetreatment site
Absorption of laser light by darkly pigmented Absorption of laser light by darkly pigmented materials (ie the clot) occurred inside the 1-mm materials (ie the clot) occurred inside the 1-mm catheter tipcatheter tip
the system was designed to minimize scattering the system was designed to minimize scattering of laser light of laser light
Absorption converted photo energy to acoustic Absorption converted photo energy to acoustic energy which then emulsified the clot inside the energy which then emulsified the clot inside the catheter tip catheter tip
EKOS ultrasound( the EKOS ultrasound( the Ultrasound Thrombolytic Ultrasound Thrombolytic
Infusion Catheter) Infusion Catheter) combines the use of a distal ultrasound transducer with combines the use of a distal ultrasound transducer with
infusion of a thrombolytic agent through the infusion of a thrombolytic agent through the microcathetermicrocatheter
Ultrasound changes the structure of the clot to Ultrasound changes the structure of the clot to temporarily increase its permeability while providing an temporarily increase its permeability while providing an acoustic pressure gradient to move the drug into the clot acoustic pressure gradient to move the drug into the clot to speed its dissolution to speed its dissolution
The EKOS catheter is placed in the proximal portion of the The EKOS catheter is placed in the proximal portion of the clot clot
After a 2-mg bolus of tPA was injected through the After a 2-mg bolus of tPA was injected through the catheter catheter
the patient received a continuous infusion of IA tPA 03 the patient received a continuous infusion of IA tPA 03 mgmin to a maximum of 20 mg and simultaneous mgmin to a maximum of 20 mg and simultaneous ultrasound transmission for as long as 60 minutes ultrasound transmission for as long as 60 minutes
One patient was treated with a total of 4 units of One patient was treated with a total of 4 units of recombinant reteplase (Retavase) hand-injected over 60 recombinant reteplase (Retavase) hand-injected over 60 minutes minutes
Penumbra system Penumbra system The Penumbra system (Penumbra Inc) provides a dual The Penumbra system (Penumbra Inc) provides a dual
approach to clot extraction using aspiration followed by approach to clot extraction using aspiration followed by clot retrieval with a ring device if needed clot retrieval with a ring device if needed
Mechanical Embolus Removal in Cerebral Ischemia Mechanical Embolus Removal in Cerebral Ischemia (MERCI)(MERCI)
a corkscrew-like apparatus to remove blood clots from a corkscrew-like apparatus to remove blood clots from the brain in patients experiencing an ischemic stroke the brain in patients experiencing an ischemic stroke
The corkscrew itself resides in the catheter tip which The corkscrew itself resides in the catheter tip which shields it from the wall of the vessel until it is ready to be shields it from the wall of the vessel until it is ready to be burrowed into the clot Once lodged in the clot the device burrowed into the clot Once lodged in the clot the device and clot are withdrawn from the vessel and clot are withdrawn from the vessel
Snarelike devicesSnarelike devices Snares such as the Neuronet snare (Guidant Snares such as the Neuronet snare (Guidant
Endovascular Santa Clara CA) have been developed Endovascular Santa Clara CA) have been developed specifically for use in the treatment of strokes specifically for use in the treatment of strokes
These devices are simple in design and do not require the These devices are simple in design and do not require the clot to be amenable to emulsification clot to be amenable to emulsification
X-Sizer deviceX-Sizer device a device with small moving blades at the a device with small moving blades at the
catheter tip catheter tip This device the X-Sizer device (EndiCor Medical This device the X-Sizer device (EndiCor Medical
San Clemente CA) can be used to excise the San Clemente CA) can be used to excise the thrombus and aspirate it thrombus and aspirate it
The device was being evaluated in randomized The device was being evaluated in randomized studies of coronary vessels and in a registry of studies of coronary vessels and in a registry of patients with acute myocardial infarctionpatients with acute myocardial infarction
Although the manufacturer had modified the Although the manufacturer had modified the device for use in cerebral vessels a safety and device for use in cerebral vessels a safety and feasibility study was indefinitely suspended after feasibility study was indefinitely suspended after only 1 patient was treated with the device in only 1 patient was treated with the device in Europe Europe
Suction thrombectomySuction thrombectomy This method of mechanical thrombolysis is one of the This method of mechanical thrombolysis is one of the
simplestsimplest In this readily available technique suction is applied with In this readily available technique suction is applied with
a syringe to remove thrombus in the ICA a syringe to remove thrombus in the ICA It requires no other devicesIt requires no other devices A catheter with a large inner diameter (Brite Tip Cordis A catheter with a large inner diameter (Brite Tip Cordis
Corporation Miami FL) was placed in the symptomatic Corporation Miami FL) was placed in the symptomatic vessel and navigated over a guidewire into the thrombusvessel and navigated over a guidewire into the thrombus
A 60-mL syringe was used to aspirate the thrombus A 60-mL syringe was used to aspirate the thrombus Each patient required angioplasty and stenting of carotid Each patient required angioplasty and stenting of carotid
bifurcation stenosis and received daily aspirin and bifurcation stenosis and received daily aspirin and ticlopidine after the procedure No complications ticlopidine after the procedure No complications occurred occurred
Summary Acute Stroke Summary Acute Stroke ImagingImaging
PhysiologyPhysiology importance collaterals importance collaterals
ndash ndashGrowing role for perfusion Growing role for perfusion assessmentassessment
tPAtPA guidelines amp limitations guidelines amp limitations Signs on CT amp MRSigns on CT amp MR follow physiology follow physiology Stroke trialsStroke trials PWI-DWI mismatch PWI-DWI mismatch
ndash ndashTreat based on physiology not timeTreat based on physiology not time ProtocolsProtocols should be fast and should be fast and
comprehensivecomprehensive
Third-Generation AgentsThird-Generation Agents
ReteplaseReteplase is a structurally modified is a structurally modified form of alteplase form of alteplase
with a longer half-life (15ndash18 minutes) In with a longer half-life (15ndash18 minutes) In addition it does not bind as highly to fibrin addition it does not bind as highly to fibrin unbound reteplase can thus theoretically better unbound reteplase can thus theoretically better penetrate the clot and potentially penetrate the clot and potentially improve in improve in vivo fibrinolytic activity vivo fibrinolytic activity
TenecteplaseTenecteplase is another modified form of rtPA with a longer is another modified form of rtPA with a longer
half-life (17 minutes)half-life (17 minutes) greater fibrin specificity and greater greater fibrin specificity and greater
resistance to plasminogen activator inhibitor-1 resistance to plasminogen activator inhibitor-1 IV tenecteplase in acute ischemic stroke IV tenecteplase in acute ischemic stroke
suggest that the drug is safe and promisingsuggest that the drug is safe and promising
Newer plasminogen activatorNewer plasminogen activator
DesmoteplaseDesmoteplase is a genetically engineered is a genetically engineered version of the clot-dissolving factor version of the clot-dissolving factor
found in the saliva found in the saliva of the vampire bat Desmodus rotundusof the vampire bat Desmodus rotundus moremore potent and more selective for fibrin-bound potent and more selective for fibrin-bound
plasminogen than any other known plasminogen plasminogen than any other known plasminogen activatoractivator
Unlike tissue plasminogen activator (tPA) desmoteplase Unlike tissue plasminogen activator (tPA) desmoteplase is not activated by fibrinogen or -amyloid proteins is not activated by fibrinogen or -amyloid proteins factors that may exacerbate the risk for ICH factors that may exacerbate the risk for ICH
The effect of IV administration of desmoteplase 3ndash9 The effect of IV administration of desmoteplase 3ndash9 hours after symptom onset in patients with stroke who hours after symptom onset in patients with stroke who present with mismatch on MR imaging or CT perfusion present with mismatch on MR imaging or CT perfusion
3 DefibrinogenatingFibrinogenolytic 3 DefibrinogenatingFibrinogenolytic Agents Agents
AncrodAncrod(Viprinex)(Viprinex) is is the purified fraction of the Malayan pit viper venomthe purified fraction of the Malayan pit viper venom It acts by directly cleaving and inactivating fibrinogen It acts by directly cleaving and inactivating fibrinogen
and thus indirectly promoting anticoagulation and thus indirectly promoting anticoagulation The reduction in the blood levels of fibrinogen also The reduction in the blood levels of fibrinogen also
leads to a reduced blood viscosity which may improve leads to a reduced blood viscosity which may improve blood flow to the affected areas of the brain blood flow to the affected areas of the brain
In the Stroke Treatment with Ancrod Trial 500 In the Stroke Treatment with Ancrod Trial 500 patients with stroke presenting within 3 hours of patients with stroke presenting within 3 hours of symptom onset were randomized to receive ancrod (symptom onset were randomized to receive ancrod (n n 248) or a placebo (n 252) Good outcome (Barthel 248) or a placebo (n 252) Good outcome (Barthel Index 95ndash100 at 3 months) was achieved in 4221 Index 95ndash100 at 3 months) was achieved in 4221 and 344 of the patients respectively and 344 of the patients respectively
2 Direct Fibrinolytics2 Direct Fibrinolytics
Microplasmin (Microplasmin (ThromboGenics Heverlee Belgium)ThromboGenics Heverlee Belgium) is a truncated form of plasmin that is more resistant to the effects is a truncated form of plasmin that is more resistant to the effects
of antiplasmin of antiplasmin microplasmin can be used upto 4ndash12 hours after stroke onset microplasmin can be used upto 4ndash12 hours after stroke onset There was no evidence of increased bleeding risk with There was no evidence of increased bleeding risk with
microplasminmicroplasmin
Alfimeprase (Nuvelo San Carlos Calif)Alfimeprase (Nuvelo San Carlos Calif) is a recombinant truncated form of fibrolase a fibrinolytic zinc metalloproteinase is a recombinant truncated form of fibrolase a fibrinolytic zinc metalloproteinase
isolated from the venom of the southern copperhead snake isolated from the venom of the southern copperhead snake It degrades fibrin directly and achieves thrombolysis independent It degrades fibrin directly and achieves thrombolysis independent
of plasmin formationof plasmin formation its thrombolytic activity appears to be localized to the site of its thrombolytic activity appears to be localized to the site of
delivery These properties should theoretically result in faster delivery These properties should theoretically result in faster recanalization and lower hemorrhagic conversion riskrecanalization and lower hemorrhagic conversion risk
Anti-fibrinolyticsAnti-fibrinolytics
to limit fibrinolytic activityto limit fibrinolytic activity -aminocaproic acid (EACA) -aminocaproic acid (EACA) competitively inhibitscompetitively inhibits plasminogen and plasminogen activators from plasminogen and plasminogen activators from
binding to fibrinbinding to fibrin
alpha2-antiplasminalpha2-antiplasmin a serine protease inhibitor that a serine protease inhibitor that neutralizes any free circulating plasminneutralizes any free circulating plasmin
Plasminogen activator inhibitor-1Plasminogen activator inhibitor-1 a serine protease a serine protease inhibitor that inhibits tissue-type plasminogen inhibitor that inhibits tissue-type plasminogen activatoractivator
Glycoprotein (GP) IIbIIIa antagonistsGlycoprotein (GP) IIbIIIa antagonists
such as ReoPro (abciximab) Integrilin such as ReoPro (abciximab) Integrilin (eptifibatide) or Aggrastat (tirofiban) in (eptifibatide) or Aggrastat (tirofiban) in ischemic stroke remains investigational ischemic stroke remains investigational Deshmukh et al38 reported 21 patients with Deshmukh et al38 reported 21 patients with large-vessel occlusion refractory to IAT with large-vessel occlusion refractory to IAT with rtPA who were treated with IV andor IA rtPA who were treated with IV andor IA abciximab eptifibatide or tirofiban abciximab eptifibatide or tirofiban
IA Mechanical Approaches in Acute Ischemic Stroke IA Mechanical Approaches in Acute Ischemic Stroke Mechanical strategies have several advantagesMechanical strategies have several advantages First they lessen and may even preclude the use of chemical First they lessen and may even preclude the use of chemical
thrombolytics in this manner very likely reducing the risk of ICHthrombolytics in this manner very likely reducing the risk of ICH Second by avoiding the use of chemical thrombolytics it is Second by avoiding the use of chemical thrombolytics it is
possible to extend the treatment window beyond the limit of 6ndash8 possible to extend the treatment window beyond the limit of 6ndash8 hours hours
Third mechanically fragmenting a clot increases the surface area Third mechanically fragmenting a clot increases the surface area accessible to fibrinolytic agents and allows inflow of fresh accessible to fibrinolytic agents and allows inflow of fresh plasminogen which in turn may increase the speed of plasminogen which in turn may increase the speed of thrombolysis thrombolysis
Finally clot-retrieval devices may provide faster recanalization Finally clot-retrieval devices may provide faster recanalization
The disadvantages of the mechanical The disadvantages of the mechanical approaches approaches technical difficulty of navigating mechanical technical difficulty of navigating mechanical
devices into the intracranial circulation excessive devices into the intracranial circulation excessive trauma to the vasculature (potentially leading to trauma to the vasculature (potentially leading to vasospasm vessel dissection perforation or vasospasm vessel dissection perforation or rupture) rupture)
fragmented thrombus causing distal embolization fragmented thrombus causing distal embolization into previously unaffected territories into previously unaffected territories
Nevertheless the advantages of mechanical stroke Nevertheless the advantages of mechanical stroke therapy appear to significantly outweigh its therapy appear to significantly outweigh its disadvantages and risksdisadvantages and risks
Contraindications to Thrombolytic Contraindications to Thrombolytic agents agents
Recent thoracic abdominal or Recent thoracic abdominal or intracranial surgeryintracranial surgery
Recent haemorrhagic CVA Head injury Recent haemorrhagic CVA Head injury or neoplasmor neoplasm
Bleeding ulcerBleeding ulcer Anticipated invasive procedures (arterial Anticipated invasive procedures (arterial
punctures biopsies)punctures biopsies) Concurrent hemostatic dysfunctionConcurrent hemostatic dysfunction
Monitoring of thrombolytic Monitoring of thrombolytic therapytherapy
Thrombin time Measures the availability of functional
fibrinogen Normal thrombin time is 10-14 sec Prolonged when fibrinogen level is below
75-100 mgdl
Half Life of ThrombolyticsHalf Life of ThrombolyticsAgent Administration Half Life
Streptokinase IA 60-80min
Urokinase IAIV 9-12min
rTPA IAIV 6min
Abciximab(Reopro) IAIV 12hour
Aspirin POIV 15-20min
Heparin IVSC 60min
Coumadin PO 15-25 days
Anti Platelet DrugsAnti Platelet DrugsDrug Drug Mechanism Mechanism UsesUsesAspirinAspirin Permanently inhibits Permanently inhibits
COX-1 and COX-2COX-1 and COX-2CADCAD
Stroke-TIAsStroke-TIAs
NSAIDsNSAIDs Reversibly inhibits Reversibly inhibits COX-1COX-1
LimitedLimited
DipyridamoleDipyridamole Inhibits PDE increases Inhibits PDE increases cAMPcAMP
TIAsTIAs
ThenopyridinesThenopyridines
(Ticlopidine(Ticlopidine
ClopidrgrelClopidrgrel))
Inhibits ADP Inhibits ADP
PlatAg PlatAg
TIAsStrokeTIAsStroke
CAD PVDCAD PVD
Abciximab (ReoPro)Abciximab (ReoPro)
Eptifibatide (Integrilin)Eptifibatide (Integrilin)
TirofibanTirofiban
GP IIBIIIA InhibitorsGP IIBIIIA Inhibitors
Stroke- TIAs Stroke- TIAs
MonitoringMonitoring
Bleeding timeBleeding time
Optical aggregometryOptical aggregometry
Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay
Bleeding timeBleeding time
Requires a skin incision (usually made on the ear lobe or Requires a skin incision (usually made on the ear lobe or forearm offorearm of
a depth that results in disruption of capillary loops and a depth that results in disruption of capillary loops and small vessels)small vessels)
AdvantagesAdvantages Universally availableUniversally available Relatively simple techniquesRelatively simple techniques Can be performed bedsideCan be performed bedside
DisadvantagesDisadvantages Insensitive inaccurate non-specific techniqueInsensitive inaccurate non-specific technique
Poorly reproducible (as depends on multiple variables)Poorly reproducible (as depends on multiple variables)
Optical aggregometryOptical aggregometry
Gold standard assay for platelet functionGold standard assay for platelet function Agonist induced aggregation is measuredAgonist induced aggregation is measured Different agonist are available for different Different agonist are available for different
agentsagents However require unique expertise and are not However require unique expertise and are not
universally availableuniversally available Aspirin measured with ADP or AA(gt70 Aspirin measured with ADP or AA(gt70
aggregation so resistance)aggregation so resistance) Clopidogrel( ADP gt 90 aggregation means Clopidogrel( ADP gt 90 aggregation means
resistance) resistance)
Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay
Can be performed bed sideCan be performed bed side Different assay devices with different Different assay devices with different
agonist are used for each of different agonist are used for each of different antiplatelet agents antiplatelet agents
For Aspirin AA is used (result is reported as aspirin For Aspirin AA is used (result is reported as aspirin reaction units [ARU] ARUgt 550 indicates non-reaction units [ARU] ARUgt 550 indicates non-responsiveness)responsiveness)
Verify IIbIIIa assay device uses TRAP as agonist for Verify IIbIIIa assay device uses TRAP as agonist for Abciximab and TirofibanAbciximab and Tirofiban
Practical Applications Practical Applications related to specific related to specific
Neurovascular Neurovascular interventionsinterventions
Acute ischemic StrokeAcute ischemic Stroke When an artery occludes neurons are affected When an artery occludes neurons are affected
differently depending upon the amount of residual blood differently depending upon the amount of residual blood flowflow
Normal cerebral blood flow is greater than 50 mL100 Normal cerebral blood flow is greater than 50 mL100 mgminmgmin
Once blood flow decreases to less than 20 mL100 Once blood flow decreases to less than 20 mL100 mgmin infarction occursmgmin infarction occurs
If blood flow decreases to less than 10 mL100 mgmin If blood flow decreases to less than 10 mL100 mgmin irreversible neuronal death occurs rapidly irreversible neuronal death occurs rapidly
Blood flow between 11 and 20 mL100 mgmin is thought Blood flow between 11 and 20 mL100 mgmin is thought to represent the ischemic penumbra an area where the to represent the ischemic penumbra an area where the cells are functionally silent because of ischemia but are cells are functionally silent because of ischemia but are still able to recover if blood flow is restored still able to recover if blood flow is restored
Many acute stroke therapies are targeted toward Many acute stroke therapies are targeted toward restoring flow or function to the ischemic penumbrarestoring flow or function to the ischemic penumbra
Therapeutic window in Therapeutic window in management of acute Ischemic management of acute Ischemic
StrokeStrokeThe early diagnosis of ischemic stroke is critical to the The early diagnosis of ischemic stroke is critical to the
with only a narrow therapeutic window in the first few with only a narrow therapeutic window in the first few hours following stroke ictushours following stroke ictus
Diagnosis in the first 3 hours postictus provides the Diagnosis in the first 3 hours postictus provides the opportunity for intravenous or intraarterial thrombolysis opportunity for intravenous or intraarterial thrombolysis and intra-arterial clot mechanical treatment which and intra-arterial clot mechanical treatment which improve the outcome improve the outcome
Diagnosis in the time period between 3 and 6 hours Diagnosis in the time period between 3 and 6 hours provides an opportunity for intra-arterial thrombolysis provides an opportunity for intra-arterial thrombolysis and mechanical treatment and mechanical treatment
Involvement of the posterior circulation especially the Involvement of the posterior circulation especially the basilar artery is treated by some regardless of time of basilar artery is treated by some regardless of time of onset or up until 12 to 24 hours in some practices This is onset or up until 12 to 24 hours in some practices This is related to the potentially high mortality and morbidity related to the potentially high mortality and morbidity associated with basilar artery thrombosisassociated with basilar artery thrombosis
Infarct evaluation on angiographyInfarct evaluation on angiography(CT angiography and catheter (CT angiography and catheter
angiography)angiography)CTA is an excellent first-line examination for CTA is an excellent first-line examination for
evaluation of the head and neck arteries evaluation of the head and neck arteries In comparison with catheter angiography In comparison with catheter angiography
what it gives up in resolution and dynamic what it gives up in resolution and dynamic properties it makes up for with rapid properties it makes up for with rapid acquisition of a 3-D dataset and the potential acquisition of a 3-D dataset and the potential for assessment of whole-brain perfusion and for assessment of whole-brain perfusion and better parenchymal evaluationbetter parenchymal evaluation
Moreover CTA illustrates not only arterial Moreover CTA illustrates not only arterial stenosis or occlusion but also the vessel wall stenosis or occlusion but also the vessel wall This factor is most important for evaluation of This factor is most important for evaluation of intramural dissection and thrombosed intramural dissection and thrombosed aneurysms which may both complicate aneurysms which may both complicate evaluation of stroke patientsevaluation of stroke patients
Early angiographic signs of strokes Early angiographic signs of strokes both CTA both CTA and DSA and DSA
Vessel occlusion or cutoff related to Vessel occlusion or cutoff related to thromboembolithromboemboli
aneurysms aneurysms arterial dissection arterial dissection Meniscus or flattened shape to clot Meniscus or flattened shape to clot
(recent) versus reverse meniscus (older)(recent) versus reverse meniscus (older) tram track (nonocclusive or recanalized tram track (nonocclusive or recanalized
clot) clot) delayed (antegrade) flow (manifest as delayed (antegrade) flow (manifest as
decreased whole-brain perfusion on CTA)decreased whole-brain perfusion on CTA) retrograde collateral flowretrograde collateral flow
Non-occlusive left MCA thrombus on 3-D imaging performed from CTA source data and was confirmed at catheter angiography
Therapy to be started within a 6-hr Therapy to be started within a 6-hr time to treatment (TTT) window time to treatment (TTT) window (while in case of IV thrombolysis (while in case of IV thrombolysis therapy to be started with in 3hrs)therapy to be started with in 3hrs)
Exclusion criteria Exclusion criteria Rapidly improving neurologic deficit or Rapidly improving neurologic deficit or Sustained blood pressure of gt180100 Sustained blood pressure of gt180100 Hemorrhage is detected on CTHemorrhage is detected on CT Infarct involving gt more than 13 rd Infarct involving gt more than 13 rd
territory of MCAterritory of MCA MRADWI-Perfusion mismatchlt 20MRADWI-Perfusion mismatchlt 20 Definite hypodensity on CTDefinite hypodensity on CT
Intra-arterial Thrombolysis
Fibrinolytics + AntiplateletsFibrinolytics + Antiplatelets
PlasminogenPlasminogen activators through fibrinolysis exposes activators through fibrinolysis exposes free thrombin and paradoxically stimulatesfree thrombin and paradoxically stimulates platelet platelet aggregation which leads to formation of aaggregation which leads to formation of a platelet platelet thrombus (white clot) thrombus (white clot)
This new thrombus is relatively resistant to This new thrombus is relatively resistant to fibrinolyticsfibrinolytics
So new regimen in case of acute stroke isSo new regimen in case of acute stroke is fibrinolytics + antiplatelet drugsfibrinolytics + antiplatelet drugs
rtPA + IIbIIIa inhibitors( tirofiban rtPA + IIbIIIa inhibitors( tirofiban abciximab) orabciximab) or
Urokinase + IIbIIIa Urokinase + IIbIIIa inhibitors( tirofiban abciximab)inhibitors( tirofiban abciximab)
Intra-arterial Thrombolysis Tirofiban (04 microgkgmin bolus for 3 min followed by Tirofiban (04 microgkgmin bolus for 3 min followed by
0125 ugkgmin)0125 ugkgmin)
++
Heparin (2000ndash3000 IU bolus followed by Heparin (2000ndash3000 IU bolus followed by 1000 IUhour infusion 1000 IUhour infusion
with ACT maintained bw 200-300) throughout the with ACT maintained bw 200-300) throughout the interventional procedure and for 24ndash48 hours thereafter when interventional procedure and for 24ndash48 hours thereafter when there is neither intraprocedural bleeding nor suspicion of there is neither intraprocedural bleeding nor suspicion of increased risk of bleeding increased risk of bleeding
Maximum dose of Urokinase Maximum dose of Urokinase Anterior circulation stroke - 500000 IU (mean 400000 Anterior circulation stroke - 500000 IU (mean 400000
IU range 300000ndash500000 IU)IU range 300000ndash500000 IU) Posterior circulation stroke -1000000 IU (mean 837000 Posterior circulation stroke -1000000 IU (mean 837000
IU range 300000ndash1000000 IU)IU range 300000ndash1000000 IU)American Journal of NeuroradiologyAmerican Journal of Neuroradiology 262595-2601 2005262595-2601 2005
Intravenous ThrombolysisIntravenous Thrombolysis
The first method to restore cerebral The first method to restore cerebral perfusion is clot lysis with the goal perfusion is clot lysis with the goal of re-establishing blood flow to the of re-establishing blood flow to the affected tissue affected tissue
IV thrombolysis rt-PA is the only IV thrombolysis rt-PA is the only FDA- approved treatment for AIS FDA- approved treatment for AIS
Fibrinolysis is enhanced powerfully Fibrinolysis is enhanced powerfully by rt-PAby rt-PA
Intravenous rTPA Intravenous rTPA administration administration protocolprotocol
Total dose of rt-PA 09 mgkg (maximum dose Total dose of rt-PA 09 mgkg (maximum dose 90 mg)90 mg)
Give 10 as initial IV bolusGive 10 as initial IV bolus Infuse remainder over 1 hourInfuse remainder over 1 hour Admit patient to an ICU or stroke unit for Admit patient to an ICU or stroke unit for
monitoringmonitoring Neurologic assessments every 15 minutes Neurologic assessments every 15 minutes
during infusion then every 30 minutes for next during infusion then every 30 minutes for next 6 hours then every hour until 24hours after 6 hours then every hour until 24hours after treatmenttreatment
Favorable Outcome vs Treatment Time Favorable Outcome vs Treatment Time with IV rTPAwith IV rTPA
Protocol limit = 3 hrs
Benefit ~ 45 hrs
Thromboembolism During coilingThromboembolism During coiling Most feared and frequent complication Most feared and frequent complication Reported incidence - Approx 7 Reported incidence - Approx 7 SourcesSources of Thromboembolism are of Thromboembolism are
- Clots at the aneurysmal neck during or immediately- Clots at the aneurysmal neck during or immediately after after embolization embolization
- Thrombus forming on catheters during- Thrombus forming on catheters during proceduresprocedures
- Stenosis of an adjacent artery dt coil mass- Stenosis of an adjacent artery dt coil mass or herniationor herniation
- Migration of intraaneurysmal- Migration of intraaneurysmal thrombus during coil thrombus during coil placement placement
- Slow flow dt vasospasm - Slow flow dt vasospasm
- Rare and unlikely causes are hypercoagulable- Rare and unlikely causes are hypercoagulable state such state such as antiphospholipid antibody syndrome or due to HITas antiphospholipid antibody syndrome or due to HIT
Occur more often with wide-necked aneurysms (dt Occur more often with wide-necked aneurysms (dt increased exposed surface area of thrombogenic coil increased exposed surface area of thrombogenic coil material)material)
Current regimen of endovascular Current regimen of endovascular managementmanagement
The The glycoprotein IIbIIIa antagonist tirofiban glycoprotein IIbIIIa antagonist tirofiban (04 (04 microgkgmin bolus for 30 minutes followed by infusion of microgkgmin bolus for 30 minutes followed by infusion of 0125 ugkgmin until the thrombus dissolved) 0125 ugkgmin until the thrombus dissolved)
Intraarterial thrombolysis with Intraarterial thrombolysis with urokinase or r- TPA urokinase or r- TPA increase of intravenous (IV) heparin (measured by increase of intravenous (IV) heparin (measured by
ACT) ACT) Intravenous aspirin Intravenous aspirin
Coil-related platelet aggregation (white clot) is Coil-related platelet aggregation (white clot) is unlikely to respond to fibrinolytics but has a high risk unlikely to respond to fibrinolytics but has a high risk of hemorrhage (In ISAT) all 5 patients who had of hemorrhage (In ISAT) all 5 patients who had received thrombolytic therapy with tPA to treat a received thrombolytic therapy with tPA to treat a thromboembolic complication after endovascular thromboembolic complication after endovascular treatment rebleed and all of these patients died)treatment rebleed and all of these patients died)
IntracranialIntracranial Stenting Stenting Metallic foreign body such as stent will accumulate Metallic foreign body such as stent will accumulate
thrombus in the absence of platelet inhibitionthrombus in the absence of platelet inhibition Antiplatelet drugs are important to prevent peri or Antiplatelet drugs are important to prevent peri or
post-interventional thromboembolic eventspost-interventional thromboembolic events Optimal treatment regimens has not been determined Optimal treatment regimens has not been determined
but usually but usually Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-
procedureprocedureOrOr
Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on
morning of proceduremorning of procedure
If need to use stent is not pre-planned thanIf need to use stent is not pre-planned than
Abciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkgAbciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkg IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)
Glycoprotein IIbIIIa inhibitor are not used routinely during elective Glycoprotein IIbIIIa inhibitor are not used routinely during elective stenting procedure dt increased risk of ICH stenting procedure dt increased risk of ICH
Carotid StentingCarotid Stenting
Pre-procedurePre-procedure
Double Antiplatelet therapy is routinely given Double Antiplatelet therapy is routinely given beginning at least 3beginning at least 3
days before the proceduredays before the procedure
Aspirin 325mgd+Clopidogrel 75mgdAspirin 325mgd+Clopidogrel 75mgd During procedureDuring procedure
Heparin is given with target clotting time of 250-Heparin is given with target clotting time of 250-300sec300sec
Post-procedure Post-procedure
Aspirin 325mg is continued indefinitely and Aspirin 325mg is continued indefinitely and
Clopidogrel 75mgd for at least 6 weeks Clopidogrel 75mgd for at least 6 weeks
Inclusion criteria for Local ThrombolysisInclusion criteria for Local Thrombolysis a)a) Patients in severe clinical grade on admission Patients in severe clinical grade on admission
with evidence of dural venous sinus with evidence of dural venous sinus thrombosis and restrictive venous outflow on thrombosis and restrictive venous outflow on cerebral angiogramcerebral angiogram
b)b) Patients in clinical grade 3 worsening on Patients in clinical grade 3 worsening on heparin therapy Restriction to venous heparin therapy Restriction to venous outflow was defined as an increase in brain outflow was defined as an increase in brain circulation time gt 12 s delay in the drainage circulation time gt 12 s delay in the drainage of cortical veins with cortical veins hanging of cortical veins with cortical veins hanging in spacein space
Treatment Options for Venous Thrombosis
CT Grading for Venous ThrombosisCT Grading for Venous Thrombosis Grade I no parenchymal change Grade I no parenchymal change
(hyperdense (hyperdense sinuses cortical veins empty sinuses cortical veins empty delta sign)delta sign)
Grade II non hemorrhagic venous infarct Grade II non hemorrhagic venous infarct without mass effect without mass effect
Grade III non-hemorrhagic infarct with Grade III non-hemorrhagic infarct with mass effectmass effect
Grade IV hemorrhagic venous infarct (max Grade IV hemorrhagic venous infarct (max diameter lt 3 cm) with no mass effectdiameter lt 3 cm) with no mass effect
Grade V hemorrhagic venous infarct (max Grade V hemorrhagic venous infarct (max diameter gt 3 cm) with mass effect diameter gt 3 cm) with mass effect
Local ThrombolysisLocal Thrombolysis
Femoral Jugular access was secured and a guiding Femoral Jugular access was secured and a guiding catheter was placed in the jugular bulb catheter was placed in the jugular bulb Mechanical Mechanical clot maceration clot maceration was done with the guidewire was done with the guidewire following which a microcatheter (was navigated and following which a microcatheter (was navigated and placed in the thrombosed segment of sinus confirmed placed in the thrombosed segment of sinus confirmed on a selective venogram on a selective venogram
Urokinase infusion Bolus dose of 2-6 lacs followed Urokinase infusion Bolus dose of 2-6 lacs followed by 60000 to 100000 units per hour along with by 60000 to 100000 units per hour along with periodic check venogram Along with maintenance periodic check venogram Along with maintenance systemic infusion of Heparinsystemic infusion of Heparin Other agents such as Other agents such as streptokinase altepase or rTPAstreptokinase altepase or rTPA can be also used can be also used
After thrombolysis patient should subjected to oral After thrombolysis patient should subjected to oral anticoagulation for six monthsanticoagulation for six months
Low-molecular-weight Low-molecular-weight heparinheparin
PharmacologyPharmacologyLMWH as its name suggests is a glycosaminoglycan that is approximatelyLMWH as its name suggests is a glycosaminoglycan that is approximately
one third the molecular weight of UFH It is derived from UFH through one third the molecular weight of UFH It is derived from UFH through variousvarious
depolymerization processes LMWH binds to antithrombin which in turn depolymerization processes LMWH binds to antithrombin which in turn
Neutralizes actors Xa and IIa Because LMWH lacks many of the longer Neutralizes actors Xa and IIa Because LMWH lacks many of the longer chains chains
required for binding to thrombin it has less ability to neutralize thrombin required for binding to thrombin it has less ability to neutralize thrombin
relativeto its ability to neutralize factor Xa LMWH also has less relativeto its ability to neutralize factor Xa LMWH also has less nonspecific nonspecific
binding to other proteins There is greater bioavailability with more binding to other proteins There is greater bioavailability with more predictable predictable
pharmacokinetics that eliminates the need for monitoring The smaller pharmacokinetics that eliminates the need for monitoring The smaller size also size also
allows for enhanced subcutaneous absorption when compared with UFHallows for enhanced subcutaneous absorption when compared with UFH
Three LMWH preparations are Three LMWH preparations are currently approved for use in the currently approved for use in the United States (1) enoxaparin (2) United States (1) enoxaparin (2) dalteparin and (3) tinzaparin dalteparin and (3) tinzaparin
They are all administered They are all administered subcutaneously at intervals of either subcutaneously at intervals of either once or twice daily for both once or twice daily for both prophylaxis and treatment dosesprophylaxis and treatment doses
Few Experiences of Few Experiences of ThrombolysisThrombolysis
Vickey 25 Yrs male patient presented Vickey 25 Yrs male patient presented with 12with 12thth day HO severe headache with day HO severe headache with right sided hemiplegiaright sided hemiplegia
MRI shows thrombosis of the superior MRI shows thrombosis of the superior sagittal left transverse left sigmoid sagittal left transverse left sigmoid sinuses and cortical veins in the fronto-sinuses and cortical veins in the fronto-parietal regions with eo haemorrhagic parietal regions with eo haemorrhagic infarct in the left cerebral hemisphere infarct in the left cerebral hemisphere with mass effect( Grade ndashV)with mass effect( Grade ndashV)
Sashi Srivastava 64 yrs FSashi Srivastava 64 yrs F In a follow up case of MRD with infra-renal In a follow up case of MRD with infra-renal
aortic abdominal and bilateral renal artery aortic abdominal and bilateral renal artery thrombosis renal angiogram shows filling thrombosis renal angiogram shows filling defects in the right Renal artery defects in the right Renal artery
Initially Renal angioplasty was done Initially Renal angioplasty was done Following angioplasty few thrombi are seem Following angioplasty few thrombi are seem to extends into the segmental branches and to extends into the segmental branches and causing blockage So Thrombolysis was causing blockage So Thrombolysis was plane to dissolve the run-out thrombi with plane to dissolve the run-out thrombi with urokinase urokinase
Rakesh 34yrsMRakesh 34yrsM Left SFA pseudoaneurysm with Left SFA pseudoaneurysm with
Covered stent placementCovered stent placement Pre operative antiplatelets with post Pre operative antiplatelets with post
procedure heparin Tirofiban procedure heparin Tirofiban followed by aspirin and clopidogrel followed by aspirin and clopidogrel were usedwere used
IAT may be a treatment option for selected patients IAT may be a treatment option for selected patients Possible selection criteria include Possible selection criteria include
presentation between 3 and 6 hours from symptom onsetpresentation between 3 and 6 hours from symptom onset major cerebral artery occlusion major cerebral artery occlusion severe neurologic deficits severe neurologic deficits high risk of systemic hemorrhage with IV rt-PA (eg recent high risk of systemic hemorrhage with IV rt-PA (eg recent
surgery) surgery) The MERCI (Mechanical Embolus Removal in Cerebral The MERCI (Mechanical Embolus Removal in Cerebral
Ischemia) retrievalIschemia) retrieval system system
Has been FDA-approved for recanalizing acutely occluded Has been FDA-approved for recanalizing acutely occluded cerebral arteries cerebral arteries
In the Multi-MERCI study patients who did not improve In the Multi-MERCI study patients who did not improve immediately after IV rt-PA underwent mechanical immediately after IV rt-PA underwent mechanical embolectomy within 8 hours of symptom onset embolectomy within 8 hours of symptom onset
Partial or complete recanalization occurred in 74 of Partial or complete recanalization occurred in 74 of patientspatients
with a symptomatic intracerebral hemorrhage (sICH) rate of with a symptomatic intracerebral hemorrhage (sICH) rate of 67 67
Mechanical embolectomy with the MERCI retriever may be a Mechanical embolectomy with the MERCI retriever may be a feasible and safe option for patients after IV rt-PAfeasible and safe option for patients after IV rt-PA
Penumbra stroke systemPenumbra stroke system This device combines two methods of clot This device combines two methods of clot
extraction aspiration and mechanical extraction aspiration and mechanical extraction extraction
First the clot is aspirated then a thrombus First the clot is aspirated then a thrombus removal ring can be used if necessary to removal ring can be used if necessary to remove remaining clot remove remaining clot
successful recanalizing 82successful recanalizing 82 Bridging therapyBridging therapy
06 mgkg IV rt-PA followed by IAT with IA rt-06 mgkg IV rt-PA followed by IAT with IA rt-PA (up to 20 mg)PA (up to 20 mg)
achieved a higher recanalization rateachieved a higher recanalization rate
Criteria for thrombolysis with rTPACriteria for thrombolysis with rTPA
Inclusion criteriaInclusion criteria Clinical signs and symptoms consistent with ischemic Clinical signs and symptoms consistent with ischemic
strokestroke Patient last seen normal within 3 hoursPatient last seen normal within 3 hours Measurable neurologic deficitMeasurable neurologic deficit
Exclusion criteriaExclusion criteria Any hemorrhage on neuroimaging (CT or MRI)Any hemorrhage on neuroimaging (CT or MRI) Symptoms suggestive of subarachnoid hemorrhageSymptoms suggestive of subarachnoid hemorrhage Seizure at stroke onset that is thought to contribute to Seizure at stroke onset that is thought to contribute to
neurologic deficitneurologic deficit Hypodensity greater than one third cerebral hemisphere Hypodensity greater than one third cerebral hemisphere
on CTon CT SBP greater than 185 mm Hg or DBP greater than 110 SBP greater than 185 mm Hg or DBP greater than 110
mm Hgmm Hg International normalized ratio (INR) greater than 17International normalized ratio (INR) greater than 17
Ischemic Stroke Ischemic Stroke Treatment ndash 2006Treatment ndash 2006
IV tissue plasminogen activator (tPA)IV tissue plasminogen activator (tPA) ndash ndash Only FDA-approved acute stroke drugOnly FDA-approved acute stroke drug ndash ndash 3 hour treatment window3 hour treatment window
MERCI - Concentric clot retrieval MERCI - Concentric clot retrieval devicedevice ndash ndash Rescue therapy - approved 2004Rescue therapy - approved 2004 ndash ndash Device approval (not outcomes-based)Device approval (not outcomes-based)
Off label approachesOff label approaches ndash ndash IV tPA after 3 hoursIV tPA after 3 hours ndash ndash IV-IA tPA sequential strategiesIV-IA tPA sequential strategies ndash ndash IA tPA clot angioplasty fragmentationIA tPA clot angioplasty fragmentation ndash ndash Ultrasound-assisted tPA lysisUltrasound-assisted tPA lysis
rt-PA Trials NINDSrt-PA Trials NINDS
Acute stroke - 624 patientsAcute stroke - 624 patients Treat within 3 hrsTreat within 3 hrs Intravenous 09 mgkg rt-PA vs placeboIntravenous 09 mgkg rt-PA vs placebo Hemorrhage 64 tPA 06 placeboHemorrhage 64 tPA 06 placebo Neurologic recovery better with tPA 30 Neurologic recovery better with tPA 30
more like to have minimal or no disabilitymore like to have minimal or no disability
First proven approved treatment for First proven approved treatment for strokestroke
Limitations of tPALimitations of tPA Only 4 of acute strokes receive tPAOnly 4 of acute strokes receive tPA (Kleindorfer et al Stroke 2004 35 e27-e29)(Kleindorfer et al Stroke 2004 35 e27-e29)
Only 22 of patients present within 3 hoursOnly 22 of patients present within 3 hours1048707 1048707 51 of these ineligible due to51 of these ineligible due to
bull bull Mild severityMild severity bull bull Medical or surgical historyMedical or surgical history bull bull Blood testsBlood tests
Sustained recanalization only 13Sustained recanalization only 13 (Alexandrov et al NEJM 2004 351 2170-8)(Alexandrov et al NEJM 2004 351 2170-8)
Concern for hemorrhageConcern for hemorrhage tPA potentiates apoptotic injury tPA potentiates apoptotic injury (Liu et al Nature Med 2004 101379-83)(Liu et al Nature Med 2004 101379-83)
PROACT II IA Lysis TrialPROACT II IA Lysis Trial Baseline 24 hours 8 days
Baseline 60 minutes 120 minutes
9mg IAProurokinase
Desmoteplase Trials DEDAS Desmoteplase Trials DEDAS DIASDIAS
Trial OverviewTrial Overview Double blind randomized placebo Double blind randomized placebo
controlled trialscontrolled trials IV delivery 3-9 hour time windowIV delivery 3-9 hour time window Plasminogen activator ndash from Plasminogen activator ndash from vampire bat vampire bat
salivasaliva Selection based on PWI-DWI MismatchSelection based on PWI-DWI Mismatch
MRI InclusionMRI Inclusion PWI defect at least 2 cm AND ~20 larger PWI defect at least 2 cm AND ~20 larger
than DWIthan DWI PWI should be obvious even visible on PWI should be obvious even visible on
raw imagesraw imagesMRI ExclusionMRI Exclusion
DWI gt 13 MCADWI gt 13 MCA MRA ICA occlusionMRA ICA occlusion
Desmoteplase ndash DIAS Desmoteplase ndash DIAS ResultsResults
Mechanical Thrombolysis Mechanical Thrombolysis devicesdevices
mechanical thrombolysis potentially extends the treatment mechanical thrombolysis potentially extends the treatment window because they act promptly at the site of the thrombuswindow because they act promptly at the site of the thrombus
The devices can retrieve large clots that pharmaceutical agents The devices can retrieve large clots that pharmaceutical agents may not successfully lysemay not successfully lyse
Patients treated with IV tPA may be considered for treatment of Patients treated with IV tPA may be considered for treatment of residual clot with some of these devicesresidual clot with some of these devices
suction-creating saline jets suction-creating saline jets laser energy ultrasound laser energy ultrasound a corkscrew apparatus to treat strokesa corkscrew apparatus to treat strokes The AngioJet systemThe AngioJet system uses saline jets that are directed back into the catheter to uses saline jets that are directed back into the catheter to
create a low-pressure zone around the catheter tip inducing create a low-pressure zone around the catheter tip inducing suction suction
The clot is pulled into the exhaust lumen and removed from the The clot is pulled into the exhaust lumen and removed from the vessel Although US Food and Drug Administration (FDA) has vessel Although US Food and Drug Administration (FDA) has approved this device for use in arteriovenous dialysis grafts and approved this device for use in arteriovenous dialysis grafts and fistulae and for the treatment of coronary arteries saphenous fistulae and for the treatment of coronary arteries saphenous vein grafts and peripheral vessels clinical trials for the vein grafts and peripheral vessels clinical trials for the treatment of acute stroke are no longer in progress treatment of acute stroke are no longer in progress
Most devices are used in cerebral vessels that 2-5 mm
The Latis laser device The Latis laser device used laser energy to ablate clots used laser energy to ablate clots Arteries 2-5 mm in diameter could be Arteries 2-5 mm in diameter could be
treated including the ICA M1 or M2 treated including the ICA M1 or M2 branch of the MCA A1 branch of the branch of the MCA A1 branch of the anterior cerebral artery (ACA) basilar anterior cerebral artery (ACA) basilar artery posterior cerebral artery (PCA) artery posterior cerebral artery (PCA) and vertebral and vertebral
Patients could receive treatment as late Patients could receive treatment as late as 8 hours after symptom onset in the as 8 hours after symptom onset in the anterior circulation and within 24 hours in anterior circulation and within 24 hours in the posterior circulation the posterior circulation
Endovascular Photo Acoustic Endovascular Photo Acoustic Recanalization (EPAR) Recanalization (EPAR)
A laser power source generated energy for the A laser power source generated energy for the systemsystem
The energy was delivered by means of The energy was delivered by means of fiberoptics to the tip of the catheter at the fiberoptics to the tip of the catheter at the treatment sitetreatment site
Absorption of laser light by darkly pigmented Absorption of laser light by darkly pigmented materials (ie the clot) occurred inside the 1-mm materials (ie the clot) occurred inside the 1-mm catheter tipcatheter tip
the system was designed to minimize scattering the system was designed to minimize scattering of laser light of laser light
Absorption converted photo energy to acoustic Absorption converted photo energy to acoustic energy which then emulsified the clot inside the energy which then emulsified the clot inside the catheter tip catheter tip
EKOS ultrasound( the EKOS ultrasound( the Ultrasound Thrombolytic Ultrasound Thrombolytic
Infusion Catheter) Infusion Catheter) combines the use of a distal ultrasound transducer with combines the use of a distal ultrasound transducer with
infusion of a thrombolytic agent through the infusion of a thrombolytic agent through the microcathetermicrocatheter
Ultrasound changes the structure of the clot to Ultrasound changes the structure of the clot to temporarily increase its permeability while providing an temporarily increase its permeability while providing an acoustic pressure gradient to move the drug into the clot acoustic pressure gradient to move the drug into the clot to speed its dissolution to speed its dissolution
The EKOS catheter is placed in the proximal portion of the The EKOS catheter is placed in the proximal portion of the clot clot
After a 2-mg bolus of tPA was injected through the After a 2-mg bolus of tPA was injected through the catheter catheter
the patient received a continuous infusion of IA tPA 03 the patient received a continuous infusion of IA tPA 03 mgmin to a maximum of 20 mg and simultaneous mgmin to a maximum of 20 mg and simultaneous ultrasound transmission for as long as 60 minutes ultrasound transmission for as long as 60 minutes
One patient was treated with a total of 4 units of One patient was treated with a total of 4 units of recombinant reteplase (Retavase) hand-injected over 60 recombinant reteplase (Retavase) hand-injected over 60 minutes minutes
Penumbra system Penumbra system The Penumbra system (Penumbra Inc) provides a dual The Penumbra system (Penumbra Inc) provides a dual
approach to clot extraction using aspiration followed by approach to clot extraction using aspiration followed by clot retrieval with a ring device if needed clot retrieval with a ring device if needed
Mechanical Embolus Removal in Cerebral Ischemia Mechanical Embolus Removal in Cerebral Ischemia (MERCI)(MERCI)
a corkscrew-like apparatus to remove blood clots from a corkscrew-like apparatus to remove blood clots from the brain in patients experiencing an ischemic stroke the brain in patients experiencing an ischemic stroke
The corkscrew itself resides in the catheter tip which The corkscrew itself resides in the catheter tip which shields it from the wall of the vessel until it is ready to be shields it from the wall of the vessel until it is ready to be burrowed into the clot Once lodged in the clot the device burrowed into the clot Once lodged in the clot the device and clot are withdrawn from the vessel and clot are withdrawn from the vessel
Snarelike devicesSnarelike devices Snares such as the Neuronet snare (Guidant Snares such as the Neuronet snare (Guidant
Endovascular Santa Clara CA) have been developed Endovascular Santa Clara CA) have been developed specifically for use in the treatment of strokes specifically for use in the treatment of strokes
These devices are simple in design and do not require the These devices are simple in design and do not require the clot to be amenable to emulsification clot to be amenable to emulsification
X-Sizer deviceX-Sizer device a device with small moving blades at the a device with small moving blades at the
catheter tip catheter tip This device the X-Sizer device (EndiCor Medical This device the X-Sizer device (EndiCor Medical
San Clemente CA) can be used to excise the San Clemente CA) can be used to excise the thrombus and aspirate it thrombus and aspirate it
The device was being evaluated in randomized The device was being evaluated in randomized studies of coronary vessels and in a registry of studies of coronary vessels and in a registry of patients with acute myocardial infarctionpatients with acute myocardial infarction
Although the manufacturer had modified the Although the manufacturer had modified the device for use in cerebral vessels a safety and device for use in cerebral vessels a safety and feasibility study was indefinitely suspended after feasibility study was indefinitely suspended after only 1 patient was treated with the device in only 1 patient was treated with the device in Europe Europe
Suction thrombectomySuction thrombectomy This method of mechanical thrombolysis is one of the This method of mechanical thrombolysis is one of the
simplestsimplest In this readily available technique suction is applied with In this readily available technique suction is applied with
a syringe to remove thrombus in the ICA a syringe to remove thrombus in the ICA It requires no other devicesIt requires no other devices A catheter with a large inner diameter (Brite Tip Cordis A catheter with a large inner diameter (Brite Tip Cordis
Corporation Miami FL) was placed in the symptomatic Corporation Miami FL) was placed in the symptomatic vessel and navigated over a guidewire into the thrombusvessel and navigated over a guidewire into the thrombus
A 60-mL syringe was used to aspirate the thrombus A 60-mL syringe was used to aspirate the thrombus Each patient required angioplasty and stenting of carotid Each patient required angioplasty and stenting of carotid
bifurcation stenosis and received daily aspirin and bifurcation stenosis and received daily aspirin and ticlopidine after the procedure No complications ticlopidine after the procedure No complications occurred occurred
Summary Acute Stroke Summary Acute Stroke ImagingImaging
PhysiologyPhysiology importance collaterals importance collaterals
ndash ndashGrowing role for perfusion Growing role for perfusion assessmentassessment
tPAtPA guidelines amp limitations guidelines amp limitations Signs on CT amp MRSigns on CT amp MR follow physiology follow physiology Stroke trialsStroke trials PWI-DWI mismatch PWI-DWI mismatch
ndash ndashTreat based on physiology not timeTreat based on physiology not time ProtocolsProtocols should be fast and should be fast and
comprehensivecomprehensive
Newer plasminogen activatorNewer plasminogen activator
DesmoteplaseDesmoteplase is a genetically engineered is a genetically engineered version of the clot-dissolving factor version of the clot-dissolving factor
found in the saliva found in the saliva of the vampire bat Desmodus rotundusof the vampire bat Desmodus rotundus moremore potent and more selective for fibrin-bound potent and more selective for fibrin-bound
plasminogen than any other known plasminogen plasminogen than any other known plasminogen activatoractivator
Unlike tissue plasminogen activator (tPA) desmoteplase Unlike tissue plasminogen activator (tPA) desmoteplase is not activated by fibrinogen or -amyloid proteins is not activated by fibrinogen or -amyloid proteins factors that may exacerbate the risk for ICH factors that may exacerbate the risk for ICH
The effect of IV administration of desmoteplase 3ndash9 The effect of IV administration of desmoteplase 3ndash9 hours after symptom onset in patients with stroke who hours after symptom onset in patients with stroke who present with mismatch on MR imaging or CT perfusion present with mismatch on MR imaging or CT perfusion
3 DefibrinogenatingFibrinogenolytic 3 DefibrinogenatingFibrinogenolytic Agents Agents
AncrodAncrod(Viprinex)(Viprinex) is is the purified fraction of the Malayan pit viper venomthe purified fraction of the Malayan pit viper venom It acts by directly cleaving and inactivating fibrinogen It acts by directly cleaving and inactivating fibrinogen
and thus indirectly promoting anticoagulation and thus indirectly promoting anticoagulation The reduction in the blood levels of fibrinogen also The reduction in the blood levels of fibrinogen also
leads to a reduced blood viscosity which may improve leads to a reduced blood viscosity which may improve blood flow to the affected areas of the brain blood flow to the affected areas of the brain
In the Stroke Treatment with Ancrod Trial 500 In the Stroke Treatment with Ancrod Trial 500 patients with stroke presenting within 3 hours of patients with stroke presenting within 3 hours of symptom onset were randomized to receive ancrod (symptom onset were randomized to receive ancrod (n n 248) or a placebo (n 252) Good outcome (Barthel 248) or a placebo (n 252) Good outcome (Barthel Index 95ndash100 at 3 months) was achieved in 4221 Index 95ndash100 at 3 months) was achieved in 4221 and 344 of the patients respectively and 344 of the patients respectively
2 Direct Fibrinolytics2 Direct Fibrinolytics
Microplasmin (Microplasmin (ThromboGenics Heverlee Belgium)ThromboGenics Heverlee Belgium) is a truncated form of plasmin that is more resistant to the effects is a truncated form of plasmin that is more resistant to the effects
of antiplasmin of antiplasmin microplasmin can be used upto 4ndash12 hours after stroke onset microplasmin can be used upto 4ndash12 hours after stroke onset There was no evidence of increased bleeding risk with There was no evidence of increased bleeding risk with
microplasminmicroplasmin
Alfimeprase (Nuvelo San Carlos Calif)Alfimeprase (Nuvelo San Carlos Calif) is a recombinant truncated form of fibrolase a fibrinolytic zinc metalloproteinase is a recombinant truncated form of fibrolase a fibrinolytic zinc metalloproteinase
isolated from the venom of the southern copperhead snake isolated from the venom of the southern copperhead snake It degrades fibrin directly and achieves thrombolysis independent It degrades fibrin directly and achieves thrombolysis independent
of plasmin formationof plasmin formation its thrombolytic activity appears to be localized to the site of its thrombolytic activity appears to be localized to the site of
delivery These properties should theoretically result in faster delivery These properties should theoretically result in faster recanalization and lower hemorrhagic conversion riskrecanalization and lower hemorrhagic conversion risk
Anti-fibrinolyticsAnti-fibrinolytics
to limit fibrinolytic activityto limit fibrinolytic activity -aminocaproic acid (EACA) -aminocaproic acid (EACA) competitively inhibitscompetitively inhibits plasminogen and plasminogen activators from plasminogen and plasminogen activators from
binding to fibrinbinding to fibrin
alpha2-antiplasminalpha2-antiplasmin a serine protease inhibitor that a serine protease inhibitor that neutralizes any free circulating plasminneutralizes any free circulating plasmin
Plasminogen activator inhibitor-1Plasminogen activator inhibitor-1 a serine protease a serine protease inhibitor that inhibits tissue-type plasminogen inhibitor that inhibits tissue-type plasminogen activatoractivator
Glycoprotein (GP) IIbIIIa antagonistsGlycoprotein (GP) IIbIIIa antagonists
such as ReoPro (abciximab) Integrilin such as ReoPro (abciximab) Integrilin (eptifibatide) or Aggrastat (tirofiban) in (eptifibatide) or Aggrastat (tirofiban) in ischemic stroke remains investigational ischemic stroke remains investigational Deshmukh et al38 reported 21 patients with Deshmukh et al38 reported 21 patients with large-vessel occlusion refractory to IAT with large-vessel occlusion refractory to IAT with rtPA who were treated with IV andor IA rtPA who were treated with IV andor IA abciximab eptifibatide or tirofiban abciximab eptifibatide or tirofiban
IA Mechanical Approaches in Acute Ischemic Stroke IA Mechanical Approaches in Acute Ischemic Stroke Mechanical strategies have several advantagesMechanical strategies have several advantages First they lessen and may even preclude the use of chemical First they lessen and may even preclude the use of chemical
thrombolytics in this manner very likely reducing the risk of ICHthrombolytics in this manner very likely reducing the risk of ICH Second by avoiding the use of chemical thrombolytics it is Second by avoiding the use of chemical thrombolytics it is
possible to extend the treatment window beyond the limit of 6ndash8 possible to extend the treatment window beyond the limit of 6ndash8 hours hours
Third mechanically fragmenting a clot increases the surface area Third mechanically fragmenting a clot increases the surface area accessible to fibrinolytic agents and allows inflow of fresh accessible to fibrinolytic agents and allows inflow of fresh plasminogen which in turn may increase the speed of plasminogen which in turn may increase the speed of thrombolysis thrombolysis
Finally clot-retrieval devices may provide faster recanalization Finally clot-retrieval devices may provide faster recanalization
The disadvantages of the mechanical The disadvantages of the mechanical approaches approaches technical difficulty of navigating mechanical technical difficulty of navigating mechanical
devices into the intracranial circulation excessive devices into the intracranial circulation excessive trauma to the vasculature (potentially leading to trauma to the vasculature (potentially leading to vasospasm vessel dissection perforation or vasospasm vessel dissection perforation or rupture) rupture)
fragmented thrombus causing distal embolization fragmented thrombus causing distal embolization into previously unaffected territories into previously unaffected territories
Nevertheless the advantages of mechanical stroke Nevertheless the advantages of mechanical stroke therapy appear to significantly outweigh its therapy appear to significantly outweigh its disadvantages and risksdisadvantages and risks
Contraindications to Thrombolytic Contraindications to Thrombolytic agents agents
Recent thoracic abdominal or Recent thoracic abdominal or intracranial surgeryintracranial surgery
Recent haemorrhagic CVA Head injury Recent haemorrhagic CVA Head injury or neoplasmor neoplasm
Bleeding ulcerBleeding ulcer Anticipated invasive procedures (arterial Anticipated invasive procedures (arterial
punctures biopsies)punctures biopsies) Concurrent hemostatic dysfunctionConcurrent hemostatic dysfunction
Monitoring of thrombolytic Monitoring of thrombolytic therapytherapy
Thrombin time Measures the availability of functional
fibrinogen Normal thrombin time is 10-14 sec Prolonged when fibrinogen level is below
75-100 mgdl
Half Life of ThrombolyticsHalf Life of ThrombolyticsAgent Administration Half Life
Streptokinase IA 60-80min
Urokinase IAIV 9-12min
rTPA IAIV 6min
Abciximab(Reopro) IAIV 12hour
Aspirin POIV 15-20min
Heparin IVSC 60min
Coumadin PO 15-25 days
Anti Platelet DrugsAnti Platelet DrugsDrug Drug Mechanism Mechanism UsesUsesAspirinAspirin Permanently inhibits Permanently inhibits
COX-1 and COX-2COX-1 and COX-2CADCAD
Stroke-TIAsStroke-TIAs
NSAIDsNSAIDs Reversibly inhibits Reversibly inhibits COX-1COX-1
LimitedLimited
DipyridamoleDipyridamole Inhibits PDE increases Inhibits PDE increases cAMPcAMP
TIAsTIAs
ThenopyridinesThenopyridines
(Ticlopidine(Ticlopidine
ClopidrgrelClopidrgrel))
Inhibits ADP Inhibits ADP
PlatAg PlatAg
TIAsStrokeTIAsStroke
CAD PVDCAD PVD
Abciximab (ReoPro)Abciximab (ReoPro)
Eptifibatide (Integrilin)Eptifibatide (Integrilin)
TirofibanTirofiban
GP IIBIIIA InhibitorsGP IIBIIIA Inhibitors
Stroke- TIAs Stroke- TIAs
MonitoringMonitoring
Bleeding timeBleeding time
Optical aggregometryOptical aggregometry
Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay
Bleeding timeBleeding time
Requires a skin incision (usually made on the ear lobe or Requires a skin incision (usually made on the ear lobe or forearm offorearm of
a depth that results in disruption of capillary loops and a depth that results in disruption of capillary loops and small vessels)small vessels)
AdvantagesAdvantages Universally availableUniversally available Relatively simple techniquesRelatively simple techniques Can be performed bedsideCan be performed bedside
DisadvantagesDisadvantages Insensitive inaccurate non-specific techniqueInsensitive inaccurate non-specific technique
Poorly reproducible (as depends on multiple variables)Poorly reproducible (as depends on multiple variables)
Optical aggregometryOptical aggregometry
Gold standard assay for platelet functionGold standard assay for platelet function Agonist induced aggregation is measuredAgonist induced aggregation is measured Different agonist are available for different Different agonist are available for different
agentsagents However require unique expertise and are not However require unique expertise and are not
universally availableuniversally available Aspirin measured with ADP or AA(gt70 Aspirin measured with ADP or AA(gt70
aggregation so resistance)aggregation so resistance) Clopidogrel( ADP gt 90 aggregation means Clopidogrel( ADP gt 90 aggregation means
resistance) resistance)
Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay
Can be performed bed sideCan be performed bed side Different assay devices with different Different assay devices with different
agonist are used for each of different agonist are used for each of different antiplatelet agents antiplatelet agents
For Aspirin AA is used (result is reported as aspirin For Aspirin AA is used (result is reported as aspirin reaction units [ARU] ARUgt 550 indicates non-reaction units [ARU] ARUgt 550 indicates non-responsiveness)responsiveness)
Verify IIbIIIa assay device uses TRAP as agonist for Verify IIbIIIa assay device uses TRAP as agonist for Abciximab and TirofibanAbciximab and Tirofiban
Practical Applications Practical Applications related to specific related to specific
Neurovascular Neurovascular interventionsinterventions
Acute ischemic StrokeAcute ischemic Stroke When an artery occludes neurons are affected When an artery occludes neurons are affected
differently depending upon the amount of residual blood differently depending upon the amount of residual blood flowflow
Normal cerebral blood flow is greater than 50 mL100 Normal cerebral blood flow is greater than 50 mL100 mgminmgmin
Once blood flow decreases to less than 20 mL100 Once blood flow decreases to less than 20 mL100 mgmin infarction occursmgmin infarction occurs
If blood flow decreases to less than 10 mL100 mgmin If blood flow decreases to less than 10 mL100 mgmin irreversible neuronal death occurs rapidly irreversible neuronal death occurs rapidly
Blood flow between 11 and 20 mL100 mgmin is thought Blood flow between 11 and 20 mL100 mgmin is thought to represent the ischemic penumbra an area where the to represent the ischemic penumbra an area where the cells are functionally silent because of ischemia but are cells are functionally silent because of ischemia but are still able to recover if blood flow is restored still able to recover if blood flow is restored
Many acute stroke therapies are targeted toward Many acute stroke therapies are targeted toward restoring flow or function to the ischemic penumbrarestoring flow or function to the ischemic penumbra
Therapeutic window in Therapeutic window in management of acute Ischemic management of acute Ischemic
StrokeStrokeThe early diagnosis of ischemic stroke is critical to the The early diagnosis of ischemic stroke is critical to the
with only a narrow therapeutic window in the first few with only a narrow therapeutic window in the first few hours following stroke ictushours following stroke ictus
Diagnosis in the first 3 hours postictus provides the Diagnosis in the first 3 hours postictus provides the opportunity for intravenous or intraarterial thrombolysis opportunity for intravenous or intraarterial thrombolysis and intra-arterial clot mechanical treatment which and intra-arterial clot mechanical treatment which improve the outcome improve the outcome
Diagnosis in the time period between 3 and 6 hours Diagnosis in the time period between 3 and 6 hours provides an opportunity for intra-arterial thrombolysis provides an opportunity for intra-arterial thrombolysis and mechanical treatment and mechanical treatment
Involvement of the posterior circulation especially the Involvement of the posterior circulation especially the basilar artery is treated by some regardless of time of basilar artery is treated by some regardless of time of onset or up until 12 to 24 hours in some practices This is onset or up until 12 to 24 hours in some practices This is related to the potentially high mortality and morbidity related to the potentially high mortality and morbidity associated with basilar artery thrombosisassociated with basilar artery thrombosis
Infarct evaluation on angiographyInfarct evaluation on angiography(CT angiography and catheter (CT angiography and catheter
angiography)angiography)CTA is an excellent first-line examination for CTA is an excellent first-line examination for
evaluation of the head and neck arteries evaluation of the head and neck arteries In comparison with catheter angiography In comparison with catheter angiography
what it gives up in resolution and dynamic what it gives up in resolution and dynamic properties it makes up for with rapid properties it makes up for with rapid acquisition of a 3-D dataset and the potential acquisition of a 3-D dataset and the potential for assessment of whole-brain perfusion and for assessment of whole-brain perfusion and better parenchymal evaluationbetter parenchymal evaluation
Moreover CTA illustrates not only arterial Moreover CTA illustrates not only arterial stenosis or occlusion but also the vessel wall stenosis or occlusion but also the vessel wall This factor is most important for evaluation of This factor is most important for evaluation of intramural dissection and thrombosed intramural dissection and thrombosed aneurysms which may both complicate aneurysms which may both complicate evaluation of stroke patientsevaluation of stroke patients
Early angiographic signs of strokes Early angiographic signs of strokes both CTA both CTA and DSA and DSA
Vessel occlusion or cutoff related to Vessel occlusion or cutoff related to thromboembolithromboemboli
aneurysms aneurysms arterial dissection arterial dissection Meniscus or flattened shape to clot Meniscus or flattened shape to clot
(recent) versus reverse meniscus (older)(recent) versus reverse meniscus (older) tram track (nonocclusive or recanalized tram track (nonocclusive or recanalized
clot) clot) delayed (antegrade) flow (manifest as delayed (antegrade) flow (manifest as
decreased whole-brain perfusion on CTA)decreased whole-brain perfusion on CTA) retrograde collateral flowretrograde collateral flow
Non-occlusive left MCA thrombus on 3-D imaging performed from CTA source data and was confirmed at catheter angiography
Therapy to be started within a 6-hr Therapy to be started within a 6-hr time to treatment (TTT) window time to treatment (TTT) window (while in case of IV thrombolysis (while in case of IV thrombolysis therapy to be started with in 3hrs)therapy to be started with in 3hrs)
Exclusion criteria Exclusion criteria Rapidly improving neurologic deficit or Rapidly improving neurologic deficit or Sustained blood pressure of gt180100 Sustained blood pressure of gt180100 Hemorrhage is detected on CTHemorrhage is detected on CT Infarct involving gt more than 13 rd Infarct involving gt more than 13 rd
territory of MCAterritory of MCA MRADWI-Perfusion mismatchlt 20MRADWI-Perfusion mismatchlt 20 Definite hypodensity on CTDefinite hypodensity on CT
Intra-arterial Thrombolysis
Fibrinolytics + AntiplateletsFibrinolytics + Antiplatelets
PlasminogenPlasminogen activators through fibrinolysis exposes activators through fibrinolysis exposes free thrombin and paradoxically stimulatesfree thrombin and paradoxically stimulates platelet platelet aggregation which leads to formation of aaggregation which leads to formation of a platelet platelet thrombus (white clot) thrombus (white clot)
This new thrombus is relatively resistant to This new thrombus is relatively resistant to fibrinolyticsfibrinolytics
So new regimen in case of acute stroke isSo new regimen in case of acute stroke is fibrinolytics + antiplatelet drugsfibrinolytics + antiplatelet drugs
rtPA + IIbIIIa inhibitors( tirofiban rtPA + IIbIIIa inhibitors( tirofiban abciximab) orabciximab) or
Urokinase + IIbIIIa Urokinase + IIbIIIa inhibitors( tirofiban abciximab)inhibitors( tirofiban abciximab)
Intra-arterial Thrombolysis Tirofiban (04 microgkgmin bolus for 3 min followed by Tirofiban (04 microgkgmin bolus for 3 min followed by
0125 ugkgmin)0125 ugkgmin)
++
Heparin (2000ndash3000 IU bolus followed by Heparin (2000ndash3000 IU bolus followed by 1000 IUhour infusion 1000 IUhour infusion
with ACT maintained bw 200-300) throughout the with ACT maintained bw 200-300) throughout the interventional procedure and for 24ndash48 hours thereafter when interventional procedure and for 24ndash48 hours thereafter when there is neither intraprocedural bleeding nor suspicion of there is neither intraprocedural bleeding nor suspicion of increased risk of bleeding increased risk of bleeding
Maximum dose of Urokinase Maximum dose of Urokinase Anterior circulation stroke - 500000 IU (mean 400000 Anterior circulation stroke - 500000 IU (mean 400000
IU range 300000ndash500000 IU)IU range 300000ndash500000 IU) Posterior circulation stroke -1000000 IU (mean 837000 Posterior circulation stroke -1000000 IU (mean 837000
IU range 300000ndash1000000 IU)IU range 300000ndash1000000 IU)American Journal of NeuroradiologyAmerican Journal of Neuroradiology 262595-2601 2005262595-2601 2005
Intravenous ThrombolysisIntravenous Thrombolysis
The first method to restore cerebral The first method to restore cerebral perfusion is clot lysis with the goal perfusion is clot lysis with the goal of re-establishing blood flow to the of re-establishing blood flow to the affected tissue affected tissue
IV thrombolysis rt-PA is the only IV thrombolysis rt-PA is the only FDA- approved treatment for AIS FDA- approved treatment for AIS
Fibrinolysis is enhanced powerfully Fibrinolysis is enhanced powerfully by rt-PAby rt-PA
Intravenous rTPA Intravenous rTPA administration administration protocolprotocol
Total dose of rt-PA 09 mgkg (maximum dose Total dose of rt-PA 09 mgkg (maximum dose 90 mg)90 mg)
Give 10 as initial IV bolusGive 10 as initial IV bolus Infuse remainder over 1 hourInfuse remainder over 1 hour Admit patient to an ICU or stroke unit for Admit patient to an ICU or stroke unit for
monitoringmonitoring Neurologic assessments every 15 minutes Neurologic assessments every 15 minutes
during infusion then every 30 minutes for next during infusion then every 30 minutes for next 6 hours then every hour until 24hours after 6 hours then every hour until 24hours after treatmenttreatment
Favorable Outcome vs Treatment Time Favorable Outcome vs Treatment Time with IV rTPAwith IV rTPA
Protocol limit = 3 hrs
Benefit ~ 45 hrs
Thromboembolism During coilingThromboembolism During coiling Most feared and frequent complication Most feared and frequent complication Reported incidence - Approx 7 Reported incidence - Approx 7 SourcesSources of Thromboembolism are of Thromboembolism are
- Clots at the aneurysmal neck during or immediately- Clots at the aneurysmal neck during or immediately after after embolization embolization
- Thrombus forming on catheters during- Thrombus forming on catheters during proceduresprocedures
- Stenosis of an adjacent artery dt coil mass- Stenosis of an adjacent artery dt coil mass or herniationor herniation
- Migration of intraaneurysmal- Migration of intraaneurysmal thrombus during coil thrombus during coil placement placement
- Slow flow dt vasospasm - Slow flow dt vasospasm
- Rare and unlikely causes are hypercoagulable- Rare and unlikely causes are hypercoagulable state such state such as antiphospholipid antibody syndrome or due to HITas antiphospholipid antibody syndrome or due to HIT
Occur more often with wide-necked aneurysms (dt Occur more often with wide-necked aneurysms (dt increased exposed surface area of thrombogenic coil increased exposed surface area of thrombogenic coil material)material)
Current regimen of endovascular Current regimen of endovascular managementmanagement
The The glycoprotein IIbIIIa antagonist tirofiban glycoprotein IIbIIIa antagonist tirofiban (04 (04 microgkgmin bolus for 30 minutes followed by infusion of microgkgmin bolus for 30 minutes followed by infusion of 0125 ugkgmin until the thrombus dissolved) 0125 ugkgmin until the thrombus dissolved)
Intraarterial thrombolysis with Intraarterial thrombolysis with urokinase or r- TPA urokinase or r- TPA increase of intravenous (IV) heparin (measured by increase of intravenous (IV) heparin (measured by
ACT) ACT) Intravenous aspirin Intravenous aspirin
Coil-related platelet aggregation (white clot) is Coil-related platelet aggregation (white clot) is unlikely to respond to fibrinolytics but has a high risk unlikely to respond to fibrinolytics but has a high risk of hemorrhage (In ISAT) all 5 patients who had of hemorrhage (In ISAT) all 5 patients who had received thrombolytic therapy with tPA to treat a received thrombolytic therapy with tPA to treat a thromboembolic complication after endovascular thromboembolic complication after endovascular treatment rebleed and all of these patients died)treatment rebleed and all of these patients died)
IntracranialIntracranial Stenting Stenting Metallic foreign body such as stent will accumulate Metallic foreign body such as stent will accumulate
thrombus in the absence of platelet inhibitionthrombus in the absence of platelet inhibition Antiplatelet drugs are important to prevent peri or Antiplatelet drugs are important to prevent peri or
post-interventional thromboembolic eventspost-interventional thromboembolic events Optimal treatment regimens has not been determined Optimal treatment regimens has not been determined
but usually but usually Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-
procedureprocedureOrOr
Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on
morning of proceduremorning of procedure
If need to use stent is not pre-planned thanIf need to use stent is not pre-planned than
Abciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkgAbciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkg IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)
Glycoprotein IIbIIIa inhibitor are not used routinely during elective Glycoprotein IIbIIIa inhibitor are not used routinely during elective stenting procedure dt increased risk of ICH stenting procedure dt increased risk of ICH
Carotid StentingCarotid Stenting
Pre-procedurePre-procedure
Double Antiplatelet therapy is routinely given Double Antiplatelet therapy is routinely given beginning at least 3beginning at least 3
days before the proceduredays before the procedure
Aspirin 325mgd+Clopidogrel 75mgdAspirin 325mgd+Clopidogrel 75mgd During procedureDuring procedure
Heparin is given with target clotting time of 250-Heparin is given with target clotting time of 250-300sec300sec
Post-procedure Post-procedure
Aspirin 325mg is continued indefinitely and Aspirin 325mg is continued indefinitely and
Clopidogrel 75mgd for at least 6 weeks Clopidogrel 75mgd for at least 6 weeks
Inclusion criteria for Local ThrombolysisInclusion criteria for Local Thrombolysis a)a) Patients in severe clinical grade on admission Patients in severe clinical grade on admission
with evidence of dural venous sinus with evidence of dural venous sinus thrombosis and restrictive venous outflow on thrombosis and restrictive venous outflow on cerebral angiogramcerebral angiogram
b)b) Patients in clinical grade 3 worsening on Patients in clinical grade 3 worsening on heparin therapy Restriction to venous heparin therapy Restriction to venous outflow was defined as an increase in brain outflow was defined as an increase in brain circulation time gt 12 s delay in the drainage circulation time gt 12 s delay in the drainage of cortical veins with cortical veins hanging of cortical veins with cortical veins hanging in spacein space
Treatment Options for Venous Thrombosis
CT Grading for Venous ThrombosisCT Grading for Venous Thrombosis Grade I no parenchymal change Grade I no parenchymal change
(hyperdense (hyperdense sinuses cortical veins empty sinuses cortical veins empty delta sign)delta sign)
Grade II non hemorrhagic venous infarct Grade II non hemorrhagic venous infarct without mass effect without mass effect
Grade III non-hemorrhagic infarct with Grade III non-hemorrhagic infarct with mass effectmass effect
Grade IV hemorrhagic venous infarct (max Grade IV hemorrhagic venous infarct (max diameter lt 3 cm) with no mass effectdiameter lt 3 cm) with no mass effect
Grade V hemorrhagic venous infarct (max Grade V hemorrhagic venous infarct (max diameter gt 3 cm) with mass effect diameter gt 3 cm) with mass effect
Local ThrombolysisLocal Thrombolysis
Femoral Jugular access was secured and a guiding Femoral Jugular access was secured and a guiding catheter was placed in the jugular bulb catheter was placed in the jugular bulb Mechanical Mechanical clot maceration clot maceration was done with the guidewire was done with the guidewire following which a microcatheter (was navigated and following which a microcatheter (was navigated and placed in the thrombosed segment of sinus confirmed placed in the thrombosed segment of sinus confirmed on a selective venogram on a selective venogram
Urokinase infusion Bolus dose of 2-6 lacs followed Urokinase infusion Bolus dose of 2-6 lacs followed by 60000 to 100000 units per hour along with by 60000 to 100000 units per hour along with periodic check venogram Along with maintenance periodic check venogram Along with maintenance systemic infusion of Heparinsystemic infusion of Heparin Other agents such as Other agents such as streptokinase altepase or rTPAstreptokinase altepase or rTPA can be also used can be also used
After thrombolysis patient should subjected to oral After thrombolysis patient should subjected to oral anticoagulation for six monthsanticoagulation for six months
Low-molecular-weight Low-molecular-weight heparinheparin
PharmacologyPharmacologyLMWH as its name suggests is a glycosaminoglycan that is approximatelyLMWH as its name suggests is a glycosaminoglycan that is approximately
one third the molecular weight of UFH It is derived from UFH through one third the molecular weight of UFH It is derived from UFH through variousvarious
depolymerization processes LMWH binds to antithrombin which in turn depolymerization processes LMWH binds to antithrombin which in turn
Neutralizes actors Xa and IIa Because LMWH lacks many of the longer Neutralizes actors Xa and IIa Because LMWH lacks many of the longer chains chains
required for binding to thrombin it has less ability to neutralize thrombin required for binding to thrombin it has less ability to neutralize thrombin
relativeto its ability to neutralize factor Xa LMWH also has less relativeto its ability to neutralize factor Xa LMWH also has less nonspecific nonspecific
binding to other proteins There is greater bioavailability with more binding to other proteins There is greater bioavailability with more predictable predictable
pharmacokinetics that eliminates the need for monitoring The smaller pharmacokinetics that eliminates the need for monitoring The smaller size also size also
allows for enhanced subcutaneous absorption when compared with UFHallows for enhanced subcutaneous absorption when compared with UFH
Three LMWH preparations are Three LMWH preparations are currently approved for use in the currently approved for use in the United States (1) enoxaparin (2) United States (1) enoxaparin (2) dalteparin and (3) tinzaparin dalteparin and (3) tinzaparin
They are all administered They are all administered subcutaneously at intervals of either subcutaneously at intervals of either once or twice daily for both once or twice daily for both prophylaxis and treatment dosesprophylaxis and treatment doses
Few Experiences of Few Experiences of ThrombolysisThrombolysis
Vickey 25 Yrs male patient presented Vickey 25 Yrs male patient presented with 12with 12thth day HO severe headache with day HO severe headache with right sided hemiplegiaright sided hemiplegia
MRI shows thrombosis of the superior MRI shows thrombosis of the superior sagittal left transverse left sigmoid sagittal left transverse left sigmoid sinuses and cortical veins in the fronto-sinuses and cortical veins in the fronto-parietal regions with eo haemorrhagic parietal regions with eo haemorrhagic infarct in the left cerebral hemisphere infarct in the left cerebral hemisphere with mass effect( Grade ndashV)with mass effect( Grade ndashV)
Sashi Srivastava 64 yrs FSashi Srivastava 64 yrs F In a follow up case of MRD with infra-renal In a follow up case of MRD with infra-renal
aortic abdominal and bilateral renal artery aortic abdominal and bilateral renal artery thrombosis renal angiogram shows filling thrombosis renal angiogram shows filling defects in the right Renal artery defects in the right Renal artery
Initially Renal angioplasty was done Initially Renal angioplasty was done Following angioplasty few thrombi are seem Following angioplasty few thrombi are seem to extends into the segmental branches and to extends into the segmental branches and causing blockage So Thrombolysis was causing blockage So Thrombolysis was plane to dissolve the run-out thrombi with plane to dissolve the run-out thrombi with urokinase urokinase
Rakesh 34yrsMRakesh 34yrsM Left SFA pseudoaneurysm with Left SFA pseudoaneurysm with
Covered stent placementCovered stent placement Pre operative antiplatelets with post Pre operative antiplatelets with post
procedure heparin Tirofiban procedure heparin Tirofiban followed by aspirin and clopidogrel followed by aspirin and clopidogrel were usedwere used
IAT may be a treatment option for selected patients IAT may be a treatment option for selected patients Possible selection criteria include Possible selection criteria include
presentation between 3 and 6 hours from symptom onsetpresentation between 3 and 6 hours from symptom onset major cerebral artery occlusion major cerebral artery occlusion severe neurologic deficits severe neurologic deficits high risk of systemic hemorrhage with IV rt-PA (eg recent high risk of systemic hemorrhage with IV rt-PA (eg recent
surgery) surgery) The MERCI (Mechanical Embolus Removal in Cerebral The MERCI (Mechanical Embolus Removal in Cerebral
Ischemia) retrievalIschemia) retrieval system system
Has been FDA-approved for recanalizing acutely occluded Has been FDA-approved for recanalizing acutely occluded cerebral arteries cerebral arteries
In the Multi-MERCI study patients who did not improve In the Multi-MERCI study patients who did not improve immediately after IV rt-PA underwent mechanical immediately after IV rt-PA underwent mechanical embolectomy within 8 hours of symptom onset embolectomy within 8 hours of symptom onset
Partial or complete recanalization occurred in 74 of Partial or complete recanalization occurred in 74 of patientspatients
with a symptomatic intracerebral hemorrhage (sICH) rate of with a symptomatic intracerebral hemorrhage (sICH) rate of 67 67
Mechanical embolectomy with the MERCI retriever may be a Mechanical embolectomy with the MERCI retriever may be a feasible and safe option for patients after IV rt-PAfeasible and safe option for patients after IV rt-PA
Penumbra stroke systemPenumbra stroke system This device combines two methods of clot This device combines two methods of clot
extraction aspiration and mechanical extraction aspiration and mechanical extraction extraction
First the clot is aspirated then a thrombus First the clot is aspirated then a thrombus removal ring can be used if necessary to removal ring can be used if necessary to remove remaining clot remove remaining clot
successful recanalizing 82successful recanalizing 82 Bridging therapyBridging therapy
06 mgkg IV rt-PA followed by IAT with IA rt-06 mgkg IV rt-PA followed by IAT with IA rt-PA (up to 20 mg)PA (up to 20 mg)
achieved a higher recanalization rateachieved a higher recanalization rate
Criteria for thrombolysis with rTPACriteria for thrombolysis with rTPA
Inclusion criteriaInclusion criteria Clinical signs and symptoms consistent with ischemic Clinical signs and symptoms consistent with ischemic
strokestroke Patient last seen normal within 3 hoursPatient last seen normal within 3 hours Measurable neurologic deficitMeasurable neurologic deficit
Exclusion criteriaExclusion criteria Any hemorrhage on neuroimaging (CT or MRI)Any hemorrhage on neuroimaging (CT or MRI) Symptoms suggestive of subarachnoid hemorrhageSymptoms suggestive of subarachnoid hemorrhage Seizure at stroke onset that is thought to contribute to Seizure at stroke onset that is thought to contribute to
neurologic deficitneurologic deficit Hypodensity greater than one third cerebral hemisphere Hypodensity greater than one third cerebral hemisphere
on CTon CT SBP greater than 185 mm Hg or DBP greater than 110 SBP greater than 185 mm Hg or DBP greater than 110
mm Hgmm Hg International normalized ratio (INR) greater than 17International normalized ratio (INR) greater than 17
Ischemic Stroke Ischemic Stroke Treatment ndash 2006Treatment ndash 2006
IV tissue plasminogen activator (tPA)IV tissue plasminogen activator (tPA) ndash ndash Only FDA-approved acute stroke drugOnly FDA-approved acute stroke drug ndash ndash 3 hour treatment window3 hour treatment window
MERCI - Concentric clot retrieval MERCI - Concentric clot retrieval devicedevice ndash ndash Rescue therapy - approved 2004Rescue therapy - approved 2004 ndash ndash Device approval (not outcomes-based)Device approval (not outcomes-based)
Off label approachesOff label approaches ndash ndash IV tPA after 3 hoursIV tPA after 3 hours ndash ndash IV-IA tPA sequential strategiesIV-IA tPA sequential strategies ndash ndash IA tPA clot angioplasty fragmentationIA tPA clot angioplasty fragmentation ndash ndash Ultrasound-assisted tPA lysisUltrasound-assisted tPA lysis
rt-PA Trials NINDSrt-PA Trials NINDS
Acute stroke - 624 patientsAcute stroke - 624 patients Treat within 3 hrsTreat within 3 hrs Intravenous 09 mgkg rt-PA vs placeboIntravenous 09 mgkg rt-PA vs placebo Hemorrhage 64 tPA 06 placeboHemorrhage 64 tPA 06 placebo Neurologic recovery better with tPA 30 Neurologic recovery better with tPA 30
more like to have minimal or no disabilitymore like to have minimal or no disability
First proven approved treatment for First proven approved treatment for strokestroke
Limitations of tPALimitations of tPA Only 4 of acute strokes receive tPAOnly 4 of acute strokes receive tPA (Kleindorfer et al Stroke 2004 35 e27-e29)(Kleindorfer et al Stroke 2004 35 e27-e29)
Only 22 of patients present within 3 hoursOnly 22 of patients present within 3 hours1048707 1048707 51 of these ineligible due to51 of these ineligible due to
bull bull Mild severityMild severity bull bull Medical or surgical historyMedical or surgical history bull bull Blood testsBlood tests
Sustained recanalization only 13Sustained recanalization only 13 (Alexandrov et al NEJM 2004 351 2170-8)(Alexandrov et al NEJM 2004 351 2170-8)
Concern for hemorrhageConcern for hemorrhage tPA potentiates apoptotic injury tPA potentiates apoptotic injury (Liu et al Nature Med 2004 101379-83)(Liu et al Nature Med 2004 101379-83)
PROACT II IA Lysis TrialPROACT II IA Lysis Trial Baseline 24 hours 8 days
Baseline 60 minutes 120 minutes
9mg IAProurokinase
Desmoteplase Trials DEDAS Desmoteplase Trials DEDAS DIASDIAS
Trial OverviewTrial Overview Double blind randomized placebo Double blind randomized placebo
controlled trialscontrolled trials IV delivery 3-9 hour time windowIV delivery 3-9 hour time window Plasminogen activator ndash from Plasminogen activator ndash from vampire bat vampire bat
salivasaliva Selection based on PWI-DWI MismatchSelection based on PWI-DWI Mismatch
MRI InclusionMRI Inclusion PWI defect at least 2 cm AND ~20 larger PWI defect at least 2 cm AND ~20 larger
than DWIthan DWI PWI should be obvious even visible on PWI should be obvious even visible on
raw imagesraw imagesMRI ExclusionMRI Exclusion
DWI gt 13 MCADWI gt 13 MCA MRA ICA occlusionMRA ICA occlusion
Desmoteplase ndash DIAS Desmoteplase ndash DIAS ResultsResults
Mechanical Thrombolysis Mechanical Thrombolysis devicesdevices
mechanical thrombolysis potentially extends the treatment mechanical thrombolysis potentially extends the treatment window because they act promptly at the site of the thrombuswindow because they act promptly at the site of the thrombus
The devices can retrieve large clots that pharmaceutical agents The devices can retrieve large clots that pharmaceutical agents may not successfully lysemay not successfully lyse
Patients treated with IV tPA may be considered for treatment of Patients treated with IV tPA may be considered for treatment of residual clot with some of these devicesresidual clot with some of these devices
suction-creating saline jets suction-creating saline jets laser energy ultrasound laser energy ultrasound a corkscrew apparatus to treat strokesa corkscrew apparatus to treat strokes The AngioJet systemThe AngioJet system uses saline jets that are directed back into the catheter to uses saline jets that are directed back into the catheter to
create a low-pressure zone around the catheter tip inducing create a low-pressure zone around the catheter tip inducing suction suction
The clot is pulled into the exhaust lumen and removed from the The clot is pulled into the exhaust lumen and removed from the vessel Although US Food and Drug Administration (FDA) has vessel Although US Food and Drug Administration (FDA) has approved this device for use in arteriovenous dialysis grafts and approved this device for use in arteriovenous dialysis grafts and fistulae and for the treatment of coronary arteries saphenous fistulae and for the treatment of coronary arteries saphenous vein grafts and peripheral vessels clinical trials for the vein grafts and peripheral vessels clinical trials for the treatment of acute stroke are no longer in progress treatment of acute stroke are no longer in progress
Most devices are used in cerebral vessels that 2-5 mm
The Latis laser device The Latis laser device used laser energy to ablate clots used laser energy to ablate clots Arteries 2-5 mm in diameter could be Arteries 2-5 mm in diameter could be
treated including the ICA M1 or M2 treated including the ICA M1 or M2 branch of the MCA A1 branch of the branch of the MCA A1 branch of the anterior cerebral artery (ACA) basilar anterior cerebral artery (ACA) basilar artery posterior cerebral artery (PCA) artery posterior cerebral artery (PCA) and vertebral and vertebral
Patients could receive treatment as late Patients could receive treatment as late as 8 hours after symptom onset in the as 8 hours after symptom onset in the anterior circulation and within 24 hours in anterior circulation and within 24 hours in the posterior circulation the posterior circulation
Endovascular Photo Acoustic Endovascular Photo Acoustic Recanalization (EPAR) Recanalization (EPAR)
A laser power source generated energy for the A laser power source generated energy for the systemsystem
The energy was delivered by means of The energy was delivered by means of fiberoptics to the tip of the catheter at the fiberoptics to the tip of the catheter at the treatment sitetreatment site
Absorption of laser light by darkly pigmented Absorption of laser light by darkly pigmented materials (ie the clot) occurred inside the 1-mm materials (ie the clot) occurred inside the 1-mm catheter tipcatheter tip
the system was designed to minimize scattering the system was designed to minimize scattering of laser light of laser light
Absorption converted photo energy to acoustic Absorption converted photo energy to acoustic energy which then emulsified the clot inside the energy which then emulsified the clot inside the catheter tip catheter tip
EKOS ultrasound( the EKOS ultrasound( the Ultrasound Thrombolytic Ultrasound Thrombolytic
Infusion Catheter) Infusion Catheter) combines the use of a distal ultrasound transducer with combines the use of a distal ultrasound transducer with
infusion of a thrombolytic agent through the infusion of a thrombolytic agent through the microcathetermicrocatheter
Ultrasound changes the structure of the clot to Ultrasound changes the structure of the clot to temporarily increase its permeability while providing an temporarily increase its permeability while providing an acoustic pressure gradient to move the drug into the clot acoustic pressure gradient to move the drug into the clot to speed its dissolution to speed its dissolution
The EKOS catheter is placed in the proximal portion of the The EKOS catheter is placed in the proximal portion of the clot clot
After a 2-mg bolus of tPA was injected through the After a 2-mg bolus of tPA was injected through the catheter catheter
the patient received a continuous infusion of IA tPA 03 the patient received a continuous infusion of IA tPA 03 mgmin to a maximum of 20 mg and simultaneous mgmin to a maximum of 20 mg and simultaneous ultrasound transmission for as long as 60 minutes ultrasound transmission for as long as 60 minutes
One patient was treated with a total of 4 units of One patient was treated with a total of 4 units of recombinant reteplase (Retavase) hand-injected over 60 recombinant reteplase (Retavase) hand-injected over 60 minutes minutes
Penumbra system Penumbra system The Penumbra system (Penumbra Inc) provides a dual The Penumbra system (Penumbra Inc) provides a dual
approach to clot extraction using aspiration followed by approach to clot extraction using aspiration followed by clot retrieval with a ring device if needed clot retrieval with a ring device if needed
Mechanical Embolus Removal in Cerebral Ischemia Mechanical Embolus Removal in Cerebral Ischemia (MERCI)(MERCI)
a corkscrew-like apparatus to remove blood clots from a corkscrew-like apparatus to remove blood clots from the brain in patients experiencing an ischemic stroke the brain in patients experiencing an ischemic stroke
The corkscrew itself resides in the catheter tip which The corkscrew itself resides in the catheter tip which shields it from the wall of the vessel until it is ready to be shields it from the wall of the vessel until it is ready to be burrowed into the clot Once lodged in the clot the device burrowed into the clot Once lodged in the clot the device and clot are withdrawn from the vessel and clot are withdrawn from the vessel
Snarelike devicesSnarelike devices Snares such as the Neuronet snare (Guidant Snares such as the Neuronet snare (Guidant
Endovascular Santa Clara CA) have been developed Endovascular Santa Clara CA) have been developed specifically for use in the treatment of strokes specifically for use in the treatment of strokes
These devices are simple in design and do not require the These devices are simple in design and do not require the clot to be amenable to emulsification clot to be amenable to emulsification
X-Sizer deviceX-Sizer device a device with small moving blades at the a device with small moving blades at the
catheter tip catheter tip This device the X-Sizer device (EndiCor Medical This device the X-Sizer device (EndiCor Medical
San Clemente CA) can be used to excise the San Clemente CA) can be used to excise the thrombus and aspirate it thrombus and aspirate it
The device was being evaluated in randomized The device was being evaluated in randomized studies of coronary vessels and in a registry of studies of coronary vessels and in a registry of patients with acute myocardial infarctionpatients with acute myocardial infarction
Although the manufacturer had modified the Although the manufacturer had modified the device for use in cerebral vessels a safety and device for use in cerebral vessels a safety and feasibility study was indefinitely suspended after feasibility study was indefinitely suspended after only 1 patient was treated with the device in only 1 patient was treated with the device in Europe Europe
Suction thrombectomySuction thrombectomy This method of mechanical thrombolysis is one of the This method of mechanical thrombolysis is one of the
simplestsimplest In this readily available technique suction is applied with In this readily available technique suction is applied with
a syringe to remove thrombus in the ICA a syringe to remove thrombus in the ICA It requires no other devicesIt requires no other devices A catheter with a large inner diameter (Brite Tip Cordis A catheter with a large inner diameter (Brite Tip Cordis
Corporation Miami FL) was placed in the symptomatic Corporation Miami FL) was placed in the symptomatic vessel and navigated over a guidewire into the thrombusvessel and navigated over a guidewire into the thrombus
A 60-mL syringe was used to aspirate the thrombus A 60-mL syringe was used to aspirate the thrombus Each patient required angioplasty and stenting of carotid Each patient required angioplasty and stenting of carotid
bifurcation stenosis and received daily aspirin and bifurcation stenosis and received daily aspirin and ticlopidine after the procedure No complications ticlopidine after the procedure No complications occurred occurred
Summary Acute Stroke Summary Acute Stroke ImagingImaging
PhysiologyPhysiology importance collaterals importance collaterals
ndash ndashGrowing role for perfusion Growing role for perfusion assessmentassessment
tPAtPA guidelines amp limitations guidelines amp limitations Signs on CT amp MRSigns on CT amp MR follow physiology follow physiology Stroke trialsStroke trials PWI-DWI mismatch PWI-DWI mismatch
ndash ndashTreat based on physiology not timeTreat based on physiology not time ProtocolsProtocols should be fast and should be fast and
comprehensivecomprehensive
3 DefibrinogenatingFibrinogenolytic 3 DefibrinogenatingFibrinogenolytic Agents Agents
AncrodAncrod(Viprinex)(Viprinex) is is the purified fraction of the Malayan pit viper venomthe purified fraction of the Malayan pit viper venom It acts by directly cleaving and inactivating fibrinogen It acts by directly cleaving and inactivating fibrinogen
and thus indirectly promoting anticoagulation and thus indirectly promoting anticoagulation The reduction in the blood levels of fibrinogen also The reduction in the blood levels of fibrinogen also
leads to a reduced blood viscosity which may improve leads to a reduced blood viscosity which may improve blood flow to the affected areas of the brain blood flow to the affected areas of the brain
In the Stroke Treatment with Ancrod Trial 500 In the Stroke Treatment with Ancrod Trial 500 patients with stroke presenting within 3 hours of patients with stroke presenting within 3 hours of symptom onset were randomized to receive ancrod (symptom onset were randomized to receive ancrod (n n 248) or a placebo (n 252) Good outcome (Barthel 248) or a placebo (n 252) Good outcome (Barthel Index 95ndash100 at 3 months) was achieved in 4221 Index 95ndash100 at 3 months) was achieved in 4221 and 344 of the patients respectively and 344 of the patients respectively
2 Direct Fibrinolytics2 Direct Fibrinolytics
Microplasmin (Microplasmin (ThromboGenics Heverlee Belgium)ThromboGenics Heverlee Belgium) is a truncated form of plasmin that is more resistant to the effects is a truncated form of plasmin that is more resistant to the effects
of antiplasmin of antiplasmin microplasmin can be used upto 4ndash12 hours after stroke onset microplasmin can be used upto 4ndash12 hours after stroke onset There was no evidence of increased bleeding risk with There was no evidence of increased bleeding risk with
microplasminmicroplasmin
Alfimeprase (Nuvelo San Carlos Calif)Alfimeprase (Nuvelo San Carlos Calif) is a recombinant truncated form of fibrolase a fibrinolytic zinc metalloproteinase is a recombinant truncated form of fibrolase a fibrinolytic zinc metalloproteinase
isolated from the venom of the southern copperhead snake isolated from the venom of the southern copperhead snake It degrades fibrin directly and achieves thrombolysis independent It degrades fibrin directly and achieves thrombolysis independent
of plasmin formationof plasmin formation its thrombolytic activity appears to be localized to the site of its thrombolytic activity appears to be localized to the site of
delivery These properties should theoretically result in faster delivery These properties should theoretically result in faster recanalization and lower hemorrhagic conversion riskrecanalization and lower hemorrhagic conversion risk
Anti-fibrinolyticsAnti-fibrinolytics
to limit fibrinolytic activityto limit fibrinolytic activity -aminocaproic acid (EACA) -aminocaproic acid (EACA) competitively inhibitscompetitively inhibits plasminogen and plasminogen activators from plasminogen and plasminogen activators from
binding to fibrinbinding to fibrin
alpha2-antiplasminalpha2-antiplasmin a serine protease inhibitor that a serine protease inhibitor that neutralizes any free circulating plasminneutralizes any free circulating plasmin
Plasminogen activator inhibitor-1Plasminogen activator inhibitor-1 a serine protease a serine protease inhibitor that inhibits tissue-type plasminogen inhibitor that inhibits tissue-type plasminogen activatoractivator
Glycoprotein (GP) IIbIIIa antagonistsGlycoprotein (GP) IIbIIIa antagonists
such as ReoPro (abciximab) Integrilin such as ReoPro (abciximab) Integrilin (eptifibatide) or Aggrastat (tirofiban) in (eptifibatide) or Aggrastat (tirofiban) in ischemic stroke remains investigational ischemic stroke remains investigational Deshmukh et al38 reported 21 patients with Deshmukh et al38 reported 21 patients with large-vessel occlusion refractory to IAT with large-vessel occlusion refractory to IAT with rtPA who were treated with IV andor IA rtPA who were treated with IV andor IA abciximab eptifibatide or tirofiban abciximab eptifibatide or tirofiban
IA Mechanical Approaches in Acute Ischemic Stroke IA Mechanical Approaches in Acute Ischemic Stroke Mechanical strategies have several advantagesMechanical strategies have several advantages First they lessen and may even preclude the use of chemical First they lessen and may even preclude the use of chemical
thrombolytics in this manner very likely reducing the risk of ICHthrombolytics in this manner very likely reducing the risk of ICH Second by avoiding the use of chemical thrombolytics it is Second by avoiding the use of chemical thrombolytics it is
possible to extend the treatment window beyond the limit of 6ndash8 possible to extend the treatment window beyond the limit of 6ndash8 hours hours
Third mechanically fragmenting a clot increases the surface area Third mechanically fragmenting a clot increases the surface area accessible to fibrinolytic agents and allows inflow of fresh accessible to fibrinolytic agents and allows inflow of fresh plasminogen which in turn may increase the speed of plasminogen which in turn may increase the speed of thrombolysis thrombolysis
Finally clot-retrieval devices may provide faster recanalization Finally clot-retrieval devices may provide faster recanalization
The disadvantages of the mechanical The disadvantages of the mechanical approaches approaches technical difficulty of navigating mechanical technical difficulty of navigating mechanical
devices into the intracranial circulation excessive devices into the intracranial circulation excessive trauma to the vasculature (potentially leading to trauma to the vasculature (potentially leading to vasospasm vessel dissection perforation or vasospasm vessel dissection perforation or rupture) rupture)
fragmented thrombus causing distal embolization fragmented thrombus causing distal embolization into previously unaffected territories into previously unaffected territories
Nevertheless the advantages of mechanical stroke Nevertheless the advantages of mechanical stroke therapy appear to significantly outweigh its therapy appear to significantly outweigh its disadvantages and risksdisadvantages and risks
Contraindications to Thrombolytic Contraindications to Thrombolytic agents agents
Recent thoracic abdominal or Recent thoracic abdominal or intracranial surgeryintracranial surgery
Recent haemorrhagic CVA Head injury Recent haemorrhagic CVA Head injury or neoplasmor neoplasm
Bleeding ulcerBleeding ulcer Anticipated invasive procedures (arterial Anticipated invasive procedures (arterial
punctures biopsies)punctures biopsies) Concurrent hemostatic dysfunctionConcurrent hemostatic dysfunction
Monitoring of thrombolytic Monitoring of thrombolytic therapytherapy
Thrombin time Measures the availability of functional
fibrinogen Normal thrombin time is 10-14 sec Prolonged when fibrinogen level is below
75-100 mgdl
Half Life of ThrombolyticsHalf Life of ThrombolyticsAgent Administration Half Life
Streptokinase IA 60-80min
Urokinase IAIV 9-12min
rTPA IAIV 6min
Abciximab(Reopro) IAIV 12hour
Aspirin POIV 15-20min
Heparin IVSC 60min
Coumadin PO 15-25 days
Anti Platelet DrugsAnti Platelet DrugsDrug Drug Mechanism Mechanism UsesUsesAspirinAspirin Permanently inhibits Permanently inhibits
COX-1 and COX-2COX-1 and COX-2CADCAD
Stroke-TIAsStroke-TIAs
NSAIDsNSAIDs Reversibly inhibits Reversibly inhibits COX-1COX-1
LimitedLimited
DipyridamoleDipyridamole Inhibits PDE increases Inhibits PDE increases cAMPcAMP
TIAsTIAs
ThenopyridinesThenopyridines
(Ticlopidine(Ticlopidine
ClopidrgrelClopidrgrel))
Inhibits ADP Inhibits ADP
PlatAg PlatAg
TIAsStrokeTIAsStroke
CAD PVDCAD PVD
Abciximab (ReoPro)Abciximab (ReoPro)
Eptifibatide (Integrilin)Eptifibatide (Integrilin)
TirofibanTirofiban
GP IIBIIIA InhibitorsGP IIBIIIA Inhibitors
Stroke- TIAs Stroke- TIAs
MonitoringMonitoring
Bleeding timeBleeding time
Optical aggregometryOptical aggregometry
Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay
Bleeding timeBleeding time
Requires a skin incision (usually made on the ear lobe or Requires a skin incision (usually made on the ear lobe or forearm offorearm of
a depth that results in disruption of capillary loops and a depth that results in disruption of capillary loops and small vessels)small vessels)
AdvantagesAdvantages Universally availableUniversally available Relatively simple techniquesRelatively simple techniques Can be performed bedsideCan be performed bedside
DisadvantagesDisadvantages Insensitive inaccurate non-specific techniqueInsensitive inaccurate non-specific technique
Poorly reproducible (as depends on multiple variables)Poorly reproducible (as depends on multiple variables)
Optical aggregometryOptical aggregometry
Gold standard assay for platelet functionGold standard assay for platelet function Agonist induced aggregation is measuredAgonist induced aggregation is measured Different agonist are available for different Different agonist are available for different
agentsagents However require unique expertise and are not However require unique expertise and are not
universally availableuniversally available Aspirin measured with ADP or AA(gt70 Aspirin measured with ADP or AA(gt70
aggregation so resistance)aggregation so resistance) Clopidogrel( ADP gt 90 aggregation means Clopidogrel( ADP gt 90 aggregation means
resistance) resistance)
Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay
Can be performed bed sideCan be performed bed side Different assay devices with different Different assay devices with different
agonist are used for each of different agonist are used for each of different antiplatelet agents antiplatelet agents
For Aspirin AA is used (result is reported as aspirin For Aspirin AA is used (result is reported as aspirin reaction units [ARU] ARUgt 550 indicates non-reaction units [ARU] ARUgt 550 indicates non-responsiveness)responsiveness)
Verify IIbIIIa assay device uses TRAP as agonist for Verify IIbIIIa assay device uses TRAP as agonist for Abciximab and TirofibanAbciximab and Tirofiban
Practical Applications Practical Applications related to specific related to specific
Neurovascular Neurovascular interventionsinterventions
Acute ischemic StrokeAcute ischemic Stroke When an artery occludes neurons are affected When an artery occludes neurons are affected
differently depending upon the amount of residual blood differently depending upon the amount of residual blood flowflow
Normal cerebral blood flow is greater than 50 mL100 Normal cerebral blood flow is greater than 50 mL100 mgminmgmin
Once blood flow decreases to less than 20 mL100 Once blood flow decreases to less than 20 mL100 mgmin infarction occursmgmin infarction occurs
If blood flow decreases to less than 10 mL100 mgmin If blood flow decreases to less than 10 mL100 mgmin irreversible neuronal death occurs rapidly irreversible neuronal death occurs rapidly
Blood flow between 11 and 20 mL100 mgmin is thought Blood flow between 11 and 20 mL100 mgmin is thought to represent the ischemic penumbra an area where the to represent the ischemic penumbra an area where the cells are functionally silent because of ischemia but are cells are functionally silent because of ischemia but are still able to recover if blood flow is restored still able to recover if blood flow is restored
Many acute stroke therapies are targeted toward Many acute stroke therapies are targeted toward restoring flow or function to the ischemic penumbrarestoring flow or function to the ischemic penumbra
Therapeutic window in Therapeutic window in management of acute Ischemic management of acute Ischemic
StrokeStrokeThe early diagnosis of ischemic stroke is critical to the The early diagnosis of ischemic stroke is critical to the
with only a narrow therapeutic window in the first few with only a narrow therapeutic window in the first few hours following stroke ictushours following stroke ictus
Diagnosis in the first 3 hours postictus provides the Diagnosis in the first 3 hours postictus provides the opportunity for intravenous or intraarterial thrombolysis opportunity for intravenous or intraarterial thrombolysis and intra-arterial clot mechanical treatment which and intra-arterial clot mechanical treatment which improve the outcome improve the outcome
Diagnosis in the time period between 3 and 6 hours Diagnosis in the time period between 3 and 6 hours provides an opportunity for intra-arterial thrombolysis provides an opportunity for intra-arterial thrombolysis and mechanical treatment and mechanical treatment
Involvement of the posterior circulation especially the Involvement of the posterior circulation especially the basilar artery is treated by some regardless of time of basilar artery is treated by some regardless of time of onset or up until 12 to 24 hours in some practices This is onset or up until 12 to 24 hours in some practices This is related to the potentially high mortality and morbidity related to the potentially high mortality and morbidity associated with basilar artery thrombosisassociated with basilar artery thrombosis
Infarct evaluation on angiographyInfarct evaluation on angiography(CT angiography and catheter (CT angiography and catheter
angiography)angiography)CTA is an excellent first-line examination for CTA is an excellent first-line examination for
evaluation of the head and neck arteries evaluation of the head and neck arteries In comparison with catheter angiography In comparison with catheter angiography
what it gives up in resolution and dynamic what it gives up in resolution and dynamic properties it makes up for with rapid properties it makes up for with rapid acquisition of a 3-D dataset and the potential acquisition of a 3-D dataset and the potential for assessment of whole-brain perfusion and for assessment of whole-brain perfusion and better parenchymal evaluationbetter parenchymal evaluation
Moreover CTA illustrates not only arterial Moreover CTA illustrates not only arterial stenosis or occlusion but also the vessel wall stenosis or occlusion but also the vessel wall This factor is most important for evaluation of This factor is most important for evaluation of intramural dissection and thrombosed intramural dissection and thrombosed aneurysms which may both complicate aneurysms which may both complicate evaluation of stroke patientsevaluation of stroke patients
Early angiographic signs of strokes Early angiographic signs of strokes both CTA both CTA and DSA and DSA
Vessel occlusion or cutoff related to Vessel occlusion or cutoff related to thromboembolithromboemboli
aneurysms aneurysms arterial dissection arterial dissection Meniscus or flattened shape to clot Meniscus or flattened shape to clot
(recent) versus reverse meniscus (older)(recent) versus reverse meniscus (older) tram track (nonocclusive or recanalized tram track (nonocclusive or recanalized
clot) clot) delayed (antegrade) flow (manifest as delayed (antegrade) flow (manifest as
decreased whole-brain perfusion on CTA)decreased whole-brain perfusion on CTA) retrograde collateral flowretrograde collateral flow
Non-occlusive left MCA thrombus on 3-D imaging performed from CTA source data and was confirmed at catheter angiography
Therapy to be started within a 6-hr Therapy to be started within a 6-hr time to treatment (TTT) window time to treatment (TTT) window (while in case of IV thrombolysis (while in case of IV thrombolysis therapy to be started with in 3hrs)therapy to be started with in 3hrs)
Exclusion criteria Exclusion criteria Rapidly improving neurologic deficit or Rapidly improving neurologic deficit or Sustained blood pressure of gt180100 Sustained blood pressure of gt180100 Hemorrhage is detected on CTHemorrhage is detected on CT Infarct involving gt more than 13 rd Infarct involving gt more than 13 rd
territory of MCAterritory of MCA MRADWI-Perfusion mismatchlt 20MRADWI-Perfusion mismatchlt 20 Definite hypodensity on CTDefinite hypodensity on CT
Intra-arterial Thrombolysis
Fibrinolytics + AntiplateletsFibrinolytics + Antiplatelets
PlasminogenPlasminogen activators through fibrinolysis exposes activators through fibrinolysis exposes free thrombin and paradoxically stimulatesfree thrombin and paradoxically stimulates platelet platelet aggregation which leads to formation of aaggregation which leads to formation of a platelet platelet thrombus (white clot) thrombus (white clot)
This new thrombus is relatively resistant to This new thrombus is relatively resistant to fibrinolyticsfibrinolytics
So new regimen in case of acute stroke isSo new regimen in case of acute stroke is fibrinolytics + antiplatelet drugsfibrinolytics + antiplatelet drugs
rtPA + IIbIIIa inhibitors( tirofiban rtPA + IIbIIIa inhibitors( tirofiban abciximab) orabciximab) or
Urokinase + IIbIIIa Urokinase + IIbIIIa inhibitors( tirofiban abciximab)inhibitors( tirofiban abciximab)
Intra-arterial Thrombolysis Tirofiban (04 microgkgmin bolus for 3 min followed by Tirofiban (04 microgkgmin bolus for 3 min followed by
0125 ugkgmin)0125 ugkgmin)
++
Heparin (2000ndash3000 IU bolus followed by Heparin (2000ndash3000 IU bolus followed by 1000 IUhour infusion 1000 IUhour infusion
with ACT maintained bw 200-300) throughout the with ACT maintained bw 200-300) throughout the interventional procedure and for 24ndash48 hours thereafter when interventional procedure and for 24ndash48 hours thereafter when there is neither intraprocedural bleeding nor suspicion of there is neither intraprocedural bleeding nor suspicion of increased risk of bleeding increased risk of bleeding
Maximum dose of Urokinase Maximum dose of Urokinase Anterior circulation stroke - 500000 IU (mean 400000 Anterior circulation stroke - 500000 IU (mean 400000
IU range 300000ndash500000 IU)IU range 300000ndash500000 IU) Posterior circulation stroke -1000000 IU (mean 837000 Posterior circulation stroke -1000000 IU (mean 837000
IU range 300000ndash1000000 IU)IU range 300000ndash1000000 IU)American Journal of NeuroradiologyAmerican Journal of Neuroradiology 262595-2601 2005262595-2601 2005
Intravenous ThrombolysisIntravenous Thrombolysis
The first method to restore cerebral The first method to restore cerebral perfusion is clot lysis with the goal perfusion is clot lysis with the goal of re-establishing blood flow to the of re-establishing blood flow to the affected tissue affected tissue
IV thrombolysis rt-PA is the only IV thrombolysis rt-PA is the only FDA- approved treatment for AIS FDA- approved treatment for AIS
Fibrinolysis is enhanced powerfully Fibrinolysis is enhanced powerfully by rt-PAby rt-PA
Intravenous rTPA Intravenous rTPA administration administration protocolprotocol
Total dose of rt-PA 09 mgkg (maximum dose Total dose of rt-PA 09 mgkg (maximum dose 90 mg)90 mg)
Give 10 as initial IV bolusGive 10 as initial IV bolus Infuse remainder over 1 hourInfuse remainder over 1 hour Admit patient to an ICU or stroke unit for Admit patient to an ICU or stroke unit for
monitoringmonitoring Neurologic assessments every 15 minutes Neurologic assessments every 15 minutes
during infusion then every 30 minutes for next during infusion then every 30 minutes for next 6 hours then every hour until 24hours after 6 hours then every hour until 24hours after treatmenttreatment
Favorable Outcome vs Treatment Time Favorable Outcome vs Treatment Time with IV rTPAwith IV rTPA
Protocol limit = 3 hrs
Benefit ~ 45 hrs
Thromboembolism During coilingThromboembolism During coiling Most feared and frequent complication Most feared and frequent complication Reported incidence - Approx 7 Reported incidence - Approx 7 SourcesSources of Thromboembolism are of Thromboembolism are
- Clots at the aneurysmal neck during or immediately- Clots at the aneurysmal neck during or immediately after after embolization embolization
- Thrombus forming on catheters during- Thrombus forming on catheters during proceduresprocedures
- Stenosis of an adjacent artery dt coil mass- Stenosis of an adjacent artery dt coil mass or herniationor herniation
- Migration of intraaneurysmal- Migration of intraaneurysmal thrombus during coil thrombus during coil placement placement
- Slow flow dt vasospasm - Slow flow dt vasospasm
- Rare and unlikely causes are hypercoagulable- Rare and unlikely causes are hypercoagulable state such state such as antiphospholipid antibody syndrome or due to HITas antiphospholipid antibody syndrome or due to HIT
Occur more often with wide-necked aneurysms (dt Occur more often with wide-necked aneurysms (dt increased exposed surface area of thrombogenic coil increased exposed surface area of thrombogenic coil material)material)
Current regimen of endovascular Current regimen of endovascular managementmanagement
The The glycoprotein IIbIIIa antagonist tirofiban glycoprotein IIbIIIa antagonist tirofiban (04 (04 microgkgmin bolus for 30 minutes followed by infusion of microgkgmin bolus for 30 minutes followed by infusion of 0125 ugkgmin until the thrombus dissolved) 0125 ugkgmin until the thrombus dissolved)
Intraarterial thrombolysis with Intraarterial thrombolysis with urokinase or r- TPA urokinase or r- TPA increase of intravenous (IV) heparin (measured by increase of intravenous (IV) heparin (measured by
ACT) ACT) Intravenous aspirin Intravenous aspirin
Coil-related platelet aggregation (white clot) is Coil-related platelet aggregation (white clot) is unlikely to respond to fibrinolytics but has a high risk unlikely to respond to fibrinolytics but has a high risk of hemorrhage (In ISAT) all 5 patients who had of hemorrhage (In ISAT) all 5 patients who had received thrombolytic therapy with tPA to treat a received thrombolytic therapy with tPA to treat a thromboembolic complication after endovascular thromboembolic complication after endovascular treatment rebleed and all of these patients died)treatment rebleed and all of these patients died)
IntracranialIntracranial Stenting Stenting Metallic foreign body such as stent will accumulate Metallic foreign body such as stent will accumulate
thrombus in the absence of platelet inhibitionthrombus in the absence of platelet inhibition Antiplatelet drugs are important to prevent peri or Antiplatelet drugs are important to prevent peri or
post-interventional thromboembolic eventspost-interventional thromboembolic events Optimal treatment regimens has not been determined Optimal treatment regimens has not been determined
but usually but usually Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-
procedureprocedureOrOr
Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on
morning of proceduremorning of procedure
If need to use stent is not pre-planned thanIf need to use stent is not pre-planned than
Abciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkgAbciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkg IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)
Glycoprotein IIbIIIa inhibitor are not used routinely during elective Glycoprotein IIbIIIa inhibitor are not used routinely during elective stenting procedure dt increased risk of ICH stenting procedure dt increased risk of ICH
Carotid StentingCarotid Stenting
Pre-procedurePre-procedure
Double Antiplatelet therapy is routinely given Double Antiplatelet therapy is routinely given beginning at least 3beginning at least 3
days before the proceduredays before the procedure
Aspirin 325mgd+Clopidogrel 75mgdAspirin 325mgd+Clopidogrel 75mgd During procedureDuring procedure
Heparin is given with target clotting time of 250-Heparin is given with target clotting time of 250-300sec300sec
Post-procedure Post-procedure
Aspirin 325mg is continued indefinitely and Aspirin 325mg is continued indefinitely and
Clopidogrel 75mgd for at least 6 weeks Clopidogrel 75mgd for at least 6 weeks
Inclusion criteria for Local ThrombolysisInclusion criteria for Local Thrombolysis a)a) Patients in severe clinical grade on admission Patients in severe clinical grade on admission
with evidence of dural venous sinus with evidence of dural venous sinus thrombosis and restrictive venous outflow on thrombosis and restrictive venous outflow on cerebral angiogramcerebral angiogram
b)b) Patients in clinical grade 3 worsening on Patients in clinical grade 3 worsening on heparin therapy Restriction to venous heparin therapy Restriction to venous outflow was defined as an increase in brain outflow was defined as an increase in brain circulation time gt 12 s delay in the drainage circulation time gt 12 s delay in the drainage of cortical veins with cortical veins hanging of cortical veins with cortical veins hanging in spacein space
Treatment Options for Venous Thrombosis
CT Grading for Venous ThrombosisCT Grading for Venous Thrombosis Grade I no parenchymal change Grade I no parenchymal change
(hyperdense (hyperdense sinuses cortical veins empty sinuses cortical veins empty delta sign)delta sign)
Grade II non hemorrhagic venous infarct Grade II non hemorrhagic venous infarct without mass effect without mass effect
Grade III non-hemorrhagic infarct with Grade III non-hemorrhagic infarct with mass effectmass effect
Grade IV hemorrhagic venous infarct (max Grade IV hemorrhagic venous infarct (max diameter lt 3 cm) with no mass effectdiameter lt 3 cm) with no mass effect
Grade V hemorrhagic venous infarct (max Grade V hemorrhagic venous infarct (max diameter gt 3 cm) with mass effect diameter gt 3 cm) with mass effect
Local ThrombolysisLocal Thrombolysis
Femoral Jugular access was secured and a guiding Femoral Jugular access was secured and a guiding catheter was placed in the jugular bulb catheter was placed in the jugular bulb Mechanical Mechanical clot maceration clot maceration was done with the guidewire was done with the guidewire following which a microcatheter (was navigated and following which a microcatheter (was navigated and placed in the thrombosed segment of sinus confirmed placed in the thrombosed segment of sinus confirmed on a selective venogram on a selective venogram
Urokinase infusion Bolus dose of 2-6 lacs followed Urokinase infusion Bolus dose of 2-6 lacs followed by 60000 to 100000 units per hour along with by 60000 to 100000 units per hour along with periodic check venogram Along with maintenance periodic check venogram Along with maintenance systemic infusion of Heparinsystemic infusion of Heparin Other agents such as Other agents such as streptokinase altepase or rTPAstreptokinase altepase or rTPA can be also used can be also used
After thrombolysis patient should subjected to oral After thrombolysis patient should subjected to oral anticoagulation for six monthsanticoagulation for six months
Low-molecular-weight Low-molecular-weight heparinheparin
PharmacologyPharmacologyLMWH as its name suggests is a glycosaminoglycan that is approximatelyLMWH as its name suggests is a glycosaminoglycan that is approximately
one third the molecular weight of UFH It is derived from UFH through one third the molecular weight of UFH It is derived from UFH through variousvarious
depolymerization processes LMWH binds to antithrombin which in turn depolymerization processes LMWH binds to antithrombin which in turn
Neutralizes actors Xa and IIa Because LMWH lacks many of the longer Neutralizes actors Xa and IIa Because LMWH lacks many of the longer chains chains
required for binding to thrombin it has less ability to neutralize thrombin required for binding to thrombin it has less ability to neutralize thrombin
relativeto its ability to neutralize factor Xa LMWH also has less relativeto its ability to neutralize factor Xa LMWH also has less nonspecific nonspecific
binding to other proteins There is greater bioavailability with more binding to other proteins There is greater bioavailability with more predictable predictable
pharmacokinetics that eliminates the need for monitoring The smaller pharmacokinetics that eliminates the need for monitoring The smaller size also size also
allows for enhanced subcutaneous absorption when compared with UFHallows for enhanced subcutaneous absorption when compared with UFH
Three LMWH preparations are Three LMWH preparations are currently approved for use in the currently approved for use in the United States (1) enoxaparin (2) United States (1) enoxaparin (2) dalteparin and (3) tinzaparin dalteparin and (3) tinzaparin
They are all administered They are all administered subcutaneously at intervals of either subcutaneously at intervals of either once or twice daily for both once or twice daily for both prophylaxis and treatment dosesprophylaxis and treatment doses
Few Experiences of Few Experiences of ThrombolysisThrombolysis
Vickey 25 Yrs male patient presented Vickey 25 Yrs male patient presented with 12with 12thth day HO severe headache with day HO severe headache with right sided hemiplegiaright sided hemiplegia
MRI shows thrombosis of the superior MRI shows thrombosis of the superior sagittal left transverse left sigmoid sagittal left transverse left sigmoid sinuses and cortical veins in the fronto-sinuses and cortical veins in the fronto-parietal regions with eo haemorrhagic parietal regions with eo haemorrhagic infarct in the left cerebral hemisphere infarct in the left cerebral hemisphere with mass effect( Grade ndashV)with mass effect( Grade ndashV)
Sashi Srivastava 64 yrs FSashi Srivastava 64 yrs F In a follow up case of MRD with infra-renal In a follow up case of MRD with infra-renal
aortic abdominal and bilateral renal artery aortic abdominal and bilateral renal artery thrombosis renal angiogram shows filling thrombosis renal angiogram shows filling defects in the right Renal artery defects in the right Renal artery
Initially Renal angioplasty was done Initially Renal angioplasty was done Following angioplasty few thrombi are seem Following angioplasty few thrombi are seem to extends into the segmental branches and to extends into the segmental branches and causing blockage So Thrombolysis was causing blockage So Thrombolysis was plane to dissolve the run-out thrombi with plane to dissolve the run-out thrombi with urokinase urokinase
Rakesh 34yrsMRakesh 34yrsM Left SFA pseudoaneurysm with Left SFA pseudoaneurysm with
Covered stent placementCovered stent placement Pre operative antiplatelets with post Pre operative antiplatelets with post
procedure heparin Tirofiban procedure heparin Tirofiban followed by aspirin and clopidogrel followed by aspirin and clopidogrel were usedwere used
IAT may be a treatment option for selected patients IAT may be a treatment option for selected patients Possible selection criteria include Possible selection criteria include
presentation between 3 and 6 hours from symptom onsetpresentation between 3 and 6 hours from symptom onset major cerebral artery occlusion major cerebral artery occlusion severe neurologic deficits severe neurologic deficits high risk of systemic hemorrhage with IV rt-PA (eg recent high risk of systemic hemorrhage with IV rt-PA (eg recent
surgery) surgery) The MERCI (Mechanical Embolus Removal in Cerebral The MERCI (Mechanical Embolus Removal in Cerebral
Ischemia) retrievalIschemia) retrieval system system
Has been FDA-approved for recanalizing acutely occluded Has been FDA-approved for recanalizing acutely occluded cerebral arteries cerebral arteries
In the Multi-MERCI study patients who did not improve In the Multi-MERCI study patients who did not improve immediately after IV rt-PA underwent mechanical immediately after IV rt-PA underwent mechanical embolectomy within 8 hours of symptom onset embolectomy within 8 hours of symptom onset
Partial or complete recanalization occurred in 74 of Partial or complete recanalization occurred in 74 of patientspatients
with a symptomatic intracerebral hemorrhage (sICH) rate of with a symptomatic intracerebral hemorrhage (sICH) rate of 67 67
Mechanical embolectomy with the MERCI retriever may be a Mechanical embolectomy with the MERCI retriever may be a feasible and safe option for patients after IV rt-PAfeasible and safe option for patients after IV rt-PA
Penumbra stroke systemPenumbra stroke system This device combines two methods of clot This device combines two methods of clot
extraction aspiration and mechanical extraction aspiration and mechanical extraction extraction
First the clot is aspirated then a thrombus First the clot is aspirated then a thrombus removal ring can be used if necessary to removal ring can be used if necessary to remove remaining clot remove remaining clot
successful recanalizing 82successful recanalizing 82 Bridging therapyBridging therapy
06 mgkg IV rt-PA followed by IAT with IA rt-06 mgkg IV rt-PA followed by IAT with IA rt-PA (up to 20 mg)PA (up to 20 mg)
achieved a higher recanalization rateachieved a higher recanalization rate
Criteria for thrombolysis with rTPACriteria for thrombolysis with rTPA
Inclusion criteriaInclusion criteria Clinical signs and symptoms consistent with ischemic Clinical signs and symptoms consistent with ischemic
strokestroke Patient last seen normal within 3 hoursPatient last seen normal within 3 hours Measurable neurologic deficitMeasurable neurologic deficit
Exclusion criteriaExclusion criteria Any hemorrhage on neuroimaging (CT or MRI)Any hemorrhage on neuroimaging (CT or MRI) Symptoms suggestive of subarachnoid hemorrhageSymptoms suggestive of subarachnoid hemorrhage Seizure at stroke onset that is thought to contribute to Seizure at stroke onset that is thought to contribute to
neurologic deficitneurologic deficit Hypodensity greater than one third cerebral hemisphere Hypodensity greater than one third cerebral hemisphere
on CTon CT SBP greater than 185 mm Hg or DBP greater than 110 SBP greater than 185 mm Hg or DBP greater than 110
mm Hgmm Hg International normalized ratio (INR) greater than 17International normalized ratio (INR) greater than 17
Ischemic Stroke Ischemic Stroke Treatment ndash 2006Treatment ndash 2006
IV tissue plasminogen activator (tPA)IV tissue plasminogen activator (tPA) ndash ndash Only FDA-approved acute stroke drugOnly FDA-approved acute stroke drug ndash ndash 3 hour treatment window3 hour treatment window
MERCI - Concentric clot retrieval MERCI - Concentric clot retrieval devicedevice ndash ndash Rescue therapy - approved 2004Rescue therapy - approved 2004 ndash ndash Device approval (not outcomes-based)Device approval (not outcomes-based)
Off label approachesOff label approaches ndash ndash IV tPA after 3 hoursIV tPA after 3 hours ndash ndash IV-IA tPA sequential strategiesIV-IA tPA sequential strategies ndash ndash IA tPA clot angioplasty fragmentationIA tPA clot angioplasty fragmentation ndash ndash Ultrasound-assisted tPA lysisUltrasound-assisted tPA lysis
rt-PA Trials NINDSrt-PA Trials NINDS
Acute stroke - 624 patientsAcute stroke - 624 patients Treat within 3 hrsTreat within 3 hrs Intravenous 09 mgkg rt-PA vs placeboIntravenous 09 mgkg rt-PA vs placebo Hemorrhage 64 tPA 06 placeboHemorrhage 64 tPA 06 placebo Neurologic recovery better with tPA 30 Neurologic recovery better with tPA 30
more like to have minimal or no disabilitymore like to have minimal or no disability
First proven approved treatment for First proven approved treatment for strokestroke
Limitations of tPALimitations of tPA Only 4 of acute strokes receive tPAOnly 4 of acute strokes receive tPA (Kleindorfer et al Stroke 2004 35 e27-e29)(Kleindorfer et al Stroke 2004 35 e27-e29)
Only 22 of patients present within 3 hoursOnly 22 of patients present within 3 hours1048707 1048707 51 of these ineligible due to51 of these ineligible due to
bull bull Mild severityMild severity bull bull Medical or surgical historyMedical or surgical history bull bull Blood testsBlood tests
Sustained recanalization only 13Sustained recanalization only 13 (Alexandrov et al NEJM 2004 351 2170-8)(Alexandrov et al NEJM 2004 351 2170-8)
Concern for hemorrhageConcern for hemorrhage tPA potentiates apoptotic injury tPA potentiates apoptotic injury (Liu et al Nature Med 2004 101379-83)(Liu et al Nature Med 2004 101379-83)
PROACT II IA Lysis TrialPROACT II IA Lysis Trial Baseline 24 hours 8 days
Baseline 60 minutes 120 minutes
9mg IAProurokinase
Desmoteplase Trials DEDAS Desmoteplase Trials DEDAS DIASDIAS
Trial OverviewTrial Overview Double blind randomized placebo Double blind randomized placebo
controlled trialscontrolled trials IV delivery 3-9 hour time windowIV delivery 3-9 hour time window Plasminogen activator ndash from Plasminogen activator ndash from vampire bat vampire bat
salivasaliva Selection based on PWI-DWI MismatchSelection based on PWI-DWI Mismatch
MRI InclusionMRI Inclusion PWI defect at least 2 cm AND ~20 larger PWI defect at least 2 cm AND ~20 larger
than DWIthan DWI PWI should be obvious even visible on PWI should be obvious even visible on
raw imagesraw imagesMRI ExclusionMRI Exclusion
DWI gt 13 MCADWI gt 13 MCA MRA ICA occlusionMRA ICA occlusion
Desmoteplase ndash DIAS Desmoteplase ndash DIAS ResultsResults
Mechanical Thrombolysis Mechanical Thrombolysis devicesdevices
mechanical thrombolysis potentially extends the treatment mechanical thrombolysis potentially extends the treatment window because they act promptly at the site of the thrombuswindow because they act promptly at the site of the thrombus
The devices can retrieve large clots that pharmaceutical agents The devices can retrieve large clots that pharmaceutical agents may not successfully lysemay not successfully lyse
Patients treated with IV tPA may be considered for treatment of Patients treated with IV tPA may be considered for treatment of residual clot with some of these devicesresidual clot with some of these devices
suction-creating saline jets suction-creating saline jets laser energy ultrasound laser energy ultrasound a corkscrew apparatus to treat strokesa corkscrew apparatus to treat strokes The AngioJet systemThe AngioJet system uses saline jets that are directed back into the catheter to uses saline jets that are directed back into the catheter to
create a low-pressure zone around the catheter tip inducing create a low-pressure zone around the catheter tip inducing suction suction
The clot is pulled into the exhaust lumen and removed from the The clot is pulled into the exhaust lumen and removed from the vessel Although US Food and Drug Administration (FDA) has vessel Although US Food and Drug Administration (FDA) has approved this device for use in arteriovenous dialysis grafts and approved this device for use in arteriovenous dialysis grafts and fistulae and for the treatment of coronary arteries saphenous fistulae and for the treatment of coronary arteries saphenous vein grafts and peripheral vessels clinical trials for the vein grafts and peripheral vessels clinical trials for the treatment of acute stroke are no longer in progress treatment of acute stroke are no longer in progress
Most devices are used in cerebral vessels that 2-5 mm
The Latis laser device The Latis laser device used laser energy to ablate clots used laser energy to ablate clots Arteries 2-5 mm in diameter could be Arteries 2-5 mm in diameter could be
treated including the ICA M1 or M2 treated including the ICA M1 or M2 branch of the MCA A1 branch of the branch of the MCA A1 branch of the anterior cerebral artery (ACA) basilar anterior cerebral artery (ACA) basilar artery posterior cerebral artery (PCA) artery posterior cerebral artery (PCA) and vertebral and vertebral
Patients could receive treatment as late Patients could receive treatment as late as 8 hours after symptom onset in the as 8 hours after symptom onset in the anterior circulation and within 24 hours in anterior circulation and within 24 hours in the posterior circulation the posterior circulation
Endovascular Photo Acoustic Endovascular Photo Acoustic Recanalization (EPAR) Recanalization (EPAR)
A laser power source generated energy for the A laser power source generated energy for the systemsystem
The energy was delivered by means of The energy was delivered by means of fiberoptics to the tip of the catheter at the fiberoptics to the tip of the catheter at the treatment sitetreatment site
Absorption of laser light by darkly pigmented Absorption of laser light by darkly pigmented materials (ie the clot) occurred inside the 1-mm materials (ie the clot) occurred inside the 1-mm catheter tipcatheter tip
the system was designed to minimize scattering the system was designed to minimize scattering of laser light of laser light
Absorption converted photo energy to acoustic Absorption converted photo energy to acoustic energy which then emulsified the clot inside the energy which then emulsified the clot inside the catheter tip catheter tip
EKOS ultrasound( the EKOS ultrasound( the Ultrasound Thrombolytic Ultrasound Thrombolytic
Infusion Catheter) Infusion Catheter) combines the use of a distal ultrasound transducer with combines the use of a distal ultrasound transducer with
infusion of a thrombolytic agent through the infusion of a thrombolytic agent through the microcathetermicrocatheter
Ultrasound changes the structure of the clot to Ultrasound changes the structure of the clot to temporarily increase its permeability while providing an temporarily increase its permeability while providing an acoustic pressure gradient to move the drug into the clot acoustic pressure gradient to move the drug into the clot to speed its dissolution to speed its dissolution
The EKOS catheter is placed in the proximal portion of the The EKOS catheter is placed in the proximal portion of the clot clot
After a 2-mg bolus of tPA was injected through the After a 2-mg bolus of tPA was injected through the catheter catheter
the patient received a continuous infusion of IA tPA 03 the patient received a continuous infusion of IA tPA 03 mgmin to a maximum of 20 mg and simultaneous mgmin to a maximum of 20 mg and simultaneous ultrasound transmission for as long as 60 minutes ultrasound transmission for as long as 60 minutes
One patient was treated with a total of 4 units of One patient was treated with a total of 4 units of recombinant reteplase (Retavase) hand-injected over 60 recombinant reteplase (Retavase) hand-injected over 60 minutes minutes
Penumbra system Penumbra system The Penumbra system (Penumbra Inc) provides a dual The Penumbra system (Penumbra Inc) provides a dual
approach to clot extraction using aspiration followed by approach to clot extraction using aspiration followed by clot retrieval with a ring device if needed clot retrieval with a ring device if needed
Mechanical Embolus Removal in Cerebral Ischemia Mechanical Embolus Removal in Cerebral Ischemia (MERCI)(MERCI)
a corkscrew-like apparatus to remove blood clots from a corkscrew-like apparatus to remove blood clots from the brain in patients experiencing an ischemic stroke the brain in patients experiencing an ischemic stroke
The corkscrew itself resides in the catheter tip which The corkscrew itself resides in the catheter tip which shields it from the wall of the vessel until it is ready to be shields it from the wall of the vessel until it is ready to be burrowed into the clot Once lodged in the clot the device burrowed into the clot Once lodged in the clot the device and clot are withdrawn from the vessel and clot are withdrawn from the vessel
Snarelike devicesSnarelike devices Snares such as the Neuronet snare (Guidant Snares such as the Neuronet snare (Guidant
Endovascular Santa Clara CA) have been developed Endovascular Santa Clara CA) have been developed specifically for use in the treatment of strokes specifically for use in the treatment of strokes
These devices are simple in design and do not require the These devices are simple in design and do not require the clot to be amenable to emulsification clot to be amenable to emulsification
X-Sizer deviceX-Sizer device a device with small moving blades at the a device with small moving blades at the
catheter tip catheter tip This device the X-Sizer device (EndiCor Medical This device the X-Sizer device (EndiCor Medical
San Clemente CA) can be used to excise the San Clemente CA) can be used to excise the thrombus and aspirate it thrombus and aspirate it
The device was being evaluated in randomized The device was being evaluated in randomized studies of coronary vessels and in a registry of studies of coronary vessels and in a registry of patients with acute myocardial infarctionpatients with acute myocardial infarction
Although the manufacturer had modified the Although the manufacturer had modified the device for use in cerebral vessels a safety and device for use in cerebral vessels a safety and feasibility study was indefinitely suspended after feasibility study was indefinitely suspended after only 1 patient was treated with the device in only 1 patient was treated with the device in Europe Europe
Suction thrombectomySuction thrombectomy This method of mechanical thrombolysis is one of the This method of mechanical thrombolysis is one of the
simplestsimplest In this readily available technique suction is applied with In this readily available technique suction is applied with
a syringe to remove thrombus in the ICA a syringe to remove thrombus in the ICA It requires no other devicesIt requires no other devices A catheter with a large inner diameter (Brite Tip Cordis A catheter with a large inner diameter (Brite Tip Cordis
Corporation Miami FL) was placed in the symptomatic Corporation Miami FL) was placed in the symptomatic vessel and navigated over a guidewire into the thrombusvessel and navigated over a guidewire into the thrombus
A 60-mL syringe was used to aspirate the thrombus A 60-mL syringe was used to aspirate the thrombus Each patient required angioplasty and stenting of carotid Each patient required angioplasty and stenting of carotid
bifurcation stenosis and received daily aspirin and bifurcation stenosis and received daily aspirin and ticlopidine after the procedure No complications ticlopidine after the procedure No complications occurred occurred
Summary Acute Stroke Summary Acute Stroke ImagingImaging
PhysiologyPhysiology importance collaterals importance collaterals
ndash ndashGrowing role for perfusion Growing role for perfusion assessmentassessment
tPAtPA guidelines amp limitations guidelines amp limitations Signs on CT amp MRSigns on CT amp MR follow physiology follow physiology Stroke trialsStroke trials PWI-DWI mismatch PWI-DWI mismatch
ndash ndashTreat based on physiology not timeTreat based on physiology not time ProtocolsProtocols should be fast and should be fast and
comprehensivecomprehensive
2 Direct Fibrinolytics2 Direct Fibrinolytics
Microplasmin (Microplasmin (ThromboGenics Heverlee Belgium)ThromboGenics Heverlee Belgium) is a truncated form of plasmin that is more resistant to the effects is a truncated form of plasmin that is more resistant to the effects
of antiplasmin of antiplasmin microplasmin can be used upto 4ndash12 hours after stroke onset microplasmin can be used upto 4ndash12 hours after stroke onset There was no evidence of increased bleeding risk with There was no evidence of increased bleeding risk with
microplasminmicroplasmin
Alfimeprase (Nuvelo San Carlos Calif)Alfimeprase (Nuvelo San Carlos Calif) is a recombinant truncated form of fibrolase a fibrinolytic zinc metalloproteinase is a recombinant truncated form of fibrolase a fibrinolytic zinc metalloproteinase
isolated from the venom of the southern copperhead snake isolated from the venom of the southern copperhead snake It degrades fibrin directly and achieves thrombolysis independent It degrades fibrin directly and achieves thrombolysis independent
of plasmin formationof plasmin formation its thrombolytic activity appears to be localized to the site of its thrombolytic activity appears to be localized to the site of
delivery These properties should theoretically result in faster delivery These properties should theoretically result in faster recanalization and lower hemorrhagic conversion riskrecanalization and lower hemorrhagic conversion risk
Anti-fibrinolyticsAnti-fibrinolytics
to limit fibrinolytic activityto limit fibrinolytic activity -aminocaproic acid (EACA) -aminocaproic acid (EACA) competitively inhibitscompetitively inhibits plasminogen and plasminogen activators from plasminogen and plasminogen activators from
binding to fibrinbinding to fibrin
alpha2-antiplasminalpha2-antiplasmin a serine protease inhibitor that a serine protease inhibitor that neutralizes any free circulating plasminneutralizes any free circulating plasmin
Plasminogen activator inhibitor-1Plasminogen activator inhibitor-1 a serine protease a serine protease inhibitor that inhibits tissue-type plasminogen inhibitor that inhibits tissue-type plasminogen activatoractivator
Glycoprotein (GP) IIbIIIa antagonistsGlycoprotein (GP) IIbIIIa antagonists
such as ReoPro (abciximab) Integrilin such as ReoPro (abciximab) Integrilin (eptifibatide) or Aggrastat (tirofiban) in (eptifibatide) or Aggrastat (tirofiban) in ischemic stroke remains investigational ischemic stroke remains investigational Deshmukh et al38 reported 21 patients with Deshmukh et al38 reported 21 patients with large-vessel occlusion refractory to IAT with large-vessel occlusion refractory to IAT with rtPA who were treated with IV andor IA rtPA who were treated with IV andor IA abciximab eptifibatide or tirofiban abciximab eptifibatide or tirofiban
IA Mechanical Approaches in Acute Ischemic Stroke IA Mechanical Approaches in Acute Ischemic Stroke Mechanical strategies have several advantagesMechanical strategies have several advantages First they lessen and may even preclude the use of chemical First they lessen and may even preclude the use of chemical
thrombolytics in this manner very likely reducing the risk of ICHthrombolytics in this manner very likely reducing the risk of ICH Second by avoiding the use of chemical thrombolytics it is Second by avoiding the use of chemical thrombolytics it is
possible to extend the treatment window beyond the limit of 6ndash8 possible to extend the treatment window beyond the limit of 6ndash8 hours hours
Third mechanically fragmenting a clot increases the surface area Third mechanically fragmenting a clot increases the surface area accessible to fibrinolytic agents and allows inflow of fresh accessible to fibrinolytic agents and allows inflow of fresh plasminogen which in turn may increase the speed of plasminogen which in turn may increase the speed of thrombolysis thrombolysis
Finally clot-retrieval devices may provide faster recanalization Finally clot-retrieval devices may provide faster recanalization
The disadvantages of the mechanical The disadvantages of the mechanical approaches approaches technical difficulty of navigating mechanical technical difficulty of navigating mechanical
devices into the intracranial circulation excessive devices into the intracranial circulation excessive trauma to the vasculature (potentially leading to trauma to the vasculature (potentially leading to vasospasm vessel dissection perforation or vasospasm vessel dissection perforation or rupture) rupture)
fragmented thrombus causing distal embolization fragmented thrombus causing distal embolization into previously unaffected territories into previously unaffected territories
Nevertheless the advantages of mechanical stroke Nevertheless the advantages of mechanical stroke therapy appear to significantly outweigh its therapy appear to significantly outweigh its disadvantages and risksdisadvantages and risks
Contraindications to Thrombolytic Contraindications to Thrombolytic agents agents
Recent thoracic abdominal or Recent thoracic abdominal or intracranial surgeryintracranial surgery
Recent haemorrhagic CVA Head injury Recent haemorrhagic CVA Head injury or neoplasmor neoplasm
Bleeding ulcerBleeding ulcer Anticipated invasive procedures (arterial Anticipated invasive procedures (arterial
punctures biopsies)punctures biopsies) Concurrent hemostatic dysfunctionConcurrent hemostatic dysfunction
Monitoring of thrombolytic Monitoring of thrombolytic therapytherapy
Thrombin time Measures the availability of functional
fibrinogen Normal thrombin time is 10-14 sec Prolonged when fibrinogen level is below
75-100 mgdl
Half Life of ThrombolyticsHalf Life of ThrombolyticsAgent Administration Half Life
Streptokinase IA 60-80min
Urokinase IAIV 9-12min
rTPA IAIV 6min
Abciximab(Reopro) IAIV 12hour
Aspirin POIV 15-20min
Heparin IVSC 60min
Coumadin PO 15-25 days
Anti Platelet DrugsAnti Platelet DrugsDrug Drug Mechanism Mechanism UsesUsesAspirinAspirin Permanently inhibits Permanently inhibits
COX-1 and COX-2COX-1 and COX-2CADCAD
Stroke-TIAsStroke-TIAs
NSAIDsNSAIDs Reversibly inhibits Reversibly inhibits COX-1COX-1
LimitedLimited
DipyridamoleDipyridamole Inhibits PDE increases Inhibits PDE increases cAMPcAMP
TIAsTIAs
ThenopyridinesThenopyridines
(Ticlopidine(Ticlopidine
ClopidrgrelClopidrgrel))
Inhibits ADP Inhibits ADP
PlatAg PlatAg
TIAsStrokeTIAsStroke
CAD PVDCAD PVD
Abciximab (ReoPro)Abciximab (ReoPro)
Eptifibatide (Integrilin)Eptifibatide (Integrilin)
TirofibanTirofiban
GP IIBIIIA InhibitorsGP IIBIIIA Inhibitors
Stroke- TIAs Stroke- TIAs
MonitoringMonitoring
Bleeding timeBleeding time
Optical aggregometryOptical aggregometry
Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay
Bleeding timeBleeding time
Requires a skin incision (usually made on the ear lobe or Requires a skin incision (usually made on the ear lobe or forearm offorearm of
a depth that results in disruption of capillary loops and a depth that results in disruption of capillary loops and small vessels)small vessels)
AdvantagesAdvantages Universally availableUniversally available Relatively simple techniquesRelatively simple techniques Can be performed bedsideCan be performed bedside
DisadvantagesDisadvantages Insensitive inaccurate non-specific techniqueInsensitive inaccurate non-specific technique
Poorly reproducible (as depends on multiple variables)Poorly reproducible (as depends on multiple variables)
Optical aggregometryOptical aggregometry
Gold standard assay for platelet functionGold standard assay for platelet function Agonist induced aggregation is measuredAgonist induced aggregation is measured Different agonist are available for different Different agonist are available for different
agentsagents However require unique expertise and are not However require unique expertise and are not
universally availableuniversally available Aspirin measured with ADP or AA(gt70 Aspirin measured with ADP or AA(gt70
aggregation so resistance)aggregation so resistance) Clopidogrel( ADP gt 90 aggregation means Clopidogrel( ADP gt 90 aggregation means
resistance) resistance)
Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay
Can be performed bed sideCan be performed bed side Different assay devices with different Different assay devices with different
agonist are used for each of different agonist are used for each of different antiplatelet agents antiplatelet agents
For Aspirin AA is used (result is reported as aspirin For Aspirin AA is used (result is reported as aspirin reaction units [ARU] ARUgt 550 indicates non-reaction units [ARU] ARUgt 550 indicates non-responsiveness)responsiveness)
Verify IIbIIIa assay device uses TRAP as agonist for Verify IIbIIIa assay device uses TRAP as agonist for Abciximab and TirofibanAbciximab and Tirofiban
Practical Applications Practical Applications related to specific related to specific
Neurovascular Neurovascular interventionsinterventions
Acute ischemic StrokeAcute ischemic Stroke When an artery occludes neurons are affected When an artery occludes neurons are affected
differently depending upon the amount of residual blood differently depending upon the amount of residual blood flowflow
Normal cerebral blood flow is greater than 50 mL100 Normal cerebral blood flow is greater than 50 mL100 mgminmgmin
Once blood flow decreases to less than 20 mL100 Once blood flow decreases to less than 20 mL100 mgmin infarction occursmgmin infarction occurs
If blood flow decreases to less than 10 mL100 mgmin If blood flow decreases to less than 10 mL100 mgmin irreversible neuronal death occurs rapidly irreversible neuronal death occurs rapidly
Blood flow between 11 and 20 mL100 mgmin is thought Blood flow between 11 and 20 mL100 mgmin is thought to represent the ischemic penumbra an area where the to represent the ischemic penumbra an area where the cells are functionally silent because of ischemia but are cells are functionally silent because of ischemia but are still able to recover if blood flow is restored still able to recover if blood flow is restored
Many acute stroke therapies are targeted toward Many acute stroke therapies are targeted toward restoring flow or function to the ischemic penumbrarestoring flow or function to the ischemic penumbra
Therapeutic window in Therapeutic window in management of acute Ischemic management of acute Ischemic
StrokeStrokeThe early diagnosis of ischemic stroke is critical to the The early diagnosis of ischemic stroke is critical to the
with only a narrow therapeutic window in the first few with only a narrow therapeutic window in the first few hours following stroke ictushours following stroke ictus
Diagnosis in the first 3 hours postictus provides the Diagnosis in the first 3 hours postictus provides the opportunity for intravenous or intraarterial thrombolysis opportunity for intravenous or intraarterial thrombolysis and intra-arterial clot mechanical treatment which and intra-arterial clot mechanical treatment which improve the outcome improve the outcome
Diagnosis in the time period between 3 and 6 hours Diagnosis in the time period between 3 and 6 hours provides an opportunity for intra-arterial thrombolysis provides an opportunity for intra-arterial thrombolysis and mechanical treatment and mechanical treatment
Involvement of the posterior circulation especially the Involvement of the posterior circulation especially the basilar artery is treated by some regardless of time of basilar artery is treated by some regardless of time of onset or up until 12 to 24 hours in some practices This is onset or up until 12 to 24 hours in some practices This is related to the potentially high mortality and morbidity related to the potentially high mortality and morbidity associated with basilar artery thrombosisassociated with basilar artery thrombosis
Infarct evaluation on angiographyInfarct evaluation on angiography(CT angiography and catheter (CT angiography and catheter
angiography)angiography)CTA is an excellent first-line examination for CTA is an excellent first-line examination for
evaluation of the head and neck arteries evaluation of the head and neck arteries In comparison with catheter angiography In comparison with catheter angiography
what it gives up in resolution and dynamic what it gives up in resolution and dynamic properties it makes up for with rapid properties it makes up for with rapid acquisition of a 3-D dataset and the potential acquisition of a 3-D dataset and the potential for assessment of whole-brain perfusion and for assessment of whole-brain perfusion and better parenchymal evaluationbetter parenchymal evaluation
Moreover CTA illustrates not only arterial Moreover CTA illustrates not only arterial stenosis or occlusion but also the vessel wall stenosis or occlusion but also the vessel wall This factor is most important for evaluation of This factor is most important for evaluation of intramural dissection and thrombosed intramural dissection and thrombosed aneurysms which may both complicate aneurysms which may both complicate evaluation of stroke patientsevaluation of stroke patients
Early angiographic signs of strokes Early angiographic signs of strokes both CTA both CTA and DSA and DSA
Vessel occlusion or cutoff related to Vessel occlusion or cutoff related to thromboembolithromboemboli
aneurysms aneurysms arterial dissection arterial dissection Meniscus or flattened shape to clot Meniscus or flattened shape to clot
(recent) versus reverse meniscus (older)(recent) versus reverse meniscus (older) tram track (nonocclusive or recanalized tram track (nonocclusive or recanalized
clot) clot) delayed (antegrade) flow (manifest as delayed (antegrade) flow (manifest as
decreased whole-brain perfusion on CTA)decreased whole-brain perfusion on CTA) retrograde collateral flowretrograde collateral flow
Non-occlusive left MCA thrombus on 3-D imaging performed from CTA source data and was confirmed at catheter angiography
Therapy to be started within a 6-hr Therapy to be started within a 6-hr time to treatment (TTT) window time to treatment (TTT) window (while in case of IV thrombolysis (while in case of IV thrombolysis therapy to be started with in 3hrs)therapy to be started with in 3hrs)
Exclusion criteria Exclusion criteria Rapidly improving neurologic deficit or Rapidly improving neurologic deficit or Sustained blood pressure of gt180100 Sustained blood pressure of gt180100 Hemorrhage is detected on CTHemorrhage is detected on CT Infarct involving gt more than 13 rd Infarct involving gt more than 13 rd
territory of MCAterritory of MCA MRADWI-Perfusion mismatchlt 20MRADWI-Perfusion mismatchlt 20 Definite hypodensity on CTDefinite hypodensity on CT
Intra-arterial Thrombolysis
Fibrinolytics + AntiplateletsFibrinolytics + Antiplatelets
PlasminogenPlasminogen activators through fibrinolysis exposes activators through fibrinolysis exposes free thrombin and paradoxically stimulatesfree thrombin and paradoxically stimulates platelet platelet aggregation which leads to formation of aaggregation which leads to formation of a platelet platelet thrombus (white clot) thrombus (white clot)
This new thrombus is relatively resistant to This new thrombus is relatively resistant to fibrinolyticsfibrinolytics
So new regimen in case of acute stroke isSo new regimen in case of acute stroke is fibrinolytics + antiplatelet drugsfibrinolytics + antiplatelet drugs
rtPA + IIbIIIa inhibitors( tirofiban rtPA + IIbIIIa inhibitors( tirofiban abciximab) orabciximab) or
Urokinase + IIbIIIa Urokinase + IIbIIIa inhibitors( tirofiban abciximab)inhibitors( tirofiban abciximab)
Intra-arterial Thrombolysis Tirofiban (04 microgkgmin bolus for 3 min followed by Tirofiban (04 microgkgmin bolus for 3 min followed by
0125 ugkgmin)0125 ugkgmin)
++
Heparin (2000ndash3000 IU bolus followed by Heparin (2000ndash3000 IU bolus followed by 1000 IUhour infusion 1000 IUhour infusion
with ACT maintained bw 200-300) throughout the with ACT maintained bw 200-300) throughout the interventional procedure and for 24ndash48 hours thereafter when interventional procedure and for 24ndash48 hours thereafter when there is neither intraprocedural bleeding nor suspicion of there is neither intraprocedural bleeding nor suspicion of increased risk of bleeding increased risk of bleeding
Maximum dose of Urokinase Maximum dose of Urokinase Anterior circulation stroke - 500000 IU (mean 400000 Anterior circulation stroke - 500000 IU (mean 400000
IU range 300000ndash500000 IU)IU range 300000ndash500000 IU) Posterior circulation stroke -1000000 IU (mean 837000 Posterior circulation stroke -1000000 IU (mean 837000
IU range 300000ndash1000000 IU)IU range 300000ndash1000000 IU)American Journal of NeuroradiologyAmerican Journal of Neuroradiology 262595-2601 2005262595-2601 2005
Intravenous ThrombolysisIntravenous Thrombolysis
The first method to restore cerebral The first method to restore cerebral perfusion is clot lysis with the goal perfusion is clot lysis with the goal of re-establishing blood flow to the of re-establishing blood flow to the affected tissue affected tissue
IV thrombolysis rt-PA is the only IV thrombolysis rt-PA is the only FDA- approved treatment for AIS FDA- approved treatment for AIS
Fibrinolysis is enhanced powerfully Fibrinolysis is enhanced powerfully by rt-PAby rt-PA
Intravenous rTPA Intravenous rTPA administration administration protocolprotocol
Total dose of rt-PA 09 mgkg (maximum dose Total dose of rt-PA 09 mgkg (maximum dose 90 mg)90 mg)
Give 10 as initial IV bolusGive 10 as initial IV bolus Infuse remainder over 1 hourInfuse remainder over 1 hour Admit patient to an ICU or stroke unit for Admit patient to an ICU or stroke unit for
monitoringmonitoring Neurologic assessments every 15 minutes Neurologic assessments every 15 minutes
during infusion then every 30 minutes for next during infusion then every 30 minutes for next 6 hours then every hour until 24hours after 6 hours then every hour until 24hours after treatmenttreatment
Favorable Outcome vs Treatment Time Favorable Outcome vs Treatment Time with IV rTPAwith IV rTPA
Protocol limit = 3 hrs
Benefit ~ 45 hrs
Thromboembolism During coilingThromboembolism During coiling Most feared and frequent complication Most feared and frequent complication Reported incidence - Approx 7 Reported incidence - Approx 7 SourcesSources of Thromboembolism are of Thromboembolism are
- Clots at the aneurysmal neck during or immediately- Clots at the aneurysmal neck during or immediately after after embolization embolization
- Thrombus forming on catheters during- Thrombus forming on catheters during proceduresprocedures
- Stenosis of an adjacent artery dt coil mass- Stenosis of an adjacent artery dt coil mass or herniationor herniation
- Migration of intraaneurysmal- Migration of intraaneurysmal thrombus during coil thrombus during coil placement placement
- Slow flow dt vasospasm - Slow flow dt vasospasm
- Rare and unlikely causes are hypercoagulable- Rare and unlikely causes are hypercoagulable state such state such as antiphospholipid antibody syndrome or due to HITas antiphospholipid antibody syndrome or due to HIT
Occur more often with wide-necked aneurysms (dt Occur more often with wide-necked aneurysms (dt increased exposed surface area of thrombogenic coil increased exposed surface area of thrombogenic coil material)material)
Current regimen of endovascular Current regimen of endovascular managementmanagement
The The glycoprotein IIbIIIa antagonist tirofiban glycoprotein IIbIIIa antagonist tirofiban (04 (04 microgkgmin bolus for 30 minutes followed by infusion of microgkgmin bolus for 30 minutes followed by infusion of 0125 ugkgmin until the thrombus dissolved) 0125 ugkgmin until the thrombus dissolved)
Intraarterial thrombolysis with Intraarterial thrombolysis with urokinase or r- TPA urokinase or r- TPA increase of intravenous (IV) heparin (measured by increase of intravenous (IV) heparin (measured by
ACT) ACT) Intravenous aspirin Intravenous aspirin
Coil-related platelet aggregation (white clot) is Coil-related platelet aggregation (white clot) is unlikely to respond to fibrinolytics but has a high risk unlikely to respond to fibrinolytics but has a high risk of hemorrhage (In ISAT) all 5 patients who had of hemorrhage (In ISAT) all 5 patients who had received thrombolytic therapy with tPA to treat a received thrombolytic therapy with tPA to treat a thromboembolic complication after endovascular thromboembolic complication after endovascular treatment rebleed and all of these patients died)treatment rebleed and all of these patients died)
IntracranialIntracranial Stenting Stenting Metallic foreign body such as stent will accumulate Metallic foreign body such as stent will accumulate
thrombus in the absence of platelet inhibitionthrombus in the absence of platelet inhibition Antiplatelet drugs are important to prevent peri or Antiplatelet drugs are important to prevent peri or
post-interventional thromboembolic eventspost-interventional thromboembolic events Optimal treatment regimens has not been determined Optimal treatment regimens has not been determined
but usually but usually Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-
procedureprocedureOrOr
Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on
morning of proceduremorning of procedure
If need to use stent is not pre-planned thanIf need to use stent is not pre-planned than
Abciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkgAbciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkg IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)
Glycoprotein IIbIIIa inhibitor are not used routinely during elective Glycoprotein IIbIIIa inhibitor are not used routinely during elective stenting procedure dt increased risk of ICH stenting procedure dt increased risk of ICH
Carotid StentingCarotid Stenting
Pre-procedurePre-procedure
Double Antiplatelet therapy is routinely given Double Antiplatelet therapy is routinely given beginning at least 3beginning at least 3
days before the proceduredays before the procedure
Aspirin 325mgd+Clopidogrel 75mgdAspirin 325mgd+Clopidogrel 75mgd During procedureDuring procedure
Heparin is given with target clotting time of 250-Heparin is given with target clotting time of 250-300sec300sec
Post-procedure Post-procedure
Aspirin 325mg is continued indefinitely and Aspirin 325mg is continued indefinitely and
Clopidogrel 75mgd for at least 6 weeks Clopidogrel 75mgd for at least 6 weeks
Inclusion criteria for Local ThrombolysisInclusion criteria for Local Thrombolysis a)a) Patients in severe clinical grade on admission Patients in severe clinical grade on admission
with evidence of dural venous sinus with evidence of dural venous sinus thrombosis and restrictive venous outflow on thrombosis and restrictive venous outflow on cerebral angiogramcerebral angiogram
b)b) Patients in clinical grade 3 worsening on Patients in clinical grade 3 worsening on heparin therapy Restriction to venous heparin therapy Restriction to venous outflow was defined as an increase in brain outflow was defined as an increase in brain circulation time gt 12 s delay in the drainage circulation time gt 12 s delay in the drainage of cortical veins with cortical veins hanging of cortical veins with cortical veins hanging in spacein space
Treatment Options for Venous Thrombosis
CT Grading for Venous ThrombosisCT Grading for Venous Thrombosis Grade I no parenchymal change Grade I no parenchymal change
(hyperdense (hyperdense sinuses cortical veins empty sinuses cortical veins empty delta sign)delta sign)
Grade II non hemorrhagic venous infarct Grade II non hemorrhagic venous infarct without mass effect without mass effect
Grade III non-hemorrhagic infarct with Grade III non-hemorrhagic infarct with mass effectmass effect
Grade IV hemorrhagic venous infarct (max Grade IV hemorrhagic venous infarct (max diameter lt 3 cm) with no mass effectdiameter lt 3 cm) with no mass effect
Grade V hemorrhagic venous infarct (max Grade V hemorrhagic venous infarct (max diameter gt 3 cm) with mass effect diameter gt 3 cm) with mass effect
Local ThrombolysisLocal Thrombolysis
Femoral Jugular access was secured and a guiding Femoral Jugular access was secured and a guiding catheter was placed in the jugular bulb catheter was placed in the jugular bulb Mechanical Mechanical clot maceration clot maceration was done with the guidewire was done with the guidewire following which a microcatheter (was navigated and following which a microcatheter (was navigated and placed in the thrombosed segment of sinus confirmed placed in the thrombosed segment of sinus confirmed on a selective venogram on a selective venogram
Urokinase infusion Bolus dose of 2-6 lacs followed Urokinase infusion Bolus dose of 2-6 lacs followed by 60000 to 100000 units per hour along with by 60000 to 100000 units per hour along with periodic check venogram Along with maintenance periodic check venogram Along with maintenance systemic infusion of Heparinsystemic infusion of Heparin Other agents such as Other agents such as streptokinase altepase or rTPAstreptokinase altepase or rTPA can be also used can be also used
After thrombolysis patient should subjected to oral After thrombolysis patient should subjected to oral anticoagulation for six monthsanticoagulation for six months
Low-molecular-weight Low-molecular-weight heparinheparin
PharmacologyPharmacologyLMWH as its name suggests is a glycosaminoglycan that is approximatelyLMWH as its name suggests is a glycosaminoglycan that is approximately
one third the molecular weight of UFH It is derived from UFH through one third the molecular weight of UFH It is derived from UFH through variousvarious
depolymerization processes LMWH binds to antithrombin which in turn depolymerization processes LMWH binds to antithrombin which in turn
Neutralizes actors Xa and IIa Because LMWH lacks many of the longer Neutralizes actors Xa and IIa Because LMWH lacks many of the longer chains chains
required for binding to thrombin it has less ability to neutralize thrombin required for binding to thrombin it has less ability to neutralize thrombin
relativeto its ability to neutralize factor Xa LMWH also has less relativeto its ability to neutralize factor Xa LMWH also has less nonspecific nonspecific
binding to other proteins There is greater bioavailability with more binding to other proteins There is greater bioavailability with more predictable predictable
pharmacokinetics that eliminates the need for monitoring The smaller pharmacokinetics that eliminates the need for monitoring The smaller size also size also
allows for enhanced subcutaneous absorption when compared with UFHallows for enhanced subcutaneous absorption when compared with UFH
Three LMWH preparations are Three LMWH preparations are currently approved for use in the currently approved for use in the United States (1) enoxaparin (2) United States (1) enoxaparin (2) dalteparin and (3) tinzaparin dalteparin and (3) tinzaparin
They are all administered They are all administered subcutaneously at intervals of either subcutaneously at intervals of either once or twice daily for both once or twice daily for both prophylaxis and treatment dosesprophylaxis and treatment doses
Few Experiences of Few Experiences of ThrombolysisThrombolysis
Vickey 25 Yrs male patient presented Vickey 25 Yrs male patient presented with 12with 12thth day HO severe headache with day HO severe headache with right sided hemiplegiaright sided hemiplegia
MRI shows thrombosis of the superior MRI shows thrombosis of the superior sagittal left transverse left sigmoid sagittal left transverse left sigmoid sinuses and cortical veins in the fronto-sinuses and cortical veins in the fronto-parietal regions with eo haemorrhagic parietal regions with eo haemorrhagic infarct in the left cerebral hemisphere infarct in the left cerebral hemisphere with mass effect( Grade ndashV)with mass effect( Grade ndashV)
Sashi Srivastava 64 yrs FSashi Srivastava 64 yrs F In a follow up case of MRD with infra-renal In a follow up case of MRD with infra-renal
aortic abdominal and bilateral renal artery aortic abdominal and bilateral renal artery thrombosis renal angiogram shows filling thrombosis renal angiogram shows filling defects in the right Renal artery defects in the right Renal artery
Initially Renal angioplasty was done Initially Renal angioplasty was done Following angioplasty few thrombi are seem Following angioplasty few thrombi are seem to extends into the segmental branches and to extends into the segmental branches and causing blockage So Thrombolysis was causing blockage So Thrombolysis was plane to dissolve the run-out thrombi with plane to dissolve the run-out thrombi with urokinase urokinase
Rakesh 34yrsMRakesh 34yrsM Left SFA pseudoaneurysm with Left SFA pseudoaneurysm with
Covered stent placementCovered stent placement Pre operative antiplatelets with post Pre operative antiplatelets with post
procedure heparin Tirofiban procedure heparin Tirofiban followed by aspirin and clopidogrel followed by aspirin and clopidogrel were usedwere used
IAT may be a treatment option for selected patients IAT may be a treatment option for selected patients Possible selection criteria include Possible selection criteria include
presentation between 3 and 6 hours from symptom onsetpresentation between 3 and 6 hours from symptom onset major cerebral artery occlusion major cerebral artery occlusion severe neurologic deficits severe neurologic deficits high risk of systemic hemorrhage with IV rt-PA (eg recent high risk of systemic hemorrhage with IV rt-PA (eg recent
surgery) surgery) The MERCI (Mechanical Embolus Removal in Cerebral The MERCI (Mechanical Embolus Removal in Cerebral
Ischemia) retrievalIschemia) retrieval system system
Has been FDA-approved for recanalizing acutely occluded Has been FDA-approved for recanalizing acutely occluded cerebral arteries cerebral arteries
In the Multi-MERCI study patients who did not improve In the Multi-MERCI study patients who did not improve immediately after IV rt-PA underwent mechanical immediately after IV rt-PA underwent mechanical embolectomy within 8 hours of symptom onset embolectomy within 8 hours of symptom onset
Partial or complete recanalization occurred in 74 of Partial or complete recanalization occurred in 74 of patientspatients
with a symptomatic intracerebral hemorrhage (sICH) rate of with a symptomatic intracerebral hemorrhage (sICH) rate of 67 67
Mechanical embolectomy with the MERCI retriever may be a Mechanical embolectomy with the MERCI retriever may be a feasible and safe option for patients after IV rt-PAfeasible and safe option for patients after IV rt-PA
Penumbra stroke systemPenumbra stroke system This device combines two methods of clot This device combines two methods of clot
extraction aspiration and mechanical extraction aspiration and mechanical extraction extraction
First the clot is aspirated then a thrombus First the clot is aspirated then a thrombus removal ring can be used if necessary to removal ring can be used if necessary to remove remaining clot remove remaining clot
successful recanalizing 82successful recanalizing 82 Bridging therapyBridging therapy
06 mgkg IV rt-PA followed by IAT with IA rt-06 mgkg IV rt-PA followed by IAT with IA rt-PA (up to 20 mg)PA (up to 20 mg)
achieved a higher recanalization rateachieved a higher recanalization rate
Criteria for thrombolysis with rTPACriteria for thrombolysis with rTPA
Inclusion criteriaInclusion criteria Clinical signs and symptoms consistent with ischemic Clinical signs and symptoms consistent with ischemic
strokestroke Patient last seen normal within 3 hoursPatient last seen normal within 3 hours Measurable neurologic deficitMeasurable neurologic deficit
Exclusion criteriaExclusion criteria Any hemorrhage on neuroimaging (CT or MRI)Any hemorrhage on neuroimaging (CT or MRI) Symptoms suggestive of subarachnoid hemorrhageSymptoms suggestive of subarachnoid hemorrhage Seizure at stroke onset that is thought to contribute to Seizure at stroke onset that is thought to contribute to
neurologic deficitneurologic deficit Hypodensity greater than one third cerebral hemisphere Hypodensity greater than one third cerebral hemisphere
on CTon CT SBP greater than 185 mm Hg or DBP greater than 110 SBP greater than 185 mm Hg or DBP greater than 110
mm Hgmm Hg International normalized ratio (INR) greater than 17International normalized ratio (INR) greater than 17
Ischemic Stroke Ischemic Stroke Treatment ndash 2006Treatment ndash 2006
IV tissue plasminogen activator (tPA)IV tissue plasminogen activator (tPA) ndash ndash Only FDA-approved acute stroke drugOnly FDA-approved acute stroke drug ndash ndash 3 hour treatment window3 hour treatment window
MERCI - Concentric clot retrieval MERCI - Concentric clot retrieval devicedevice ndash ndash Rescue therapy - approved 2004Rescue therapy - approved 2004 ndash ndash Device approval (not outcomes-based)Device approval (not outcomes-based)
Off label approachesOff label approaches ndash ndash IV tPA after 3 hoursIV tPA after 3 hours ndash ndash IV-IA tPA sequential strategiesIV-IA tPA sequential strategies ndash ndash IA tPA clot angioplasty fragmentationIA tPA clot angioplasty fragmentation ndash ndash Ultrasound-assisted tPA lysisUltrasound-assisted tPA lysis
rt-PA Trials NINDSrt-PA Trials NINDS
Acute stroke - 624 patientsAcute stroke - 624 patients Treat within 3 hrsTreat within 3 hrs Intravenous 09 mgkg rt-PA vs placeboIntravenous 09 mgkg rt-PA vs placebo Hemorrhage 64 tPA 06 placeboHemorrhage 64 tPA 06 placebo Neurologic recovery better with tPA 30 Neurologic recovery better with tPA 30
more like to have minimal or no disabilitymore like to have minimal or no disability
First proven approved treatment for First proven approved treatment for strokestroke
Limitations of tPALimitations of tPA Only 4 of acute strokes receive tPAOnly 4 of acute strokes receive tPA (Kleindorfer et al Stroke 2004 35 e27-e29)(Kleindorfer et al Stroke 2004 35 e27-e29)
Only 22 of patients present within 3 hoursOnly 22 of patients present within 3 hours1048707 1048707 51 of these ineligible due to51 of these ineligible due to
bull bull Mild severityMild severity bull bull Medical or surgical historyMedical or surgical history bull bull Blood testsBlood tests
Sustained recanalization only 13Sustained recanalization only 13 (Alexandrov et al NEJM 2004 351 2170-8)(Alexandrov et al NEJM 2004 351 2170-8)
Concern for hemorrhageConcern for hemorrhage tPA potentiates apoptotic injury tPA potentiates apoptotic injury (Liu et al Nature Med 2004 101379-83)(Liu et al Nature Med 2004 101379-83)
PROACT II IA Lysis TrialPROACT II IA Lysis Trial Baseline 24 hours 8 days
Baseline 60 minutes 120 minutes
9mg IAProurokinase
Desmoteplase Trials DEDAS Desmoteplase Trials DEDAS DIASDIAS
Trial OverviewTrial Overview Double blind randomized placebo Double blind randomized placebo
controlled trialscontrolled trials IV delivery 3-9 hour time windowIV delivery 3-9 hour time window Plasminogen activator ndash from Plasminogen activator ndash from vampire bat vampire bat
salivasaliva Selection based on PWI-DWI MismatchSelection based on PWI-DWI Mismatch
MRI InclusionMRI Inclusion PWI defect at least 2 cm AND ~20 larger PWI defect at least 2 cm AND ~20 larger
than DWIthan DWI PWI should be obvious even visible on PWI should be obvious even visible on
raw imagesraw imagesMRI ExclusionMRI Exclusion
DWI gt 13 MCADWI gt 13 MCA MRA ICA occlusionMRA ICA occlusion
Desmoteplase ndash DIAS Desmoteplase ndash DIAS ResultsResults
Mechanical Thrombolysis Mechanical Thrombolysis devicesdevices
mechanical thrombolysis potentially extends the treatment mechanical thrombolysis potentially extends the treatment window because they act promptly at the site of the thrombuswindow because they act promptly at the site of the thrombus
The devices can retrieve large clots that pharmaceutical agents The devices can retrieve large clots that pharmaceutical agents may not successfully lysemay not successfully lyse
Patients treated with IV tPA may be considered for treatment of Patients treated with IV tPA may be considered for treatment of residual clot with some of these devicesresidual clot with some of these devices
suction-creating saline jets suction-creating saline jets laser energy ultrasound laser energy ultrasound a corkscrew apparatus to treat strokesa corkscrew apparatus to treat strokes The AngioJet systemThe AngioJet system uses saline jets that are directed back into the catheter to uses saline jets that are directed back into the catheter to
create a low-pressure zone around the catheter tip inducing create a low-pressure zone around the catheter tip inducing suction suction
The clot is pulled into the exhaust lumen and removed from the The clot is pulled into the exhaust lumen and removed from the vessel Although US Food and Drug Administration (FDA) has vessel Although US Food and Drug Administration (FDA) has approved this device for use in arteriovenous dialysis grafts and approved this device for use in arteriovenous dialysis grafts and fistulae and for the treatment of coronary arteries saphenous fistulae and for the treatment of coronary arteries saphenous vein grafts and peripheral vessels clinical trials for the vein grafts and peripheral vessels clinical trials for the treatment of acute stroke are no longer in progress treatment of acute stroke are no longer in progress
Most devices are used in cerebral vessels that 2-5 mm
The Latis laser device The Latis laser device used laser energy to ablate clots used laser energy to ablate clots Arteries 2-5 mm in diameter could be Arteries 2-5 mm in diameter could be
treated including the ICA M1 or M2 treated including the ICA M1 or M2 branch of the MCA A1 branch of the branch of the MCA A1 branch of the anterior cerebral artery (ACA) basilar anterior cerebral artery (ACA) basilar artery posterior cerebral artery (PCA) artery posterior cerebral artery (PCA) and vertebral and vertebral
Patients could receive treatment as late Patients could receive treatment as late as 8 hours after symptom onset in the as 8 hours after symptom onset in the anterior circulation and within 24 hours in anterior circulation and within 24 hours in the posterior circulation the posterior circulation
Endovascular Photo Acoustic Endovascular Photo Acoustic Recanalization (EPAR) Recanalization (EPAR)
A laser power source generated energy for the A laser power source generated energy for the systemsystem
The energy was delivered by means of The energy was delivered by means of fiberoptics to the tip of the catheter at the fiberoptics to the tip of the catheter at the treatment sitetreatment site
Absorption of laser light by darkly pigmented Absorption of laser light by darkly pigmented materials (ie the clot) occurred inside the 1-mm materials (ie the clot) occurred inside the 1-mm catheter tipcatheter tip
the system was designed to minimize scattering the system was designed to minimize scattering of laser light of laser light
Absorption converted photo energy to acoustic Absorption converted photo energy to acoustic energy which then emulsified the clot inside the energy which then emulsified the clot inside the catheter tip catheter tip
EKOS ultrasound( the EKOS ultrasound( the Ultrasound Thrombolytic Ultrasound Thrombolytic
Infusion Catheter) Infusion Catheter) combines the use of a distal ultrasound transducer with combines the use of a distal ultrasound transducer with
infusion of a thrombolytic agent through the infusion of a thrombolytic agent through the microcathetermicrocatheter
Ultrasound changes the structure of the clot to Ultrasound changes the structure of the clot to temporarily increase its permeability while providing an temporarily increase its permeability while providing an acoustic pressure gradient to move the drug into the clot acoustic pressure gradient to move the drug into the clot to speed its dissolution to speed its dissolution
The EKOS catheter is placed in the proximal portion of the The EKOS catheter is placed in the proximal portion of the clot clot
After a 2-mg bolus of tPA was injected through the After a 2-mg bolus of tPA was injected through the catheter catheter
the patient received a continuous infusion of IA tPA 03 the patient received a continuous infusion of IA tPA 03 mgmin to a maximum of 20 mg and simultaneous mgmin to a maximum of 20 mg and simultaneous ultrasound transmission for as long as 60 minutes ultrasound transmission for as long as 60 minutes
One patient was treated with a total of 4 units of One patient was treated with a total of 4 units of recombinant reteplase (Retavase) hand-injected over 60 recombinant reteplase (Retavase) hand-injected over 60 minutes minutes
Penumbra system Penumbra system The Penumbra system (Penumbra Inc) provides a dual The Penumbra system (Penumbra Inc) provides a dual
approach to clot extraction using aspiration followed by approach to clot extraction using aspiration followed by clot retrieval with a ring device if needed clot retrieval with a ring device if needed
Mechanical Embolus Removal in Cerebral Ischemia Mechanical Embolus Removal in Cerebral Ischemia (MERCI)(MERCI)
a corkscrew-like apparatus to remove blood clots from a corkscrew-like apparatus to remove blood clots from the brain in patients experiencing an ischemic stroke the brain in patients experiencing an ischemic stroke
The corkscrew itself resides in the catheter tip which The corkscrew itself resides in the catheter tip which shields it from the wall of the vessel until it is ready to be shields it from the wall of the vessel until it is ready to be burrowed into the clot Once lodged in the clot the device burrowed into the clot Once lodged in the clot the device and clot are withdrawn from the vessel and clot are withdrawn from the vessel
Snarelike devicesSnarelike devices Snares such as the Neuronet snare (Guidant Snares such as the Neuronet snare (Guidant
Endovascular Santa Clara CA) have been developed Endovascular Santa Clara CA) have been developed specifically for use in the treatment of strokes specifically for use in the treatment of strokes
These devices are simple in design and do not require the These devices are simple in design and do not require the clot to be amenable to emulsification clot to be amenable to emulsification
X-Sizer deviceX-Sizer device a device with small moving blades at the a device with small moving blades at the
catheter tip catheter tip This device the X-Sizer device (EndiCor Medical This device the X-Sizer device (EndiCor Medical
San Clemente CA) can be used to excise the San Clemente CA) can be used to excise the thrombus and aspirate it thrombus and aspirate it
The device was being evaluated in randomized The device was being evaluated in randomized studies of coronary vessels and in a registry of studies of coronary vessels and in a registry of patients with acute myocardial infarctionpatients with acute myocardial infarction
Although the manufacturer had modified the Although the manufacturer had modified the device for use in cerebral vessels a safety and device for use in cerebral vessels a safety and feasibility study was indefinitely suspended after feasibility study was indefinitely suspended after only 1 patient was treated with the device in only 1 patient was treated with the device in Europe Europe
Suction thrombectomySuction thrombectomy This method of mechanical thrombolysis is one of the This method of mechanical thrombolysis is one of the
simplestsimplest In this readily available technique suction is applied with In this readily available technique suction is applied with
a syringe to remove thrombus in the ICA a syringe to remove thrombus in the ICA It requires no other devicesIt requires no other devices A catheter with a large inner diameter (Brite Tip Cordis A catheter with a large inner diameter (Brite Tip Cordis
Corporation Miami FL) was placed in the symptomatic Corporation Miami FL) was placed in the symptomatic vessel and navigated over a guidewire into the thrombusvessel and navigated over a guidewire into the thrombus
A 60-mL syringe was used to aspirate the thrombus A 60-mL syringe was used to aspirate the thrombus Each patient required angioplasty and stenting of carotid Each patient required angioplasty and stenting of carotid
bifurcation stenosis and received daily aspirin and bifurcation stenosis and received daily aspirin and ticlopidine after the procedure No complications ticlopidine after the procedure No complications occurred occurred
Summary Acute Stroke Summary Acute Stroke ImagingImaging
PhysiologyPhysiology importance collaterals importance collaterals
ndash ndashGrowing role for perfusion Growing role for perfusion assessmentassessment
tPAtPA guidelines amp limitations guidelines amp limitations Signs on CT amp MRSigns on CT amp MR follow physiology follow physiology Stroke trialsStroke trials PWI-DWI mismatch PWI-DWI mismatch
ndash ndashTreat based on physiology not timeTreat based on physiology not time ProtocolsProtocols should be fast and should be fast and
comprehensivecomprehensive
Anti-fibrinolyticsAnti-fibrinolytics
to limit fibrinolytic activityto limit fibrinolytic activity -aminocaproic acid (EACA) -aminocaproic acid (EACA) competitively inhibitscompetitively inhibits plasminogen and plasminogen activators from plasminogen and plasminogen activators from
binding to fibrinbinding to fibrin
alpha2-antiplasminalpha2-antiplasmin a serine protease inhibitor that a serine protease inhibitor that neutralizes any free circulating plasminneutralizes any free circulating plasmin
Plasminogen activator inhibitor-1Plasminogen activator inhibitor-1 a serine protease a serine protease inhibitor that inhibits tissue-type plasminogen inhibitor that inhibits tissue-type plasminogen activatoractivator
Glycoprotein (GP) IIbIIIa antagonistsGlycoprotein (GP) IIbIIIa antagonists
such as ReoPro (abciximab) Integrilin such as ReoPro (abciximab) Integrilin (eptifibatide) or Aggrastat (tirofiban) in (eptifibatide) or Aggrastat (tirofiban) in ischemic stroke remains investigational ischemic stroke remains investigational Deshmukh et al38 reported 21 patients with Deshmukh et al38 reported 21 patients with large-vessel occlusion refractory to IAT with large-vessel occlusion refractory to IAT with rtPA who were treated with IV andor IA rtPA who were treated with IV andor IA abciximab eptifibatide or tirofiban abciximab eptifibatide or tirofiban
IA Mechanical Approaches in Acute Ischemic Stroke IA Mechanical Approaches in Acute Ischemic Stroke Mechanical strategies have several advantagesMechanical strategies have several advantages First they lessen and may even preclude the use of chemical First they lessen and may even preclude the use of chemical
thrombolytics in this manner very likely reducing the risk of ICHthrombolytics in this manner very likely reducing the risk of ICH Second by avoiding the use of chemical thrombolytics it is Second by avoiding the use of chemical thrombolytics it is
possible to extend the treatment window beyond the limit of 6ndash8 possible to extend the treatment window beyond the limit of 6ndash8 hours hours
Third mechanically fragmenting a clot increases the surface area Third mechanically fragmenting a clot increases the surface area accessible to fibrinolytic agents and allows inflow of fresh accessible to fibrinolytic agents and allows inflow of fresh plasminogen which in turn may increase the speed of plasminogen which in turn may increase the speed of thrombolysis thrombolysis
Finally clot-retrieval devices may provide faster recanalization Finally clot-retrieval devices may provide faster recanalization
The disadvantages of the mechanical The disadvantages of the mechanical approaches approaches technical difficulty of navigating mechanical technical difficulty of navigating mechanical
devices into the intracranial circulation excessive devices into the intracranial circulation excessive trauma to the vasculature (potentially leading to trauma to the vasculature (potentially leading to vasospasm vessel dissection perforation or vasospasm vessel dissection perforation or rupture) rupture)
fragmented thrombus causing distal embolization fragmented thrombus causing distal embolization into previously unaffected territories into previously unaffected territories
Nevertheless the advantages of mechanical stroke Nevertheless the advantages of mechanical stroke therapy appear to significantly outweigh its therapy appear to significantly outweigh its disadvantages and risksdisadvantages and risks
Contraindications to Thrombolytic Contraindications to Thrombolytic agents agents
Recent thoracic abdominal or Recent thoracic abdominal or intracranial surgeryintracranial surgery
Recent haemorrhagic CVA Head injury Recent haemorrhagic CVA Head injury or neoplasmor neoplasm
Bleeding ulcerBleeding ulcer Anticipated invasive procedures (arterial Anticipated invasive procedures (arterial
punctures biopsies)punctures biopsies) Concurrent hemostatic dysfunctionConcurrent hemostatic dysfunction
Monitoring of thrombolytic Monitoring of thrombolytic therapytherapy
Thrombin time Measures the availability of functional
fibrinogen Normal thrombin time is 10-14 sec Prolonged when fibrinogen level is below
75-100 mgdl
Half Life of ThrombolyticsHalf Life of ThrombolyticsAgent Administration Half Life
Streptokinase IA 60-80min
Urokinase IAIV 9-12min
rTPA IAIV 6min
Abciximab(Reopro) IAIV 12hour
Aspirin POIV 15-20min
Heparin IVSC 60min
Coumadin PO 15-25 days
Anti Platelet DrugsAnti Platelet DrugsDrug Drug Mechanism Mechanism UsesUsesAspirinAspirin Permanently inhibits Permanently inhibits
COX-1 and COX-2COX-1 and COX-2CADCAD
Stroke-TIAsStroke-TIAs
NSAIDsNSAIDs Reversibly inhibits Reversibly inhibits COX-1COX-1
LimitedLimited
DipyridamoleDipyridamole Inhibits PDE increases Inhibits PDE increases cAMPcAMP
TIAsTIAs
ThenopyridinesThenopyridines
(Ticlopidine(Ticlopidine
ClopidrgrelClopidrgrel))
Inhibits ADP Inhibits ADP
PlatAg PlatAg
TIAsStrokeTIAsStroke
CAD PVDCAD PVD
Abciximab (ReoPro)Abciximab (ReoPro)
Eptifibatide (Integrilin)Eptifibatide (Integrilin)
TirofibanTirofiban
GP IIBIIIA InhibitorsGP IIBIIIA Inhibitors
Stroke- TIAs Stroke- TIAs
MonitoringMonitoring
Bleeding timeBleeding time
Optical aggregometryOptical aggregometry
Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay
Bleeding timeBleeding time
Requires a skin incision (usually made on the ear lobe or Requires a skin incision (usually made on the ear lobe or forearm offorearm of
a depth that results in disruption of capillary loops and a depth that results in disruption of capillary loops and small vessels)small vessels)
AdvantagesAdvantages Universally availableUniversally available Relatively simple techniquesRelatively simple techniques Can be performed bedsideCan be performed bedside
DisadvantagesDisadvantages Insensitive inaccurate non-specific techniqueInsensitive inaccurate non-specific technique
Poorly reproducible (as depends on multiple variables)Poorly reproducible (as depends on multiple variables)
Optical aggregometryOptical aggregometry
Gold standard assay for platelet functionGold standard assay for platelet function Agonist induced aggregation is measuredAgonist induced aggregation is measured Different agonist are available for different Different agonist are available for different
agentsagents However require unique expertise and are not However require unique expertise and are not
universally availableuniversally available Aspirin measured with ADP or AA(gt70 Aspirin measured with ADP or AA(gt70
aggregation so resistance)aggregation so resistance) Clopidogrel( ADP gt 90 aggregation means Clopidogrel( ADP gt 90 aggregation means
resistance) resistance)
Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay
Can be performed bed sideCan be performed bed side Different assay devices with different Different assay devices with different
agonist are used for each of different agonist are used for each of different antiplatelet agents antiplatelet agents
For Aspirin AA is used (result is reported as aspirin For Aspirin AA is used (result is reported as aspirin reaction units [ARU] ARUgt 550 indicates non-reaction units [ARU] ARUgt 550 indicates non-responsiveness)responsiveness)
Verify IIbIIIa assay device uses TRAP as agonist for Verify IIbIIIa assay device uses TRAP as agonist for Abciximab and TirofibanAbciximab and Tirofiban
Practical Applications Practical Applications related to specific related to specific
Neurovascular Neurovascular interventionsinterventions
Acute ischemic StrokeAcute ischemic Stroke When an artery occludes neurons are affected When an artery occludes neurons are affected
differently depending upon the amount of residual blood differently depending upon the amount of residual blood flowflow
Normal cerebral blood flow is greater than 50 mL100 Normal cerebral blood flow is greater than 50 mL100 mgminmgmin
Once blood flow decreases to less than 20 mL100 Once blood flow decreases to less than 20 mL100 mgmin infarction occursmgmin infarction occurs
If blood flow decreases to less than 10 mL100 mgmin If blood flow decreases to less than 10 mL100 mgmin irreversible neuronal death occurs rapidly irreversible neuronal death occurs rapidly
Blood flow between 11 and 20 mL100 mgmin is thought Blood flow between 11 and 20 mL100 mgmin is thought to represent the ischemic penumbra an area where the to represent the ischemic penumbra an area where the cells are functionally silent because of ischemia but are cells are functionally silent because of ischemia but are still able to recover if blood flow is restored still able to recover if blood flow is restored
Many acute stroke therapies are targeted toward Many acute stroke therapies are targeted toward restoring flow or function to the ischemic penumbrarestoring flow or function to the ischemic penumbra
Therapeutic window in Therapeutic window in management of acute Ischemic management of acute Ischemic
StrokeStrokeThe early diagnosis of ischemic stroke is critical to the The early diagnosis of ischemic stroke is critical to the
with only a narrow therapeutic window in the first few with only a narrow therapeutic window in the first few hours following stroke ictushours following stroke ictus
Diagnosis in the first 3 hours postictus provides the Diagnosis in the first 3 hours postictus provides the opportunity for intravenous or intraarterial thrombolysis opportunity for intravenous or intraarterial thrombolysis and intra-arterial clot mechanical treatment which and intra-arterial clot mechanical treatment which improve the outcome improve the outcome
Diagnosis in the time period between 3 and 6 hours Diagnosis in the time period between 3 and 6 hours provides an opportunity for intra-arterial thrombolysis provides an opportunity for intra-arterial thrombolysis and mechanical treatment and mechanical treatment
Involvement of the posterior circulation especially the Involvement of the posterior circulation especially the basilar artery is treated by some regardless of time of basilar artery is treated by some regardless of time of onset or up until 12 to 24 hours in some practices This is onset or up until 12 to 24 hours in some practices This is related to the potentially high mortality and morbidity related to the potentially high mortality and morbidity associated with basilar artery thrombosisassociated with basilar artery thrombosis
Infarct evaluation on angiographyInfarct evaluation on angiography(CT angiography and catheter (CT angiography and catheter
angiography)angiography)CTA is an excellent first-line examination for CTA is an excellent first-line examination for
evaluation of the head and neck arteries evaluation of the head and neck arteries In comparison with catheter angiography In comparison with catheter angiography
what it gives up in resolution and dynamic what it gives up in resolution and dynamic properties it makes up for with rapid properties it makes up for with rapid acquisition of a 3-D dataset and the potential acquisition of a 3-D dataset and the potential for assessment of whole-brain perfusion and for assessment of whole-brain perfusion and better parenchymal evaluationbetter parenchymal evaluation
Moreover CTA illustrates not only arterial Moreover CTA illustrates not only arterial stenosis or occlusion but also the vessel wall stenosis or occlusion but also the vessel wall This factor is most important for evaluation of This factor is most important for evaluation of intramural dissection and thrombosed intramural dissection and thrombosed aneurysms which may both complicate aneurysms which may both complicate evaluation of stroke patientsevaluation of stroke patients
Early angiographic signs of strokes Early angiographic signs of strokes both CTA both CTA and DSA and DSA
Vessel occlusion or cutoff related to Vessel occlusion or cutoff related to thromboembolithromboemboli
aneurysms aneurysms arterial dissection arterial dissection Meniscus or flattened shape to clot Meniscus or flattened shape to clot
(recent) versus reverse meniscus (older)(recent) versus reverse meniscus (older) tram track (nonocclusive or recanalized tram track (nonocclusive or recanalized
clot) clot) delayed (antegrade) flow (manifest as delayed (antegrade) flow (manifest as
decreased whole-brain perfusion on CTA)decreased whole-brain perfusion on CTA) retrograde collateral flowretrograde collateral flow
Non-occlusive left MCA thrombus on 3-D imaging performed from CTA source data and was confirmed at catheter angiography
Therapy to be started within a 6-hr Therapy to be started within a 6-hr time to treatment (TTT) window time to treatment (TTT) window (while in case of IV thrombolysis (while in case of IV thrombolysis therapy to be started with in 3hrs)therapy to be started with in 3hrs)
Exclusion criteria Exclusion criteria Rapidly improving neurologic deficit or Rapidly improving neurologic deficit or Sustained blood pressure of gt180100 Sustained blood pressure of gt180100 Hemorrhage is detected on CTHemorrhage is detected on CT Infarct involving gt more than 13 rd Infarct involving gt more than 13 rd
territory of MCAterritory of MCA MRADWI-Perfusion mismatchlt 20MRADWI-Perfusion mismatchlt 20 Definite hypodensity on CTDefinite hypodensity on CT
Intra-arterial Thrombolysis
Fibrinolytics + AntiplateletsFibrinolytics + Antiplatelets
PlasminogenPlasminogen activators through fibrinolysis exposes activators through fibrinolysis exposes free thrombin and paradoxically stimulatesfree thrombin and paradoxically stimulates platelet platelet aggregation which leads to formation of aaggregation which leads to formation of a platelet platelet thrombus (white clot) thrombus (white clot)
This new thrombus is relatively resistant to This new thrombus is relatively resistant to fibrinolyticsfibrinolytics
So new regimen in case of acute stroke isSo new regimen in case of acute stroke is fibrinolytics + antiplatelet drugsfibrinolytics + antiplatelet drugs
rtPA + IIbIIIa inhibitors( tirofiban rtPA + IIbIIIa inhibitors( tirofiban abciximab) orabciximab) or
Urokinase + IIbIIIa Urokinase + IIbIIIa inhibitors( tirofiban abciximab)inhibitors( tirofiban abciximab)
Intra-arterial Thrombolysis Tirofiban (04 microgkgmin bolus for 3 min followed by Tirofiban (04 microgkgmin bolus for 3 min followed by
0125 ugkgmin)0125 ugkgmin)
++
Heparin (2000ndash3000 IU bolus followed by Heparin (2000ndash3000 IU bolus followed by 1000 IUhour infusion 1000 IUhour infusion
with ACT maintained bw 200-300) throughout the with ACT maintained bw 200-300) throughout the interventional procedure and for 24ndash48 hours thereafter when interventional procedure and for 24ndash48 hours thereafter when there is neither intraprocedural bleeding nor suspicion of there is neither intraprocedural bleeding nor suspicion of increased risk of bleeding increased risk of bleeding
Maximum dose of Urokinase Maximum dose of Urokinase Anterior circulation stroke - 500000 IU (mean 400000 Anterior circulation stroke - 500000 IU (mean 400000
IU range 300000ndash500000 IU)IU range 300000ndash500000 IU) Posterior circulation stroke -1000000 IU (mean 837000 Posterior circulation stroke -1000000 IU (mean 837000
IU range 300000ndash1000000 IU)IU range 300000ndash1000000 IU)American Journal of NeuroradiologyAmerican Journal of Neuroradiology 262595-2601 2005262595-2601 2005
Intravenous ThrombolysisIntravenous Thrombolysis
The first method to restore cerebral The first method to restore cerebral perfusion is clot lysis with the goal perfusion is clot lysis with the goal of re-establishing blood flow to the of re-establishing blood flow to the affected tissue affected tissue
IV thrombolysis rt-PA is the only IV thrombolysis rt-PA is the only FDA- approved treatment for AIS FDA- approved treatment for AIS
Fibrinolysis is enhanced powerfully Fibrinolysis is enhanced powerfully by rt-PAby rt-PA
Intravenous rTPA Intravenous rTPA administration administration protocolprotocol
Total dose of rt-PA 09 mgkg (maximum dose Total dose of rt-PA 09 mgkg (maximum dose 90 mg)90 mg)
Give 10 as initial IV bolusGive 10 as initial IV bolus Infuse remainder over 1 hourInfuse remainder over 1 hour Admit patient to an ICU or stroke unit for Admit patient to an ICU or stroke unit for
monitoringmonitoring Neurologic assessments every 15 minutes Neurologic assessments every 15 minutes
during infusion then every 30 minutes for next during infusion then every 30 minutes for next 6 hours then every hour until 24hours after 6 hours then every hour until 24hours after treatmenttreatment
Favorable Outcome vs Treatment Time Favorable Outcome vs Treatment Time with IV rTPAwith IV rTPA
Protocol limit = 3 hrs
Benefit ~ 45 hrs
Thromboembolism During coilingThromboembolism During coiling Most feared and frequent complication Most feared and frequent complication Reported incidence - Approx 7 Reported incidence - Approx 7 SourcesSources of Thromboembolism are of Thromboembolism are
- Clots at the aneurysmal neck during or immediately- Clots at the aneurysmal neck during or immediately after after embolization embolization
- Thrombus forming on catheters during- Thrombus forming on catheters during proceduresprocedures
- Stenosis of an adjacent artery dt coil mass- Stenosis of an adjacent artery dt coil mass or herniationor herniation
- Migration of intraaneurysmal- Migration of intraaneurysmal thrombus during coil thrombus during coil placement placement
- Slow flow dt vasospasm - Slow flow dt vasospasm
- Rare and unlikely causes are hypercoagulable- Rare and unlikely causes are hypercoagulable state such state such as antiphospholipid antibody syndrome or due to HITas antiphospholipid antibody syndrome or due to HIT
Occur more often with wide-necked aneurysms (dt Occur more often with wide-necked aneurysms (dt increased exposed surface area of thrombogenic coil increased exposed surface area of thrombogenic coil material)material)
Current regimen of endovascular Current regimen of endovascular managementmanagement
The The glycoprotein IIbIIIa antagonist tirofiban glycoprotein IIbIIIa antagonist tirofiban (04 (04 microgkgmin bolus for 30 minutes followed by infusion of microgkgmin bolus for 30 minutes followed by infusion of 0125 ugkgmin until the thrombus dissolved) 0125 ugkgmin until the thrombus dissolved)
Intraarterial thrombolysis with Intraarterial thrombolysis with urokinase or r- TPA urokinase or r- TPA increase of intravenous (IV) heparin (measured by increase of intravenous (IV) heparin (measured by
ACT) ACT) Intravenous aspirin Intravenous aspirin
Coil-related platelet aggregation (white clot) is Coil-related platelet aggregation (white clot) is unlikely to respond to fibrinolytics but has a high risk unlikely to respond to fibrinolytics but has a high risk of hemorrhage (In ISAT) all 5 patients who had of hemorrhage (In ISAT) all 5 patients who had received thrombolytic therapy with tPA to treat a received thrombolytic therapy with tPA to treat a thromboembolic complication after endovascular thromboembolic complication after endovascular treatment rebleed and all of these patients died)treatment rebleed and all of these patients died)
IntracranialIntracranial Stenting Stenting Metallic foreign body such as stent will accumulate Metallic foreign body such as stent will accumulate
thrombus in the absence of platelet inhibitionthrombus in the absence of platelet inhibition Antiplatelet drugs are important to prevent peri or Antiplatelet drugs are important to prevent peri or
post-interventional thromboembolic eventspost-interventional thromboembolic events Optimal treatment regimens has not been determined Optimal treatment regimens has not been determined
but usually but usually Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-
procedureprocedureOrOr
Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on
morning of proceduremorning of procedure
If need to use stent is not pre-planned thanIf need to use stent is not pre-planned than
Abciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkgAbciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkg IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)
Glycoprotein IIbIIIa inhibitor are not used routinely during elective Glycoprotein IIbIIIa inhibitor are not used routinely during elective stenting procedure dt increased risk of ICH stenting procedure dt increased risk of ICH
Carotid StentingCarotid Stenting
Pre-procedurePre-procedure
Double Antiplatelet therapy is routinely given Double Antiplatelet therapy is routinely given beginning at least 3beginning at least 3
days before the proceduredays before the procedure
Aspirin 325mgd+Clopidogrel 75mgdAspirin 325mgd+Clopidogrel 75mgd During procedureDuring procedure
Heparin is given with target clotting time of 250-Heparin is given with target clotting time of 250-300sec300sec
Post-procedure Post-procedure
Aspirin 325mg is continued indefinitely and Aspirin 325mg is continued indefinitely and
Clopidogrel 75mgd for at least 6 weeks Clopidogrel 75mgd for at least 6 weeks
Inclusion criteria for Local ThrombolysisInclusion criteria for Local Thrombolysis a)a) Patients in severe clinical grade on admission Patients in severe clinical grade on admission
with evidence of dural venous sinus with evidence of dural venous sinus thrombosis and restrictive venous outflow on thrombosis and restrictive venous outflow on cerebral angiogramcerebral angiogram
b)b) Patients in clinical grade 3 worsening on Patients in clinical grade 3 worsening on heparin therapy Restriction to venous heparin therapy Restriction to venous outflow was defined as an increase in brain outflow was defined as an increase in brain circulation time gt 12 s delay in the drainage circulation time gt 12 s delay in the drainage of cortical veins with cortical veins hanging of cortical veins with cortical veins hanging in spacein space
Treatment Options for Venous Thrombosis
CT Grading for Venous ThrombosisCT Grading for Venous Thrombosis Grade I no parenchymal change Grade I no parenchymal change
(hyperdense (hyperdense sinuses cortical veins empty sinuses cortical veins empty delta sign)delta sign)
Grade II non hemorrhagic venous infarct Grade II non hemorrhagic venous infarct without mass effect without mass effect
Grade III non-hemorrhagic infarct with Grade III non-hemorrhagic infarct with mass effectmass effect
Grade IV hemorrhagic venous infarct (max Grade IV hemorrhagic venous infarct (max diameter lt 3 cm) with no mass effectdiameter lt 3 cm) with no mass effect
Grade V hemorrhagic venous infarct (max Grade V hemorrhagic venous infarct (max diameter gt 3 cm) with mass effect diameter gt 3 cm) with mass effect
Local ThrombolysisLocal Thrombolysis
Femoral Jugular access was secured and a guiding Femoral Jugular access was secured and a guiding catheter was placed in the jugular bulb catheter was placed in the jugular bulb Mechanical Mechanical clot maceration clot maceration was done with the guidewire was done with the guidewire following which a microcatheter (was navigated and following which a microcatheter (was navigated and placed in the thrombosed segment of sinus confirmed placed in the thrombosed segment of sinus confirmed on a selective venogram on a selective venogram
Urokinase infusion Bolus dose of 2-6 lacs followed Urokinase infusion Bolus dose of 2-6 lacs followed by 60000 to 100000 units per hour along with by 60000 to 100000 units per hour along with periodic check venogram Along with maintenance periodic check venogram Along with maintenance systemic infusion of Heparinsystemic infusion of Heparin Other agents such as Other agents such as streptokinase altepase or rTPAstreptokinase altepase or rTPA can be also used can be also used
After thrombolysis patient should subjected to oral After thrombolysis patient should subjected to oral anticoagulation for six monthsanticoagulation for six months
Low-molecular-weight Low-molecular-weight heparinheparin
PharmacologyPharmacologyLMWH as its name suggests is a glycosaminoglycan that is approximatelyLMWH as its name suggests is a glycosaminoglycan that is approximately
one third the molecular weight of UFH It is derived from UFH through one third the molecular weight of UFH It is derived from UFH through variousvarious
depolymerization processes LMWH binds to antithrombin which in turn depolymerization processes LMWH binds to antithrombin which in turn
Neutralizes actors Xa and IIa Because LMWH lacks many of the longer Neutralizes actors Xa and IIa Because LMWH lacks many of the longer chains chains
required for binding to thrombin it has less ability to neutralize thrombin required for binding to thrombin it has less ability to neutralize thrombin
relativeto its ability to neutralize factor Xa LMWH also has less relativeto its ability to neutralize factor Xa LMWH also has less nonspecific nonspecific
binding to other proteins There is greater bioavailability with more binding to other proteins There is greater bioavailability with more predictable predictable
pharmacokinetics that eliminates the need for monitoring The smaller pharmacokinetics that eliminates the need for monitoring The smaller size also size also
allows for enhanced subcutaneous absorption when compared with UFHallows for enhanced subcutaneous absorption when compared with UFH
Three LMWH preparations are Three LMWH preparations are currently approved for use in the currently approved for use in the United States (1) enoxaparin (2) United States (1) enoxaparin (2) dalteparin and (3) tinzaparin dalteparin and (3) tinzaparin
They are all administered They are all administered subcutaneously at intervals of either subcutaneously at intervals of either once or twice daily for both once or twice daily for both prophylaxis and treatment dosesprophylaxis and treatment doses
Few Experiences of Few Experiences of ThrombolysisThrombolysis
Vickey 25 Yrs male patient presented Vickey 25 Yrs male patient presented with 12with 12thth day HO severe headache with day HO severe headache with right sided hemiplegiaright sided hemiplegia
MRI shows thrombosis of the superior MRI shows thrombosis of the superior sagittal left transverse left sigmoid sagittal left transverse left sigmoid sinuses and cortical veins in the fronto-sinuses and cortical veins in the fronto-parietal regions with eo haemorrhagic parietal regions with eo haemorrhagic infarct in the left cerebral hemisphere infarct in the left cerebral hemisphere with mass effect( Grade ndashV)with mass effect( Grade ndashV)
Sashi Srivastava 64 yrs FSashi Srivastava 64 yrs F In a follow up case of MRD with infra-renal In a follow up case of MRD with infra-renal
aortic abdominal and bilateral renal artery aortic abdominal and bilateral renal artery thrombosis renal angiogram shows filling thrombosis renal angiogram shows filling defects in the right Renal artery defects in the right Renal artery
Initially Renal angioplasty was done Initially Renal angioplasty was done Following angioplasty few thrombi are seem Following angioplasty few thrombi are seem to extends into the segmental branches and to extends into the segmental branches and causing blockage So Thrombolysis was causing blockage So Thrombolysis was plane to dissolve the run-out thrombi with plane to dissolve the run-out thrombi with urokinase urokinase
Rakesh 34yrsMRakesh 34yrsM Left SFA pseudoaneurysm with Left SFA pseudoaneurysm with
Covered stent placementCovered stent placement Pre operative antiplatelets with post Pre operative antiplatelets with post
procedure heparin Tirofiban procedure heparin Tirofiban followed by aspirin and clopidogrel followed by aspirin and clopidogrel were usedwere used
IAT may be a treatment option for selected patients IAT may be a treatment option for selected patients Possible selection criteria include Possible selection criteria include
presentation between 3 and 6 hours from symptom onsetpresentation between 3 and 6 hours from symptom onset major cerebral artery occlusion major cerebral artery occlusion severe neurologic deficits severe neurologic deficits high risk of systemic hemorrhage with IV rt-PA (eg recent high risk of systemic hemorrhage with IV rt-PA (eg recent
surgery) surgery) The MERCI (Mechanical Embolus Removal in Cerebral The MERCI (Mechanical Embolus Removal in Cerebral
Ischemia) retrievalIschemia) retrieval system system
Has been FDA-approved for recanalizing acutely occluded Has been FDA-approved for recanalizing acutely occluded cerebral arteries cerebral arteries
In the Multi-MERCI study patients who did not improve In the Multi-MERCI study patients who did not improve immediately after IV rt-PA underwent mechanical immediately after IV rt-PA underwent mechanical embolectomy within 8 hours of symptom onset embolectomy within 8 hours of symptom onset
Partial or complete recanalization occurred in 74 of Partial or complete recanalization occurred in 74 of patientspatients
with a symptomatic intracerebral hemorrhage (sICH) rate of with a symptomatic intracerebral hemorrhage (sICH) rate of 67 67
Mechanical embolectomy with the MERCI retriever may be a Mechanical embolectomy with the MERCI retriever may be a feasible and safe option for patients after IV rt-PAfeasible and safe option for patients after IV rt-PA
Penumbra stroke systemPenumbra stroke system This device combines two methods of clot This device combines two methods of clot
extraction aspiration and mechanical extraction aspiration and mechanical extraction extraction
First the clot is aspirated then a thrombus First the clot is aspirated then a thrombus removal ring can be used if necessary to removal ring can be used if necessary to remove remaining clot remove remaining clot
successful recanalizing 82successful recanalizing 82 Bridging therapyBridging therapy
06 mgkg IV rt-PA followed by IAT with IA rt-06 mgkg IV rt-PA followed by IAT with IA rt-PA (up to 20 mg)PA (up to 20 mg)
achieved a higher recanalization rateachieved a higher recanalization rate
Criteria for thrombolysis with rTPACriteria for thrombolysis with rTPA
Inclusion criteriaInclusion criteria Clinical signs and symptoms consistent with ischemic Clinical signs and symptoms consistent with ischemic
strokestroke Patient last seen normal within 3 hoursPatient last seen normal within 3 hours Measurable neurologic deficitMeasurable neurologic deficit
Exclusion criteriaExclusion criteria Any hemorrhage on neuroimaging (CT or MRI)Any hemorrhage on neuroimaging (CT or MRI) Symptoms suggestive of subarachnoid hemorrhageSymptoms suggestive of subarachnoid hemorrhage Seizure at stroke onset that is thought to contribute to Seizure at stroke onset that is thought to contribute to
neurologic deficitneurologic deficit Hypodensity greater than one third cerebral hemisphere Hypodensity greater than one third cerebral hemisphere
on CTon CT SBP greater than 185 mm Hg or DBP greater than 110 SBP greater than 185 mm Hg or DBP greater than 110
mm Hgmm Hg International normalized ratio (INR) greater than 17International normalized ratio (INR) greater than 17
Ischemic Stroke Ischemic Stroke Treatment ndash 2006Treatment ndash 2006
IV tissue plasminogen activator (tPA)IV tissue plasminogen activator (tPA) ndash ndash Only FDA-approved acute stroke drugOnly FDA-approved acute stroke drug ndash ndash 3 hour treatment window3 hour treatment window
MERCI - Concentric clot retrieval MERCI - Concentric clot retrieval devicedevice ndash ndash Rescue therapy - approved 2004Rescue therapy - approved 2004 ndash ndash Device approval (not outcomes-based)Device approval (not outcomes-based)
Off label approachesOff label approaches ndash ndash IV tPA after 3 hoursIV tPA after 3 hours ndash ndash IV-IA tPA sequential strategiesIV-IA tPA sequential strategies ndash ndash IA tPA clot angioplasty fragmentationIA tPA clot angioplasty fragmentation ndash ndash Ultrasound-assisted tPA lysisUltrasound-assisted tPA lysis
rt-PA Trials NINDSrt-PA Trials NINDS
Acute stroke - 624 patientsAcute stroke - 624 patients Treat within 3 hrsTreat within 3 hrs Intravenous 09 mgkg rt-PA vs placeboIntravenous 09 mgkg rt-PA vs placebo Hemorrhage 64 tPA 06 placeboHemorrhage 64 tPA 06 placebo Neurologic recovery better with tPA 30 Neurologic recovery better with tPA 30
more like to have minimal or no disabilitymore like to have minimal or no disability
First proven approved treatment for First proven approved treatment for strokestroke
Limitations of tPALimitations of tPA Only 4 of acute strokes receive tPAOnly 4 of acute strokes receive tPA (Kleindorfer et al Stroke 2004 35 e27-e29)(Kleindorfer et al Stroke 2004 35 e27-e29)
Only 22 of patients present within 3 hoursOnly 22 of patients present within 3 hours1048707 1048707 51 of these ineligible due to51 of these ineligible due to
bull bull Mild severityMild severity bull bull Medical or surgical historyMedical or surgical history bull bull Blood testsBlood tests
Sustained recanalization only 13Sustained recanalization only 13 (Alexandrov et al NEJM 2004 351 2170-8)(Alexandrov et al NEJM 2004 351 2170-8)
Concern for hemorrhageConcern for hemorrhage tPA potentiates apoptotic injury tPA potentiates apoptotic injury (Liu et al Nature Med 2004 101379-83)(Liu et al Nature Med 2004 101379-83)
PROACT II IA Lysis TrialPROACT II IA Lysis Trial Baseline 24 hours 8 days
Baseline 60 minutes 120 minutes
9mg IAProurokinase
Desmoteplase Trials DEDAS Desmoteplase Trials DEDAS DIASDIAS
Trial OverviewTrial Overview Double blind randomized placebo Double blind randomized placebo
controlled trialscontrolled trials IV delivery 3-9 hour time windowIV delivery 3-9 hour time window Plasminogen activator ndash from Plasminogen activator ndash from vampire bat vampire bat
salivasaliva Selection based on PWI-DWI MismatchSelection based on PWI-DWI Mismatch
MRI InclusionMRI Inclusion PWI defect at least 2 cm AND ~20 larger PWI defect at least 2 cm AND ~20 larger
than DWIthan DWI PWI should be obvious even visible on PWI should be obvious even visible on
raw imagesraw imagesMRI ExclusionMRI Exclusion
DWI gt 13 MCADWI gt 13 MCA MRA ICA occlusionMRA ICA occlusion
Desmoteplase ndash DIAS Desmoteplase ndash DIAS ResultsResults
Mechanical Thrombolysis Mechanical Thrombolysis devicesdevices
mechanical thrombolysis potentially extends the treatment mechanical thrombolysis potentially extends the treatment window because they act promptly at the site of the thrombuswindow because they act promptly at the site of the thrombus
The devices can retrieve large clots that pharmaceutical agents The devices can retrieve large clots that pharmaceutical agents may not successfully lysemay not successfully lyse
Patients treated with IV tPA may be considered for treatment of Patients treated with IV tPA may be considered for treatment of residual clot with some of these devicesresidual clot with some of these devices
suction-creating saline jets suction-creating saline jets laser energy ultrasound laser energy ultrasound a corkscrew apparatus to treat strokesa corkscrew apparatus to treat strokes The AngioJet systemThe AngioJet system uses saline jets that are directed back into the catheter to uses saline jets that are directed back into the catheter to
create a low-pressure zone around the catheter tip inducing create a low-pressure zone around the catheter tip inducing suction suction
The clot is pulled into the exhaust lumen and removed from the The clot is pulled into the exhaust lumen and removed from the vessel Although US Food and Drug Administration (FDA) has vessel Although US Food and Drug Administration (FDA) has approved this device for use in arteriovenous dialysis grafts and approved this device for use in arteriovenous dialysis grafts and fistulae and for the treatment of coronary arteries saphenous fistulae and for the treatment of coronary arteries saphenous vein grafts and peripheral vessels clinical trials for the vein grafts and peripheral vessels clinical trials for the treatment of acute stroke are no longer in progress treatment of acute stroke are no longer in progress
Most devices are used in cerebral vessels that 2-5 mm
The Latis laser device The Latis laser device used laser energy to ablate clots used laser energy to ablate clots Arteries 2-5 mm in diameter could be Arteries 2-5 mm in diameter could be
treated including the ICA M1 or M2 treated including the ICA M1 or M2 branch of the MCA A1 branch of the branch of the MCA A1 branch of the anterior cerebral artery (ACA) basilar anterior cerebral artery (ACA) basilar artery posterior cerebral artery (PCA) artery posterior cerebral artery (PCA) and vertebral and vertebral
Patients could receive treatment as late Patients could receive treatment as late as 8 hours after symptom onset in the as 8 hours after symptom onset in the anterior circulation and within 24 hours in anterior circulation and within 24 hours in the posterior circulation the posterior circulation
Endovascular Photo Acoustic Endovascular Photo Acoustic Recanalization (EPAR) Recanalization (EPAR)
A laser power source generated energy for the A laser power source generated energy for the systemsystem
The energy was delivered by means of The energy was delivered by means of fiberoptics to the tip of the catheter at the fiberoptics to the tip of the catheter at the treatment sitetreatment site
Absorption of laser light by darkly pigmented Absorption of laser light by darkly pigmented materials (ie the clot) occurred inside the 1-mm materials (ie the clot) occurred inside the 1-mm catheter tipcatheter tip
the system was designed to minimize scattering the system was designed to minimize scattering of laser light of laser light
Absorption converted photo energy to acoustic Absorption converted photo energy to acoustic energy which then emulsified the clot inside the energy which then emulsified the clot inside the catheter tip catheter tip
EKOS ultrasound( the EKOS ultrasound( the Ultrasound Thrombolytic Ultrasound Thrombolytic
Infusion Catheter) Infusion Catheter) combines the use of a distal ultrasound transducer with combines the use of a distal ultrasound transducer with
infusion of a thrombolytic agent through the infusion of a thrombolytic agent through the microcathetermicrocatheter
Ultrasound changes the structure of the clot to Ultrasound changes the structure of the clot to temporarily increase its permeability while providing an temporarily increase its permeability while providing an acoustic pressure gradient to move the drug into the clot acoustic pressure gradient to move the drug into the clot to speed its dissolution to speed its dissolution
The EKOS catheter is placed in the proximal portion of the The EKOS catheter is placed in the proximal portion of the clot clot
After a 2-mg bolus of tPA was injected through the After a 2-mg bolus of tPA was injected through the catheter catheter
the patient received a continuous infusion of IA tPA 03 the patient received a continuous infusion of IA tPA 03 mgmin to a maximum of 20 mg and simultaneous mgmin to a maximum of 20 mg and simultaneous ultrasound transmission for as long as 60 minutes ultrasound transmission for as long as 60 minutes
One patient was treated with a total of 4 units of One patient was treated with a total of 4 units of recombinant reteplase (Retavase) hand-injected over 60 recombinant reteplase (Retavase) hand-injected over 60 minutes minutes
Penumbra system Penumbra system The Penumbra system (Penumbra Inc) provides a dual The Penumbra system (Penumbra Inc) provides a dual
approach to clot extraction using aspiration followed by approach to clot extraction using aspiration followed by clot retrieval with a ring device if needed clot retrieval with a ring device if needed
Mechanical Embolus Removal in Cerebral Ischemia Mechanical Embolus Removal in Cerebral Ischemia (MERCI)(MERCI)
a corkscrew-like apparatus to remove blood clots from a corkscrew-like apparatus to remove blood clots from the brain in patients experiencing an ischemic stroke the brain in patients experiencing an ischemic stroke
The corkscrew itself resides in the catheter tip which The corkscrew itself resides in the catheter tip which shields it from the wall of the vessel until it is ready to be shields it from the wall of the vessel until it is ready to be burrowed into the clot Once lodged in the clot the device burrowed into the clot Once lodged in the clot the device and clot are withdrawn from the vessel and clot are withdrawn from the vessel
Snarelike devicesSnarelike devices Snares such as the Neuronet snare (Guidant Snares such as the Neuronet snare (Guidant
Endovascular Santa Clara CA) have been developed Endovascular Santa Clara CA) have been developed specifically for use in the treatment of strokes specifically for use in the treatment of strokes
These devices are simple in design and do not require the These devices are simple in design and do not require the clot to be amenable to emulsification clot to be amenable to emulsification
X-Sizer deviceX-Sizer device a device with small moving blades at the a device with small moving blades at the
catheter tip catheter tip This device the X-Sizer device (EndiCor Medical This device the X-Sizer device (EndiCor Medical
San Clemente CA) can be used to excise the San Clemente CA) can be used to excise the thrombus and aspirate it thrombus and aspirate it
The device was being evaluated in randomized The device was being evaluated in randomized studies of coronary vessels and in a registry of studies of coronary vessels and in a registry of patients with acute myocardial infarctionpatients with acute myocardial infarction
Although the manufacturer had modified the Although the manufacturer had modified the device for use in cerebral vessels a safety and device for use in cerebral vessels a safety and feasibility study was indefinitely suspended after feasibility study was indefinitely suspended after only 1 patient was treated with the device in only 1 patient was treated with the device in Europe Europe
Suction thrombectomySuction thrombectomy This method of mechanical thrombolysis is one of the This method of mechanical thrombolysis is one of the
simplestsimplest In this readily available technique suction is applied with In this readily available technique suction is applied with
a syringe to remove thrombus in the ICA a syringe to remove thrombus in the ICA It requires no other devicesIt requires no other devices A catheter with a large inner diameter (Brite Tip Cordis A catheter with a large inner diameter (Brite Tip Cordis
Corporation Miami FL) was placed in the symptomatic Corporation Miami FL) was placed in the symptomatic vessel and navigated over a guidewire into the thrombusvessel and navigated over a guidewire into the thrombus
A 60-mL syringe was used to aspirate the thrombus A 60-mL syringe was used to aspirate the thrombus Each patient required angioplasty and stenting of carotid Each patient required angioplasty and stenting of carotid
bifurcation stenosis and received daily aspirin and bifurcation stenosis and received daily aspirin and ticlopidine after the procedure No complications ticlopidine after the procedure No complications occurred occurred
Summary Acute Stroke Summary Acute Stroke ImagingImaging
PhysiologyPhysiology importance collaterals importance collaterals
ndash ndashGrowing role for perfusion Growing role for perfusion assessmentassessment
tPAtPA guidelines amp limitations guidelines amp limitations Signs on CT amp MRSigns on CT amp MR follow physiology follow physiology Stroke trialsStroke trials PWI-DWI mismatch PWI-DWI mismatch
ndash ndashTreat based on physiology not timeTreat based on physiology not time ProtocolsProtocols should be fast and should be fast and
comprehensivecomprehensive
Glycoprotein (GP) IIbIIIa antagonistsGlycoprotein (GP) IIbIIIa antagonists
such as ReoPro (abciximab) Integrilin such as ReoPro (abciximab) Integrilin (eptifibatide) or Aggrastat (tirofiban) in (eptifibatide) or Aggrastat (tirofiban) in ischemic stroke remains investigational ischemic stroke remains investigational Deshmukh et al38 reported 21 patients with Deshmukh et al38 reported 21 patients with large-vessel occlusion refractory to IAT with large-vessel occlusion refractory to IAT with rtPA who were treated with IV andor IA rtPA who were treated with IV andor IA abciximab eptifibatide or tirofiban abciximab eptifibatide or tirofiban
IA Mechanical Approaches in Acute Ischemic Stroke IA Mechanical Approaches in Acute Ischemic Stroke Mechanical strategies have several advantagesMechanical strategies have several advantages First they lessen and may even preclude the use of chemical First they lessen and may even preclude the use of chemical
thrombolytics in this manner very likely reducing the risk of ICHthrombolytics in this manner very likely reducing the risk of ICH Second by avoiding the use of chemical thrombolytics it is Second by avoiding the use of chemical thrombolytics it is
possible to extend the treatment window beyond the limit of 6ndash8 possible to extend the treatment window beyond the limit of 6ndash8 hours hours
Third mechanically fragmenting a clot increases the surface area Third mechanically fragmenting a clot increases the surface area accessible to fibrinolytic agents and allows inflow of fresh accessible to fibrinolytic agents and allows inflow of fresh plasminogen which in turn may increase the speed of plasminogen which in turn may increase the speed of thrombolysis thrombolysis
Finally clot-retrieval devices may provide faster recanalization Finally clot-retrieval devices may provide faster recanalization
The disadvantages of the mechanical The disadvantages of the mechanical approaches approaches technical difficulty of navigating mechanical technical difficulty of navigating mechanical
devices into the intracranial circulation excessive devices into the intracranial circulation excessive trauma to the vasculature (potentially leading to trauma to the vasculature (potentially leading to vasospasm vessel dissection perforation or vasospasm vessel dissection perforation or rupture) rupture)
fragmented thrombus causing distal embolization fragmented thrombus causing distal embolization into previously unaffected territories into previously unaffected territories
Nevertheless the advantages of mechanical stroke Nevertheless the advantages of mechanical stroke therapy appear to significantly outweigh its therapy appear to significantly outweigh its disadvantages and risksdisadvantages and risks
Contraindications to Thrombolytic Contraindications to Thrombolytic agents agents
Recent thoracic abdominal or Recent thoracic abdominal or intracranial surgeryintracranial surgery
Recent haemorrhagic CVA Head injury Recent haemorrhagic CVA Head injury or neoplasmor neoplasm
Bleeding ulcerBleeding ulcer Anticipated invasive procedures (arterial Anticipated invasive procedures (arterial
punctures biopsies)punctures biopsies) Concurrent hemostatic dysfunctionConcurrent hemostatic dysfunction
Monitoring of thrombolytic Monitoring of thrombolytic therapytherapy
Thrombin time Measures the availability of functional
fibrinogen Normal thrombin time is 10-14 sec Prolonged when fibrinogen level is below
75-100 mgdl
Half Life of ThrombolyticsHalf Life of ThrombolyticsAgent Administration Half Life
Streptokinase IA 60-80min
Urokinase IAIV 9-12min
rTPA IAIV 6min
Abciximab(Reopro) IAIV 12hour
Aspirin POIV 15-20min
Heparin IVSC 60min
Coumadin PO 15-25 days
Anti Platelet DrugsAnti Platelet DrugsDrug Drug Mechanism Mechanism UsesUsesAspirinAspirin Permanently inhibits Permanently inhibits
COX-1 and COX-2COX-1 and COX-2CADCAD
Stroke-TIAsStroke-TIAs
NSAIDsNSAIDs Reversibly inhibits Reversibly inhibits COX-1COX-1
LimitedLimited
DipyridamoleDipyridamole Inhibits PDE increases Inhibits PDE increases cAMPcAMP
TIAsTIAs
ThenopyridinesThenopyridines
(Ticlopidine(Ticlopidine
ClopidrgrelClopidrgrel))
Inhibits ADP Inhibits ADP
PlatAg PlatAg
TIAsStrokeTIAsStroke
CAD PVDCAD PVD
Abciximab (ReoPro)Abciximab (ReoPro)
Eptifibatide (Integrilin)Eptifibatide (Integrilin)
TirofibanTirofiban
GP IIBIIIA InhibitorsGP IIBIIIA Inhibitors
Stroke- TIAs Stroke- TIAs
MonitoringMonitoring
Bleeding timeBleeding time
Optical aggregometryOptical aggregometry
Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay
Bleeding timeBleeding time
Requires a skin incision (usually made on the ear lobe or Requires a skin incision (usually made on the ear lobe or forearm offorearm of
a depth that results in disruption of capillary loops and a depth that results in disruption of capillary loops and small vessels)small vessels)
AdvantagesAdvantages Universally availableUniversally available Relatively simple techniquesRelatively simple techniques Can be performed bedsideCan be performed bedside
DisadvantagesDisadvantages Insensitive inaccurate non-specific techniqueInsensitive inaccurate non-specific technique
Poorly reproducible (as depends on multiple variables)Poorly reproducible (as depends on multiple variables)
Optical aggregometryOptical aggregometry
Gold standard assay for platelet functionGold standard assay for platelet function Agonist induced aggregation is measuredAgonist induced aggregation is measured Different agonist are available for different Different agonist are available for different
agentsagents However require unique expertise and are not However require unique expertise and are not
universally availableuniversally available Aspirin measured with ADP or AA(gt70 Aspirin measured with ADP or AA(gt70
aggregation so resistance)aggregation so resistance) Clopidogrel( ADP gt 90 aggregation means Clopidogrel( ADP gt 90 aggregation means
resistance) resistance)
Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay
Can be performed bed sideCan be performed bed side Different assay devices with different Different assay devices with different
agonist are used for each of different agonist are used for each of different antiplatelet agents antiplatelet agents
For Aspirin AA is used (result is reported as aspirin For Aspirin AA is used (result is reported as aspirin reaction units [ARU] ARUgt 550 indicates non-reaction units [ARU] ARUgt 550 indicates non-responsiveness)responsiveness)
Verify IIbIIIa assay device uses TRAP as agonist for Verify IIbIIIa assay device uses TRAP as agonist for Abciximab and TirofibanAbciximab and Tirofiban
Practical Applications Practical Applications related to specific related to specific
Neurovascular Neurovascular interventionsinterventions
Acute ischemic StrokeAcute ischemic Stroke When an artery occludes neurons are affected When an artery occludes neurons are affected
differently depending upon the amount of residual blood differently depending upon the amount of residual blood flowflow
Normal cerebral blood flow is greater than 50 mL100 Normal cerebral blood flow is greater than 50 mL100 mgminmgmin
Once blood flow decreases to less than 20 mL100 Once blood flow decreases to less than 20 mL100 mgmin infarction occursmgmin infarction occurs
If blood flow decreases to less than 10 mL100 mgmin If blood flow decreases to less than 10 mL100 mgmin irreversible neuronal death occurs rapidly irreversible neuronal death occurs rapidly
Blood flow between 11 and 20 mL100 mgmin is thought Blood flow between 11 and 20 mL100 mgmin is thought to represent the ischemic penumbra an area where the to represent the ischemic penumbra an area where the cells are functionally silent because of ischemia but are cells are functionally silent because of ischemia but are still able to recover if blood flow is restored still able to recover if blood flow is restored
Many acute stroke therapies are targeted toward Many acute stroke therapies are targeted toward restoring flow or function to the ischemic penumbrarestoring flow or function to the ischemic penumbra
Therapeutic window in Therapeutic window in management of acute Ischemic management of acute Ischemic
StrokeStrokeThe early diagnosis of ischemic stroke is critical to the The early diagnosis of ischemic stroke is critical to the
with only a narrow therapeutic window in the first few with only a narrow therapeutic window in the first few hours following stroke ictushours following stroke ictus
Diagnosis in the first 3 hours postictus provides the Diagnosis in the first 3 hours postictus provides the opportunity for intravenous or intraarterial thrombolysis opportunity for intravenous or intraarterial thrombolysis and intra-arterial clot mechanical treatment which and intra-arterial clot mechanical treatment which improve the outcome improve the outcome
Diagnosis in the time period between 3 and 6 hours Diagnosis in the time period between 3 and 6 hours provides an opportunity for intra-arterial thrombolysis provides an opportunity for intra-arterial thrombolysis and mechanical treatment and mechanical treatment
Involvement of the posterior circulation especially the Involvement of the posterior circulation especially the basilar artery is treated by some regardless of time of basilar artery is treated by some regardless of time of onset or up until 12 to 24 hours in some practices This is onset or up until 12 to 24 hours in some practices This is related to the potentially high mortality and morbidity related to the potentially high mortality and morbidity associated with basilar artery thrombosisassociated with basilar artery thrombosis
Infarct evaluation on angiographyInfarct evaluation on angiography(CT angiography and catheter (CT angiography and catheter
angiography)angiography)CTA is an excellent first-line examination for CTA is an excellent first-line examination for
evaluation of the head and neck arteries evaluation of the head and neck arteries In comparison with catheter angiography In comparison with catheter angiography
what it gives up in resolution and dynamic what it gives up in resolution and dynamic properties it makes up for with rapid properties it makes up for with rapid acquisition of a 3-D dataset and the potential acquisition of a 3-D dataset and the potential for assessment of whole-brain perfusion and for assessment of whole-brain perfusion and better parenchymal evaluationbetter parenchymal evaluation
Moreover CTA illustrates not only arterial Moreover CTA illustrates not only arterial stenosis or occlusion but also the vessel wall stenosis or occlusion but also the vessel wall This factor is most important for evaluation of This factor is most important for evaluation of intramural dissection and thrombosed intramural dissection and thrombosed aneurysms which may both complicate aneurysms which may both complicate evaluation of stroke patientsevaluation of stroke patients
Early angiographic signs of strokes Early angiographic signs of strokes both CTA both CTA and DSA and DSA
Vessel occlusion or cutoff related to Vessel occlusion or cutoff related to thromboembolithromboemboli
aneurysms aneurysms arterial dissection arterial dissection Meniscus or flattened shape to clot Meniscus or flattened shape to clot
(recent) versus reverse meniscus (older)(recent) versus reverse meniscus (older) tram track (nonocclusive or recanalized tram track (nonocclusive or recanalized
clot) clot) delayed (antegrade) flow (manifest as delayed (antegrade) flow (manifest as
decreased whole-brain perfusion on CTA)decreased whole-brain perfusion on CTA) retrograde collateral flowretrograde collateral flow
Non-occlusive left MCA thrombus on 3-D imaging performed from CTA source data and was confirmed at catheter angiography
Therapy to be started within a 6-hr Therapy to be started within a 6-hr time to treatment (TTT) window time to treatment (TTT) window (while in case of IV thrombolysis (while in case of IV thrombolysis therapy to be started with in 3hrs)therapy to be started with in 3hrs)
Exclusion criteria Exclusion criteria Rapidly improving neurologic deficit or Rapidly improving neurologic deficit or Sustained blood pressure of gt180100 Sustained blood pressure of gt180100 Hemorrhage is detected on CTHemorrhage is detected on CT Infarct involving gt more than 13 rd Infarct involving gt more than 13 rd
territory of MCAterritory of MCA MRADWI-Perfusion mismatchlt 20MRADWI-Perfusion mismatchlt 20 Definite hypodensity on CTDefinite hypodensity on CT
Intra-arterial Thrombolysis
Fibrinolytics + AntiplateletsFibrinolytics + Antiplatelets
PlasminogenPlasminogen activators through fibrinolysis exposes activators through fibrinolysis exposes free thrombin and paradoxically stimulatesfree thrombin and paradoxically stimulates platelet platelet aggregation which leads to formation of aaggregation which leads to formation of a platelet platelet thrombus (white clot) thrombus (white clot)
This new thrombus is relatively resistant to This new thrombus is relatively resistant to fibrinolyticsfibrinolytics
So new regimen in case of acute stroke isSo new regimen in case of acute stroke is fibrinolytics + antiplatelet drugsfibrinolytics + antiplatelet drugs
rtPA + IIbIIIa inhibitors( tirofiban rtPA + IIbIIIa inhibitors( tirofiban abciximab) orabciximab) or
Urokinase + IIbIIIa Urokinase + IIbIIIa inhibitors( tirofiban abciximab)inhibitors( tirofiban abciximab)
Intra-arterial Thrombolysis Tirofiban (04 microgkgmin bolus for 3 min followed by Tirofiban (04 microgkgmin bolus for 3 min followed by
0125 ugkgmin)0125 ugkgmin)
++
Heparin (2000ndash3000 IU bolus followed by Heparin (2000ndash3000 IU bolus followed by 1000 IUhour infusion 1000 IUhour infusion
with ACT maintained bw 200-300) throughout the with ACT maintained bw 200-300) throughout the interventional procedure and for 24ndash48 hours thereafter when interventional procedure and for 24ndash48 hours thereafter when there is neither intraprocedural bleeding nor suspicion of there is neither intraprocedural bleeding nor suspicion of increased risk of bleeding increased risk of bleeding
Maximum dose of Urokinase Maximum dose of Urokinase Anterior circulation stroke - 500000 IU (mean 400000 Anterior circulation stroke - 500000 IU (mean 400000
IU range 300000ndash500000 IU)IU range 300000ndash500000 IU) Posterior circulation stroke -1000000 IU (mean 837000 Posterior circulation stroke -1000000 IU (mean 837000
IU range 300000ndash1000000 IU)IU range 300000ndash1000000 IU)American Journal of NeuroradiologyAmerican Journal of Neuroradiology 262595-2601 2005262595-2601 2005
Intravenous ThrombolysisIntravenous Thrombolysis
The first method to restore cerebral The first method to restore cerebral perfusion is clot lysis with the goal perfusion is clot lysis with the goal of re-establishing blood flow to the of re-establishing blood flow to the affected tissue affected tissue
IV thrombolysis rt-PA is the only IV thrombolysis rt-PA is the only FDA- approved treatment for AIS FDA- approved treatment for AIS
Fibrinolysis is enhanced powerfully Fibrinolysis is enhanced powerfully by rt-PAby rt-PA
Intravenous rTPA Intravenous rTPA administration administration protocolprotocol
Total dose of rt-PA 09 mgkg (maximum dose Total dose of rt-PA 09 mgkg (maximum dose 90 mg)90 mg)
Give 10 as initial IV bolusGive 10 as initial IV bolus Infuse remainder over 1 hourInfuse remainder over 1 hour Admit patient to an ICU or stroke unit for Admit patient to an ICU or stroke unit for
monitoringmonitoring Neurologic assessments every 15 minutes Neurologic assessments every 15 minutes
during infusion then every 30 minutes for next during infusion then every 30 minutes for next 6 hours then every hour until 24hours after 6 hours then every hour until 24hours after treatmenttreatment
Favorable Outcome vs Treatment Time Favorable Outcome vs Treatment Time with IV rTPAwith IV rTPA
Protocol limit = 3 hrs
Benefit ~ 45 hrs
Thromboembolism During coilingThromboembolism During coiling Most feared and frequent complication Most feared and frequent complication Reported incidence - Approx 7 Reported incidence - Approx 7 SourcesSources of Thromboembolism are of Thromboembolism are
- Clots at the aneurysmal neck during or immediately- Clots at the aneurysmal neck during or immediately after after embolization embolization
- Thrombus forming on catheters during- Thrombus forming on catheters during proceduresprocedures
- Stenosis of an adjacent artery dt coil mass- Stenosis of an adjacent artery dt coil mass or herniationor herniation
- Migration of intraaneurysmal- Migration of intraaneurysmal thrombus during coil thrombus during coil placement placement
- Slow flow dt vasospasm - Slow flow dt vasospasm
- Rare and unlikely causes are hypercoagulable- Rare and unlikely causes are hypercoagulable state such state such as antiphospholipid antibody syndrome or due to HITas antiphospholipid antibody syndrome or due to HIT
Occur more often with wide-necked aneurysms (dt Occur more often with wide-necked aneurysms (dt increased exposed surface area of thrombogenic coil increased exposed surface area of thrombogenic coil material)material)
Current regimen of endovascular Current regimen of endovascular managementmanagement
The The glycoprotein IIbIIIa antagonist tirofiban glycoprotein IIbIIIa antagonist tirofiban (04 (04 microgkgmin bolus for 30 minutes followed by infusion of microgkgmin bolus for 30 minutes followed by infusion of 0125 ugkgmin until the thrombus dissolved) 0125 ugkgmin until the thrombus dissolved)
Intraarterial thrombolysis with Intraarterial thrombolysis with urokinase or r- TPA urokinase or r- TPA increase of intravenous (IV) heparin (measured by increase of intravenous (IV) heparin (measured by
ACT) ACT) Intravenous aspirin Intravenous aspirin
Coil-related platelet aggregation (white clot) is Coil-related platelet aggregation (white clot) is unlikely to respond to fibrinolytics but has a high risk unlikely to respond to fibrinolytics but has a high risk of hemorrhage (In ISAT) all 5 patients who had of hemorrhage (In ISAT) all 5 patients who had received thrombolytic therapy with tPA to treat a received thrombolytic therapy with tPA to treat a thromboembolic complication after endovascular thromboembolic complication after endovascular treatment rebleed and all of these patients died)treatment rebleed and all of these patients died)
IntracranialIntracranial Stenting Stenting Metallic foreign body such as stent will accumulate Metallic foreign body such as stent will accumulate
thrombus in the absence of platelet inhibitionthrombus in the absence of platelet inhibition Antiplatelet drugs are important to prevent peri or Antiplatelet drugs are important to prevent peri or
post-interventional thromboembolic eventspost-interventional thromboembolic events Optimal treatment regimens has not been determined Optimal treatment regimens has not been determined
but usually but usually Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-
procedureprocedureOrOr
Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on
morning of proceduremorning of procedure
If need to use stent is not pre-planned thanIf need to use stent is not pre-planned than
Abciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkgAbciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkg IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)
Glycoprotein IIbIIIa inhibitor are not used routinely during elective Glycoprotein IIbIIIa inhibitor are not used routinely during elective stenting procedure dt increased risk of ICH stenting procedure dt increased risk of ICH
Carotid StentingCarotid Stenting
Pre-procedurePre-procedure
Double Antiplatelet therapy is routinely given Double Antiplatelet therapy is routinely given beginning at least 3beginning at least 3
days before the proceduredays before the procedure
Aspirin 325mgd+Clopidogrel 75mgdAspirin 325mgd+Clopidogrel 75mgd During procedureDuring procedure
Heparin is given with target clotting time of 250-Heparin is given with target clotting time of 250-300sec300sec
Post-procedure Post-procedure
Aspirin 325mg is continued indefinitely and Aspirin 325mg is continued indefinitely and
Clopidogrel 75mgd for at least 6 weeks Clopidogrel 75mgd for at least 6 weeks
Inclusion criteria for Local ThrombolysisInclusion criteria for Local Thrombolysis a)a) Patients in severe clinical grade on admission Patients in severe clinical grade on admission
with evidence of dural venous sinus with evidence of dural venous sinus thrombosis and restrictive venous outflow on thrombosis and restrictive venous outflow on cerebral angiogramcerebral angiogram
b)b) Patients in clinical grade 3 worsening on Patients in clinical grade 3 worsening on heparin therapy Restriction to venous heparin therapy Restriction to venous outflow was defined as an increase in brain outflow was defined as an increase in brain circulation time gt 12 s delay in the drainage circulation time gt 12 s delay in the drainage of cortical veins with cortical veins hanging of cortical veins with cortical veins hanging in spacein space
Treatment Options for Venous Thrombosis
CT Grading for Venous ThrombosisCT Grading for Venous Thrombosis Grade I no parenchymal change Grade I no parenchymal change
(hyperdense (hyperdense sinuses cortical veins empty sinuses cortical veins empty delta sign)delta sign)
Grade II non hemorrhagic venous infarct Grade II non hemorrhagic venous infarct without mass effect without mass effect
Grade III non-hemorrhagic infarct with Grade III non-hemorrhagic infarct with mass effectmass effect
Grade IV hemorrhagic venous infarct (max Grade IV hemorrhagic venous infarct (max diameter lt 3 cm) with no mass effectdiameter lt 3 cm) with no mass effect
Grade V hemorrhagic venous infarct (max Grade V hemorrhagic venous infarct (max diameter gt 3 cm) with mass effect diameter gt 3 cm) with mass effect
Local ThrombolysisLocal Thrombolysis
Femoral Jugular access was secured and a guiding Femoral Jugular access was secured and a guiding catheter was placed in the jugular bulb catheter was placed in the jugular bulb Mechanical Mechanical clot maceration clot maceration was done with the guidewire was done with the guidewire following which a microcatheter (was navigated and following which a microcatheter (was navigated and placed in the thrombosed segment of sinus confirmed placed in the thrombosed segment of sinus confirmed on a selective venogram on a selective venogram
Urokinase infusion Bolus dose of 2-6 lacs followed Urokinase infusion Bolus dose of 2-6 lacs followed by 60000 to 100000 units per hour along with by 60000 to 100000 units per hour along with periodic check venogram Along with maintenance periodic check venogram Along with maintenance systemic infusion of Heparinsystemic infusion of Heparin Other agents such as Other agents such as streptokinase altepase or rTPAstreptokinase altepase or rTPA can be also used can be also used
After thrombolysis patient should subjected to oral After thrombolysis patient should subjected to oral anticoagulation for six monthsanticoagulation for six months
Low-molecular-weight Low-molecular-weight heparinheparin
PharmacologyPharmacologyLMWH as its name suggests is a glycosaminoglycan that is approximatelyLMWH as its name suggests is a glycosaminoglycan that is approximately
one third the molecular weight of UFH It is derived from UFH through one third the molecular weight of UFH It is derived from UFH through variousvarious
depolymerization processes LMWH binds to antithrombin which in turn depolymerization processes LMWH binds to antithrombin which in turn
Neutralizes actors Xa and IIa Because LMWH lacks many of the longer Neutralizes actors Xa and IIa Because LMWH lacks many of the longer chains chains
required for binding to thrombin it has less ability to neutralize thrombin required for binding to thrombin it has less ability to neutralize thrombin
relativeto its ability to neutralize factor Xa LMWH also has less relativeto its ability to neutralize factor Xa LMWH also has less nonspecific nonspecific
binding to other proteins There is greater bioavailability with more binding to other proteins There is greater bioavailability with more predictable predictable
pharmacokinetics that eliminates the need for monitoring The smaller pharmacokinetics that eliminates the need for monitoring The smaller size also size also
allows for enhanced subcutaneous absorption when compared with UFHallows for enhanced subcutaneous absorption when compared with UFH
Three LMWH preparations are Three LMWH preparations are currently approved for use in the currently approved for use in the United States (1) enoxaparin (2) United States (1) enoxaparin (2) dalteparin and (3) tinzaparin dalteparin and (3) tinzaparin
They are all administered They are all administered subcutaneously at intervals of either subcutaneously at intervals of either once or twice daily for both once or twice daily for both prophylaxis and treatment dosesprophylaxis and treatment doses
Few Experiences of Few Experiences of ThrombolysisThrombolysis
Vickey 25 Yrs male patient presented Vickey 25 Yrs male patient presented with 12with 12thth day HO severe headache with day HO severe headache with right sided hemiplegiaright sided hemiplegia
MRI shows thrombosis of the superior MRI shows thrombosis of the superior sagittal left transverse left sigmoid sagittal left transverse left sigmoid sinuses and cortical veins in the fronto-sinuses and cortical veins in the fronto-parietal regions with eo haemorrhagic parietal regions with eo haemorrhagic infarct in the left cerebral hemisphere infarct in the left cerebral hemisphere with mass effect( Grade ndashV)with mass effect( Grade ndashV)
Sashi Srivastava 64 yrs FSashi Srivastava 64 yrs F In a follow up case of MRD with infra-renal In a follow up case of MRD with infra-renal
aortic abdominal and bilateral renal artery aortic abdominal and bilateral renal artery thrombosis renal angiogram shows filling thrombosis renal angiogram shows filling defects in the right Renal artery defects in the right Renal artery
Initially Renal angioplasty was done Initially Renal angioplasty was done Following angioplasty few thrombi are seem Following angioplasty few thrombi are seem to extends into the segmental branches and to extends into the segmental branches and causing blockage So Thrombolysis was causing blockage So Thrombolysis was plane to dissolve the run-out thrombi with plane to dissolve the run-out thrombi with urokinase urokinase
Rakesh 34yrsMRakesh 34yrsM Left SFA pseudoaneurysm with Left SFA pseudoaneurysm with
Covered stent placementCovered stent placement Pre operative antiplatelets with post Pre operative antiplatelets with post
procedure heparin Tirofiban procedure heparin Tirofiban followed by aspirin and clopidogrel followed by aspirin and clopidogrel were usedwere used
IAT may be a treatment option for selected patients IAT may be a treatment option for selected patients Possible selection criteria include Possible selection criteria include
presentation between 3 and 6 hours from symptom onsetpresentation between 3 and 6 hours from symptom onset major cerebral artery occlusion major cerebral artery occlusion severe neurologic deficits severe neurologic deficits high risk of systemic hemorrhage with IV rt-PA (eg recent high risk of systemic hemorrhage with IV rt-PA (eg recent
surgery) surgery) The MERCI (Mechanical Embolus Removal in Cerebral The MERCI (Mechanical Embolus Removal in Cerebral
Ischemia) retrievalIschemia) retrieval system system
Has been FDA-approved for recanalizing acutely occluded Has been FDA-approved for recanalizing acutely occluded cerebral arteries cerebral arteries
In the Multi-MERCI study patients who did not improve In the Multi-MERCI study patients who did not improve immediately after IV rt-PA underwent mechanical immediately after IV rt-PA underwent mechanical embolectomy within 8 hours of symptom onset embolectomy within 8 hours of symptom onset
Partial or complete recanalization occurred in 74 of Partial or complete recanalization occurred in 74 of patientspatients
with a symptomatic intracerebral hemorrhage (sICH) rate of with a symptomatic intracerebral hemorrhage (sICH) rate of 67 67
Mechanical embolectomy with the MERCI retriever may be a Mechanical embolectomy with the MERCI retriever may be a feasible and safe option for patients after IV rt-PAfeasible and safe option for patients after IV rt-PA
Penumbra stroke systemPenumbra stroke system This device combines two methods of clot This device combines two methods of clot
extraction aspiration and mechanical extraction aspiration and mechanical extraction extraction
First the clot is aspirated then a thrombus First the clot is aspirated then a thrombus removal ring can be used if necessary to removal ring can be used if necessary to remove remaining clot remove remaining clot
successful recanalizing 82successful recanalizing 82 Bridging therapyBridging therapy
06 mgkg IV rt-PA followed by IAT with IA rt-06 mgkg IV rt-PA followed by IAT with IA rt-PA (up to 20 mg)PA (up to 20 mg)
achieved a higher recanalization rateachieved a higher recanalization rate
Criteria for thrombolysis with rTPACriteria for thrombolysis with rTPA
Inclusion criteriaInclusion criteria Clinical signs and symptoms consistent with ischemic Clinical signs and symptoms consistent with ischemic
strokestroke Patient last seen normal within 3 hoursPatient last seen normal within 3 hours Measurable neurologic deficitMeasurable neurologic deficit
Exclusion criteriaExclusion criteria Any hemorrhage on neuroimaging (CT or MRI)Any hemorrhage on neuroimaging (CT or MRI) Symptoms suggestive of subarachnoid hemorrhageSymptoms suggestive of subarachnoid hemorrhage Seizure at stroke onset that is thought to contribute to Seizure at stroke onset that is thought to contribute to
neurologic deficitneurologic deficit Hypodensity greater than one third cerebral hemisphere Hypodensity greater than one third cerebral hemisphere
on CTon CT SBP greater than 185 mm Hg or DBP greater than 110 SBP greater than 185 mm Hg or DBP greater than 110
mm Hgmm Hg International normalized ratio (INR) greater than 17International normalized ratio (INR) greater than 17
Ischemic Stroke Ischemic Stroke Treatment ndash 2006Treatment ndash 2006
IV tissue plasminogen activator (tPA)IV tissue plasminogen activator (tPA) ndash ndash Only FDA-approved acute stroke drugOnly FDA-approved acute stroke drug ndash ndash 3 hour treatment window3 hour treatment window
MERCI - Concentric clot retrieval MERCI - Concentric clot retrieval devicedevice ndash ndash Rescue therapy - approved 2004Rescue therapy - approved 2004 ndash ndash Device approval (not outcomes-based)Device approval (not outcomes-based)
Off label approachesOff label approaches ndash ndash IV tPA after 3 hoursIV tPA after 3 hours ndash ndash IV-IA tPA sequential strategiesIV-IA tPA sequential strategies ndash ndash IA tPA clot angioplasty fragmentationIA tPA clot angioplasty fragmentation ndash ndash Ultrasound-assisted tPA lysisUltrasound-assisted tPA lysis
rt-PA Trials NINDSrt-PA Trials NINDS
Acute stroke - 624 patientsAcute stroke - 624 patients Treat within 3 hrsTreat within 3 hrs Intravenous 09 mgkg rt-PA vs placeboIntravenous 09 mgkg rt-PA vs placebo Hemorrhage 64 tPA 06 placeboHemorrhage 64 tPA 06 placebo Neurologic recovery better with tPA 30 Neurologic recovery better with tPA 30
more like to have minimal or no disabilitymore like to have minimal or no disability
First proven approved treatment for First proven approved treatment for strokestroke
Limitations of tPALimitations of tPA Only 4 of acute strokes receive tPAOnly 4 of acute strokes receive tPA (Kleindorfer et al Stroke 2004 35 e27-e29)(Kleindorfer et al Stroke 2004 35 e27-e29)
Only 22 of patients present within 3 hoursOnly 22 of patients present within 3 hours1048707 1048707 51 of these ineligible due to51 of these ineligible due to
bull bull Mild severityMild severity bull bull Medical or surgical historyMedical or surgical history bull bull Blood testsBlood tests
Sustained recanalization only 13Sustained recanalization only 13 (Alexandrov et al NEJM 2004 351 2170-8)(Alexandrov et al NEJM 2004 351 2170-8)
Concern for hemorrhageConcern for hemorrhage tPA potentiates apoptotic injury tPA potentiates apoptotic injury (Liu et al Nature Med 2004 101379-83)(Liu et al Nature Med 2004 101379-83)
PROACT II IA Lysis TrialPROACT II IA Lysis Trial Baseline 24 hours 8 days
Baseline 60 minutes 120 minutes
9mg IAProurokinase
Desmoteplase Trials DEDAS Desmoteplase Trials DEDAS DIASDIAS
Trial OverviewTrial Overview Double blind randomized placebo Double blind randomized placebo
controlled trialscontrolled trials IV delivery 3-9 hour time windowIV delivery 3-9 hour time window Plasminogen activator ndash from Plasminogen activator ndash from vampire bat vampire bat
salivasaliva Selection based on PWI-DWI MismatchSelection based on PWI-DWI Mismatch
MRI InclusionMRI Inclusion PWI defect at least 2 cm AND ~20 larger PWI defect at least 2 cm AND ~20 larger
than DWIthan DWI PWI should be obvious even visible on PWI should be obvious even visible on
raw imagesraw imagesMRI ExclusionMRI Exclusion
DWI gt 13 MCADWI gt 13 MCA MRA ICA occlusionMRA ICA occlusion
Desmoteplase ndash DIAS Desmoteplase ndash DIAS ResultsResults
Mechanical Thrombolysis Mechanical Thrombolysis devicesdevices
mechanical thrombolysis potentially extends the treatment mechanical thrombolysis potentially extends the treatment window because they act promptly at the site of the thrombuswindow because they act promptly at the site of the thrombus
The devices can retrieve large clots that pharmaceutical agents The devices can retrieve large clots that pharmaceutical agents may not successfully lysemay not successfully lyse
Patients treated with IV tPA may be considered for treatment of Patients treated with IV tPA may be considered for treatment of residual clot with some of these devicesresidual clot with some of these devices
suction-creating saline jets suction-creating saline jets laser energy ultrasound laser energy ultrasound a corkscrew apparatus to treat strokesa corkscrew apparatus to treat strokes The AngioJet systemThe AngioJet system uses saline jets that are directed back into the catheter to uses saline jets that are directed back into the catheter to
create a low-pressure zone around the catheter tip inducing create a low-pressure zone around the catheter tip inducing suction suction
The clot is pulled into the exhaust lumen and removed from the The clot is pulled into the exhaust lumen and removed from the vessel Although US Food and Drug Administration (FDA) has vessel Although US Food and Drug Administration (FDA) has approved this device for use in arteriovenous dialysis grafts and approved this device for use in arteriovenous dialysis grafts and fistulae and for the treatment of coronary arteries saphenous fistulae and for the treatment of coronary arteries saphenous vein grafts and peripheral vessels clinical trials for the vein grafts and peripheral vessels clinical trials for the treatment of acute stroke are no longer in progress treatment of acute stroke are no longer in progress
Most devices are used in cerebral vessels that 2-5 mm
The Latis laser device The Latis laser device used laser energy to ablate clots used laser energy to ablate clots Arteries 2-5 mm in diameter could be Arteries 2-5 mm in diameter could be
treated including the ICA M1 or M2 treated including the ICA M1 or M2 branch of the MCA A1 branch of the branch of the MCA A1 branch of the anterior cerebral artery (ACA) basilar anterior cerebral artery (ACA) basilar artery posterior cerebral artery (PCA) artery posterior cerebral artery (PCA) and vertebral and vertebral
Patients could receive treatment as late Patients could receive treatment as late as 8 hours after symptom onset in the as 8 hours after symptom onset in the anterior circulation and within 24 hours in anterior circulation and within 24 hours in the posterior circulation the posterior circulation
Endovascular Photo Acoustic Endovascular Photo Acoustic Recanalization (EPAR) Recanalization (EPAR)
A laser power source generated energy for the A laser power source generated energy for the systemsystem
The energy was delivered by means of The energy was delivered by means of fiberoptics to the tip of the catheter at the fiberoptics to the tip of the catheter at the treatment sitetreatment site
Absorption of laser light by darkly pigmented Absorption of laser light by darkly pigmented materials (ie the clot) occurred inside the 1-mm materials (ie the clot) occurred inside the 1-mm catheter tipcatheter tip
the system was designed to minimize scattering the system was designed to minimize scattering of laser light of laser light
Absorption converted photo energy to acoustic Absorption converted photo energy to acoustic energy which then emulsified the clot inside the energy which then emulsified the clot inside the catheter tip catheter tip
EKOS ultrasound( the EKOS ultrasound( the Ultrasound Thrombolytic Ultrasound Thrombolytic
Infusion Catheter) Infusion Catheter) combines the use of a distal ultrasound transducer with combines the use of a distal ultrasound transducer with
infusion of a thrombolytic agent through the infusion of a thrombolytic agent through the microcathetermicrocatheter
Ultrasound changes the structure of the clot to Ultrasound changes the structure of the clot to temporarily increase its permeability while providing an temporarily increase its permeability while providing an acoustic pressure gradient to move the drug into the clot acoustic pressure gradient to move the drug into the clot to speed its dissolution to speed its dissolution
The EKOS catheter is placed in the proximal portion of the The EKOS catheter is placed in the proximal portion of the clot clot
After a 2-mg bolus of tPA was injected through the After a 2-mg bolus of tPA was injected through the catheter catheter
the patient received a continuous infusion of IA tPA 03 the patient received a continuous infusion of IA tPA 03 mgmin to a maximum of 20 mg and simultaneous mgmin to a maximum of 20 mg and simultaneous ultrasound transmission for as long as 60 minutes ultrasound transmission for as long as 60 minutes
One patient was treated with a total of 4 units of One patient was treated with a total of 4 units of recombinant reteplase (Retavase) hand-injected over 60 recombinant reteplase (Retavase) hand-injected over 60 minutes minutes
Penumbra system Penumbra system The Penumbra system (Penumbra Inc) provides a dual The Penumbra system (Penumbra Inc) provides a dual
approach to clot extraction using aspiration followed by approach to clot extraction using aspiration followed by clot retrieval with a ring device if needed clot retrieval with a ring device if needed
Mechanical Embolus Removal in Cerebral Ischemia Mechanical Embolus Removal in Cerebral Ischemia (MERCI)(MERCI)
a corkscrew-like apparatus to remove blood clots from a corkscrew-like apparatus to remove blood clots from the brain in patients experiencing an ischemic stroke the brain in patients experiencing an ischemic stroke
The corkscrew itself resides in the catheter tip which The corkscrew itself resides in the catheter tip which shields it from the wall of the vessel until it is ready to be shields it from the wall of the vessel until it is ready to be burrowed into the clot Once lodged in the clot the device burrowed into the clot Once lodged in the clot the device and clot are withdrawn from the vessel and clot are withdrawn from the vessel
Snarelike devicesSnarelike devices Snares such as the Neuronet snare (Guidant Snares such as the Neuronet snare (Guidant
Endovascular Santa Clara CA) have been developed Endovascular Santa Clara CA) have been developed specifically for use in the treatment of strokes specifically for use in the treatment of strokes
These devices are simple in design and do not require the These devices are simple in design and do not require the clot to be amenable to emulsification clot to be amenable to emulsification
X-Sizer deviceX-Sizer device a device with small moving blades at the a device with small moving blades at the
catheter tip catheter tip This device the X-Sizer device (EndiCor Medical This device the X-Sizer device (EndiCor Medical
San Clemente CA) can be used to excise the San Clemente CA) can be used to excise the thrombus and aspirate it thrombus and aspirate it
The device was being evaluated in randomized The device was being evaluated in randomized studies of coronary vessels and in a registry of studies of coronary vessels and in a registry of patients with acute myocardial infarctionpatients with acute myocardial infarction
Although the manufacturer had modified the Although the manufacturer had modified the device for use in cerebral vessels a safety and device for use in cerebral vessels a safety and feasibility study was indefinitely suspended after feasibility study was indefinitely suspended after only 1 patient was treated with the device in only 1 patient was treated with the device in Europe Europe
Suction thrombectomySuction thrombectomy This method of mechanical thrombolysis is one of the This method of mechanical thrombolysis is one of the
simplestsimplest In this readily available technique suction is applied with In this readily available technique suction is applied with
a syringe to remove thrombus in the ICA a syringe to remove thrombus in the ICA It requires no other devicesIt requires no other devices A catheter with a large inner diameter (Brite Tip Cordis A catheter with a large inner diameter (Brite Tip Cordis
Corporation Miami FL) was placed in the symptomatic Corporation Miami FL) was placed in the symptomatic vessel and navigated over a guidewire into the thrombusvessel and navigated over a guidewire into the thrombus
A 60-mL syringe was used to aspirate the thrombus A 60-mL syringe was used to aspirate the thrombus Each patient required angioplasty and stenting of carotid Each patient required angioplasty and stenting of carotid
bifurcation stenosis and received daily aspirin and bifurcation stenosis and received daily aspirin and ticlopidine after the procedure No complications ticlopidine after the procedure No complications occurred occurred
Summary Acute Stroke Summary Acute Stroke ImagingImaging
PhysiologyPhysiology importance collaterals importance collaterals
ndash ndashGrowing role for perfusion Growing role for perfusion assessmentassessment
tPAtPA guidelines amp limitations guidelines amp limitations Signs on CT amp MRSigns on CT amp MR follow physiology follow physiology Stroke trialsStroke trials PWI-DWI mismatch PWI-DWI mismatch
ndash ndashTreat based on physiology not timeTreat based on physiology not time ProtocolsProtocols should be fast and should be fast and
comprehensivecomprehensive
IA Mechanical Approaches in Acute Ischemic Stroke IA Mechanical Approaches in Acute Ischemic Stroke Mechanical strategies have several advantagesMechanical strategies have several advantages First they lessen and may even preclude the use of chemical First they lessen and may even preclude the use of chemical
thrombolytics in this manner very likely reducing the risk of ICHthrombolytics in this manner very likely reducing the risk of ICH Second by avoiding the use of chemical thrombolytics it is Second by avoiding the use of chemical thrombolytics it is
possible to extend the treatment window beyond the limit of 6ndash8 possible to extend the treatment window beyond the limit of 6ndash8 hours hours
Third mechanically fragmenting a clot increases the surface area Third mechanically fragmenting a clot increases the surface area accessible to fibrinolytic agents and allows inflow of fresh accessible to fibrinolytic agents and allows inflow of fresh plasminogen which in turn may increase the speed of plasminogen which in turn may increase the speed of thrombolysis thrombolysis
Finally clot-retrieval devices may provide faster recanalization Finally clot-retrieval devices may provide faster recanalization
The disadvantages of the mechanical The disadvantages of the mechanical approaches approaches technical difficulty of navigating mechanical technical difficulty of navigating mechanical
devices into the intracranial circulation excessive devices into the intracranial circulation excessive trauma to the vasculature (potentially leading to trauma to the vasculature (potentially leading to vasospasm vessel dissection perforation or vasospasm vessel dissection perforation or rupture) rupture)
fragmented thrombus causing distal embolization fragmented thrombus causing distal embolization into previously unaffected territories into previously unaffected territories
Nevertheless the advantages of mechanical stroke Nevertheless the advantages of mechanical stroke therapy appear to significantly outweigh its therapy appear to significantly outweigh its disadvantages and risksdisadvantages and risks
Contraindications to Thrombolytic Contraindications to Thrombolytic agents agents
Recent thoracic abdominal or Recent thoracic abdominal or intracranial surgeryintracranial surgery
Recent haemorrhagic CVA Head injury Recent haemorrhagic CVA Head injury or neoplasmor neoplasm
Bleeding ulcerBleeding ulcer Anticipated invasive procedures (arterial Anticipated invasive procedures (arterial
punctures biopsies)punctures biopsies) Concurrent hemostatic dysfunctionConcurrent hemostatic dysfunction
Monitoring of thrombolytic Monitoring of thrombolytic therapytherapy
Thrombin time Measures the availability of functional
fibrinogen Normal thrombin time is 10-14 sec Prolonged when fibrinogen level is below
75-100 mgdl
Half Life of ThrombolyticsHalf Life of ThrombolyticsAgent Administration Half Life
Streptokinase IA 60-80min
Urokinase IAIV 9-12min
rTPA IAIV 6min
Abciximab(Reopro) IAIV 12hour
Aspirin POIV 15-20min
Heparin IVSC 60min
Coumadin PO 15-25 days
Anti Platelet DrugsAnti Platelet DrugsDrug Drug Mechanism Mechanism UsesUsesAspirinAspirin Permanently inhibits Permanently inhibits
COX-1 and COX-2COX-1 and COX-2CADCAD
Stroke-TIAsStroke-TIAs
NSAIDsNSAIDs Reversibly inhibits Reversibly inhibits COX-1COX-1
LimitedLimited
DipyridamoleDipyridamole Inhibits PDE increases Inhibits PDE increases cAMPcAMP
TIAsTIAs
ThenopyridinesThenopyridines
(Ticlopidine(Ticlopidine
ClopidrgrelClopidrgrel))
Inhibits ADP Inhibits ADP
PlatAg PlatAg
TIAsStrokeTIAsStroke
CAD PVDCAD PVD
Abciximab (ReoPro)Abciximab (ReoPro)
Eptifibatide (Integrilin)Eptifibatide (Integrilin)
TirofibanTirofiban
GP IIBIIIA InhibitorsGP IIBIIIA Inhibitors
Stroke- TIAs Stroke- TIAs
MonitoringMonitoring
Bleeding timeBleeding time
Optical aggregometryOptical aggregometry
Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay
Bleeding timeBleeding time
Requires a skin incision (usually made on the ear lobe or Requires a skin incision (usually made on the ear lobe or forearm offorearm of
a depth that results in disruption of capillary loops and a depth that results in disruption of capillary loops and small vessels)small vessels)
AdvantagesAdvantages Universally availableUniversally available Relatively simple techniquesRelatively simple techniques Can be performed bedsideCan be performed bedside
DisadvantagesDisadvantages Insensitive inaccurate non-specific techniqueInsensitive inaccurate non-specific technique
Poorly reproducible (as depends on multiple variables)Poorly reproducible (as depends on multiple variables)
Optical aggregometryOptical aggregometry
Gold standard assay for platelet functionGold standard assay for platelet function Agonist induced aggregation is measuredAgonist induced aggregation is measured Different agonist are available for different Different agonist are available for different
agentsagents However require unique expertise and are not However require unique expertise and are not
universally availableuniversally available Aspirin measured with ADP or AA(gt70 Aspirin measured with ADP or AA(gt70
aggregation so resistance)aggregation so resistance) Clopidogrel( ADP gt 90 aggregation means Clopidogrel( ADP gt 90 aggregation means
resistance) resistance)
Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay
Can be performed bed sideCan be performed bed side Different assay devices with different Different assay devices with different
agonist are used for each of different agonist are used for each of different antiplatelet agents antiplatelet agents
For Aspirin AA is used (result is reported as aspirin For Aspirin AA is used (result is reported as aspirin reaction units [ARU] ARUgt 550 indicates non-reaction units [ARU] ARUgt 550 indicates non-responsiveness)responsiveness)
Verify IIbIIIa assay device uses TRAP as agonist for Verify IIbIIIa assay device uses TRAP as agonist for Abciximab and TirofibanAbciximab and Tirofiban
Practical Applications Practical Applications related to specific related to specific
Neurovascular Neurovascular interventionsinterventions
Acute ischemic StrokeAcute ischemic Stroke When an artery occludes neurons are affected When an artery occludes neurons are affected
differently depending upon the amount of residual blood differently depending upon the amount of residual blood flowflow
Normal cerebral blood flow is greater than 50 mL100 Normal cerebral blood flow is greater than 50 mL100 mgminmgmin
Once blood flow decreases to less than 20 mL100 Once blood flow decreases to less than 20 mL100 mgmin infarction occursmgmin infarction occurs
If blood flow decreases to less than 10 mL100 mgmin If blood flow decreases to less than 10 mL100 mgmin irreversible neuronal death occurs rapidly irreversible neuronal death occurs rapidly
Blood flow between 11 and 20 mL100 mgmin is thought Blood flow between 11 and 20 mL100 mgmin is thought to represent the ischemic penumbra an area where the to represent the ischemic penumbra an area where the cells are functionally silent because of ischemia but are cells are functionally silent because of ischemia but are still able to recover if blood flow is restored still able to recover if blood flow is restored
Many acute stroke therapies are targeted toward Many acute stroke therapies are targeted toward restoring flow or function to the ischemic penumbrarestoring flow or function to the ischemic penumbra
Therapeutic window in Therapeutic window in management of acute Ischemic management of acute Ischemic
StrokeStrokeThe early diagnosis of ischemic stroke is critical to the The early diagnosis of ischemic stroke is critical to the
with only a narrow therapeutic window in the first few with only a narrow therapeutic window in the first few hours following stroke ictushours following stroke ictus
Diagnosis in the first 3 hours postictus provides the Diagnosis in the first 3 hours postictus provides the opportunity for intravenous or intraarterial thrombolysis opportunity for intravenous or intraarterial thrombolysis and intra-arterial clot mechanical treatment which and intra-arterial clot mechanical treatment which improve the outcome improve the outcome
Diagnosis in the time period between 3 and 6 hours Diagnosis in the time period between 3 and 6 hours provides an opportunity for intra-arterial thrombolysis provides an opportunity for intra-arterial thrombolysis and mechanical treatment and mechanical treatment
Involvement of the posterior circulation especially the Involvement of the posterior circulation especially the basilar artery is treated by some regardless of time of basilar artery is treated by some regardless of time of onset or up until 12 to 24 hours in some practices This is onset or up until 12 to 24 hours in some practices This is related to the potentially high mortality and morbidity related to the potentially high mortality and morbidity associated with basilar artery thrombosisassociated with basilar artery thrombosis
Infarct evaluation on angiographyInfarct evaluation on angiography(CT angiography and catheter (CT angiography and catheter
angiography)angiography)CTA is an excellent first-line examination for CTA is an excellent first-line examination for
evaluation of the head and neck arteries evaluation of the head and neck arteries In comparison with catheter angiography In comparison with catheter angiography
what it gives up in resolution and dynamic what it gives up in resolution and dynamic properties it makes up for with rapid properties it makes up for with rapid acquisition of a 3-D dataset and the potential acquisition of a 3-D dataset and the potential for assessment of whole-brain perfusion and for assessment of whole-brain perfusion and better parenchymal evaluationbetter parenchymal evaluation
Moreover CTA illustrates not only arterial Moreover CTA illustrates not only arterial stenosis or occlusion but also the vessel wall stenosis or occlusion but also the vessel wall This factor is most important for evaluation of This factor is most important for evaluation of intramural dissection and thrombosed intramural dissection and thrombosed aneurysms which may both complicate aneurysms which may both complicate evaluation of stroke patientsevaluation of stroke patients
Early angiographic signs of strokes Early angiographic signs of strokes both CTA both CTA and DSA and DSA
Vessel occlusion or cutoff related to Vessel occlusion or cutoff related to thromboembolithromboemboli
aneurysms aneurysms arterial dissection arterial dissection Meniscus or flattened shape to clot Meniscus or flattened shape to clot
(recent) versus reverse meniscus (older)(recent) versus reverse meniscus (older) tram track (nonocclusive or recanalized tram track (nonocclusive or recanalized
clot) clot) delayed (antegrade) flow (manifest as delayed (antegrade) flow (manifest as
decreased whole-brain perfusion on CTA)decreased whole-brain perfusion on CTA) retrograde collateral flowretrograde collateral flow
Non-occlusive left MCA thrombus on 3-D imaging performed from CTA source data and was confirmed at catheter angiography
Therapy to be started within a 6-hr Therapy to be started within a 6-hr time to treatment (TTT) window time to treatment (TTT) window (while in case of IV thrombolysis (while in case of IV thrombolysis therapy to be started with in 3hrs)therapy to be started with in 3hrs)
Exclusion criteria Exclusion criteria Rapidly improving neurologic deficit or Rapidly improving neurologic deficit or Sustained blood pressure of gt180100 Sustained blood pressure of gt180100 Hemorrhage is detected on CTHemorrhage is detected on CT Infarct involving gt more than 13 rd Infarct involving gt more than 13 rd
territory of MCAterritory of MCA MRADWI-Perfusion mismatchlt 20MRADWI-Perfusion mismatchlt 20 Definite hypodensity on CTDefinite hypodensity on CT
Intra-arterial Thrombolysis
Fibrinolytics + AntiplateletsFibrinolytics + Antiplatelets
PlasminogenPlasminogen activators through fibrinolysis exposes activators through fibrinolysis exposes free thrombin and paradoxically stimulatesfree thrombin and paradoxically stimulates platelet platelet aggregation which leads to formation of aaggregation which leads to formation of a platelet platelet thrombus (white clot) thrombus (white clot)
This new thrombus is relatively resistant to This new thrombus is relatively resistant to fibrinolyticsfibrinolytics
So new regimen in case of acute stroke isSo new regimen in case of acute stroke is fibrinolytics + antiplatelet drugsfibrinolytics + antiplatelet drugs
rtPA + IIbIIIa inhibitors( tirofiban rtPA + IIbIIIa inhibitors( tirofiban abciximab) orabciximab) or
Urokinase + IIbIIIa Urokinase + IIbIIIa inhibitors( tirofiban abciximab)inhibitors( tirofiban abciximab)
Intra-arterial Thrombolysis Tirofiban (04 microgkgmin bolus for 3 min followed by Tirofiban (04 microgkgmin bolus for 3 min followed by
0125 ugkgmin)0125 ugkgmin)
++
Heparin (2000ndash3000 IU bolus followed by Heparin (2000ndash3000 IU bolus followed by 1000 IUhour infusion 1000 IUhour infusion
with ACT maintained bw 200-300) throughout the with ACT maintained bw 200-300) throughout the interventional procedure and for 24ndash48 hours thereafter when interventional procedure and for 24ndash48 hours thereafter when there is neither intraprocedural bleeding nor suspicion of there is neither intraprocedural bleeding nor suspicion of increased risk of bleeding increased risk of bleeding
Maximum dose of Urokinase Maximum dose of Urokinase Anterior circulation stroke - 500000 IU (mean 400000 Anterior circulation stroke - 500000 IU (mean 400000
IU range 300000ndash500000 IU)IU range 300000ndash500000 IU) Posterior circulation stroke -1000000 IU (mean 837000 Posterior circulation stroke -1000000 IU (mean 837000
IU range 300000ndash1000000 IU)IU range 300000ndash1000000 IU)American Journal of NeuroradiologyAmerican Journal of Neuroradiology 262595-2601 2005262595-2601 2005
Intravenous ThrombolysisIntravenous Thrombolysis
The first method to restore cerebral The first method to restore cerebral perfusion is clot lysis with the goal perfusion is clot lysis with the goal of re-establishing blood flow to the of re-establishing blood flow to the affected tissue affected tissue
IV thrombolysis rt-PA is the only IV thrombolysis rt-PA is the only FDA- approved treatment for AIS FDA- approved treatment for AIS
Fibrinolysis is enhanced powerfully Fibrinolysis is enhanced powerfully by rt-PAby rt-PA
Intravenous rTPA Intravenous rTPA administration administration protocolprotocol
Total dose of rt-PA 09 mgkg (maximum dose Total dose of rt-PA 09 mgkg (maximum dose 90 mg)90 mg)
Give 10 as initial IV bolusGive 10 as initial IV bolus Infuse remainder over 1 hourInfuse remainder over 1 hour Admit patient to an ICU or stroke unit for Admit patient to an ICU or stroke unit for
monitoringmonitoring Neurologic assessments every 15 minutes Neurologic assessments every 15 minutes
during infusion then every 30 minutes for next during infusion then every 30 minutes for next 6 hours then every hour until 24hours after 6 hours then every hour until 24hours after treatmenttreatment
Favorable Outcome vs Treatment Time Favorable Outcome vs Treatment Time with IV rTPAwith IV rTPA
Protocol limit = 3 hrs
Benefit ~ 45 hrs
Thromboembolism During coilingThromboembolism During coiling Most feared and frequent complication Most feared and frequent complication Reported incidence - Approx 7 Reported incidence - Approx 7 SourcesSources of Thromboembolism are of Thromboembolism are
- Clots at the aneurysmal neck during or immediately- Clots at the aneurysmal neck during or immediately after after embolization embolization
- Thrombus forming on catheters during- Thrombus forming on catheters during proceduresprocedures
- Stenosis of an adjacent artery dt coil mass- Stenosis of an adjacent artery dt coil mass or herniationor herniation
- Migration of intraaneurysmal- Migration of intraaneurysmal thrombus during coil thrombus during coil placement placement
- Slow flow dt vasospasm - Slow flow dt vasospasm
- Rare and unlikely causes are hypercoagulable- Rare and unlikely causes are hypercoagulable state such state such as antiphospholipid antibody syndrome or due to HITas antiphospholipid antibody syndrome or due to HIT
Occur more often with wide-necked aneurysms (dt Occur more often with wide-necked aneurysms (dt increased exposed surface area of thrombogenic coil increased exposed surface area of thrombogenic coil material)material)
Current regimen of endovascular Current regimen of endovascular managementmanagement
The The glycoprotein IIbIIIa antagonist tirofiban glycoprotein IIbIIIa antagonist tirofiban (04 (04 microgkgmin bolus for 30 minutes followed by infusion of microgkgmin bolus for 30 minutes followed by infusion of 0125 ugkgmin until the thrombus dissolved) 0125 ugkgmin until the thrombus dissolved)
Intraarterial thrombolysis with Intraarterial thrombolysis with urokinase or r- TPA urokinase or r- TPA increase of intravenous (IV) heparin (measured by increase of intravenous (IV) heparin (measured by
ACT) ACT) Intravenous aspirin Intravenous aspirin
Coil-related platelet aggregation (white clot) is Coil-related platelet aggregation (white clot) is unlikely to respond to fibrinolytics but has a high risk unlikely to respond to fibrinolytics but has a high risk of hemorrhage (In ISAT) all 5 patients who had of hemorrhage (In ISAT) all 5 patients who had received thrombolytic therapy with tPA to treat a received thrombolytic therapy with tPA to treat a thromboembolic complication after endovascular thromboembolic complication after endovascular treatment rebleed and all of these patients died)treatment rebleed and all of these patients died)
IntracranialIntracranial Stenting Stenting Metallic foreign body such as stent will accumulate Metallic foreign body such as stent will accumulate
thrombus in the absence of platelet inhibitionthrombus in the absence of platelet inhibition Antiplatelet drugs are important to prevent peri or Antiplatelet drugs are important to prevent peri or
post-interventional thromboembolic eventspost-interventional thromboembolic events Optimal treatment regimens has not been determined Optimal treatment regimens has not been determined
but usually but usually Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-
procedureprocedureOrOr
Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on
morning of proceduremorning of procedure
If need to use stent is not pre-planned thanIf need to use stent is not pre-planned than
Abciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkgAbciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkg IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)
Glycoprotein IIbIIIa inhibitor are not used routinely during elective Glycoprotein IIbIIIa inhibitor are not used routinely during elective stenting procedure dt increased risk of ICH stenting procedure dt increased risk of ICH
Carotid StentingCarotid Stenting
Pre-procedurePre-procedure
Double Antiplatelet therapy is routinely given Double Antiplatelet therapy is routinely given beginning at least 3beginning at least 3
days before the proceduredays before the procedure
Aspirin 325mgd+Clopidogrel 75mgdAspirin 325mgd+Clopidogrel 75mgd During procedureDuring procedure
Heparin is given with target clotting time of 250-Heparin is given with target clotting time of 250-300sec300sec
Post-procedure Post-procedure
Aspirin 325mg is continued indefinitely and Aspirin 325mg is continued indefinitely and
Clopidogrel 75mgd for at least 6 weeks Clopidogrel 75mgd for at least 6 weeks
Inclusion criteria for Local ThrombolysisInclusion criteria for Local Thrombolysis a)a) Patients in severe clinical grade on admission Patients in severe clinical grade on admission
with evidence of dural venous sinus with evidence of dural venous sinus thrombosis and restrictive venous outflow on thrombosis and restrictive venous outflow on cerebral angiogramcerebral angiogram
b)b) Patients in clinical grade 3 worsening on Patients in clinical grade 3 worsening on heparin therapy Restriction to venous heparin therapy Restriction to venous outflow was defined as an increase in brain outflow was defined as an increase in brain circulation time gt 12 s delay in the drainage circulation time gt 12 s delay in the drainage of cortical veins with cortical veins hanging of cortical veins with cortical veins hanging in spacein space
Treatment Options for Venous Thrombosis
CT Grading for Venous ThrombosisCT Grading for Venous Thrombosis Grade I no parenchymal change Grade I no parenchymal change
(hyperdense (hyperdense sinuses cortical veins empty sinuses cortical veins empty delta sign)delta sign)
Grade II non hemorrhagic venous infarct Grade II non hemorrhagic venous infarct without mass effect without mass effect
Grade III non-hemorrhagic infarct with Grade III non-hemorrhagic infarct with mass effectmass effect
Grade IV hemorrhagic venous infarct (max Grade IV hemorrhagic venous infarct (max diameter lt 3 cm) with no mass effectdiameter lt 3 cm) with no mass effect
Grade V hemorrhagic venous infarct (max Grade V hemorrhagic venous infarct (max diameter gt 3 cm) with mass effect diameter gt 3 cm) with mass effect
Local ThrombolysisLocal Thrombolysis
Femoral Jugular access was secured and a guiding Femoral Jugular access was secured and a guiding catheter was placed in the jugular bulb catheter was placed in the jugular bulb Mechanical Mechanical clot maceration clot maceration was done with the guidewire was done with the guidewire following which a microcatheter (was navigated and following which a microcatheter (was navigated and placed in the thrombosed segment of sinus confirmed placed in the thrombosed segment of sinus confirmed on a selective venogram on a selective venogram
Urokinase infusion Bolus dose of 2-6 lacs followed Urokinase infusion Bolus dose of 2-6 lacs followed by 60000 to 100000 units per hour along with by 60000 to 100000 units per hour along with periodic check venogram Along with maintenance periodic check venogram Along with maintenance systemic infusion of Heparinsystemic infusion of Heparin Other agents such as Other agents such as streptokinase altepase or rTPAstreptokinase altepase or rTPA can be also used can be also used
After thrombolysis patient should subjected to oral After thrombolysis patient should subjected to oral anticoagulation for six monthsanticoagulation for six months
Low-molecular-weight Low-molecular-weight heparinheparin
PharmacologyPharmacologyLMWH as its name suggests is a glycosaminoglycan that is approximatelyLMWH as its name suggests is a glycosaminoglycan that is approximately
one third the molecular weight of UFH It is derived from UFH through one third the molecular weight of UFH It is derived from UFH through variousvarious
depolymerization processes LMWH binds to antithrombin which in turn depolymerization processes LMWH binds to antithrombin which in turn
Neutralizes actors Xa and IIa Because LMWH lacks many of the longer Neutralizes actors Xa and IIa Because LMWH lacks many of the longer chains chains
required for binding to thrombin it has less ability to neutralize thrombin required for binding to thrombin it has less ability to neutralize thrombin
relativeto its ability to neutralize factor Xa LMWH also has less relativeto its ability to neutralize factor Xa LMWH also has less nonspecific nonspecific
binding to other proteins There is greater bioavailability with more binding to other proteins There is greater bioavailability with more predictable predictable
pharmacokinetics that eliminates the need for monitoring The smaller pharmacokinetics that eliminates the need for monitoring The smaller size also size also
allows for enhanced subcutaneous absorption when compared with UFHallows for enhanced subcutaneous absorption when compared with UFH
Three LMWH preparations are Three LMWH preparations are currently approved for use in the currently approved for use in the United States (1) enoxaparin (2) United States (1) enoxaparin (2) dalteparin and (3) tinzaparin dalteparin and (3) tinzaparin
They are all administered They are all administered subcutaneously at intervals of either subcutaneously at intervals of either once or twice daily for both once or twice daily for both prophylaxis and treatment dosesprophylaxis and treatment doses
Few Experiences of Few Experiences of ThrombolysisThrombolysis
Vickey 25 Yrs male patient presented Vickey 25 Yrs male patient presented with 12with 12thth day HO severe headache with day HO severe headache with right sided hemiplegiaright sided hemiplegia
MRI shows thrombosis of the superior MRI shows thrombosis of the superior sagittal left transverse left sigmoid sagittal left transverse left sigmoid sinuses and cortical veins in the fronto-sinuses and cortical veins in the fronto-parietal regions with eo haemorrhagic parietal regions with eo haemorrhagic infarct in the left cerebral hemisphere infarct in the left cerebral hemisphere with mass effect( Grade ndashV)with mass effect( Grade ndashV)
Sashi Srivastava 64 yrs FSashi Srivastava 64 yrs F In a follow up case of MRD with infra-renal In a follow up case of MRD with infra-renal
aortic abdominal and bilateral renal artery aortic abdominal and bilateral renal artery thrombosis renal angiogram shows filling thrombosis renal angiogram shows filling defects in the right Renal artery defects in the right Renal artery
Initially Renal angioplasty was done Initially Renal angioplasty was done Following angioplasty few thrombi are seem Following angioplasty few thrombi are seem to extends into the segmental branches and to extends into the segmental branches and causing blockage So Thrombolysis was causing blockage So Thrombolysis was plane to dissolve the run-out thrombi with plane to dissolve the run-out thrombi with urokinase urokinase
Rakesh 34yrsMRakesh 34yrsM Left SFA pseudoaneurysm with Left SFA pseudoaneurysm with
Covered stent placementCovered stent placement Pre operative antiplatelets with post Pre operative antiplatelets with post
procedure heparin Tirofiban procedure heparin Tirofiban followed by aspirin and clopidogrel followed by aspirin and clopidogrel were usedwere used
IAT may be a treatment option for selected patients IAT may be a treatment option for selected patients Possible selection criteria include Possible selection criteria include
presentation between 3 and 6 hours from symptom onsetpresentation between 3 and 6 hours from symptom onset major cerebral artery occlusion major cerebral artery occlusion severe neurologic deficits severe neurologic deficits high risk of systemic hemorrhage with IV rt-PA (eg recent high risk of systemic hemorrhage with IV rt-PA (eg recent
surgery) surgery) The MERCI (Mechanical Embolus Removal in Cerebral The MERCI (Mechanical Embolus Removal in Cerebral
Ischemia) retrievalIschemia) retrieval system system
Has been FDA-approved for recanalizing acutely occluded Has been FDA-approved for recanalizing acutely occluded cerebral arteries cerebral arteries
In the Multi-MERCI study patients who did not improve In the Multi-MERCI study patients who did not improve immediately after IV rt-PA underwent mechanical immediately after IV rt-PA underwent mechanical embolectomy within 8 hours of symptom onset embolectomy within 8 hours of symptom onset
Partial or complete recanalization occurred in 74 of Partial or complete recanalization occurred in 74 of patientspatients
with a symptomatic intracerebral hemorrhage (sICH) rate of with a symptomatic intracerebral hemorrhage (sICH) rate of 67 67
Mechanical embolectomy with the MERCI retriever may be a Mechanical embolectomy with the MERCI retriever may be a feasible and safe option for patients after IV rt-PAfeasible and safe option for patients after IV rt-PA
Penumbra stroke systemPenumbra stroke system This device combines two methods of clot This device combines two methods of clot
extraction aspiration and mechanical extraction aspiration and mechanical extraction extraction
First the clot is aspirated then a thrombus First the clot is aspirated then a thrombus removal ring can be used if necessary to removal ring can be used if necessary to remove remaining clot remove remaining clot
successful recanalizing 82successful recanalizing 82 Bridging therapyBridging therapy
06 mgkg IV rt-PA followed by IAT with IA rt-06 mgkg IV rt-PA followed by IAT with IA rt-PA (up to 20 mg)PA (up to 20 mg)
achieved a higher recanalization rateachieved a higher recanalization rate
Criteria for thrombolysis with rTPACriteria for thrombolysis with rTPA
Inclusion criteriaInclusion criteria Clinical signs and symptoms consistent with ischemic Clinical signs and symptoms consistent with ischemic
strokestroke Patient last seen normal within 3 hoursPatient last seen normal within 3 hours Measurable neurologic deficitMeasurable neurologic deficit
Exclusion criteriaExclusion criteria Any hemorrhage on neuroimaging (CT or MRI)Any hemorrhage on neuroimaging (CT or MRI) Symptoms suggestive of subarachnoid hemorrhageSymptoms suggestive of subarachnoid hemorrhage Seizure at stroke onset that is thought to contribute to Seizure at stroke onset that is thought to contribute to
neurologic deficitneurologic deficit Hypodensity greater than one third cerebral hemisphere Hypodensity greater than one third cerebral hemisphere
on CTon CT SBP greater than 185 mm Hg or DBP greater than 110 SBP greater than 185 mm Hg or DBP greater than 110
mm Hgmm Hg International normalized ratio (INR) greater than 17International normalized ratio (INR) greater than 17
Ischemic Stroke Ischemic Stroke Treatment ndash 2006Treatment ndash 2006
IV tissue plasminogen activator (tPA)IV tissue plasminogen activator (tPA) ndash ndash Only FDA-approved acute stroke drugOnly FDA-approved acute stroke drug ndash ndash 3 hour treatment window3 hour treatment window
MERCI - Concentric clot retrieval MERCI - Concentric clot retrieval devicedevice ndash ndash Rescue therapy - approved 2004Rescue therapy - approved 2004 ndash ndash Device approval (not outcomes-based)Device approval (not outcomes-based)
Off label approachesOff label approaches ndash ndash IV tPA after 3 hoursIV tPA after 3 hours ndash ndash IV-IA tPA sequential strategiesIV-IA tPA sequential strategies ndash ndash IA tPA clot angioplasty fragmentationIA tPA clot angioplasty fragmentation ndash ndash Ultrasound-assisted tPA lysisUltrasound-assisted tPA lysis
rt-PA Trials NINDSrt-PA Trials NINDS
Acute stroke - 624 patientsAcute stroke - 624 patients Treat within 3 hrsTreat within 3 hrs Intravenous 09 mgkg rt-PA vs placeboIntravenous 09 mgkg rt-PA vs placebo Hemorrhage 64 tPA 06 placeboHemorrhage 64 tPA 06 placebo Neurologic recovery better with tPA 30 Neurologic recovery better with tPA 30
more like to have minimal or no disabilitymore like to have minimal or no disability
First proven approved treatment for First proven approved treatment for strokestroke
Limitations of tPALimitations of tPA Only 4 of acute strokes receive tPAOnly 4 of acute strokes receive tPA (Kleindorfer et al Stroke 2004 35 e27-e29)(Kleindorfer et al Stroke 2004 35 e27-e29)
Only 22 of patients present within 3 hoursOnly 22 of patients present within 3 hours1048707 1048707 51 of these ineligible due to51 of these ineligible due to
bull bull Mild severityMild severity bull bull Medical or surgical historyMedical or surgical history bull bull Blood testsBlood tests
Sustained recanalization only 13Sustained recanalization only 13 (Alexandrov et al NEJM 2004 351 2170-8)(Alexandrov et al NEJM 2004 351 2170-8)
Concern for hemorrhageConcern for hemorrhage tPA potentiates apoptotic injury tPA potentiates apoptotic injury (Liu et al Nature Med 2004 101379-83)(Liu et al Nature Med 2004 101379-83)
PROACT II IA Lysis TrialPROACT II IA Lysis Trial Baseline 24 hours 8 days
Baseline 60 minutes 120 minutes
9mg IAProurokinase
Desmoteplase Trials DEDAS Desmoteplase Trials DEDAS DIASDIAS
Trial OverviewTrial Overview Double blind randomized placebo Double blind randomized placebo
controlled trialscontrolled trials IV delivery 3-9 hour time windowIV delivery 3-9 hour time window Plasminogen activator ndash from Plasminogen activator ndash from vampire bat vampire bat
salivasaliva Selection based on PWI-DWI MismatchSelection based on PWI-DWI Mismatch
MRI InclusionMRI Inclusion PWI defect at least 2 cm AND ~20 larger PWI defect at least 2 cm AND ~20 larger
than DWIthan DWI PWI should be obvious even visible on PWI should be obvious even visible on
raw imagesraw imagesMRI ExclusionMRI Exclusion
DWI gt 13 MCADWI gt 13 MCA MRA ICA occlusionMRA ICA occlusion
Desmoteplase ndash DIAS Desmoteplase ndash DIAS ResultsResults
Mechanical Thrombolysis Mechanical Thrombolysis devicesdevices
mechanical thrombolysis potentially extends the treatment mechanical thrombolysis potentially extends the treatment window because they act promptly at the site of the thrombuswindow because they act promptly at the site of the thrombus
The devices can retrieve large clots that pharmaceutical agents The devices can retrieve large clots that pharmaceutical agents may not successfully lysemay not successfully lyse
Patients treated with IV tPA may be considered for treatment of Patients treated with IV tPA may be considered for treatment of residual clot with some of these devicesresidual clot with some of these devices
suction-creating saline jets suction-creating saline jets laser energy ultrasound laser energy ultrasound a corkscrew apparatus to treat strokesa corkscrew apparatus to treat strokes The AngioJet systemThe AngioJet system uses saline jets that are directed back into the catheter to uses saline jets that are directed back into the catheter to
create a low-pressure zone around the catheter tip inducing create a low-pressure zone around the catheter tip inducing suction suction
The clot is pulled into the exhaust lumen and removed from the The clot is pulled into the exhaust lumen and removed from the vessel Although US Food and Drug Administration (FDA) has vessel Although US Food and Drug Administration (FDA) has approved this device for use in arteriovenous dialysis grafts and approved this device for use in arteriovenous dialysis grafts and fistulae and for the treatment of coronary arteries saphenous fistulae and for the treatment of coronary arteries saphenous vein grafts and peripheral vessels clinical trials for the vein grafts and peripheral vessels clinical trials for the treatment of acute stroke are no longer in progress treatment of acute stroke are no longer in progress
Most devices are used in cerebral vessels that 2-5 mm
The Latis laser device The Latis laser device used laser energy to ablate clots used laser energy to ablate clots Arteries 2-5 mm in diameter could be Arteries 2-5 mm in diameter could be
treated including the ICA M1 or M2 treated including the ICA M1 or M2 branch of the MCA A1 branch of the branch of the MCA A1 branch of the anterior cerebral artery (ACA) basilar anterior cerebral artery (ACA) basilar artery posterior cerebral artery (PCA) artery posterior cerebral artery (PCA) and vertebral and vertebral
Patients could receive treatment as late Patients could receive treatment as late as 8 hours after symptom onset in the as 8 hours after symptom onset in the anterior circulation and within 24 hours in anterior circulation and within 24 hours in the posterior circulation the posterior circulation
Endovascular Photo Acoustic Endovascular Photo Acoustic Recanalization (EPAR) Recanalization (EPAR)
A laser power source generated energy for the A laser power source generated energy for the systemsystem
The energy was delivered by means of The energy was delivered by means of fiberoptics to the tip of the catheter at the fiberoptics to the tip of the catheter at the treatment sitetreatment site
Absorption of laser light by darkly pigmented Absorption of laser light by darkly pigmented materials (ie the clot) occurred inside the 1-mm materials (ie the clot) occurred inside the 1-mm catheter tipcatheter tip
the system was designed to minimize scattering the system was designed to minimize scattering of laser light of laser light
Absorption converted photo energy to acoustic Absorption converted photo energy to acoustic energy which then emulsified the clot inside the energy which then emulsified the clot inside the catheter tip catheter tip
EKOS ultrasound( the EKOS ultrasound( the Ultrasound Thrombolytic Ultrasound Thrombolytic
Infusion Catheter) Infusion Catheter) combines the use of a distal ultrasound transducer with combines the use of a distal ultrasound transducer with
infusion of a thrombolytic agent through the infusion of a thrombolytic agent through the microcathetermicrocatheter
Ultrasound changes the structure of the clot to Ultrasound changes the structure of the clot to temporarily increase its permeability while providing an temporarily increase its permeability while providing an acoustic pressure gradient to move the drug into the clot acoustic pressure gradient to move the drug into the clot to speed its dissolution to speed its dissolution
The EKOS catheter is placed in the proximal portion of the The EKOS catheter is placed in the proximal portion of the clot clot
After a 2-mg bolus of tPA was injected through the After a 2-mg bolus of tPA was injected through the catheter catheter
the patient received a continuous infusion of IA tPA 03 the patient received a continuous infusion of IA tPA 03 mgmin to a maximum of 20 mg and simultaneous mgmin to a maximum of 20 mg and simultaneous ultrasound transmission for as long as 60 minutes ultrasound transmission for as long as 60 minutes
One patient was treated with a total of 4 units of One patient was treated with a total of 4 units of recombinant reteplase (Retavase) hand-injected over 60 recombinant reteplase (Retavase) hand-injected over 60 minutes minutes
Penumbra system Penumbra system The Penumbra system (Penumbra Inc) provides a dual The Penumbra system (Penumbra Inc) provides a dual
approach to clot extraction using aspiration followed by approach to clot extraction using aspiration followed by clot retrieval with a ring device if needed clot retrieval with a ring device if needed
Mechanical Embolus Removal in Cerebral Ischemia Mechanical Embolus Removal in Cerebral Ischemia (MERCI)(MERCI)
a corkscrew-like apparatus to remove blood clots from a corkscrew-like apparatus to remove blood clots from the brain in patients experiencing an ischemic stroke the brain in patients experiencing an ischemic stroke
The corkscrew itself resides in the catheter tip which The corkscrew itself resides in the catheter tip which shields it from the wall of the vessel until it is ready to be shields it from the wall of the vessel until it is ready to be burrowed into the clot Once lodged in the clot the device burrowed into the clot Once lodged in the clot the device and clot are withdrawn from the vessel and clot are withdrawn from the vessel
Snarelike devicesSnarelike devices Snares such as the Neuronet snare (Guidant Snares such as the Neuronet snare (Guidant
Endovascular Santa Clara CA) have been developed Endovascular Santa Clara CA) have been developed specifically for use in the treatment of strokes specifically for use in the treatment of strokes
These devices are simple in design and do not require the These devices are simple in design and do not require the clot to be amenable to emulsification clot to be amenable to emulsification
X-Sizer deviceX-Sizer device a device with small moving blades at the a device with small moving blades at the
catheter tip catheter tip This device the X-Sizer device (EndiCor Medical This device the X-Sizer device (EndiCor Medical
San Clemente CA) can be used to excise the San Clemente CA) can be used to excise the thrombus and aspirate it thrombus and aspirate it
The device was being evaluated in randomized The device was being evaluated in randomized studies of coronary vessels and in a registry of studies of coronary vessels and in a registry of patients with acute myocardial infarctionpatients with acute myocardial infarction
Although the manufacturer had modified the Although the manufacturer had modified the device for use in cerebral vessels a safety and device for use in cerebral vessels a safety and feasibility study was indefinitely suspended after feasibility study was indefinitely suspended after only 1 patient was treated with the device in only 1 patient was treated with the device in Europe Europe
Suction thrombectomySuction thrombectomy This method of mechanical thrombolysis is one of the This method of mechanical thrombolysis is one of the
simplestsimplest In this readily available technique suction is applied with In this readily available technique suction is applied with
a syringe to remove thrombus in the ICA a syringe to remove thrombus in the ICA It requires no other devicesIt requires no other devices A catheter with a large inner diameter (Brite Tip Cordis A catheter with a large inner diameter (Brite Tip Cordis
Corporation Miami FL) was placed in the symptomatic Corporation Miami FL) was placed in the symptomatic vessel and navigated over a guidewire into the thrombusvessel and navigated over a guidewire into the thrombus
A 60-mL syringe was used to aspirate the thrombus A 60-mL syringe was used to aspirate the thrombus Each patient required angioplasty and stenting of carotid Each patient required angioplasty and stenting of carotid
bifurcation stenosis and received daily aspirin and bifurcation stenosis and received daily aspirin and ticlopidine after the procedure No complications ticlopidine after the procedure No complications occurred occurred
Summary Acute Stroke Summary Acute Stroke ImagingImaging
PhysiologyPhysiology importance collaterals importance collaterals
ndash ndashGrowing role for perfusion Growing role for perfusion assessmentassessment
tPAtPA guidelines amp limitations guidelines amp limitations Signs on CT amp MRSigns on CT amp MR follow physiology follow physiology Stroke trialsStroke trials PWI-DWI mismatch PWI-DWI mismatch
ndash ndashTreat based on physiology not timeTreat based on physiology not time ProtocolsProtocols should be fast and should be fast and
comprehensivecomprehensive
The disadvantages of the mechanical The disadvantages of the mechanical approaches approaches technical difficulty of navigating mechanical technical difficulty of navigating mechanical
devices into the intracranial circulation excessive devices into the intracranial circulation excessive trauma to the vasculature (potentially leading to trauma to the vasculature (potentially leading to vasospasm vessel dissection perforation or vasospasm vessel dissection perforation or rupture) rupture)
fragmented thrombus causing distal embolization fragmented thrombus causing distal embolization into previously unaffected territories into previously unaffected territories
Nevertheless the advantages of mechanical stroke Nevertheless the advantages of mechanical stroke therapy appear to significantly outweigh its therapy appear to significantly outweigh its disadvantages and risksdisadvantages and risks
Contraindications to Thrombolytic Contraindications to Thrombolytic agents agents
Recent thoracic abdominal or Recent thoracic abdominal or intracranial surgeryintracranial surgery
Recent haemorrhagic CVA Head injury Recent haemorrhagic CVA Head injury or neoplasmor neoplasm
Bleeding ulcerBleeding ulcer Anticipated invasive procedures (arterial Anticipated invasive procedures (arterial
punctures biopsies)punctures biopsies) Concurrent hemostatic dysfunctionConcurrent hemostatic dysfunction
Monitoring of thrombolytic Monitoring of thrombolytic therapytherapy
Thrombin time Measures the availability of functional
fibrinogen Normal thrombin time is 10-14 sec Prolonged when fibrinogen level is below
75-100 mgdl
Half Life of ThrombolyticsHalf Life of ThrombolyticsAgent Administration Half Life
Streptokinase IA 60-80min
Urokinase IAIV 9-12min
rTPA IAIV 6min
Abciximab(Reopro) IAIV 12hour
Aspirin POIV 15-20min
Heparin IVSC 60min
Coumadin PO 15-25 days
Anti Platelet DrugsAnti Platelet DrugsDrug Drug Mechanism Mechanism UsesUsesAspirinAspirin Permanently inhibits Permanently inhibits
COX-1 and COX-2COX-1 and COX-2CADCAD
Stroke-TIAsStroke-TIAs
NSAIDsNSAIDs Reversibly inhibits Reversibly inhibits COX-1COX-1
LimitedLimited
DipyridamoleDipyridamole Inhibits PDE increases Inhibits PDE increases cAMPcAMP
TIAsTIAs
ThenopyridinesThenopyridines
(Ticlopidine(Ticlopidine
ClopidrgrelClopidrgrel))
Inhibits ADP Inhibits ADP
PlatAg PlatAg
TIAsStrokeTIAsStroke
CAD PVDCAD PVD
Abciximab (ReoPro)Abciximab (ReoPro)
Eptifibatide (Integrilin)Eptifibatide (Integrilin)
TirofibanTirofiban
GP IIBIIIA InhibitorsGP IIBIIIA Inhibitors
Stroke- TIAs Stroke- TIAs
MonitoringMonitoring
Bleeding timeBleeding time
Optical aggregometryOptical aggregometry
Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay
Bleeding timeBleeding time
Requires a skin incision (usually made on the ear lobe or Requires a skin incision (usually made on the ear lobe or forearm offorearm of
a depth that results in disruption of capillary loops and a depth that results in disruption of capillary loops and small vessels)small vessels)
AdvantagesAdvantages Universally availableUniversally available Relatively simple techniquesRelatively simple techniques Can be performed bedsideCan be performed bedside
DisadvantagesDisadvantages Insensitive inaccurate non-specific techniqueInsensitive inaccurate non-specific technique
Poorly reproducible (as depends on multiple variables)Poorly reproducible (as depends on multiple variables)
Optical aggregometryOptical aggregometry
Gold standard assay for platelet functionGold standard assay for platelet function Agonist induced aggregation is measuredAgonist induced aggregation is measured Different agonist are available for different Different agonist are available for different
agentsagents However require unique expertise and are not However require unique expertise and are not
universally availableuniversally available Aspirin measured with ADP or AA(gt70 Aspirin measured with ADP or AA(gt70
aggregation so resistance)aggregation so resistance) Clopidogrel( ADP gt 90 aggregation means Clopidogrel( ADP gt 90 aggregation means
resistance) resistance)
Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay
Can be performed bed sideCan be performed bed side Different assay devices with different Different assay devices with different
agonist are used for each of different agonist are used for each of different antiplatelet agents antiplatelet agents
For Aspirin AA is used (result is reported as aspirin For Aspirin AA is used (result is reported as aspirin reaction units [ARU] ARUgt 550 indicates non-reaction units [ARU] ARUgt 550 indicates non-responsiveness)responsiveness)
Verify IIbIIIa assay device uses TRAP as agonist for Verify IIbIIIa assay device uses TRAP as agonist for Abciximab and TirofibanAbciximab and Tirofiban
Practical Applications Practical Applications related to specific related to specific
Neurovascular Neurovascular interventionsinterventions
Acute ischemic StrokeAcute ischemic Stroke When an artery occludes neurons are affected When an artery occludes neurons are affected
differently depending upon the amount of residual blood differently depending upon the amount of residual blood flowflow
Normal cerebral blood flow is greater than 50 mL100 Normal cerebral blood flow is greater than 50 mL100 mgminmgmin
Once blood flow decreases to less than 20 mL100 Once blood flow decreases to less than 20 mL100 mgmin infarction occursmgmin infarction occurs
If blood flow decreases to less than 10 mL100 mgmin If blood flow decreases to less than 10 mL100 mgmin irreversible neuronal death occurs rapidly irreversible neuronal death occurs rapidly
Blood flow between 11 and 20 mL100 mgmin is thought Blood flow between 11 and 20 mL100 mgmin is thought to represent the ischemic penumbra an area where the to represent the ischemic penumbra an area where the cells are functionally silent because of ischemia but are cells are functionally silent because of ischemia but are still able to recover if blood flow is restored still able to recover if blood flow is restored
Many acute stroke therapies are targeted toward Many acute stroke therapies are targeted toward restoring flow or function to the ischemic penumbrarestoring flow or function to the ischemic penumbra
Therapeutic window in Therapeutic window in management of acute Ischemic management of acute Ischemic
StrokeStrokeThe early diagnosis of ischemic stroke is critical to the The early diagnosis of ischemic stroke is critical to the
with only a narrow therapeutic window in the first few with only a narrow therapeutic window in the first few hours following stroke ictushours following stroke ictus
Diagnosis in the first 3 hours postictus provides the Diagnosis in the first 3 hours postictus provides the opportunity for intravenous or intraarterial thrombolysis opportunity for intravenous or intraarterial thrombolysis and intra-arterial clot mechanical treatment which and intra-arterial clot mechanical treatment which improve the outcome improve the outcome
Diagnosis in the time period between 3 and 6 hours Diagnosis in the time period between 3 and 6 hours provides an opportunity for intra-arterial thrombolysis provides an opportunity for intra-arterial thrombolysis and mechanical treatment and mechanical treatment
Involvement of the posterior circulation especially the Involvement of the posterior circulation especially the basilar artery is treated by some regardless of time of basilar artery is treated by some regardless of time of onset or up until 12 to 24 hours in some practices This is onset or up until 12 to 24 hours in some practices This is related to the potentially high mortality and morbidity related to the potentially high mortality and morbidity associated with basilar artery thrombosisassociated with basilar artery thrombosis
Infarct evaluation on angiographyInfarct evaluation on angiography(CT angiography and catheter (CT angiography and catheter
angiography)angiography)CTA is an excellent first-line examination for CTA is an excellent first-line examination for
evaluation of the head and neck arteries evaluation of the head and neck arteries In comparison with catheter angiography In comparison with catheter angiography
what it gives up in resolution and dynamic what it gives up in resolution and dynamic properties it makes up for with rapid properties it makes up for with rapid acquisition of a 3-D dataset and the potential acquisition of a 3-D dataset and the potential for assessment of whole-brain perfusion and for assessment of whole-brain perfusion and better parenchymal evaluationbetter parenchymal evaluation
Moreover CTA illustrates not only arterial Moreover CTA illustrates not only arterial stenosis or occlusion but also the vessel wall stenosis or occlusion but also the vessel wall This factor is most important for evaluation of This factor is most important for evaluation of intramural dissection and thrombosed intramural dissection and thrombosed aneurysms which may both complicate aneurysms which may both complicate evaluation of stroke patientsevaluation of stroke patients
Early angiographic signs of strokes Early angiographic signs of strokes both CTA both CTA and DSA and DSA
Vessel occlusion or cutoff related to Vessel occlusion or cutoff related to thromboembolithromboemboli
aneurysms aneurysms arterial dissection arterial dissection Meniscus or flattened shape to clot Meniscus or flattened shape to clot
(recent) versus reverse meniscus (older)(recent) versus reverse meniscus (older) tram track (nonocclusive or recanalized tram track (nonocclusive or recanalized
clot) clot) delayed (antegrade) flow (manifest as delayed (antegrade) flow (manifest as
decreased whole-brain perfusion on CTA)decreased whole-brain perfusion on CTA) retrograde collateral flowretrograde collateral flow
Non-occlusive left MCA thrombus on 3-D imaging performed from CTA source data and was confirmed at catheter angiography
Therapy to be started within a 6-hr Therapy to be started within a 6-hr time to treatment (TTT) window time to treatment (TTT) window (while in case of IV thrombolysis (while in case of IV thrombolysis therapy to be started with in 3hrs)therapy to be started with in 3hrs)
Exclusion criteria Exclusion criteria Rapidly improving neurologic deficit or Rapidly improving neurologic deficit or Sustained blood pressure of gt180100 Sustained blood pressure of gt180100 Hemorrhage is detected on CTHemorrhage is detected on CT Infarct involving gt more than 13 rd Infarct involving gt more than 13 rd
territory of MCAterritory of MCA MRADWI-Perfusion mismatchlt 20MRADWI-Perfusion mismatchlt 20 Definite hypodensity on CTDefinite hypodensity on CT
Intra-arterial Thrombolysis
Fibrinolytics + AntiplateletsFibrinolytics + Antiplatelets
PlasminogenPlasminogen activators through fibrinolysis exposes activators through fibrinolysis exposes free thrombin and paradoxically stimulatesfree thrombin and paradoxically stimulates platelet platelet aggregation which leads to formation of aaggregation which leads to formation of a platelet platelet thrombus (white clot) thrombus (white clot)
This new thrombus is relatively resistant to This new thrombus is relatively resistant to fibrinolyticsfibrinolytics
So new regimen in case of acute stroke isSo new regimen in case of acute stroke is fibrinolytics + antiplatelet drugsfibrinolytics + antiplatelet drugs
rtPA + IIbIIIa inhibitors( tirofiban rtPA + IIbIIIa inhibitors( tirofiban abciximab) orabciximab) or
Urokinase + IIbIIIa Urokinase + IIbIIIa inhibitors( tirofiban abciximab)inhibitors( tirofiban abciximab)
Intra-arterial Thrombolysis Tirofiban (04 microgkgmin bolus for 3 min followed by Tirofiban (04 microgkgmin bolus for 3 min followed by
0125 ugkgmin)0125 ugkgmin)
++
Heparin (2000ndash3000 IU bolus followed by Heparin (2000ndash3000 IU bolus followed by 1000 IUhour infusion 1000 IUhour infusion
with ACT maintained bw 200-300) throughout the with ACT maintained bw 200-300) throughout the interventional procedure and for 24ndash48 hours thereafter when interventional procedure and for 24ndash48 hours thereafter when there is neither intraprocedural bleeding nor suspicion of there is neither intraprocedural bleeding nor suspicion of increased risk of bleeding increased risk of bleeding
Maximum dose of Urokinase Maximum dose of Urokinase Anterior circulation stroke - 500000 IU (mean 400000 Anterior circulation stroke - 500000 IU (mean 400000
IU range 300000ndash500000 IU)IU range 300000ndash500000 IU) Posterior circulation stroke -1000000 IU (mean 837000 Posterior circulation stroke -1000000 IU (mean 837000
IU range 300000ndash1000000 IU)IU range 300000ndash1000000 IU)American Journal of NeuroradiologyAmerican Journal of Neuroradiology 262595-2601 2005262595-2601 2005
Intravenous ThrombolysisIntravenous Thrombolysis
The first method to restore cerebral The first method to restore cerebral perfusion is clot lysis with the goal perfusion is clot lysis with the goal of re-establishing blood flow to the of re-establishing blood flow to the affected tissue affected tissue
IV thrombolysis rt-PA is the only IV thrombolysis rt-PA is the only FDA- approved treatment for AIS FDA- approved treatment for AIS
Fibrinolysis is enhanced powerfully Fibrinolysis is enhanced powerfully by rt-PAby rt-PA
Intravenous rTPA Intravenous rTPA administration administration protocolprotocol
Total dose of rt-PA 09 mgkg (maximum dose Total dose of rt-PA 09 mgkg (maximum dose 90 mg)90 mg)
Give 10 as initial IV bolusGive 10 as initial IV bolus Infuse remainder over 1 hourInfuse remainder over 1 hour Admit patient to an ICU or stroke unit for Admit patient to an ICU or stroke unit for
monitoringmonitoring Neurologic assessments every 15 minutes Neurologic assessments every 15 minutes
during infusion then every 30 minutes for next during infusion then every 30 minutes for next 6 hours then every hour until 24hours after 6 hours then every hour until 24hours after treatmenttreatment
Favorable Outcome vs Treatment Time Favorable Outcome vs Treatment Time with IV rTPAwith IV rTPA
Protocol limit = 3 hrs
Benefit ~ 45 hrs
Thromboembolism During coilingThromboembolism During coiling Most feared and frequent complication Most feared and frequent complication Reported incidence - Approx 7 Reported incidence - Approx 7 SourcesSources of Thromboembolism are of Thromboembolism are
- Clots at the aneurysmal neck during or immediately- Clots at the aneurysmal neck during or immediately after after embolization embolization
- Thrombus forming on catheters during- Thrombus forming on catheters during proceduresprocedures
- Stenosis of an adjacent artery dt coil mass- Stenosis of an adjacent artery dt coil mass or herniationor herniation
- Migration of intraaneurysmal- Migration of intraaneurysmal thrombus during coil thrombus during coil placement placement
- Slow flow dt vasospasm - Slow flow dt vasospasm
- Rare and unlikely causes are hypercoagulable- Rare and unlikely causes are hypercoagulable state such state such as antiphospholipid antibody syndrome or due to HITas antiphospholipid antibody syndrome or due to HIT
Occur more often with wide-necked aneurysms (dt Occur more often with wide-necked aneurysms (dt increased exposed surface area of thrombogenic coil increased exposed surface area of thrombogenic coil material)material)
Current regimen of endovascular Current regimen of endovascular managementmanagement
The The glycoprotein IIbIIIa antagonist tirofiban glycoprotein IIbIIIa antagonist tirofiban (04 (04 microgkgmin bolus for 30 minutes followed by infusion of microgkgmin bolus for 30 minutes followed by infusion of 0125 ugkgmin until the thrombus dissolved) 0125 ugkgmin until the thrombus dissolved)
Intraarterial thrombolysis with Intraarterial thrombolysis with urokinase or r- TPA urokinase or r- TPA increase of intravenous (IV) heparin (measured by increase of intravenous (IV) heparin (measured by
ACT) ACT) Intravenous aspirin Intravenous aspirin
Coil-related platelet aggregation (white clot) is Coil-related platelet aggregation (white clot) is unlikely to respond to fibrinolytics but has a high risk unlikely to respond to fibrinolytics but has a high risk of hemorrhage (In ISAT) all 5 patients who had of hemorrhage (In ISAT) all 5 patients who had received thrombolytic therapy with tPA to treat a received thrombolytic therapy with tPA to treat a thromboembolic complication after endovascular thromboembolic complication after endovascular treatment rebleed and all of these patients died)treatment rebleed and all of these patients died)
IntracranialIntracranial Stenting Stenting Metallic foreign body such as stent will accumulate Metallic foreign body such as stent will accumulate
thrombus in the absence of platelet inhibitionthrombus in the absence of platelet inhibition Antiplatelet drugs are important to prevent peri or Antiplatelet drugs are important to prevent peri or
post-interventional thromboembolic eventspost-interventional thromboembolic events Optimal treatment regimens has not been determined Optimal treatment regimens has not been determined
but usually but usually Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-
procedureprocedureOrOr
Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on
morning of proceduremorning of procedure
If need to use stent is not pre-planned thanIf need to use stent is not pre-planned than
Abciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkgAbciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkg IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)
Glycoprotein IIbIIIa inhibitor are not used routinely during elective Glycoprotein IIbIIIa inhibitor are not used routinely during elective stenting procedure dt increased risk of ICH stenting procedure dt increased risk of ICH
Carotid StentingCarotid Stenting
Pre-procedurePre-procedure
Double Antiplatelet therapy is routinely given Double Antiplatelet therapy is routinely given beginning at least 3beginning at least 3
days before the proceduredays before the procedure
Aspirin 325mgd+Clopidogrel 75mgdAspirin 325mgd+Clopidogrel 75mgd During procedureDuring procedure
Heparin is given with target clotting time of 250-Heparin is given with target clotting time of 250-300sec300sec
Post-procedure Post-procedure
Aspirin 325mg is continued indefinitely and Aspirin 325mg is continued indefinitely and
Clopidogrel 75mgd for at least 6 weeks Clopidogrel 75mgd for at least 6 weeks
Inclusion criteria for Local ThrombolysisInclusion criteria for Local Thrombolysis a)a) Patients in severe clinical grade on admission Patients in severe clinical grade on admission
with evidence of dural venous sinus with evidence of dural venous sinus thrombosis and restrictive venous outflow on thrombosis and restrictive venous outflow on cerebral angiogramcerebral angiogram
b)b) Patients in clinical grade 3 worsening on Patients in clinical grade 3 worsening on heparin therapy Restriction to venous heparin therapy Restriction to venous outflow was defined as an increase in brain outflow was defined as an increase in brain circulation time gt 12 s delay in the drainage circulation time gt 12 s delay in the drainage of cortical veins with cortical veins hanging of cortical veins with cortical veins hanging in spacein space
Treatment Options for Venous Thrombosis
CT Grading for Venous ThrombosisCT Grading for Venous Thrombosis Grade I no parenchymal change Grade I no parenchymal change
(hyperdense (hyperdense sinuses cortical veins empty sinuses cortical veins empty delta sign)delta sign)
Grade II non hemorrhagic venous infarct Grade II non hemorrhagic venous infarct without mass effect without mass effect
Grade III non-hemorrhagic infarct with Grade III non-hemorrhagic infarct with mass effectmass effect
Grade IV hemorrhagic venous infarct (max Grade IV hemorrhagic venous infarct (max diameter lt 3 cm) with no mass effectdiameter lt 3 cm) with no mass effect
Grade V hemorrhagic venous infarct (max Grade V hemorrhagic venous infarct (max diameter gt 3 cm) with mass effect diameter gt 3 cm) with mass effect
Local ThrombolysisLocal Thrombolysis
Femoral Jugular access was secured and a guiding Femoral Jugular access was secured and a guiding catheter was placed in the jugular bulb catheter was placed in the jugular bulb Mechanical Mechanical clot maceration clot maceration was done with the guidewire was done with the guidewire following which a microcatheter (was navigated and following which a microcatheter (was navigated and placed in the thrombosed segment of sinus confirmed placed in the thrombosed segment of sinus confirmed on a selective venogram on a selective venogram
Urokinase infusion Bolus dose of 2-6 lacs followed Urokinase infusion Bolus dose of 2-6 lacs followed by 60000 to 100000 units per hour along with by 60000 to 100000 units per hour along with periodic check venogram Along with maintenance periodic check venogram Along with maintenance systemic infusion of Heparinsystemic infusion of Heparin Other agents such as Other agents such as streptokinase altepase or rTPAstreptokinase altepase or rTPA can be also used can be also used
After thrombolysis patient should subjected to oral After thrombolysis patient should subjected to oral anticoagulation for six monthsanticoagulation for six months
Low-molecular-weight Low-molecular-weight heparinheparin
PharmacologyPharmacologyLMWH as its name suggests is a glycosaminoglycan that is approximatelyLMWH as its name suggests is a glycosaminoglycan that is approximately
one third the molecular weight of UFH It is derived from UFH through one third the molecular weight of UFH It is derived from UFH through variousvarious
depolymerization processes LMWH binds to antithrombin which in turn depolymerization processes LMWH binds to antithrombin which in turn
Neutralizes actors Xa and IIa Because LMWH lacks many of the longer Neutralizes actors Xa and IIa Because LMWH lacks many of the longer chains chains
required for binding to thrombin it has less ability to neutralize thrombin required for binding to thrombin it has less ability to neutralize thrombin
relativeto its ability to neutralize factor Xa LMWH also has less relativeto its ability to neutralize factor Xa LMWH also has less nonspecific nonspecific
binding to other proteins There is greater bioavailability with more binding to other proteins There is greater bioavailability with more predictable predictable
pharmacokinetics that eliminates the need for monitoring The smaller pharmacokinetics that eliminates the need for monitoring The smaller size also size also
allows for enhanced subcutaneous absorption when compared with UFHallows for enhanced subcutaneous absorption when compared with UFH
Three LMWH preparations are Three LMWH preparations are currently approved for use in the currently approved for use in the United States (1) enoxaparin (2) United States (1) enoxaparin (2) dalteparin and (3) tinzaparin dalteparin and (3) tinzaparin
They are all administered They are all administered subcutaneously at intervals of either subcutaneously at intervals of either once or twice daily for both once or twice daily for both prophylaxis and treatment dosesprophylaxis and treatment doses
Few Experiences of Few Experiences of ThrombolysisThrombolysis
Vickey 25 Yrs male patient presented Vickey 25 Yrs male patient presented with 12with 12thth day HO severe headache with day HO severe headache with right sided hemiplegiaright sided hemiplegia
MRI shows thrombosis of the superior MRI shows thrombosis of the superior sagittal left transverse left sigmoid sagittal left transverse left sigmoid sinuses and cortical veins in the fronto-sinuses and cortical veins in the fronto-parietal regions with eo haemorrhagic parietal regions with eo haemorrhagic infarct in the left cerebral hemisphere infarct in the left cerebral hemisphere with mass effect( Grade ndashV)with mass effect( Grade ndashV)
Sashi Srivastava 64 yrs FSashi Srivastava 64 yrs F In a follow up case of MRD with infra-renal In a follow up case of MRD with infra-renal
aortic abdominal and bilateral renal artery aortic abdominal and bilateral renal artery thrombosis renal angiogram shows filling thrombosis renal angiogram shows filling defects in the right Renal artery defects in the right Renal artery
Initially Renal angioplasty was done Initially Renal angioplasty was done Following angioplasty few thrombi are seem Following angioplasty few thrombi are seem to extends into the segmental branches and to extends into the segmental branches and causing blockage So Thrombolysis was causing blockage So Thrombolysis was plane to dissolve the run-out thrombi with plane to dissolve the run-out thrombi with urokinase urokinase
Rakesh 34yrsMRakesh 34yrsM Left SFA pseudoaneurysm with Left SFA pseudoaneurysm with
Covered stent placementCovered stent placement Pre operative antiplatelets with post Pre operative antiplatelets with post
procedure heparin Tirofiban procedure heparin Tirofiban followed by aspirin and clopidogrel followed by aspirin and clopidogrel were usedwere used
IAT may be a treatment option for selected patients IAT may be a treatment option for selected patients Possible selection criteria include Possible selection criteria include
presentation between 3 and 6 hours from symptom onsetpresentation between 3 and 6 hours from symptom onset major cerebral artery occlusion major cerebral artery occlusion severe neurologic deficits severe neurologic deficits high risk of systemic hemorrhage with IV rt-PA (eg recent high risk of systemic hemorrhage with IV rt-PA (eg recent
surgery) surgery) The MERCI (Mechanical Embolus Removal in Cerebral The MERCI (Mechanical Embolus Removal in Cerebral
Ischemia) retrievalIschemia) retrieval system system
Has been FDA-approved for recanalizing acutely occluded Has been FDA-approved for recanalizing acutely occluded cerebral arteries cerebral arteries
In the Multi-MERCI study patients who did not improve In the Multi-MERCI study patients who did not improve immediately after IV rt-PA underwent mechanical immediately after IV rt-PA underwent mechanical embolectomy within 8 hours of symptom onset embolectomy within 8 hours of symptom onset
Partial or complete recanalization occurred in 74 of Partial or complete recanalization occurred in 74 of patientspatients
with a symptomatic intracerebral hemorrhage (sICH) rate of with a symptomatic intracerebral hemorrhage (sICH) rate of 67 67
Mechanical embolectomy with the MERCI retriever may be a Mechanical embolectomy with the MERCI retriever may be a feasible and safe option for patients after IV rt-PAfeasible and safe option for patients after IV rt-PA
Penumbra stroke systemPenumbra stroke system This device combines two methods of clot This device combines two methods of clot
extraction aspiration and mechanical extraction aspiration and mechanical extraction extraction
First the clot is aspirated then a thrombus First the clot is aspirated then a thrombus removal ring can be used if necessary to removal ring can be used if necessary to remove remaining clot remove remaining clot
successful recanalizing 82successful recanalizing 82 Bridging therapyBridging therapy
06 mgkg IV rt-PA followed by IAT with IA rt-06 mgkg IV rt-PA followed by IAT with IA rt-PA (up to 20 mg)PA (up to 20 mg)
achieved a higher recanalization rateachieved a higher recanalization rate
Criteria for thrombolysis with rTPACriteria for thrombolysis with rTPA
Inclusion criteriaInclusion criteria Clinical signs and symptoms consistent with ischemic Clinical signs and symptoms consistent with ischemic
strokestroke Patient last seen normal within 3 hoursPatient last seen normal within 3 hours Measurable neurologic deficitMeasurable neurologic deficit
Exclusion criteriaExclusion criteria Any hemorrhage on neuroimaging (CT or MRI)Any hemorrhage on neuroimaging (CT or MRI) Symptoms suggestive of subarachnoid hemorrhageSymptoms suggestive of subarachnoid hemorrhage Seizure at stroke onset that is thought to contribute to Seizure at stroke onset that is thought to contribute to
neurologic deficitneurologic deficit Hypodensity greater than one third cerebral hemisphere Hypodensity greater than one third cerebral hemisphere
on CTon CT SBP greater than 185 mm Hg or DBP greater than 110 SBP greater than 185 mm Hg or DBP greater than 110
mm Hgmm Hg International normalized ratio (INR) greater than 17International normalized ratio (INR) greater than 17
Ischemic Stroke Ischemic Stroke Treatment ndash 2006Treatment ndash 2006
IV tissue plasminogen activator (tPA)IV tissue plasminogen activator (tPA) ndash ndash Only FDA-approved acute stroke drugOnly FDA-approved acute stroke drug ndash ndash 3 hour treatment window3 hour treatment window
MERCI - Concentric clot retrieval MERCI - Concentric clot retrieval devicedevice ndash ndash Rescue therapy - approved 2004Rescue therapy - approved 2004 ndash ndash Device approval (not outcomes-based)Device approval (not outcomes-based)
Off label approachesOff label approaches ndash ndash IV tPA after 3 hoursIV tPA after 3 hours ndash ndash IV-IA tPA sequential strategiesIV-IA tPA sequential strategies ndash ndash IA tPA clot angioplasty fragmentationIA tPA clot angioplasty fragmentation ndash ndash Ultrasound-assisted tPA lysisUltrasound-assisted tPA lysis
rt-PA Trials NINDSrt-PA Trials NINDS
Acute stroke - 624 patientsAcute stroke - 624 patients Treat within 3 hrsTreat within 3 hrs Intravenous 09 mgkg rt-PA vs placeboIntravenous 09 mgkg rt-PA vs placebo Hemorrhage 64 tPA 06 placeboHemorrhage 64 tPA 06 placebo Neurologic recovery better with tPA 30 Neurologic recovery better with tPA 30
more like to have minimal or no disabilitymore like to have minimal or no disability
First proven approved treatment for First proven approved treatment for strokestroke
Limitations of tPALimitations of tPA Only 4 of acute strokes receive tPAOnly 4 of acute strokes receive tPA (Kleindorfer et al Stroke 2004 35 e27-e29)(Kleindorfer et al Stroke 2004 35 e27-e29)
Only 22 of patients present within 3 hoursOnly 22 of patients present within 3 hours1048707 1048707 51 of these ineligible due to51 of these ineligible due to
bull bull Mild severityMild severity bull bull Medical or surgical historyMedical or surgical history bull bull Blood testsBlood tests
Sustained recanalization only 13Sustained recanalization only 13 (Alexandrov et al NEJM 2004 351 2170-8)(Alexandrov et al NEJM 2004 351 2170-8)
Concern for hemorrhageConcern for hemorrhage tPA potentiates apoptotic injury tPA potentiates apoptotic injury (Liu et al Nature Med 2004 101379-83)(Liu et al Nature Med 2004 101379-83)
PROACT II IA Lysis TrialPROACT II IA Lysis Trial Baseline 24 hours 8 days
Baseline 60 minutes 120 minutes
9mg IAProurokinase
Desmoteplase Trials DEDAS Desmoteplase Trials DEDAS DIASDIAS
Trial OverviewTrial Overview Double blind randomized placebo Double blind randomized placebo
controlled trialscontrolled trials IV delivery 3-9 hour time windowIV delivery 3-9 hour time window Plasminogen activator ndash from Plasminogen activator ndash from vampire bat vampire bat
salivasaliva Selection based on PWI-DWI MismatchSelection based on PWI-DWI Mismatch
MRI InclusionMRI Inclusion PWI defect at least 2 cm AND ~20 larger PWI defect at least 2 cm AND ~20 larger
than DWIthan DWI PWI should be obvious even visible on PWI should be obvious even visible on
raw imagesraw imagesMRI ExclusionMRI Exclusion
DWI gt 13 MCADWI gt 13 MCA MRA ICA occlusionMRA ICA occlusion
Desmoteplase ndash DIAS Desmoteplase ndash DIAS ResultsResults
Mechanical Thrombolysis Mechanical Thrombolysis devicesdevices
mechanical thrombolysis potentially extends the treatment mechanical thrombolysis potentially extends the treatment window because they act promptly at the site of the thrombuswindow because they act promptly at the site of the thrombus
The devices can retrieve large clots that pharmaceutical agents The devices can retrieve large clots that pharmaceutical agents may not successfully lysemay not successfully lyse
Patients treated with IV tPA may be considered for treatment of Patients treated with IV tPA may be considered for treatment of residual clot with some of these devicesresidual clot with some of these devices
suction-creating saline jets suction-creating saline jets laser energy ultrasound laser energy ultrasound a corkscrew apparatus to treat strokesa corkscrew apparatus to treat strokes The AngioJet systemThe AngioJet system uses saline jets that are directed back into the catheter to uses saline jets that are directed back into the catheter to
create a low-pressure zone around the catheter tip inducing create a low-pressure zone around the catheter tip inducing suction suction
The clot is pulled into the exhaust lumen and removed from the The clot is pulled into the exhaust lumen and removed from the vessel Although US Food and Drug Administration (FDA) has vessel Although US Food and Drug Administration (FDA) has approved this device for use in arteriovenous dialysis grafts and approved this device for use in arteriovenous dialysis grafts and fistulae and for the treatment of coronary arteries saphenous fistulae and for the treatment of coronary arteries saphenous vein grafts and peripheral vessels clinical trials for the vein grafts and peripheral vessels clinical trials for the treatment of acute stroke are no longer in progress treatment of acute stroke are no longer in progress
Most devices are used in cerebral vessels that 2-5 mm
The Latis laser device The Latis laser device used laser energy to ablate clots used laser energy to ablate clots Arteries 2-5 mm in diameter could be Arteries 2-5 mm in diameter could be
treated including the ICA M1 or M2 treated including the ICA M1 or M2 branch of the MCA A1 branch of the branch of the MCA A1 branch of the anterior cerebral artery (ACA) basilar anterior cerebral artery (ACA) basilar artery posterior cerebral artery (PCA) artery posterior cerebral artery (PCA) and vertebral and vertebral
Patients could receive treatment as late Patients could receive treatment as late as 8 hours after symptom onset in the as 8 hours after symptom onset in the anterior circulation and within 24 hours in anterior circulation and within 24 hours in the posterior circulation the posterior circulation
Endovascular Photo Acoustic Endovascular Photo Acoustic Recanalization (EPAR) Recanalization (EPAR)
A laser power source generated energy for the A laser power source generated energy for the systemsystem
The energy was delivered by means of The energy was delivered by means of fiberoptics to the tip of the catheter at the fiberoptics to the tip of the catheter at the treatment sitetreatment site
Absorption of laser light by darkly pigmented Absorption of laser light by darkly pigmented materials (ie the clot) occurred inside the 1-mm materials (ie the clot) occurred inside the 1-mm catheter tipcatheter tip
the system was designed to minimize scattering the system was designed to minimize scattering of laser light of laser light
Absorption converted photo energy to acoustic Absorption converted photo energy to acoustic energy which then emulsified the clot inside the energy which then emulsified the clot inside the catheter tip catheter tip
EKOS ultrasound( the EKOS ultrasound( the Ultrasound Thrombolytic Ultrasound Thrombolytic
Infusion Catheter) Infusion Catheter) combines the use of a distal ultrasound transducer with combines the use of a distal ultrasound transducer with
infusion of a thrombolytic agent through the infusion of a thrombolytic agent through the microcathetermicrocatheter
Ultrasound changes the structure of the clot to Ultrasound changes the structure of the clot to temporarily increase its permeability while providing an temporarily increase its permeability while providing an acoustic pressure gradient to move the drug into the clot acoustic pressure gradient to move the drug into the clot to speed its dissolution to speed its dissolution
The EKOS catheter is placed in the proximal portion of the The EKOS catheter is placed in the proximal portion of the clot clot
After a 2-mg bolus of tPA was injected through the After a 2-mg bolus of tPA was injected through the catheter catheter
the patient received a continuous infusion of IA tPA 03 the patient received a continuous infusion of IA tPA 03 mgmin to a maximum of 20 mg and simultaneous mgmin to a maximum of 20 mg and simultaneous ultrasound transmission for as long as 60 minutes ultrasound transmission for as long as 60 minutes
One patient was treated with a total of 4 units of One patient was treated with a total of 4 units of recombinant reteplase (Retavase) hand-injected over 60 recombinant reteplase (Retavase) hand-injected over 60 minutes minutes
Penumbra system Penumbra system The Penumbra system (Penumbra Inc) provides a dual The Penumbra system (Penumbra Inc) provides a dual
approach to clot extraction using aspiration followed by approach to clot extraction using aspiration followed by clot retrieval with a ring device if needed clot retrieval with a ring device if needed
Mechanical Embolus Removal in Cerebral Ischemia Mechanical Embolus Removal in Cerebral Ischemia (MERCI)(MERCI)
a corkscrew-like apparatus to remove blood clots from a corkscrew-like apparatus to remove blood clots from the brain in patients experiencing an ischemic stroke the brain in patients experiencing an ischemic stroke
The corkscrew itself resides in the catheter tip which The corkscrew itself resides in the catheter tip which shields it from the wall of the vessel until it is ready to be shields it from the wall of the vessel until it is ready to be burrowed into the clot Once lodged in the clot the device burrowed into the clot Once lodged in the clot the device and clot are withdrawn from the vessel and clot are withdrawn from the vessel
Snarelike devicesSnarelike devices Snares such as the Neuronet snare (Guidant Snares such as the Neuronet snare (Guidant
Endovascular Santa Clara CA) have been developed Endovascular Santa Clara CA) have been developed specifically for use in the treatment of strokes specifically for use in the treatment of strokes
These devices are simple in design and do not require the These devices are simple in design and do not require the clot to be amenable to emulsification clot to be amenable to emulsification
X-Sizer deviceX-Sizer device a device with small moving blades at the a device with small moving blades at the
catheter tip catheter tip This device the X-Sizer device (EndiCor Medical This device the X-Sizer device (EndiCor Medical
San Clemente CA) can be used to excise the San Clemente CA) can be used to excise the thrombus and aspirate it thrombus and aspirate it
The device was being evaluated in randomized The device was being evaluated in randomized studies of coronary vessels and in a registry of studies of coronary vessels and in a registry of patients with acute myocardial infarctionpatients with acute myocardial infarction
Although the manufacturer had modified the Although the manufacturer had modified the device for use in cerebral vessels a safety and device for use in cerebral vessels a safety and feasibility study was indefinitely suspended after feasibility study was indefinitely suspended after only 1 patient was treated with the device in only 1 patient was treated with the device in Europe Europe
Suction thrombectomySuction thrombectomy This method of mechanical thrombolysis is one of the This method of mechanical thrombolysis is one of the
simplestsimplest In this readily available technique suction is applied with In this readily available technique suction is applied with
a syringe to remove thrombus in the ICA a syringe to remove thrombus in the ICA It requires no other devicesIt requires no other devices A catheter with a large inner diameter (Brite Tip Cordis A catheter with a large inner diameter (Brite Tip Cordis
Corporation Miami FL) was placed in the symptomatic Corporation Miami FL) was placed in the symptomatic vessel and navigated over a guidewire into the thrombusvessel and navigated over a guidewire into the thrombus
A 60-mL syringe was used to aspirate the thrombus A 60-mL syringe was used to aspirate the thrombus Each patient required angioplasty and stenting of carotid Each patient required angioplasty and stenting of carotid
bifurcation stenosis and received daily aspirin and bifurcation stenosis and received daily aspirin and ticlopidine after the procedure No complications ticlopidine after the procedure No complications occurred occurred
Summary Acute Stroke Summary Acute Stroke ImagingImaging
PhysiologyPhysiology importance collaterals importance collaterals
ndash ndashGrowing role for perfusion Growing role for perfusion assessmentassessment
tPAtPA guidelines amp limitations guidelines amp limitations Signs on CT amp MRSigns on CT amp MR follow physiology follow physiology Stroke trialsStroke trials PWI-DWI mismatch PWI-DWI mismatch
ndash ndashTreat based on physiology not timeTreat based on physiology not time ProtocolsProtocols should be fast and should be fast and
comprehensivecomprehensive
Contraindications to Thrombolytic Contraindications to Thrombolytic agents agents
Recent thoracic abdominal or Recent thoracic abdominal or intracranial surgeryintracranial surgery
Recent haemorrhagic CVA Head injury Recent haemorrhagic CVA Head injury or neoplasmor neoplasm
Bleeding ulcerBleeding ulcer Anticipated invasive procedures (arterial Anticipated invasive procedures (arterial
punctures biopsies)punctures biopsies) Concurrent hemostatic dysfunctionConcurrent hemostatic dysfunction
Monitoring of thrombolytic Monitoring of thrombolytic therapytherapy
Thrombin time Measures the availability of functional
fibrinogen Normal thrombin time is 10-14 sec Prolonged when fibrinogen level is below
75-100 mgdl
Half Life of ThrombolyticsHalf Life of ThrombolyticsAgent Administration Half Life
Streptokinase IA 60-80min
Urokinase IAIV 9-12min
rTPA IAIV 6min
Abciximab(Reopro) IAIV 12hour
Aspirin POIV 15-20min
Heparin IVSC 60min
Coumadin PO 15-25 days
Anti Platelet DrugsAnti Platelet DrugsDrug Drug Mechanism Mechanism UsesUsesAspirinAspirin Permanently inhibits Permanently inhibits
COX-1 and COX-2COX-1 and COX-2CADCAD
Stroke-TIAsStroke-TIAs
NSAIDsNSAIDs Reversibly inhibits Reversibly inhibits COX-1COX-1
LimitedLimited
DipyridamoleDipyridamole Inhibits PDE increases Inhibits PDE increases cAMPcAMP
TIAsTIAs
ThenopyridinesThenopyridines
(Ticlopidine(Ticlopidine
ClopidrgrelClopidrgrel))
Inhibits ADP Inhibits ADP
PlatAg PlatAg
TIAsStrokeTIAsStroke
CAD PVDCAD PVD
Abciximab (ReoPro)Abciximab (ReoPro)
Eptifibatide (Integrilin)Eptifibatide (Integrilin)
TirofibanTirofiban
GP IIBIIIA InhibitorsGP IIBIIIA Inhibitors
Stroke- TIAs Stroke- TIAs
MonitoringMonitoring
Bleeding timeBleeding time
Optical aggregometryOptical aggregometry
Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay
Bleeding timeBleeding time
Requires a skin incision (usually made on the ear lobe or Requires a skin incision (usually made on the ear lobe or forearm offorearm of
a depth that results in disruption of capillary loops and a depth that results in disruption of capillary loops and small vessels)small vessels)
AdvantagesAdvantages Universally availableUniversally available Relatively simple techniquesRelatively simple techniques Can be performed bedsideCan be performed bedside
DisadvantagesDisadvantages Insensitive inaccurate non-specific techniqueInsensitive inaccurate non-specific technique
Poorly reproducible (as depends on multiple variables)Poorly reproducible (as depends on multiple variables)
Optical aggregometryOptical aggregometry
Gold standard assay for platelet functionGold standard assay for platelet function Agonist induced aggregation is measuredAgonist induced aggregation is measured Different agonist are available for different Different agonist are available for different
agentsagents However require unique expertise and are not However require unique expertise and are not
universally availableuniversally available Aspirin measured with ADP or AA(gt70 Aspirin measured with ADP or AA(gt70
aggregation so resistance)aggregation so resistance) Clopidogrel( ADP gt 90 aggregation means Clopidogrel( ADP gt 90 aggregation means
resistance) resistance)
Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay
Can be performed bed sideCan be performed bed side Different assay devices with different Different assay devices with different
agonist are used for each of different agonist are used for each of different antiplatelet agents antiplatelet agents
For Aspirin AA is used (result is reported as aspirin For Aspirin AA is used (result is reported as aspirin reaction units [ARU] ARUgt 550 indicates non-reaction units [ARU] ARUgt 550 indicates non-responsiveness)responsiveness)
Verify IIbIIIa assay device uses TRAP as agonist for Verify IIbIIIa assay device uses TRAP as agonist for Abciximab and TirofibanAbciximab and Tirofiban
Practical Applications Practical Applications related to specific related to specific
Neurovascular Neurovascular interventionsinterventions
Acute ischemic StrokeAcute ischemic Stroke When an artery occludes neurons are affected When an artery occludes neurons are affected
differently depending upon the amount of residual blood differently depending upon the amount of residual blood flowflow
Normal cerebral blood flow is greater than 50 mL100 Normal cerebral blood flow is greater than 50 mL100 mgminmgmin
Once blood flow decreases to less than 20 mL100 Once blood flow decreases to less than 20 mL100 mgmin infarction occursmgmin infarction occurs
If blood flow decreases to less than 10 mL100 mgmin If blood flow decreases to less than 10 mL100 mgmin irreversible neuronal death occurs rapidly irreversible neuronal death occurs rapidly
Blood flow between 11 and 20 mL100 mgmin is thought Blood flow between 11 and 20 mL100 mgmin is thought to represent the ischemic penumbra an area where the to represent the ischemic penumbra an area where the cells are functionally silent because of ischemia but are cells are functionally silent because of ischemia but are still able to recover if blood flow is restored still able to recover if blood flow is restored
Many acute stroke therapies are targeted toward Many acute stroke therapies are targeted toward restoring flow or function to the ischemic penumbrarestoring flow or function to the ischemic penumbra
Therapeutic window in Therapeutic window in management of acute Ischemic management of acute Ischemic
StrokeStrokeThe early diagnosis of ischemic stroke is critical to the The early diagnosis of ischemic stroke is critical to the
with only a narrow therapeutic window in the first few with only a narrow therapeutic window in the first few hours following stroke ictushours following stroke ictus
Diagnosis in the first 3 hours postictus provides the Diagnosis in the first 3 hours postictus provides the opportunity for intravenous or intraarterial thrombolysis opportunity for intravenous or intraarterial thrombolysis and intra-arterial clot mechanical treatment which and intra-arterial clot mechanical treatment which improve the outcome improve the outcome
Diagnosis in the time period between 3 and 6 hours Diagnosis in the time period between 3 and 6 hours provides an opportunity for intra-arterial thrombolysis provides an opportunity for intra-arterial thrombolysis and mechanical treatment and mechanical treatment
Involvement of the posterior circulation especially the Involvement of the posterior circulation especially the basilar artery is treated by some regardless of time of basilar artery is treated by some regardless of time of onset or up until 12 to 24 hours in some practices This is onset or up until 12 to 24 hours in some practices This is related to the potentially high mortality and morbidity related to the potentially high mortality and morbidity associated with basilar artery thrombosisassociated with basilar artery thrombosis
Infarct evaluation on angiographyInfarct evaluation on angiography(CT angiography and catheter (CT angiography and catheter
angiography)angiography)CTA is an excellent first-line examination for CTA is an excellent first-line examination for
evaluation of the head and neck arteries evaluation of the head and neck arteries In comparison with catheter angiography In comparison with catheter angiography
what it gives up in resolution and dynamic what it gives up in resolution and dynamic properties it makes up for with rapid properties it makes up for with rapid acquisition of a 3-D dataset and the potential acquisition of a 3-D dataset and the potential for assessment of whole-brain perfusion and for assessment of whole-brain perfusion and better parenchymal evaluationbetter parenchymal evaluation
Moreover CTA illustrates not only arterial Moreover CTA illustrates not only arterial stenosis or occlusion but also the vessel wall stenosis or occlusion but also the vessel wall This factor is most important for evaluation of This factor is most important for evaluation of intramural dissection and thrombosed intramural dissection and thrombosed aneurysms which may both complicate aneurysms which may both complicate evaluation of stroke patientsevaluation of stroke patients
Early angiographic signs of strokes Early angiographic signs of strokes both CTA both CTA and DSA and DSA
Vessel occlusion or cutoff related to Vessel occlusion or cutoff related to thromboembolithromboemboli
aneurysms aneurysms arterial dissection arterial dissection Meniscus or flattened shape to clot Meniscus or flattened shape to clot
(recent) versus reverse meniscus (older)(recent) versus reverse meniscus (older) tram track (nonocclusive or recanalized tram track (nonocclusive or recanalized
clot) clot) delayed (antegrade) flow (manifest as delayed (antegrade) flow (manifest as
decreased whole-brain perfusion on CTA)decreased whole-brain perfusion on CTA) retrograde collateral flowretrograde collateral flow
Non-occlusive left MCA thrombus on 3-D imaging performed from CTA source data and was confirmed at catheter angiography
Therapy to be started within a 6-hr Therapy to be started within a 6-hr time to treatment (TTT) window time to treatment (TTT) window (while in case of IV thrombolysis (while in case of IV thrombolysis therapy to be started with in 3hrs)therapy to be started with in 3hrs)
Exclusion criteria Exclusion criteria Rapidly improving neurologic deficit or Rapidly improving neurologic deficit or Sustained blood pressure of gt180100 Sustained blood pressure of gt180100 Hemorrhage is detected on CTHemorrhage is detected on CT Infarct involving gt more than 13 rd Infarct involving gt more than 13 rd
territory of MCAterritory of MCA MRADWI-Perfusion mismatchlt 20MRADWI-Perfusion mismatchlt 20 Definite hypodensity on CTDefinite hypodensity on CT
Intra-arterial Thrombolysis
Fibrinolytics + AntiplateletsFibrinolytics + Antiplatelets
PlasminogenPlasminogen activators through fibrinolysis exposes activators through fibrinolysis exposes free thrombin and paradoxically stimulatesfree thrombin and paradoxically stimulates platelet platelet aggregation which leads to formation of aaggregation which leads to formation of a platelet platelet thrombus (white clot) thrombus (white clot)
This new thrombus is relatively resistant to This new thrombus is relatively resistant to fibrinolyticsfibrinolytics
So new regimen in case of acute stroke isSo new regimen in case of acute stroke is fibrinolytics + antiplatelet drugsfibrinolytics + antiplatelet drugs
rtPA + IIbIIIa inhibitors( tirofiban rtPA + IIbIIIa inhibitors( tirofiban abciximab) orabciximab) or
Urokinase + IIbIIIa Urokinase + IIbIIIa inhibitors( tirofiban abciximab)inhibitors( tirofiban abciximab)
Intra-arterial Thrombolysis Tirofiban (04 microgkgmin bolus for 3 min followed by Tirofiban (04 microgkgmin bolus for 3 min followed by
0125 ugkgmin)0125 ugkgmin)
++
Heparin (2000ndash3000 IU bolus followed by Heparin (2000ndash3000 IU bolus followed by 1000 IUhour infusion 1000 IUhour infusion
with ACT maintained bw 200-300) throughout the with ACT maintained bw 200-300) throughout the interventional procedure and for 24ndash48 hours thereafter when interventional procedure and for 24ndash48 hours thereafter when there is neither intraprocedural bleeding nor suspicion of there is neither intraprocedural bleeding nor suspicion of increased risk of bleeding increased risk of bleeding
Maximum dose of Urokinase Maximum dose of Urokinase Anterior circulation stroke - 500000 IU (mean 400000 Anterior circulation stroke - 500000 IU (mean 400000
IU range 300000ndash500000 IU)IU range 300000ndash500000 IU) Posterior circulation stroke -1000000 IU (mean 837000 Posterior circulation stroke -1000000 IU (mean 837000
IU range 300000ndash1000000 IU)IU range 300000ndash1000000 IU)American Journal of NeuroradiologyAmerican Journal of Neuroradiology 262595-2601 2005262595-2601 2005
Intravenous ThrombolysisIntravenous Thrombolysis
The first method to restore cerebral The first method to restore cerebral perfusion is clot lysis with the goal perfusion is clot lysis with the goal of re-establishing blood flow to the of re-establishing blood flow to the affected tissue affected tissue
IV thrombolysis rt-PA is the only IV thrombolysis rt-PA is the only FDA- approved treatment for AIS FDA- approved treatment for AIS
Fibrinolysis is enhanced powerfully Fibrinolysis is enhanced powerfully by rt-PAby rt-PA
Intravenous rTPA Intravenous rTPA administration administration protocolprotocol
Total dose of rt-PA 09 mgkg (maximum dose Total dose of rt-PA 09 mgkg (maximum dose 90 mg)90 mg)
Give 10 as initial IV bolusGive 10 as initial IV bolus Infuse remainder over 1 hourInfuse remainder over 1 hour Admit patient to an ICU or stroke unit for Admit patient to an ICU or stroke unit for
monitoringmonitoring Neurologic assessments every 15 minutes Neurologic assessments every 15 minutes
during infusion then every 30 minutes for next during infusion then every 30 minutes for next 6 hours then every hour until 24hours after 6 hours then every hour until 24hours after treatmenttreatment
Favorable Outcome vs Treatment Time Favorable Outcome vs Treatment Time with IV rTPAwith IV rTPA
Protocol limit = 3 hrs
Benefit ~ 45 hrs
Thromboembolism During coilingThromboembolism During coiling Most feared and frequent complication Most feared and frequent complication Reported incidence - Approx 7 Reported incidence - Approx 7 SourcesSources of Thromboembolism are of Thromboembolism are
- Clots at the aneurysmal neck during or immediately- Clots at the aneurysmal neck during or immediately after after embolization embolization
- Thrombus forming on catheters during- Thrombus forming on catheters during proceduresprocedures
- Stenosis of an adjacent artery dt coil mass- Stenosis of an adjacent artery dt coil mass or herniationor herniation
- Migration of intraaneurysmal- Migration of intraaneurysmal thrombus during coil thrombus during coil placement placement
- Slow flow dt vasospasm - Slow flow dt vasospasm
- Rare and unlikely causes are hypercoagulable- Rare and unlikely causes are hypercoagulable state such state such as antiphospholipid antibody syndrome or due to HITas antiphospholipid antibody syndrome or due to HIT
Occur more often with wide-necked aneurysms (dt Occur more often with wide-necked aneurysms (dt increased exposed surface area of thrombogenic coil increased exposed surface area of thrombogenic coil material)material)
Current regimen of endovascular Current regimen of endovascular managementmanagement
The The glycoprotein IIbIIIa antagonist tirofiban glycoprotein IIbIIIa antagonist tirofiban (04 (04 microgkgmin bolus for 30 minutes followed by infusion of microgkgmin bolus for 30 minutes followed by infusion of 0125 ugkgmin until the thrombus dissolved) 0125 ugkgmin until the thrombus dissolved)
Intraarterial thrombolysis with Intraarterial thrombolysis with urokinase or r- TPA urokinase or r- TPA increase of intravenous (IV) heparin (measured by increase of intravenous (IV) heparin (measured by
ACT) ACT) Intravenous aspirin Intravenous aspirin
Coil-related platelet aggregation (white clot) is Coil-related platelet aggregation (white clot) is unlikely to respond to fibrinolytics but has a high risk unlikely to respond to fibrinolytics but has a high risk of hemorrhage (In ISAT) all 5 patients who had of hemorrhage (In ISAT) all 5 patients who had received thrombolytic therapy with tPA to treat a received thrombolytic therapy with tPA to treat a thromboembolic complication after endovascular thromboembolic complication after endovascular treatment rebleed and all of these patients died)treatment rebleed and all of these patients died)
IntracranialIntracranial Stenting Stenting Metallic foreign body such as stent will accumulate Metallic foreign body such as stent will accumulate
thrombus in the absence of platelet inhibitionthrombus in the absence of platelet inhibition Antiplatelet drugs are important to prevent peri or Antiplatelet drugs are important to prevent peri or
post-interventional thromboembolic eventspost-interventional thromboembolic events Optimal treatment regimens has not been determined Optimal treatment regimens has not been determined
but usually but usually Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-
procedureprocedureOrOr
Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on
morning of proceduremorning of procedure
If need to use stent is not pre-planned thanIf need to use stent is not pre-planned than
Abciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkgAbciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkg IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)
Glycoprotein IIbIIIa inhibitor are not used routinely during elective Glycoprotein IIbIIIa inhibitor are not used routinely during elective stenting procedure dt increased risk of ICH stenting procedure dt increased risk of ICH
Carotid StentingCarotid Stenting
Pre-procedurePre-procedure
Double Antiplatelet therapy is routinely given Double Antiplatelet therapy is routinely given beginning at least 3beginning at least 3
days before the proceduredays before the procedure
Aspirin 325mgd+Clopidogrel 75mgdAspirin 325mgd+Clopidogrel 75mgd During procedureDuring procedure
Heparin is given with target clotting time of 250-Heparin is given with target clotting time of 250-300sec300sec
Post-procedure Post-procedure
Aspirin 325mg is continued indefinitely and Aspirin 325mg is continued indefinitely and
Clopidogrel 75mgd for at least 6 weeks Clopidogrel 75mgd for at least 6 weeks
Inclusion criteria for Local ThrombolysisInclusion criteria for Local Thrombolysis a)a) Patients in severe clinical grade on admission Patients in severe clinical grade on admission
with evidence of dural venous sinus with evidence of dural venous sinus thrombosis and restrictive venous outflow on thrombosis and restrictive venous outflow on cerebral angiogramcerebral angiogram
b)b) Patients in clinical grade 3 worsening on Patients in clinical grade 3 worsening on heparin therapy Restriction to venous heparin therapy Restriction to venous outflow was defined as an increase in brain outflow was defined as an increase in brain circulation time gt 12 s delay in the drainage circulation time gt 12 s delay in the drainage of cortical veins with cortical veins hanging of cortical veins with cortical veins hanging in spacein space
Treatment Options for Venous Thrombosis
CT Grading for Venous ThrombosisCT Grading for Venous Thrombosis Grade I no parenchymal change Grade I no parenchymal change
(hyperdense (hyperdense sinuses cortical veins empty sinuses cortical veins empty delta sign)delta sign)
Grade II non hemorrhagic venous infarct Grade II non hemorrhagic venous infarct without mass effect without mass effect
Grade III non-hemorrhagic infarct with Grade III non-hemorrhagic infarct with mass effectmass effect
Grade IV hemorrhagic venous infarct (max Grade IV hemorrhagic venous infarct (max diameter lt 3 cm) with no mass effectdiameter lt 3 cm) with no mass effect
Grade V hemorrhagic venous infarct (max Grade V hemorrhagic venous infarct (max diameter gt 3 cm) with mass effect diameter gt 3 cm) with mass effect
Local ThrombolysisLocal Thrombolysis
Femoral Jugular access was secured and a guiding Femoral Jugular access was secured and a guiding catheter was placed in the jugular bulb catheter was placed in the jugular bulb Mechanical Mechanical clot maceration clot maceration was done with the guidewire was done with the guidewire following which a microcatheter (was navigated and following which a microcatheter (was navigated and placed in the thrombosed segment of sinus confirmed placed in the thrombosed segment of sinus confirmed on a selective venogram on a selective venogram
Urokinase infusion Bolus dose of 2-6 lacs followed Urokinase infusion Bolus dose of 2-6 lacs followed by 60000 to 100000 units per hour along with by 60000 to 100000 units per hour along with periodic check venogram Along with maintenance periodic check venogram Along with maintenance systemic infusion of Heparinsystemic infusion of Heparin Other agents such as Other agents such as streptokinase altepase or rTPAstreptokinase altepase or rTPA can be also used can be also used
After thrombolysis patient should subjected to oral After thrombolysis patient should subjected to oral anticoagulation for six monthsanticoagulation for six months
Low-molecular-weight Low-molecular-weight heparinheparin
PharmacologyPharmacologyLMWH as its name suggests is a glycosaminoglycan that is approximatelyLMWH as its name suggests is a glycosaminoglycan that is approximately
one third the molecular weight of UFH It is derived from UFH through one third the molecular weight of UFH It is derived from UFH through variousvarious
depolymerization processes LMWH binds to antithrombin which in turn depolymerization processes LMWH binds to antithrombin which in turn
Neutralizes actors Xa and IIa Because LMWH lacks many of the longer Neutralizes actors Xa and IIa Because LMWH lacks many of the longer chains chains
required for binding to thrombin it has less ability to neutralize thrombin required for binding to thrombin it has less ability to neutralize thrombin
relativeto its ability to neutralize factor Xa LMWH also has less relativeto its ability to neutralize factor Xa LMWH also has less nonspecific nonspecific
binding to other proteins There is greater bioavailability with more binding to other proteins There is greater bioavailability with more predictable predictable
pharmacokinetics that eliminates the need for monitoring The smaller pharmacokinetics that eliminates the need for monitoring The smaller size also size also
allows for enhanced subcutaneous absorption when compared with UFHallows for enhanced subcutaneous absorption when compared with UFH
Three LMWH preparations are Three LMWH preparations are currently approved for use in the currently approved for use in the United States (1) enoxaparin (2) United States (1) enoxaparin (2) dalteparin and (3) tinzaparin dalteparin and (3) tinzaparin
They are all administered They are all administered subcutaneously at intervals of either subcutaneously at intervals of either once or twice daily for both once or twice daily for both prophylaxis and treatment dosesprophylaxis and treatment doses
Few Experiences of Few Experiences of ThrombolysisThrombolysis
Vickey 25 Yrs male patient presented Vickey 25 Yrs male patient presented with 12with 12thth day HO severe headache with day HO severe headache with right sided hemiplegiaright sided hemiplegia
MRI shows thrombosis of the superior MRI shows thrombosis of the superior sagittal left transverse left sigmoid sagittal left transverse left sigmoid sinuses and cortical veins in the fronto-sinuses and cortical veins in the fronto-parietal regions with eo haemorrhagic parietal regions with eo haemorrhagic infarct in the left cerebral hemisphere infarct in the left cerebral hemisphere with mass effect( Grade ndashV)with mass effect( Grade ndashV)
Sashi Srivastava 64 yrs FSashi Srivastava 64 yrs F In a follow up case of MRD with infra-renal In a follow up case of MRD with infra-renal
aortic abdominal and bilateral renal artery aortic abdominal and bilateral renal artery thrombosis renal angiogram shows filling thrombosis renal angiogram shows filling defects in the right Renal artery defects in the right Renal artery
Initially Renal angioplasty was done Initially Renal angioplasty was done Following angioplasty few thrombi are seem Following angioplasty few thrombi are seem to extends into the segmental branches and to extends into the segmental branches and causing blockage So Thrombolysis was causing blockage So Thrombolysis was plane to dissolve the run-out thrombi with plane to dissolve the run-out thrombi with urokinase urokinase
Rakesh 34yrsMRakesh 34yrsM Left SFA pseudoaneurysm with Left SFA pseudoaneurysm with
Covered stent placementCovered stent placement Pre operative antiplatelets with post Pre operative antiplatelets with post
procedure heparin Tirofiban procedure heparin Tirofiban followed by aspirin and clopidogrel followed by aspirin and clopidogrel were usedwere used
IAT may be a treatment option for selected patients IAT may be a treatment option for selected patients Possible selection criteria include Possible selection criteria include
presentation between 3 and 6 hours from symptom onsetpresentation between 3 and 6 hours from symptom onset major cerebral artery occlusion major cerebral artery occlusion severe neurologic deficits severe neurologic deficits high risk of systemic hemorrhage with IV rt-PA (eg recent high risk of systemic hemorrhage with IV rt-PA (eg recent
surgery) surgery) The MERCI (Mechanical Embolus Removal in Cerebral The MERCI (Mechanical Embolus Removal in Cerebral
Ischemia) retrievalIschemia) retrieval system system
Has been FDA-approved for recanalizing acutely occluded Has been FDA-approved for recanalizing acutely occluded cerebral arteries cerebral arteries
In the Multi-MERCI study patients who did not improve In the Multi-MERCI study patients who did not improve immediately after IV rt-PA underwent mechanical immediately after IV rt-PA underwent mechanical embolectomy within 8 hours of symptom onset embolectomy within 8 hours of symptom onset
Partial or complete recanalization occurred in 74 of Partial or complete recanalization occurred in 74 of patientspatients
with a symptomatic intracerebral hemorrhage (sICH) rate of with a symptomatic intracerebral hemorrhage (sICH) rate of 67 67
Mechanical embolectomy with the MERCI retriever may be a Mechanical embolectomy with the MERCI retriever may be a feasible and safe option for patients after IV rt-PAfeasible and safe option for patients after IV rt-PA
Penumbra stroke systemPenumbra stroke system This device combines two methods of clot This device combines two methods of clot
extraction aspiration and mechanical extraction aspiration and mechanical extraction extraction
First the clot is aspirated then a thrombus First the clot is aspirated then a thrombus removal ring can be used if necessary to removal ring can be used if necessary to remove remaining clot remove remaining clot
successful recanalizing 82successful recanalizing 82 Bridging therapyBridging therapy
06 mgkg IV rt-PA followed by IAT with IA rt-06 mgkg IV rt-PA followed by IAT with IA rt-PA (up to 20 mg)PA (up to 20 mg)
achieved a higher recanalization rateachieved a higher recanalization rate
Criteria for thrombolysis with rTPACriteria for thrombolysis with rTPA
Inclusion criteriaInclusion criteria Clinical signs and symptoms consistent with ischemic Clinical signs and symptoms consistent with ischemic
strokestroke Patient last seen normal within 3 hoursPatient last seen normal within 3 hours Measurable neurologic deficitMeasurable neurologic deficit
Exclusion criteriaExclusion criteria Any hemorrhage on neuroimaging (CT or MRI)Any hemorrhage on neuroimaging (CT or MRI) Symptoms suggestive of subarachnoid hemorrhageSymptoms suggestive of subarachnoid hemorrhage Seizure at stroke onset that is thought to contribute to Seizure at stroke onset that is thought to contribute to
neurologic deficitneurologic deficit Hypodensity greater than one third cerebral hemisphere Hypodensity greater than one third cerebral hemisphere
on CTon CT SBP greater than 185 mm Hg or DBP greater than 110 SBP greater than 185 mm Hg or DBP greater than 110
mm Hgmm Hg International normalized ratio (INR) greater than 17International normalized ratio (INR) greater than 17
Ischemic Stroke Ischemic Stroke Treatment ndash 2006Treatment ndash 2006
IV tissue plasminogen activator (tPA)IV tissue plasminogen activator (tPA) ndash ndash Only FDA-approved acute stroke drugOnly FDA-approved acute stroke drug ndash ndash 3 hour treatment window3 hour treatment window
MERCI - Concentric clot retrieval MERCI - Concentric clot retrieval devicedevice ndash ndash Rescue therapy - approved 2004Rescue therapy - approved 2004 ndash ndash Device approval (not outcomes-based)Device approval (not outcomes-based)
Off label approachesOff label approaches ndash ndash IV tPA after 3 hoursIV tPA after 3 hours ndash ndash IV-IA tPA sequential strategiesIV-IA tPA sequential strategies ndash ndash IA tPA clot angioplasty fragmentationIA tPA clot angioplasty fragmentation ndash ndash Ultrasound-assisted tPA lysisUltrasound-assisted tPA lysis
rt-PA Trials NINDSrt-PA Trials NINDS
Acute stroke - 624 patientsAcute stroke - 624 patients Treat within 3 hrsTreat within 3 hrs Intravenous 09 mgkg rt-PA vs placeboIntravenous 09 mgkg rt-PA vs placebo Hemorrhage 64 tPA 06 placeboHemorrhage 64 tPA 06 placebo Neurologic recovery better with tPA 30 Neurologic recovery better with tPA 30
more like to have minimal or no disabilitymore like to have minimal or no disability
First proven approved treatment for First proven approved treatment for strokestroke
Limitations of tPALimitations of tPA Only 4 of acute strokes receive tPAOnly 4 of acute strokes receive tPA (Kleindorfer et al Stroke 2004 35 e27-e29)(Kleindorfer et al Stroke 2004 35 e27-e29)
Only 22 of patients present within 3 hoursOnly 22 of patients present within 3 hours1048707 1048707 51 of these ineligible due to51 of these ineligible due to
bull bull Mild severityMild severity bull bull Medical or surgical historyMedical or surgical history bull bull Blood testsBlood tests
Sustained recanalization only 13Sustained recanalization only 13 (Alexandrov et al NEJM 2004 351 2170-8)(Alexandrov et al NEJM 2004 351 2170-8)
Concern for hemorrhageConcern for hemorrhage tPA potentiates apoptotic injury tPA potentiates apoptotic injury (Liu et al Nature Med 2004 101379-83)(Liu et al Nature Med 2004 101379-83)
PROACT II IA Lysis TrialPROACT II IA Lysis Trial Baseline 24 hours 8 days
Baseline 60 minutes 120 minutes
9mg IAProurokinase
Desmoteplase Trials DEDAS Desmoteplase Trials DEDAS DIASDIAS
Trial OverviewTrial Overview Double blind randomized placebo Double blind randomized placebo
controlled trialscontrolled trials IV delivery 3-9 hour time windowIV delivery 3-9 hour time window Plasminogen activator ndash from Plasminogen activator ndash from vampire bat vampire bat
salivasaliva Selection based on PWI-DWI MismatchSelection based on PWI-DWI Mismatch
MRI InclusionMRI Inclusion PWI defect at least 2 cm AND ~20 larger PWI defect at least 2 cm AND ~20 larger
than DWIthan DWI PWI should be obvious even visible on PWI should be obvious even visible on
raw imagesraw imagesMRI ExclusionMRI Exclusion
DWI gt 13 MCADWI gt 13 MCA MRA ICA occlusionMRA ICA occlusion
Desmoteplase ndash DIAS Desmoteplase ndash DIAS ResultsResults
Mechanical Thrombolysis Mechanical Thrombolysis devicesdevices
mechanical thrombolysis potentially extends the treatment mechanical thrombolysis potentially extends the treatment window because they act promptly at the site of the thrombuswindow because they act promptly at the site of the thrombus
The devices can retrieve large clots that pharmaceutical agents The devices can retrieve large clots that pharmaceutical agents may not successfully lysemay not successfully lyse
Patients treated with IV tPA may be considered for treatment of Patients treated with IV tPA may be considered for treatment of residual clot with some of these devicesresidual clot with some of these devices
suction-creating saline jets suction-creating saline jets laser energy ultrasound laser energy ultrasound a corkscrew apparatus to treat strokesa corkscrew apparatus to treat strokes The AngioJet systemThe AngioJet system uses saline jets that are directed back into the catheter to uses saline jets that are directed back into the catheter to
create a low-pressure zone around the catheter tip inducing create a low-pressure zone around the catheter tip inducing suction suction
The clot is pulled into the exhaust lumen and removed from the The clot is pulled into the exhaust lumen and removed from the vessel Although US Food and Drug Administration (FDA) has vessel Although US Food and Drug Administration (FDA) has approved this device for use in arteriovenous dialysis grafts and approved this device for use in arteriovenous dialysis grafts and fistulae and for the treatment of coronary arteries saphenous fistulae and for the treatment of coronary arteries saphenous vein grafts and peripheral vessels clinical trials for the vein grafts and peripheral vessels clinical trials for the treatment of acute stroke are no longer in progress treatment of acute stroke are no longer in progress
Most devices are used in cerebral vessels that 2-5 mm
The Latis laser device The Latis laser device used laser energy to ablate clots used laser energy to ablate clots Arteries 2-5 mm in diameter could be Arteries 2-5 mm in diameter could be
treated including the ICA M1 or M2 treated including the ICA M1 or M2 branch of the MCA A1 branch of the branch of the MCA A1 branch of the anterior cerebral artery (ACA) basilar anterior cerebral artery (ACA) basilar artery posterior cerebral artery (PCA) artery posterior cerebral artery (PCA) and vertebral and vertebral
Patients could receive treatment as late Patients could receive treatment as late as 8 hours after symptom onset in the as 8 hours after symptom onset in the anterior circulation and within 24 hours in anterior circulation and within 24 hours in the posterior circulation the posterior circulation
Endovascular Photo Acoustic Endovascular Photo Acoustic Recanalization (EPAR) Recanalization (EPAR)
A laser power source generated energy for the A laser power source generated energy for the systemsystem
The energy was delivered by means of The energy was delivered by means of fiberoptics to the tip of the catheter at the fiberoptics to the tip of the catheter at the treatment sitetreatment site
Absorption of laser light by darkly pigmented Absorption of laser light by darkly pigmented materials (ie the clot) occurred inside the 1-mm materials (ie the clot) occurred inside the 1-mm catheter tipcatheter tip
the system was designed to minimize scattering the system was designed to minimize scattering of laser light of laser light
Absorption converted photo energy to acoustic Absorption converted photo energy to acoustic energy which then emulsified the clot inside the energy which then emulsified the clot inside the catheter tip catheter tip
EKOS ultrasound( the EKOS ultrasound( the Ultrasound Thrombolytic Ultrasound Thrombolytic
Infusion Catheter) Infusion Catheter) combines the use of a distal ultrasound transducer with combines the use of a distal ultrasound transducer with
infusion of a thrombolytic agent through the infusion of a thrombolytic agent through the microcathetermicrocatheter
Ultrasound changes the structure of the clot to Ultrasound changes the structure of the clot to temporarily increase its permeability while providing an temporarily increase its permeability while providing an acoustic pressure gradient to move the drug into the clot acoustic pressure gradient to move the drug into the clot to speed its dissolution to speed its dissolution
The EKOS catheter is placed in the proximal portion of the The EKOS catheter is placed in the proximal portion of the clot clot
After a 2-mg bolus of tPA was injected through the After a 2-mg bolus of tPA was injected through the catheter catheter
the patient received a continuous infusion of IA tPA 03 the patient received a continuous infusion of IA tPA 03 mgmin to a maximum of 20 mg and simultaneous mgmin to a maximum of 20 mg and simultaneous ultrasound transmission for as long as 60 minutes ultrasound transmission for as long as 60 minutes
One patient was treated with a total of 4 units of One patient was treated with a total of 4 units of recombinant reteplase (Retavase) hand-injected over 60 recombinant reteplase (Retavase) hand-injected over 60 minutes minutes
Penumbra system Penumbra system The Penumbra system (Penumbra Inc) provides a dual The Penumbra system (Penumbra Inc) provides a dual
approach to clot extraction using aspiration followed by approach to clot extraction using aspiration followed by clot retrieval with a ring device if needed clot retrieval with a ring device if needed
Mechanical Embolus Removal in Cerebral Ischemia Mechanical Embolus Removal in Cerebral Ischemia (MERCI)(MERCI)
a corkscrew-like apparatus to remove blood clots from a corkscrew-like apparatus to remove blood clots from the brain in patients experiencing an ischemic stroke the brain in patients experiencing an ischemic stroke
The corkscrew itself resides in the catheter tip which The corkscrew itself resides in the catheter tip which shields it from the wall of the vessel until it is ready to be shields it from the wall of the vessel until it is ready to be burrowed into the clot Once lodged in the clot the device burrowed into the clot Once lodged in the clot the device and clot are withdrawn from the vessel and clot are withdrawn from the vessel
Snarelike devicesSnarelike devices Snares such as the Neuronet snare (Guidant Snares such as the Neuronet snare (Guidant
Endovascular Santa Clara CA) have been developed Endovascular Santa Clara CA) have been developed specifically for use in the treatment of strokes specifically for use in the treatment of strokes
These devices are simple in design and do not require the These devices are simple in design and do not require the clot to be amenable to emulsification clot to be amenable to emulsification
X-Sizer deviceX-Sizer device a device with small moving blades at the a device with small moving blades at the
catheter tip catheter tip This device the X-Sizer device (EndiCor Medical This device the X-Sizer device (EndiCor Medical
San Clemente CA) can be used to excise the San Clemente CA) can be used to excise the thrombus and aspirate it thrombus and aspirate it
The device was being evaluated in randomized The device was being evaluated in randomized studies of coronary vessels and in a registry of studies of coronary vessels and in a registry of patients with acute myocardial infarctionpatients with acute myocardial infarction
Although the manufacturer had modified the Although the manufacturer had modified the device for use in cerebral vessels a safety and device for use in cerebral vessels a safety and feasibility study was indefinitely suspended after feasibility study was indefinitely suspended after only 1 patient was treated with the device in only 1 patient was treated with the device in Europe Europe
Suction thrombectomySuction thrombectomy This method of mechanical thrombolysis is one of the This method of mechanical thrombolysis is one of the
simplestsimplest In this readily available technique suction is applied with In this readily available technique suction is applied with
a syringe to remove thrombus in the ICA a syringe to remove thrombus in the ICA It requires no other devicesIt requires no other devices A catheter with a large inner diameter (Brite Tip Cordis A catheter with a large inner diameter (Brite Tip Cordis
Corporation Miami FL) was placed in the symptomatic Corporation Miami FL) was placed in the symptomatic vessel and navigated over a guidewire into the thrombusvessel and navigated over a guidewire into the thrombus
A 60-mL syringe was used to aspirate the thrombus A 60-mL syringe was used to aspirate the thrombus Each patient required angioplasty and stenting of carotid Each patient required angioplasty and stenting of carotid
bifurcation stenosis and received daily aspirin and bifurcation stenosis and received daily aspirin and ticlopidine after the procedure No complications ticlopidine after the procedure No complications occurred occurred
Summary Acute Stroke Summary Acute Stroke ImagingImaging
PhysiologyPhysiology importance collaterals importance collaterals
ndash ndashGrowing role for perfusion Growing role for perfusion assessmentassessment
tPAtPA guidelines amp limitations guidelines amp limitations Signs on CT amp MRSigns on CT amp MR follow physiology follow physiology Stroke trialsStroke trials PWI-DWI mismatch PWI-DWI mismatch
ndash ndashTreat based on physiology not timeTreat based on physiology not time ProtocolsProtocols should be fast and should be fast and
comprehensivecomprehensive
Monitoring of thrombolytic Monitoring of thrombolytic therapytherapy
Thrombin time Measures the availability of functional
fibrinogen Normal thrombin time is 10-14 sec Prolonged when fibrinogen level is below
75-100 mgdl
Half Life of ThrombolyticsHalf Life of ThrombolyticsAgent Administration Half Life
Streptokinase IA 60-80min
Urokinase IAIV 9-12min
rTPA IAIV 6min
Abciximab(Reopro) IAIV 12hour
Aspirin POIV 15-20min
Heparin IVSC 60min
Coumadin PO 15-25 days
Anti Platelet DrugsAnti Platelet DrugsDrug Drug Mechanism Mechanism UsesUsesAspirinAspirin Permanently inhibits Permanently inhibits
COX-1 and COX-2COX-1 and COX-2CADCAD
Stroke-TIAsStroke-TIAs
NSAIDsNSAIDs Reversibly inhibits Reversibly inhibits COX-1COX-1
LimitedLimited
DipyridamoleDipyridamole Inhibits PDE increases Inhibits PDE increases cAMPcAMP
TIAsTIAs
ThenopyridinesThenopyridines
(Ticlopidine(Ticlopidine
ClopidrgrelClopidrgrel))
Inhibits ADP Inhibits ADP
PlatAg PlatAg
TIAsStrokeTIAsStroke
CAD PVDCAD PVD
Abciximab (ReoPro)Abciximab (ReoPro)
Eptifibatide (Integrilin)Eptifibatide (Integrilin)
TirofibanTirofiban
GP IIBIIIA InhibitorsGP IIBIIIA Inhibitors
Stroke- TIAs Stroke- TIAs
MonitoringMonitoring
Bleeding timeBleeding time
Optical aggregometryOptical aggregometry
Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay
Bleeding timeBleeding time
Requires a skin incision (usually made on the ear lobe or Requires a skin incision (usually made on the ear lobe or forearm offorearm of
a depth that results in disruption of capillary loops and a depth that results in disruption of capillary loops and small vessels)small vessels)
AdvantagesAdvantages Universally availableUniversally available Relatively simple techniquesRelatively simple techniques Can be performed bedsideCan be performed bedside
DisadvantagesDisadvantages Insensitive inaccurate non-specific techniqueInsensitive inaccurate non-specific technique
Poorly reproducible (as depends on multiple variables)Poorly reproducible (as depends on multiple variables)
Optical aggregometryOptical aggregometry
Gold standard assay for platelet functionGold standard assay for platelet function Agonist induced aggregation is measuredAgonist induced aggregation is measured Different agonist are available for different Different agonist are available for different
agentsagents However require unique expertise and are not However require unique expertise and are not
universally availableuniversally available Aspirin measured with ADP or AA(gt70 Aspirin measured with ADP or AA(gt70
aggregation so resistance)aggregation so resistance) Clopidogrel( ADP gt 90 aggregation means Clopidogrel( ADP gt 90 aggregation means
resistance) resistance)
Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay
Can be performed bed sideCan be performed bed side Different assay devices with different Different assay devices with different
agonist are used for each of different agonist are used for each of different antiplatelet agents antiplatelet agents
For Aspirin AA is used (result is reported as aspirin For Aspirin AA is used (result is reported as aspirin reaction units [ARU] ARUgt 550 indicates non-reaction units [ARU] ARUgt 550 indicates non-responsiveness)responsiveness)
Verify IIbIIIa assay device uses TRAP as agonist for Verify IIbIIIa assay device uses TRAP as agonist for Abciximab and TirofibanAbciximab and Tirofiban
Practical Applications Practical Applications related to specific related to specific
Neurovascular Neurovascular interventionsinterventions
Acute ischemic StrokeAcute ischemic Stroke When an artery occludes neurons are affected When an artery occludes neurons are affected
differently depending upon the amount of residual blood differently depending upon the amount of residual blood flowflow
Normal cerebral blood flow is greater than 50 mL100 Normal cerebral blood flow is greater than 50 mL100 mgminmgmin
Once blood flow decreases to less than 20 mL100 Once blood flow decreases to less than 20 mL100 mgmin infarction occursmgmin infarction occurs
If blood flow decreases to less than 10 mL100 mgmin If blood flow decreases to less than 10 mL100 mgmin irreversible neuronal death occurs rapidly irreversible neuronal death occurs rapidly
Blood flow between 11 and 20 mL100 mgmin is thought Blood flow between 11 and 20 mL100 mgmin is thought to represent the ischemic penumbra an area where the to represent the ischemic penumbra an area where the cells are functionally silent because of ischemia but are cells are functionally silent because of ischemia but are still able to recover if blood flow is restored still able to recover if blood flow is restored
Many acute stroke therapies are targeted toward Many acute stroke therapies are targeted toward restoring flow or function to the ischemic penumbrarestoring flow or function to the ischemic penumbra
Therapeutic window in Therapeutic window in management of acute Ischemic management of acute Ischemic
StrokeStrokeThe early diagnosis of ischemic stroke is critical to the The early diagnosis of ischemic stroke is critical to the
with only a narrow therapeutic window in the first few with only a narrow therapeutic window in the first few hours following stroke ictushours following stroke ictus
Diagnosis in the first 3 hours postictus provides the Diagnosis in the first 3 hours postictus provides the opportunity for intravenous or intraarterial thrombolysis opportunity for intravenous or intraarterial thrombolysis and intra-arterial clot mechanical treatment which and intra-arterial clot mechanical treatment which improve the outcome improve the outcome
Diagnosis in the time period between 3 and 6 hours Diagnosis in the time period between 3 and 6 hours provides an opportunity for intra-arterial thrombolysis provides an opportunity for intra-arterial thrombolysis and mechanical treatment and mechanical treatment
Involvement of the posterior circulation especially the Involvement of the posterior circulation especially the basilar artery is treated by some regardless of time of basilar artery is treated by some regardless of time of onset or up until 12 to 24 hours in some practices This is onset or up until 12 to 24 hours in some practices This is related to the potentially high mortality and morbidity related to the potentially high mortality and morbidity associated with basilar artery thrombosisassociated with basilar artery thrombosis
Infarct evaluation on angiographyInfarct evaluation on angiography(CT angiography and catheter (CT angiography and catheter
angiography)angiography)CTA is an excellent first-line examination for CTA is an excellent first-line examination for
evaluation of the head and neck arteries evaluation of the head and neck arteries In comparison with catheter angiography In comparison with catheter angiography
what it gives up in resolution and dynamic what it gives up in resolution and dynamic properties it makes up for with rapid properties it makes up for with rapid acquisition of a 3-D dataset and the potential acquisition of a 3-D dataset and the potential for assessment of whole-brain perfusion and for assessment of whole-brain perfusion and better parenchymal evaluationbetter parenchymal evaluation
Moreover CTA illustrates not only arterial Moreover CTA illustrates not only arterial stenosis or occlusion but also the vessel wall stenosis or occlusion but also the vessel wall This factor is most important for evaluation of This factor is most important for evaluation of intramural dissection and thrombosed intramural dissection and thrombosed aneurysms which may both complicate aneurysms which may both complicate evaluation of stroke patientsevaluation of stroke patients
Early angiographic signs of strokes Early angiographic signs of strokes both CTA both CTA and DSA and DSA
Vessel occlusion or cutoff related to Vessel occlusion or cutoff related to thromboembolithromboemboli
aneurysms aneurysms arterial dissection arterial dissection Meniscus or flattened shape to clot Meniscus or flattened shape to clot
(recent) versus reverse meniscus (older)(recent) versus reverse meniscus (older) tram track (nonocclusive or recanalized tram track (nonocclusive or recanalized
clot) clot) delayed (antegrade) flow (manifest as delayed (antegrade) flow (manifest as
decreased whole-brain perfusion on CTA)decreased whole-brain perfusion on CTA) retrograde collateral flowretrograde collateral flow
Non-occlusive left MCA thrombus on 3-D imaging performed from CTA source data and was confirmed at catheter angiography
Therapy to be started within a 6-hr Therapy to be started within a 6-hr time to treatment (TTT) window time to treatment (TTT) window (while in case of IV thrombolysis (while in case of IV thrombolysis therapy to be started with in 3hrs)therapy to be started with in 3hrs)
Exclusion criteria Exclusion criteria Rapidly improving neurologic deficit or Rapidly improving neurologic deficit or Sustained blood pressure of gt180100 Sustained blood pressure of gt180100 Hemorrhage is detected on CTHemorrhage is detected on CT Infarct involving gt more than 13 rd Infarct involving gt more than 13 rd
territory of MCAterritory of MCA MRADWI-Perfusion mismatchlt 20MRADWI-Perfusion mismatchlt 20 Definite hypodensity on CTDefinite hypodensity on CT
Intra-arterial Thrombolysis
Fibrinolytics + AntiplateletsFibrinolytics + Antiplatelets
PlasminogenPlasminogen activators through fibrinolysis exposes activators through fibrinolysis exposes free thrombin and paradoxically stimulatesfree thrombin and paradoxically stimulates platelet platelet aggregation which leads to formation of aaggregation which leads to formation of a platelet platelet thrombus (white clot) thrombus (white clot)
This new thrombus is relatively resistant to This new thrombus is relatively resistant to fibrinolyticsfibrinolytics
So new regimen in case of acute stroke isSo new regimen in case of acute stroke is fibrinolytics + antiplatelet drugsfibrinolytics + antiplatelet drugs
rtPA + IIbIIIa inhibitors( tirofiban rtPA + IIbIIIa inhibitors( tirofiban abciximab) orabciximab) or
Urokinase + IIbIIIa Urokinase + IIbIIIa inhibitors( tirofiban abciximab)inhibitors( tirofiban abciximab)
Intra-arterial Thrombolysis Tirofiban (04 microgkgmin bolus for 3 min followed by Tirofiban (04 microgkgmin bolus for 3 min followed by
0125 ugkgmin)0125 ugkgmin)
++
Heparin (2000ndash3000 IU bolus followed by Heparin (2000ndash3000 IU bolus followed by 1000 IUhour infusion 1000 IUhour infusion
with ACT maintained bw 200-300) throughout the with ACT maintained bw 200-300) throughout the interventional procedure and for 24ndash48 hours thereafter when interventional procedure and for 24ndash48 hours thereafter when there is neither intraprocedural bleeding nor suspicion of there is neither intraprocedural bleeding nor suspicion of increased risk of bleeding increased risk of bleeding
Maximum dose of Urokinase Maximum dose of Urokinase Anterior circulation stroke - 500000 IU (mean 400000 Anterior circulation stroke - 500000 IU (mean 400000
IU range 300000ndash500000 IU)IU range 300000ndash500000 IU) Posterior circulation stroke -1000000 IU (mean 837000 Posterior circulation stroke -1000000 IU (mean 837000
IU range 300000ndash1000000 IU)IU range 300000ndash1000000 IU)American Journal of NeuroradiologyAmerican Journal of Neuroradiology 262595-2601 2005262595-2601 2005
Intravenous ThrombolysisIntravenous Thrombolysis
The first method to restore cerebral The first method to restore cerebral perfusion is clot lysis with the goal perfusion is clot lysis with the goal of re-establishing blood flow to the of re-establishing blood flow to the affected tissue affected tissue
IV thrombolysis rt-PA is the only IV thrombolysis rt-PA is the only FDA- approved treatment for AIS FDA- approved treatment for AIS
Fibrinolysis is enhanced powerfully Fibrinolysis is enhanced powerfully by rt-PAby rt-PA
Intravenous rTPA Intravenous rTPA administration administration protocolprotocol
Total dose of rt-PA 09 mgkg (maximum dose Total dose of rt-PA 09 mgkg (maximum dose 90 mg)90 mg)
Give 10 as initial IV bolusGive 10 as initial IV bolus Infuse remainder over 1 hourInfuse remainder over 1 hour Admit patient to an ICU or stroke unit for Admit patient to an ICU or stroke unit for
monitoringmonitoring Neurologic assessments every 15 minutes Neurologic assessments every 15 minutes
during infusion then every 30 minutes for next during infusion then every 30 minutes for next 6 hours then every hour until 24hours after 6 hours then every hour until 24hours after treatmenttreatment
Favorable Outcome vs Treatment Time Favorable Outcome vs Treatment Time with IV rTPAwith IV rTPA
Protocol limit = 3 hrs
Benefit ~ 45 hrs
Thromboembolism During coilingThromboembolism During coiling Most feared and frequent complication Most feared and frequent complication Reported incidence - Approx 7 Reported incidence - Approx 7 SourcesSources of Thromboembolism are of Thromboembolism are
- Clots at the aneurysmal neck during or immediately- Clots at the aneurysmal neck during or immediately after after embolization embolization
- Thrombus forming on catheters during- Thrombus forming on catheters during proceduresprocedures
- Stenosis of an adjacent artery dt coil mass- Stenosis of an adjacent artery dt coil mass or herniationor herniation
- Migration of intraaneurysmal- Migration of intraaneurysmal thrombus during coil thrombus during coil placement placement
- Slow flow dt vasospasm - Slow flow dt vasospasm
- Rare and unlikely causes are hypercoagulable- Rare and unlikely causes are hypercoagulable state such state such as antiphospholipid antibody syndrome or due to HITas antiphospholipid antibody syndrome or due to HIT
Occur more often with wide-necked aneurysms (dt Occur more often with wide-necked aneurysms (dt increased exposed surface area of thrombogenic coil increased exposed surface area of thrombogenic coil material)material)
Current regimen of endovascular Current regimen of endovascular managementmanagement
The The glycoprotein IIbIIIa antagonist tirofiban glycoprotein IIbIIIa antagonist tirofiban (04 (04 microgkgmin bolus for 30 minutes followed by infusion of microgkgmin bolus for 30 minutes followed by infusion of 0125 ugkgmin until the thrombus dissolved) 0125 ugkgmin until the thrombus dissolved)
Intraarterial thrombolysis with Intraarterial thrombolysis with urokinase or r- TPA urokinase or r- TPA increase of intravenous (IV) heparin (measured by increase of intravenous (IV) heparin (measured by
ACT) ACT) Intravenous aspirin Intravenous aspirin
Coil-related platelet aggregation (white clot) is Coil-related platelet aggregation (white clot) is unlikely to respond to fibrinolytics but has a high risk unlikely to respond to fibrinolytics but has a high risk of hemorrhage (In ISAT) all 5 patients who had of hemorrhage (In ISAT) all 5 patients who had received thrombolytic therapy with tPA to treat a received thrombolytic therapy with tPA to treat a thromboembolic complication after endovascular thromboembolic complication after endovascular treatment rebleed and all of these patients died)treatment rebleed and all of these patients died)
IntracranialIntracranial Stenting Stenting Metallic foreign body such as stent will accumulate Metallic foreign body such as stent will accumulate
thrombus in the absence of platelet inhibitionthrombus in the absence of platelet inhibition Antiplatelet drugs are important to prevent peri or Antiplatelet drugs are important to prevent peri or
post-interventional thromboembolic eventspost-interventional thromboembolic events Optimal treatment regimens has not been determined Optimal treatment regimens has not been determined
but usually but usually Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-
procedureprocedureOrOr
Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on
morning of proceduremorning of procedure
If need to use stent is not pre-planned thanIf need to use stent is not pre-planned than
Abciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkgAbciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkg IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)
Glycoprotein IIbIIIa inhibitor are not used routinely during elective Glycoprotein IIbIIIa inhibitor are not used routinely during elective stenting procedure dt increased risk of ICH stenting procedure dt increased risk of ICH
Carotid StentingCarotid Stenting
Pre-procedurePre-procedure
Double Antiplatelet therapy is routinely given Double Antiplatelet therapy is routinely given beginning at least 3beginning at least 3
days before the proceduredays before the procedure
Aspirin 325mgd+Clopidogrel 75mgdAspirin 325mgd+Clopidogrel 75mgd During procedureDuring procedure
Heparin is given with target clotting time of 250-Heparin is given with target clotting time of 250-300sec300sec
Post-procedure Post-procedure
Aspirin 325mg is continued indefinitely and Aspirin 325mg is continued indefinitely and
Clopidogrel 75mgd for at least 6 weeks Clopidogrel 75mgd for at least 6 weeks
Inclusion criteria for Local ThrombolysisInclusion criteria for Local Thrombolysis a)a) Patients in severe clinical grade on admission Patients in severe clinical grade on admission
with evidence of dural venous sinus with evidence of dural venous sinus thrombosis and restrictive venous outflow on thrombosis and restrictive venous outflow on cerebral angiogramcerebral angiogram
b)b) Patients in clinical grade 3 worsening on Patients in clinical grade 3 worsening on heparin therapy Restriction to venous heparin therapy Restriction to venous outflow was defined as an increase in brain outflow was defined as an increase in brain circulation time gt 12 s delay in the drainage circulation time gt 12 s delay in the drainage of cortical veins with cortical veins hanging of cortical veins with cortical veins hanging in spacein space
Treatment Options for Venous Thrombosis
CT Grading for Venous ThrombosisCT Grading for Venous Thrombosis Grade I no parenchymal change Grade I no parenchymal change
(hyperdense (hyperdense sinuses cortical veins empty sinuses cortical veins empty delta sign)delta sign)
Grade II non hemorrhagic venous infarct Grade II non hemorrhagic venous infarct without mass effect without mass effect
Grade III non-hemorrhagic infarct with Grade III non-hemorrhagic infarct with mass effectmass effect
Grade IV hemorrhagic venous infarct (max Grade IV hemorrhagic venous infarct (max diameter lt 3 cm) with no mass effectdiameter lt 3 cm) with no mass effect
Grade V hemorrhagic venous infarct (max Grade V hemorrhagic venous infarct (max diameter gt 3 cm) with mass effect diameter gt 3 cm) with mass effect
Local ThrombolysisLocal Thrombolysis
Femoral Jugular access was secured and a guiding Femoral Jugular access was secured and a guiding catheter was placed in the jugular bulb catheter was placed in the jugular bulb Mechanical Mechanical clot maceration clot maceration was done with the guidewire was done with the guidewire following which a microcatheter (was navigated and following which a microcatheter (was navigated and placed in the thrombosed segment of sinus confirmed placed in the thrombosed segment of sinus confirmed on a selective venogram on a selective venogram
Urokinase infusion Bolus dose of 2-6 lacs followed Urokinase infusion Bolus dose of 2-6 lacs followed by 60000 to 100000 units per hour along with by 60000 to 100000 units per hour along with periodic check venogram Along with maintenance periodic check venogram Along with maintenance systemic infusion of Heparinsystemic infusion of Heparin Other agents such as Other agents such as streptokinase altepase or rTPAstreptokinase altepase or rTPA can be also used can be also used
After thrombolysis patient should subjected to oral After thrombolysis patient should subjected to oral anticoagulation for six monthsanticoagulation for six months
Low-molecular-weight Low-molecular-weight heparinheparin
PharmacologyPharmacologyLMWH as its name suggests is a glycosaminoglycan that is approximatelyLMWH as its name suggests is a glycosaminoglycan that is approximately
one third the molecular weight of UFH It is derived from UFH through one third the molecular weight of UFH It is derived from UFH through variousvarious
depolymerization processes LMWH binds to antithrombin which in turn depolymerization processes LMWH binds to antithrombin which in turn
Neutralizes actors Xa and IIa Because LMWH lacks many of the longer Neutralizes actors Xa and IIa Because LMWH lacks many of the longer chains chains
required for binding to thrombin it has less ability to neutralize thrombin required for binding to thrombin it has less ability to neutralize thrombin
relativeto its ability to neutralize factor Xa LMWH also has less relativeto its ability to neutralize factor Xa LMWH also has less nonspecific nonspecific
binding to other proteins There is greater bioavailability with more binding to other proteins There is greater bioavailability with more predictable predictable
pharmacokinetics that eliminates the need for monitoring The smaller pharmacokinetics that eliminates the need for monitoring The smaller size also size also
allows for enhanced subcutaneous absorption when compared with UFHallows for enhanced subcutaneous absorption when compared with UFH
Three LMWH preparations are Three LMWH preparations are currently approved for use in the currently approved for use in the United States (1) enoxaparin (2) United States (1) enoxaparin (2) dalteparin and (3) tinzaparin dalteparin and (3) tinzaparin
They are all administered They are all administered subcutaneously at intervals of either subcutaneously at intervals of either once or twice daily for both once or twice daily for both prophylaxis and treatment dosesprophylaxis and treatment doses
Few Experiences of Few Experiences of ThrombolysisThrombolysis
Vickey 25 Yrs male patient presented Vickey 25 Yrs male patient presented with 12with 12thth day HO severe headache with day HO severe headache with right sided hemiplegiaright sided hemiplegia
MRI shows thrombosis of the superior MRI shows thrombosis of the superior sagittal left transverse left sigmoid sagittal left transverse left sigmoid sinuses and cortical veins in the fronto-sinuses and cortical veins in the fronto-parietal regions with eo haemorrhagic parietal regions with eo haemorrhagic infarct in the left cerebral hemisphere infarct in the left cerebral hemisphere with mass effect( Grade ndashV)with mass effect( Grade ndashV)
Sashi Srivastava 64 yrs FSashi Srivastava 64 yrs F In a follow up case of MRD with infra-renal In a follow up case of MRD with infra-renal
aortic abdominal and bilateral renal artery aortic abdominal and bilateral renal artery thrombosis renal angiogram shows filling thrombosis renal angiogram shows filling defects in the right Renal artery defects in the right Renal artery
Initially Renal angioplasty was done Initially Renal angioplasty was done Following angioplasty few thrombi are seem Following angioplasty few thrombi are seem to extends into the segmental branches and to extends into the segmental branches and causing blockage So Thrombolysis was causing blockage So Thrombolysis was plane to dissolve the run-out thrombi with plane to dissolve the run-out thrombi with urokinase urokinase
Rakesh 34yrsMRakesh 34yrsM Left SFA pseudoaneurysm with Left SFA pseudoaneurysm with
Covered stent placementCovered stent placement Pre operative antiplatelets with post Pre operative antiplatelets with post
procedure heparin Tirofiban procedure heparin Tirofiban followed by aspirin and clopidogrel followed by aspirin and clopidogrel were usedwere used
IAT may be a treatment option for selected patients IAT may be a treatment option for selected patients Possible selection criteria include Possible selection criteria include
presentation between 3 and 6 hours from symptom onsetpresentation between 3 and 6 hours from symptom onset major cerebral artery occlusion major cerebral artery occlusion severe neurologic deficits severe neurologic deficits high risk of systemic hemorrhage with IV rt-PA (eg recent high risk of systemic hemorrhage with IV rt-PA (eg recent
surgery) surgery) The MERCI (Mechanical Embolus Removal in Cerebral The MERCI (Mechanical Embolus Removal in Cerebral
Ischemia) retrievalIschemia) retrieval system system
Has been FDA-approved for recanalizing acutely occluded Has been FDA-approved for recanalizing acutely occluded cerebral arteries cerebral arteries
In the Multi-MERCI study patients who did not improve In the Multi-MERCI study patients who did not improve immediately after IV rt-PA underwent mechanical immediately after IV rt-PA underwent mechanical embolectomy within 8 hours of symptom onset embolectomy within 8 hours of symptom onset
Partial or complete recanalization occurred in 74 of Partial or complete recanalization occurred in 74 of patientspatients
with a symptomatic intracerebral hemorrhage (sICH) rate of with a symptomatic intracerebral hemorrhage (sICH) rate of 67 67
Mechanical embolectomy with the MERCI retriever may be a Mechanical embolectomy with the MERCI retriever may be a feasible and safe option for patients after IV rt-PAfeasible and safe option for patients after IV rt-PA
Penumbra stroke systemPenumbra stroke system This device combines two methods of clot This device combines two methods of clot
extraction aspiration and mechanical extraction aspiration and mechanical extraction extraction
First the clot is aspirated then a thrombus First the clot is aspirated then a thrombus removal ring can be used if necessary to removal ring can be used if necessary to remove remaining clot remove remaining clot
successful recanalizing 82successful recanalizing 82 Bridging therapyBridging therapy
06 mgkg IV rt-PA followed by IAT with IA rt-06 mgkg IV rt-PA followed by IAT with IA rt-PA (up to 20 mg)PA (up to 20 mg)
achieved a higher recanalization rateachieved a higher recanalization rate
Criteria for thrombolysis with rTPACriteria for thrombolysis with rTPA
Inclusion criteriaInclusion criteria Clinical signs and symptoms consistent with ischemic Clinical signs and symptoms consistent with ischemic
strokestroke Patient last seen normal within 3 hoursPatient last seen normal within 3 hours Measurable neurologic deficitMeasurable neurologic deficit
Exclusion criteriaExclusion criteria Any hemorrhage on neuroimaging (CT or MRI)Any hemorrhage on neuroimaging (CT or MRI) Symptoms suggestive of subarachnoid hemorrhageSymptoms suggestive of subarachnoid hemorrhage Seizure at stroke onset that is thought to contribute to Seizure at stroke onset that is thought to contribute to
neurologic deficitneurologic deficit Hypodensity greater than one third cerebral hemisphere Hypodensity greater than one third cerebral hemisphere
on CTon CT SBP greater than 185 mm Hg or DBP greater than 110 SBP greater than 185 mm Hg or DBP greater than 110
mm Hgmm Hg International normalized ratio (INR) greater than 17International normalized ratio (INR) greater than 17
Ischemic Stroke Ischemic Stroke Treatment ndash 2006Treatment ndash 2006
IV tissue plasminogen activator (tPA)IV tissue plasminogen activator (tPA) ndash ndash Only FDA-approved acute stroke drugOnly FDA-approved acute stroke drug ndash ndash 3 hour treatment window3 hour treatment window
MERCI - Concentric clot retrieval MERCI - Concentric clot retrieval devicedevice ndash ndash Rescue therapy - approved 2004Rescue therapy - approved 2004 ndash ndash Device approval (not outcomes-based)Device approval (not outcomes-based)
Off label approachesOff label approaches ndash ndash IV tPA after 3 hoursIV tPA after 3 hours ndash ndash IV-IA tPA sequential strategiesIV-IA tPA sequential strategies ndash ndash IA tPA clot angioplasty fragmentationIA tPA clot angioplasty fragmentation ndash ndash Ultrasound-assisted tPA lysisUltrasound-assisted tPA lysis
rt-PA Trials NINDSrt-PA Trials NINDS
Acute stroke - 624 patientsAcute stroke - 624 patients Treat within 3 hrsTreat within 3 hrs Intravenous 09 mgkg rt-PA vs placeboIntravenous 09 mgkg rt-PA vs placebo Hemorrhage 64 tPA 06 placeboHemorrhage 64 tPA 06 placebo Neurologic recovery better with tPA 30 Neurologic recovery better with tPA 30
more like to have minimal or no disabilitymore like to have minimal or no disability
First proven approved treatment for First proven approved treatment for strokestroke
Limitations of tPALimitations of tPA Only 4 of acute strokes receive tPAOnly 4 of acute strokes receive tPA (Kleindorfer et al Stroke 2004 35 e27-e29)(Kleindorfer et al Stroke 2004 35 e27-e29)
Only 22 of patients present within 3 hoursOnly 22 of patients present within 3 hours1048707 1048707 51 of these ineligible due to51 of these ineligible due to
bull bull Mild severityMild severity bull bull Medical or surgical historyMedical or surgical history bull bull Blood testsBlood tests
Sustained recanalization only 13Sustained recanalization only 13 (Alexandrov et al NEJM 2004 351 2170-8)(Alexandrov et al NEJM 2004 351 2170-8)
Concern for hemorrhageConcern for hemorrhage tPA potentiates apoptotic injury tPA potentiates apoptotic injury (Liu et al Nature Med 2004 101379-83)(Liu et al Nature Med 2004 101379-83)
PROACT II IA Lysis TrialPROACT II IA Lysis Trial Baseline 24 hours 8 days
Baseline 60 minutes 120 minutes
9mg IAProurokinase
Desmoteplase Trials DEDAS Desmoteplase Trials DEDAS DIASDIAS
Trial OverviewTrial Overview Double blind randomized placebo Double blind randomized placebo
controlled trialscontrolled trials IV delivery 3-9 hour time windowIV delivery 3-9 hour time window Plasminogen activator ndash from Plasminogen activator ndash from vampire bat vampire bat
salivasaliva Selection based on PWI-DWI MismatchSelection based on PWI-DWI Mismatch
MRI InclusionMRI Inclusion PWI defect at least 2 cm AND ~20 larger PWI defect at least 2 cm AND ~20 larger
than DWIthan DWI PWI should be obvious even visible on PWI should be obvious even visible on
raw imagesraw imagesMRI ExclusionMRI Exclusion
DWI gt 13 MCADWI gt 13 MCA MRA ICA occlusionMRA ICA occlusion
Desmoteplase ndash DIAS Desmoteplase ndash DIAS ResultsResults
Mechanical Thrombolysis Mechanical Thrombolysis devicesdevices
mechanical thrombolysis potentially extends the treatment mechanical thrombolysis potentially extends the treatment window because they act promptly at the site of the thrombuswindow because they act promptly at the site of the thrombus
The devices can retrieve large clots that pharmaceutical agents The devices can retrieve large clots that pharmaceutical agents may not successfully lysemay not successfully lyse
Patients treated with IV tPA may be considered for treatment of Patients treated with IV tPA may be considered for treatment of residual clot with some of these devicesresidual clot with some of these devices
suction-creating saline jets suction-creating saline jets laser energy ultrasound laser energy ultrasound a corkscrew apparatus to treat strokesa corkscrew apparatus to treat strokes The AngioJet systemThe AngioJet system uses saline jets that are directed back into the catheter to uses saline jets that are directed back into the catheter to
create a low-pressure zone around the catheter tip inducing create a low-pressure zone around the catheter tip inducing suction suction
The clot is pulled into the exhaust lumen and removed from the The clot is pulled into the exhaust lumen and removed from the vessel Although US Food and Drug Administration (FDA) has vessel Although US Food and Drug Administration (FDA) has approved this device for use in arteriovenous dialysis grafts and approved this device for use in arteriovenous dialysis grafts and fistulae and for the treatment of coronary arteries saphenous fistulae and for the treatment of coronary arteries saphenous vein grafts and peripheral vessels clinical trials for the vein grafts and peripheral vessels clinical trials for the treatment of acute stroke are no longer in progress treatment of acute stroke are no longer in progress
Most devices are used in cerebral vessels that 2-5 mm
The Latis laser device The Latis laser device used laser energy to ablate clots used laser energy to ablate clots Arteries 2-5 mm in diameter could be Arteries 2-5 mm in diameter could be
treated including the ICA M1 or M2 treated including the ICA M1 or M2 branch of the MCA A1 branch of the branch of the MCA A1 branch of the anterior cerebral artery (ACA) basilar anterior cerebral artery (ACA) basilar artery posterior cerebral artery (PCA) artery posterior cerebral artery (PCA) and vertebral and vertebral
Patients could receive treatment as late Patients could receive treatment as late as 8 hours after symptom onset in the as 8 hours after symptom onset in the anterior circulation and within 24 hours in anterior circulation and within 24 hours in the posterior circulation the posterior circulation
Endovascular Photo Acoustic Endovascular Photo Acoustic Recanalization (EPAR) Recanalization (EPAR)
A laser power source generated energy for the A laser power source generated energy for the systemsystem
The energy was delivered by means of The energy was delivered by means of fiberoptics to the tip of the catheter at the fiberoptics to the tip of the catheter at the treatment sitetreatment site
Absorption of laser light by darkly pigmented Absorption of laser light by darkly pigmented materials (ie the clot) occurred inside the 1-mm materials (ie the clot) occurred inside the 1-mm catheter tipcatheter tip
the system was designed to minimize scattering the system was designed to minimize scattering of laser light of laser light
Absorption converted photo energy to acoustic Absorption converted photo energy to acoustic energy which then emulsified the clot inside the energy which then emulsified the clot inside the catheter tip catheter tip
EKOS ultrasound( the EKOS ultrasound( the Ultrasound Thrombolytic Ultrasound Thrombolytic
Infusion Catheter) Infusion Catheter) combines the use of a distal ultrasound transducer with combines the use of a distal ultrasound transducer with
infusion of a thrombolytic agent through the infusion of a thrombolytic agent through the microcathetermicrocatheter
Ultrasound changes the structure of the clot to Ultrasound changes the structure of the clot to temporarily increase its permeability while providing an temporarily increase its permeability while providing an acoustic pressure gradient to move the drug into the clot acoustic pressure gradient to move the drug into the clot to speed its dissolution to speed its dissolution
The EKOS catheter is placed in the proximal portion of the The EKOS catheter is placed in the proximal portion of the clot clot
After a 2-mg bolus of tPA was injected through the After a 2-mg bolus of tPA was injected through the catheter catheter
the patient received a continuous infusion of IA tPA 03 the patient received a continuous infusion of IA tPA 03 mgmin to a maximum of 20 mg and simultaneous mgmin to a maximum of 20 mg and simultaneous ultrasound transmission for as long as 60 minutes ultrasound transmission for as long as 60 minutes
One patient was treated with a total of 4 units of One patient was treated with a total of 4 units of recombinant reteplase (Retavase) hand-injected over 60 recombinant reteplase (Retavase) hand-injected over 60 minutes minutes
Penumbra system Penumbra system The Penumbra system (Penumbra Inc) provides a dual The Penumbra system (Penumbra Inc) provides a dual
approach to clot extraction using aspiration followed by approach to clot extraction using aspiration followed by clot retrieval with a ring device if needed clot retrieval with a ring device if needed
Mechanical Embolus Removal in Cerebral Ischemia Mechanical Embolus Removal in Cerebral Ischemia (MERCI)(MERCI)
a corkscrew-like apparatus to remove blood clots from a corkscrew-like apparatus to remove blood clots from the brain in patients experiencing an ischemic stroke the brain in patients experiencing an ischemic stroke
The corkscrew itself resides in the catheter tip which The corkscrew itself resides in the catheter tip which shields it from the wall of the vessel until it is ready to be shields it from the wall of the vessel until it is ready to be burrowed into the clot Once lodged in the clot the device burrowed into the clot Once lodged in the clot the device and clot are withdrawn from the vessel and clot are withdrawn from the vessel
Snarelike devicesSnarelike devices Snares such as the Neuronet snare (Guidant Snares such as the Neuronet snare (Guidant
Endovascular Santa Clara CA) have been developed Endovascular Santa Clara CA) have been developed specifically for use in the treatment of strokes specifically for use in the treatment of strokes
These devices are simple in design and do not require the These devices are simple in design and do not require the clot to be amenable to emulsification clot to be amenable to emulsification
X-Sizer deviceX-Sizer device a device with small moving blades at the a device with small moving blades at the
catheter tip catheter tip This device the X-Sizer device (EndiCor Medical This device the X-Sizer device (EndiCor Medical
San Clemente CA) can be used to excise the San Clemente CA) can be used to excise the thrombus and aspirate it thrombus and aspirate it
The device was being evaluated in randomized The device was being evaluated in randomized studies of coronary vessels and in a registry of studies of coronary vessels and in a registry of patients with acute myocardial infarctionpatients with acute myocardial infarction
Although the manufacturer had modified the Although the manufacturer had modified the device for use in cerebral vessels a safety and device for use in cerebral vessels a safety and feasibility study was indefinitely suspended after feasibility study was indefinitely suspended after only 1 patient was treated with the device in only 1 patient was treated with the device in Europe Europe
Suction thrombectomySuction thrombectomy This method of mechanical thrombolysis is one of the This method of mechanical thrombolysis is one of the
simplestsimplest In this readily available technique suction is applied with In this readily available technique suction is applied with
a syringe to remove thrombus in the ICA a syringe to remove thrombus in the ICA It requires no other devicesIt requires no other devices A catheter with a large inner diameter (Brite Tip Cordis A catheter with a large inner diameter (Brite Tip Cordis
Corporation Miami FL) was placed in the symptomatic Corporation Miami FL) was placed in the symptomatic vessel and navigated over a guidewire into the thrombusvessel and navigated over a guidewire into the thrombus
A 60-mL syringe was used to aspirate the thrombus A 60-mL syringe was used to aspirate the thrombus Each patient required angioplasty and stenting of carotid Each patient required angioplasty and stenting of carotid
bifurcation stenosis and received daily aspirin and bifurcation stenosis and received daily aspirin and ticlopidine after the procedure No complications ticlopidine after the procedure No complications occurred occurred
Summary Acute Stroke Summary Acute Stroke ImagingImaging
PhysiologyPhysiology importance collaterals importance collaterals
ndash ndashGrowing role for perfusion Growing role for perfusion assessmentassessment
tPAtPA guidelines amp limitations guidelines amp limitations Signs on CT amp MRSigns on CT amp MR follow physiology follow physiology Stroke trialsStroke trials PWI-DWI mismatch PWI-DWI mismatch
ndash ndashTreat based on physiology not timeTreat based on physiology not time ProtocolsProtocols should be fast and should be fast and
comprehensivecomprehensive
Half Life of ThrombolyticsHalf Life of ThrombolyticsAgent Administration Half Life
Streptokinase IA 60-80min
Urokinase IAIV 9-12min
rTPA IAIV 6min
Abciximab(Reopro) IAIV 12hour
Aspirin POIV 15-20min
Heparin IVSC 60min
Coumadin PO 15-25 days
Anti Platelet DrugsAnti Platelet DrugsDrug Drug Mechanism Mechanism UsesUsesAspirinAspirin Permanently inhibits Permanently inhibits
COX-1 and COX-2COX-1 and COX-2CADCAD
Stroke-TIAsStroke-TIAs
NSAIDsNSAIDs Reversibly inhibits Reversibly inhibits COX-1COX-1
LimitedLimited
DipyridamoleDipyridamole Inhibits PDE increases Inhibits PDE increases cAMPcAMP
TIAsTIAs
ThenopyridinesThenopyridines
(Ticlopidine(Ticlopidine
ClopidrgrelClopidrgrel))
Inhibits ADP Inhibits ADP
PlatAg PlatAg
TIAsStrokeTIAsStroke
CAD PVDCAD PVD
Abciximab (ReoPro)Abciximab (ReoPro)
Eptifibatide (Integrilin)Eptifibatide (Integrilin)
TirofibanTirofiban
GP IIBIIIA InhibitorsGP IIBIIIA Inhibitors
Stroke- TIAs Stroke- TIAs
MonitoringMonitoring
Bleeding timeBleeding time
Optical aggregometryOptical aggregometry
Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay
Bleeding timeBleeding time
Requires a skin incision (usually made on the ear lobe or Requires a skin incision (usually made on the ear lobe or forearm offorearm of
a depth that results in disruption of capillary loops and a depth that results in disruption of capillary loops and small vessels)small vessels)
AdvantagesAdvantages Universally availableUniversally available Relatively simple techniquesRelatively simple techniques Can be performed bedsideCan be performed bedside
DisadvantagesDisadvantages Insensitive inaccurate non-specific techniqueInsensitive inaccurate non-specific technique
Poorly reproducible (as depends on multiple variables)Poorly reproducible (as depends on multiple variables)
Optical aggregometryOptical aggregometry
Gold standard assay for platelet functionGold standard assay for platelet function Agonist induced aggregation is measuredAgonist induced aggregation is measured Different agonist are available for different Different agonist are available for different
agentsagents However require unique expertise and are not However require unique expertise and are not
universally availableuniversally available Aspirin measured with ADP or AA(gt70 Aspirin measured with ADP or AA(gt70
aggregation so resistance)aggregation so resistance) Clopidogrel( ADP gt 90 aggregation means Clopidogrel( ADP gt 90 aggregation means
resistance) resistance)
Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay
Can be performed bed sideCan be performed bed side Different assay devices with different Different assay devices with different
agonist are used for each of different agonist are used for each of different antiplatelet agents antiplatelet agents
For Aspirin AA is used (result is reported as aspirin For Aspirin AA is used (result is reported as aspirin reaction units [ARU] ARUgt 550 indicates non-reaction units [ARU] ARUgt 550 indicates non-responsiveness)responsiveness)
Verify IIbIIIa assay device uses TRAP as agonist for Verify IIbIIIa assay device uses TRAP as agonist for Abciximab and TirofibanAbciximab and Tirofiban
Practical Applications Practical Applications related to specific related to specific
Neurovascular Neurovascular interventionsinterventions
Acute ischemic StrokeAcute ischemic Stroke When an artery occludes neurons are affected When an artery occludes neurons are affected
differently depending upon the amount of residual blood differently depending upon the amount of residual blood flowflow
Normal cerebral blood flow is greater than 50 mL100 Normal cerebral blood flow is greater than 50 mL100 mgminmgmin
Once blood flow decreases to less than 20 mL100 Once blood flow decreases to less than 20 mL100 mgmin infarction occursmgmin infarction occurs
If blood flow decreases to less than 10 mL100 mgmin If blood flow decreases to less than 10 mL100 mgmin irreversible neuronal death occurs rapidly irreversible neuronal death occurs rapidly
Blood flow between 11 and 20 mL100 mgmin is thought Blood flow between 11 and 20 mL100 mgmin is thought to represent the ischemic penumbra an area where the to represent the ischemic penumbra an area where the cells are functionally silent because of ischemia but are cells are functionally silent because of ischemia but are still able to recover if blood flow is restored still able to recover if blood flow is restored
Many acute stroke therapies are targeted toward Many acute stroke therapies are targeted toward restoring flow or function to the ischemic penumbrarestoring flow or function to the ischemic penumbra
Therapeutic window in Therapeutic window in management of acute Ischemic management of acute Ischemic
StrokeStrokeThe early diagnosis of ischemic stroke is critical to the The early diagnosis of ischemic stroke is critical to the
with only a narrow therapeutic window in the first few with only a narrow therapeutic window in the first few hours following stroke ictushours following stroke ictus
Diagnosis in the first 3 hours postictus provides the Diagnosis in the first 3 hours postictus provides the opportunity for intravenous or intraarterial thrombolysis opportunity for intravenous or intraarterial thrombolysis and intra-arterial clot mechanical treatment which and intra-arterial clot mechanical treatment which improve the outcome improve the outcome
Diagnosis in the time period between 3 and 6 hours Diagnosis in the time period between 3 and 6 hours provides an opportunity for intra-arterial thrombolysis provides an opportunity for intra-arterial thrombolysis and mechanical treatment and mechanical treatment
Involvement of the posterior circulation especially the Involvement of the posterior circulation especially the basilar artery is treated by some regardless of time of basilar artery is treated by some regardless of time of onset or up until 12 to 24 hours in some practices This is onset or up until 12 to 24 hours in some practices This is related to the potentially high mortality and morbidity related to the potentially high mortality and morbidity associated with basilar artery thrombosisassociated with basilar artery thrombosis
Infarct evaluation on angiographyInfarct evaluation on angiography(CT angiography and catheter (CT angiography and catheter
angiography)angiography)CTA is an excellent first-line examination for CTA is an excellent first-line examination for
evaluation of the head and neck arteries evaluation of the head and neck arteries In comparison with catheter angiography In comparison with catheter angiography
what it gives up in resolution and dynamic what it gives up in resolution and dynamic properties it makes up for with rapid properties it makes up for with rapid acquisition of a 3-D dataset and the potential acquisition of a 3-D dataset and the potential for assessment of whole-brain perfusion and for assessment of whole-brain perfusion and better parenchymal evaluationbetter parenchymal evaluation
Moreover CTA illustrates not only arterial Moreover CTA illustrates not only arterial stenosis or occlusion but also the vessel wall stenosis or occlusion but also the vessel wall This factor is most important for evaluation of This factor is most important for evaluation of intramural dissection and thrombosed intramural dissection and thrombosed aneurysms which may both complicate aneurysms which may both complicate evaluation of stroke patientsevaluation of stroke patients
Early angiographic signs of strokes Early angiographic signs of strokes both CTA both CTA and DSA and DSA
Vessel occlusion or cutoff related to Vessel occlusion or cutoff related to thromboembolithromboemboli
aneurysms aneurysms arterial dissection arterial dissection Meniscus or flattened shape to clot Meniscus or flattened shape to clot
(recent) versus reverse meniscus (older)(recent) versus reverse meniscus (older) tram track (nonocclusive or recanalized tram track (nonocclusive or recanalized
clot) clot) delayed (antegrade) flow (manifest as delayed (antegrade) flow (manifest as
decreased whole-brain perfusion on CTA)decreased whole-brain perfusion on CTA) retrograde collateral flowretrograde collateral flow
Non-occlusive left MCA thrombus on 3-D imaging performed from CTA source data and was confirmed at catheter angiography
Therapy to be started within a 6-hr Therapy to be started within a 6-hr time to treatment (TTT) window time to treatment (TTT) window (while in case of IV thrombolysis (while in case of IV thrombolysis therapy to be started with in 3hrs)therapy to be started with in 3hrs)
Exclusion criteria Exclusion criteria Rapidly improving neurologic deficit or Rapidly improving neurologic deficit or Sustained blood pressure of gt180100 Sustained blood pressure of gt180100 Hemorrhage is detected on CTHemorrhage is detected on CT Infarct involving gt more than 13 rd Infarct involving gt more than 13 rd
territory of MCAterritory of MCA MRADWI-Perfusion mismatchlt 20MRADWI-Perfusion mismatchlt 20 Definite hypodensity on CTDefinite hypodensity on CT
Intra-arterial Thrombolysis
Fibrinolytics + AntiplateletsFibrinolytics + Antiplatelets
PlasminogenPlasminogen activators through fibrinolysis exposes activators through fibrinolysis exposes free thrombin and paradoxically stimulatesfree thrombin and paradoxically stimulates platelet platelet aggregation which leads to formation of aaggregation which leads to formation of a platelet platelet thrombus (white clot) thrombus (white clot)
This new thrombus is relatively resistant to This new thrombus is relatively resistant to fibrinolyticsfibrinolytics
So new regimen in case of acute stroke isSo new regimen in case of acute stroke is fibrinolytics + antiplatelet drugsfibrinolytics + antiplatelet drugs
rtPA + IIbIIIa inhibitors( tirofiban rtPA + IIbIIIa inhibitors( tirofiban abciximab) orabciximab) or
Urokinase + IIbIIIa Urokinase + IIbIIIa inhibitors( tirofiban abciximab)inhibitors( tirofiban abciximab)
Intra-arterial Thrombolysis Tirofiban (04 microgkgmin bolus for 3 min followed by Tirofiban (04 microgkgmin bolus for 3 min followed by
0125 ugkgmin)0125 ugkgmin)
++
Heparin (2000ndash3000 IU bolus followed by Heparin (2000ndash3000 IU bolus followed by 1000 IUhour infusion 1000 IUhour infusion
with ACT maintained bw 200-300) throughout the with ACT maintained bw 200-300) throughout the interventional procedure and for 24ndash48 hours thereafter when interventional procedure and for 24ndash48 hours thereafter when there is neither intraprocedural bleeding nor suspicion of there is neither intraprocedural bleeding nor suspicion of increased risk of bleeding increased risk of bleeding
Maximum dose of Urokinase Maximum dose of Urokinase Anterior circulation stroke - 500000 IU (mean 400000 Anterior circulation stroke - 500000 IU (mean 400000
IU range 300000ndash500000 IU)IU range 300000ndash500000 IU) Posterior circulation stroke -1000000 IU (mean 837000 Posterior circulation stroke -1000000 IU (mean 837000
IU range 300000ndash1000000 IU)IU range 300000ndash1000000 IU)American Journal of NeuroradiologyAmerican Journal of Neuroradiology 262595-2601 2005262595-2601 2005
Intravenous ThrombolysisIntravenous Thrombolysis
The first method to restore cerebral The first method to restore cerebral perfusion is clot lysis with the goal perfusion is clot lysis with the goal of re-establishing blood flow to the of re-establishing blood flow to the affected tissue affected tissue
IV thrombolysis rt-PA is the only IV thrombolysis rt-PA is the only FDA- approved treatment for AIS FDA- approved treatment for AIS
Fibrinolysis is enhanced powerfully Fibrinolysis is enhanced powerfully by rt-PAby rt-PA
Intravenous rTPA Intravenous rTPA administration administration protocolprotocol
Total dose of rt-PA 09 mgkg (maximum dose Total dose of rt-PA 09 mgkg (maximum dose 90 mg)90 mg)
Give 10 as initial IV bolusGive 10 as initial IV bolus Infuse remainder over 1 hourInfuse remainder over 1 hour Admit patient to an ICU or stroke unit for Admit patient to an ICU or stroke unit for
monitoringmonitoring Neurologic assessments every 15 minutes Neurologic assessments every 15 minutes
during infusion then every 30 minutes for next during infusion then every 30 minutes for next 6 hours then every hour until 24hours after 6 hours then every hour until 24hours after treatmenttreatment
Favorable Outcome vs Treatment Time Favorable Outcome vs Treatment Time with IV rTPAwith IV rTPA
Protocol limit = 3 hrs
Benefit ~ 45 hrs
Thromboembolism During coilingThromboembolism During coiling Most feared and frequent complication Most feared and frequent complication Reported incidence - Approx 7 Reported incidence - Approx 7 SourcesSources of Thromboembolism are of Thromboembolism are
- Clots at the aneurysmal neck during or immediately- Clots at the aneurysmal neck during or immediately after after embolization embolization
- Thrombus forming on catheters during- Thrombus forming on catheters during proceduresprocedures
- Stenosis of an adjacent artery dt coil mass- Stenosis of an adjacent artery dt coil mass or herniationor herniation
- Migration of intraaneurysmal- Migration of intraaneurysmal thrombus during coil thrombus during coil placement placement
- Slow flow dt vasospasm - Slow flow dt vasospasm
- Rare and unlikely causes are hypercoagulable- Rare and unlikely causes are hypercoagulable state such state such as antiphospholipid antibody syndrome or due to HITas antiphospholipid antibody syndrome or due to HIT
Occur more often with wide-necked aneurysms (dt Occur more often with wide-necked aneurysms (dt increased exposed surface area of thrombogenic coil increased exposed surface area of thrombogenic coil material)material)
Current regimen of endovascular Current regimen of endovascular managementmanagement
The The glycoprotein IIbIIIa antagonist tirofiban glycoprotein IIbIIIa antagonist tirofiban (04 (04 microgkgmin bolus for 30 minutes followed by infusion of microgkgmin bolus for 30 minutes followed by infusion of 0125 ugkgmin until the thrombus dissolved) 0125 ugkgmin until the thrombus dissolved)
Intraarterial thrombolysis with Intraarterial thrombolysis with urokinase or r- TPA urokinase or r- TPA increase of intravenous (IV) heparin (measured by increase of intravenous (IV) heparin (measured by
ACT) ACT) Intravenous aspirin Intravenous aspirin
Coil-related platelet aggregation (white clot) is Coil-related platelet aggregation (white clot) is unlikely to respond to fibrinolytics but has a high risk unlikely to respond to fibrinolytics but has a high risk of hemorrhage (In ISAT) all 5 patients who had of hemorrhage (In ISAT) all 5 patients who had received thrombolytic therapy with tPA to treat a received thrombolytic therapy with tPA to treat a thromboembolic complication after endovascular thromboembolic complication after endovascular treatment rebleed and all of these patients died)treatment rebleed and all of these patients died)
IntracranialIntracranial Stenting Stenting Metallic foreign body such as stent will accumulate Metallic foreign body such as stent will accumulate
thrombus in the absence of platelet inhibitionthrombus in the absence of platelet inhibition Antiplatelet drugs are important to prevent peri or Antiplatelet drugs are important to prevent peri or
post-interventional thromboembolic eventspost-interventional thromboembolic events Optimal treatment regimens has not been determined Optimal treatment regimens has not been determined
but usually but usually Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-
procedureprocedureOrOr
Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on
morning of proceduremorning of procedure
If need to use stent is not pre-planned thanIf need to use stent is not pre-planned than
Abciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkgAbciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkg IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)
Glycoprotein IIbIIIa inhibitor are not used routinely during elective Glycoprotein IIbIIIa inhibitor are not used routinely during elective stenting procedure dt increased risk of ICH stenting procedure dt increased risk of ICH
Carotid StentingCarotid Stenting
Pre-procedurePre-procedure
Double Antiplatelet therapy is routinely given Double Antiplatelet therapy is routinely given beginning at least 3beginning at least 3
days before the proceduredays before the procedure
Aspirin 325mgd+Clopidogrel 75mgdAspirin 325mgd+Clopidogrel 75mgd During procedureDuring procedure
Heparin is given with target clotting time of 250-Heparin is given with target clotting time of 250-300sec300sec
Post-procedure Post-procedure
Aspirin 325mg is continued indefinitely and Aspirin 325mg is continued indefinitely and
Clopidogrel 75mgd for at least 6 weeks Clopidogrel 75mgd for at least 6 weeks
Inclusion criteria for Local ThrombolysisInclusion criteria for Local Thrombolysis a)a) Patients in severe clinical grade on admission Patients in severe clinical grade on admission
with evidence of dural venous sinus with evidence of dural venous sinus thrombosis and restrictive venous outflow on thrombosis and restrictive venous outflow on cerebral angiogramcerebral angiogram
b)b) Patients in clinical grade 3 worsening on Patients in clinical grade 3 worsening on heparin therapy Restriction to venous heparin therapy Restriction to venous outflow was defined as an increase in brain outflow was defined as an increase in brain circulation time gt 12 s delay in the drainage circulation time gt 12 s delay in the drainage of cortical veins with cortical veins hanging of cortical veins with cortical veins hanging in spacein space
Treatment Options for Venous Thrombosis
CT Grading for Venous ThrombosisCT Grading for Venous Thrombosis Grade I no parenchymal change Grade I no parenchymal change
(hyperdense (hyperdense sinuses cortical veins empty sinuses cortical veins empty delta sign)delta sign)
Grade II non hemorrhagic venous infarct Grade II non hemorrhagic venous infarct without mass effect without mass effect
Grade III non-hemorrhagic infarct with Grade III non-hemorrhagic infarct with mass effectmass effect
Grade IV hemorrhagic venous infarct (max Grade IV hemorrhagic venous infarct (max diameter lt 3 cm) with no mass effectdiameter lt 3 cm) with no mass effect
Grade V hemorrhagic venous infarct (max Grade V hemorrhagic venous infarct (max diameter gt 3 cm) with mass effect diameter gt 3 cm) with mass effect
Local ThrombolysisLocal Thrombolysis
Femoral Jugular access was secured and a guiding Femoral Jugular access was secured and a guiding catheter was placed in the jugular bulb catheter was placed in the jugular bulb Mechanical Mechanical clot maceration clot maceration was done with the guidewire was done with the guidewire following which a microcatheter (was navigated and following which a microcatheter (was navigated and placed in the thrombosed segment of sinus confirmed placed in the thrombosed segment of sinus confirmed on a selective venogram on a selective venogram
Urokinase infusion Bolus dose of 2-6 lacs followed Urokinase infusion Bolus dose of 2-6 lacs followed by 60000 to 100000 units per hour along with by 60000 to 100000 units per hour along with periodic check venogram Along with maintenance periodic check venogram Along with maintenance systemic infusion of Heparinsystemic infusion of Heparin Other agents such as Other agents such as streptokinase altepase or rTPAstreptokinase altepase or rTPA can be also used can be also used
After thrombolysis patient should subjected to oral After thrombolysis patient should subjected to oral anticoagulation for six monthsanticoagulation for six months
Low-molecular-weight Low-molecular-weight heparinheparin
PharmacologyPharmacologyLMWH as its name suggests is a glycosaminoglycan that is approximatelyLMWH as its name suggests is a glycosaminoglycan that is approximately
one third the molecular weight of UFH It is derived from UFH through one third the molecular weight of UFH It is derived from UFH through variousvarious
depolymerization processes LMWH binds to antithrombin which in turn depolymerization processes LMWH binds to antithrombin which in turn
Neutralizes actors Xa and IIa Because LMWH lacks many of the longer Neutralizes actors Xa and IIa Because LMWH lacks many of the longer chains chains
required for binding to thrombin it has less ability to neutralize thrombin required for binding to thrombin it has less ability to neutralize thrombin
relativeto its ability to neutralize factor Xa LMWH also has less relativeto its ability to neutralize factor Xa LMWH also has less nonspecific nonspecific
binding to other proteins There is greater bioavailability with more binding to other proteins There is greater bioavailability with more predictable predictable
pharmacokinetics that eliminates the need for monitoring The smaller pharmacokinetics that eliminates the need for monitoring The smaller size also size also
allows for enhanced subcutaneous absorption when compared with UFHallows for enhanced subcutaneous absorption when compared with UFH
Three LMWH preparations are Three LMWH preparations are currently approved for use in the currently approved for use in the United States (1) enoxaparin (2) United States (1) enoxaparin (2) dalteparin and (3) tinzaparin dalteparin and (3) tinzaparin
They are all administered They are all administered subcutaneously at intervals of either subcutaneously at intervals of either once or twice daily for both once or twice daily for both prophylaxis and treatment dosesprophylaxis and treatment doses
Few Experiences of Few Experiences of ThrombolysisThrombolysis
Vickey 25 Yrs male patient presented Vickey 25 Yrs male patient presented with 12with 12thth day HO severe headache with day HO severe headache with right sided hemiplegiaright sided hemiplegia
MRI shows thrombosis of the superior MRI shows thrombosis of the superior sagittal left transverse left sigmoid sagittal left transverse left sigmoid sinuses and cortical veins in the fronto-sinuses and cortical veins in the fronto-parietal regions with eo haemorrhagic parietal regions with eo haemorrhagic infarct in the left cerebral hemisphere infarct in the left cerebral hemisphere with mass effect( Grade ndashV)with mass effect( Grade ndashV)
Sashi Srivastava 64 yrs FSashi Srivastava 64 yrs F In a follow up case of MRD with infra-renal In a follow up case of MRD with infra-renal
aortic abdominal and bilateral renal artery aortic abdominal and bilateral renal artery thrombosis renal angiogram shows filling thrombosis renal angiogram shows filling defects in the right Renal artery defects in the right Renal artery
Initially Renal angioplasty was done Initially Renal angioplasty was done Following angioplasty few thrombi are seem Following angioplasty few thrombi are seem to extends into the segmental branches and to extends into the segmental branches and causing blockage So Thrombolysis was causing blockage So Thrombolysis was plane to dissolve the run-out thrombi with plane to dissolve the run-out thrombi with urokinase urokinase
Rakesh 34yrsMRakesh 34yrsM Left SFA pseudoaneurysm with Left SFA pseudoaneurysm with
Covered stent placementCovered stent placement Pre operative antiplatelets with post Pre operative antiplatelets with post
procedure heparin Tirofiban procedure heparin Tirofiban followed by aspirin and clopidogrel followed by aspirin and clopidogrel were usedwere used
IAT may be a treatment option for selected patients IAT may be a treatment option for selected patients Possible selection criteria include Possible selection criteria include
presentation between 3 and 6 hours from symptom onsetpresentation between 3 and 6 hours from symptom onset major cerebral artery occlusion major cerebral artery occlusion severe neurologic deficits severe neurologic deficits high risk of systemic hemorrhage with IV rt-PA (eg recent high risk of systemic hemorrhage with IV rt-PA (eg recent
surgery) surgery) The MERCI (Mechanical Embolus Removal in Cerebral The MERCI (Mechanical Embolus Removal in Cerebral
Ischemia) retrievalIschemia) retrieval system system
Has been FDA-approved for recanalizing acutely occluded Has been FDA-approved for recanalizing acutely occluded cerebral arteries cerebral arteries
In the Multi-MERCI study patients who did not improve In the Multi-MERCI study patients who did not improve immediately after IV rt-PA underwent mechanical immediately after IV rt-PA underwent mechanical embolectomy within 8 hours of symptom onset embolectomy within 8 hours of symptom onset
Partial or complete recanalization occurred in 74 of Partial or complete recanalization occurred in 74 of patientspatients
with a symptomatic intracerebral hemorrhage (sICH) rate of with a symptomatic intracerebral hemorrhage (sICH) rate of 67 67
Mechanical embolectomy with the MERCI retriever may be a Mechanical embolectomy with the MERCI retriever may be a feasible and safe option for patients after IV rt-PAfeasible and safe option for patients after IV rt-PA
Penumbra stroke systemPenumbra stroke system This device combines two methods of clot This device combines two methods of clot
extraction aspiration and mechanical extraction aspiration and mechanical extraction extraction
First the clot is aspirated then a thrombus First the clot is aspirated then a thrombus removal ring can be used if necessary to removal ring can be used if necessary to remove remaining clot remove remaining clot
successful recanalizing 82successful recanalizing 82 Bridging therapyBridging therapy
06 mgkg IV rt-PA followed by IAT with IA rt-06 mgkg IV rt-PA followed by IAT with IA rt-PA (up to 20 mg)PA (up to 20 mg)
achieved a higher recanalization rateachieved a higher recanalization rate
Criteria for thrombolysis with rTPACriteria for thrombolysis with rTPA
Inclusion criteriaInclusion criteria Clinical signs and symptoms consistent with ischemic Clinical signs and symptoms consistent with ischemic
strokestroke Patient last seen normal within 3 hoursPatient last seen normal within 3 hours Measurable neurologic deficitMeasurable neurologic deficit
Exclusion criteriaExclusion criteria Any hemorrhage on neuroimaging (CT or MRI)Any hemorrhage on neuroimaging (CT or MRI) Symptoms suggestive of subarachnoid hemorrhageSymptoms suggestive of subarachnoid hemorrhage Seizure at stroke onset that is thought to contribute to Seizure at stroke onset that is thought to contribute to
neurologic deficitneurologic deficit Hypodensity greater than one third cerebral hemisphere Hypodensity greater than one third cerebral hemisphere
on CTon CT SBP greater than 185 mm Hg or DBP greater than 110 SBP greater than 185 mm Hg or DBP greater than 110
mm Hgmm Hg International normalized ratio (INR) greater than 17International normalized ratio (INR) greater than 17
Ischemic Stroke Ischemic Stroke Treatment ndash 2006Treatment ndash 2006
IV tissue plasminogen activator (tPA)IV tissue plasminogen activator (tPA) ndash ndash Only FDA-approved acute stroke drugOnly FDA-approved acute stroke drug ndash ndash 3 hour treatment window3 hour treatment window
MERCI - Concentric clot retrieval MERCI - Concentric clot retrieval devicedevice ndash ndash Rescue therapy - approved 2004Rescue therapy - approved 2004 ndash ndash Device approval (not outcomes-based)Device approval (not outcomes-based)
Off label approachesOff label approaches ndash ndash IV tPA after 3 hoursIV tPA after 3 hours ndash ndash IV-IA tPA sequential strategiesIV-IA tPA sequential strategies ndash ndash IA tPA clot angioplasty fragmentationIA tPA clot angioplasty fragmentation ndash ndash Ultrasound-assisted tPA lysisUltrasound-assisted tPA lysis
rt-PA Trials NINDSrt-PA Trials NINDS
Acute stroke - 624 patientsAcute stroke - 624 patients Treat within 3 hrsTreat within 3 hrs Intravenous 09 mgkg rt-PA vs placeboIntravenous 09 mgkg rt-PA vs placebo Hemorrhage 64 tPA 06 placeboHemorrhage 64 tPA 06 placebo Neurologic recovery better with tPA 30 Neurologic recovery better with tPA 30
more like to have minimal or no disabilitymore like to have minimal or no disability
First proven approved treatment for First proven approved treatment for strokestroke
Limitations of tPALimitations of tPA Only 4 of acute strokes receive tPAOnly 4 of acute strokes receive tPA (Kleindorfer et al Stroke 2004 35 e27-e29)(Kleindorfer et al Stroke 2004 35 e27-e29)
Only 22 of patients present within 3 hoursOnly 22 of patients present within 3 hours1048707 1048707 51 of these ineligible due to51 of these ineligible due to
bull bull Mild severityMild severity bull bull Medical or surgical historyMedical or surgical history bull bull Blood testsBlood tests
Sustained recanalization only 13Sustained recanalization only 13 (Alexandrov et al NEJM 2004 351 2170-8)(Alexandrov et al NEJM 2004 351 2170-8)
Concern for hemorrhageConcern for hemorrhage tPA potentiates apoptotic injury tPA potentiates apoptotic injury (Liu et al Nature Med 2004 101379-83)(Liu et al Nature Med 2004 101379-83)
PROACT II IA Lysis TrialPROACT II IA Lysis Trial Baseline 24 hours 8 days
Baseline 60 minutes 120 minutes
9mg IAProurokinase
Desmoteplase Trials DEDAS Desmoteplase Trials DEDAS DIASDIAS
Trial OverviewTrial Overview Double blind randomized placebo Double blind randomized placebo
controlled trialscontrolled trials IV delivery 3-9 hour time windowIV delivery 3-9 hour time window Plasminogen activator ndash from Plasminogen activator ndash from vampire bat vampire bat
salivasaliva Selection based on PWI-DWI MismatchSelection based on PWI-DWI Mismatch
MRI InclusionMRI Inclusion PWI defect at least 2 cm AND ~20 larger PWI defect at least 2 cm AND ~20 larger
than DWIthan DWI PWI should be obvious even visible on PWI should be obvious even visible on
raw imagesraw imagesMRI ExclusionMRI Exclusion
DWI gt 13 MCADWI gt 13 MCA MRA ICA occlusionMRA ICA occlusion
Desmoteplase ndash DIAS Desmoteplase ndash DIAS ResultsResults
Mechanical Thrombolysis Mechanical Thrombolysis devicesdevices
mechanical thrombolysis potentially extends the treatment mechanical thrombolysis potentially extends the treatment window because they act promptly at the site of the thrombuswindow because they act promptly at the site of the thrombus
The devices can retrieve large clots that pharmaceutical agents The devices can retrieve large clots that pharmaceutical agents may not successfully lysemay not successfully lyse
Patients treated with IV tPA may be considered for treatment of Patients treated with IV tPA may be considered for treatment of residual clot with some of these devicesresidual clot with some of these devices
suction-creating saline jets suction-creating saline jets laser energy ultrasound laser energy ultrasound a corkscrew apparatus to treat strokesa corkscrew apparatus to treat strokes The AngioJet systemThe AngioJet system uses saline jets that are directed back into the catheter to uses saline jets that are directed back into the catheter to
create a low-pressure zone around the catheter tip inducing create a low-pressure zone around the catheter tip inducing suction suction
The clot is pulled into the exhaust lumen and removed from the The clot is pulled into the exhaust lumen and removed from the vessel Although US Food and Drug Administration (FDA) has vessel Although US Food and Drug Administration (FDA) has approved this device for use in arteriovenous dialysis grafts and approved this device for use in arteriovenous dialysis grafts and fistulae and for the treatment of coronary arteries saphenous fistulae and for the treatment of coronary arteries saphenous vein grafts and peripheral vessels clinical trials for the vein grafts and peripheral vessels clinical trials for the treatment of acute stroke are no longer in progress treatment of acute stroke are no longer in progress
Most devices are used in cerebral vessels that 2-5 mm
The Latis laser device The Latis laser device used laser energy to ablate clots used laser energy to ablate clots Arteries 2-5 mm in diameter could be Arteries 2-5 mm in diameter could be
treated including the ICA M1 or M2 treated including the ICA M1 or M2 branch of the MCA A1 branch of the branch of the MCA A1 branch of the anterior cerebral artery (ACA) basilar anterior cerebral artery (ACA) basilar artery posterior cerebral artery (PCA) artery posterior cerebral artery (PCA) and vertebral and vertebral
Patients could receive treatment as late Patients could receive treatment as late as 8 hours after symptom onset in the as 8 hours after symptom onset in the anterior circulation and within 24 hours in anterior circulation and within 24 hours in the posterior circulation the posterior circulation
Endovascular Photo Acoustic Endovascular Photo Acoustic Recanalization (EPAR) Recanalization (EPAR)
A laser power source generated energy for the A laser power source generated energy for the systemsystem
The energy was delivered by means of The energy was delivered by means of fiberoptics to the tip of the catheter at the fiberoptics to the tip of the catheter at the treatment sitetreatment site
Absorption of laser light by darkly pigmented Absorption of laser light by darkly pigmented materials (ie the clot) occurred inside the 1-mm materials (ie the clot) occurred inside the 1-mm catheter tipcatheter tip
the system was designed to minimize scattering the system was designed to minimize scattering of laser light of laser light
Absorption converted photo energy to acoustic Absorption converted photo energy to acoustic energy which then emulsified the clot inside the energy which then emulsified the clot inside the catheter tip catheter tip
EKOS ultrasound( the EKOS ultrasound( the Ultrasound Thrombolytic Ultrasound Thrombolytic
Infusion Catheter) Infusion Catheter) combines the use of a distal ultrasound transducer with combines the use of a distal ultrasound transducer with
infusion of a thrombolytic agent through the infusion of a thrombolytic agent through the microcathetermicrocatheter
Ultrasound changes the structure of the clot to Ultrasound changes the structure of the clot to temporarily increase its permeability while providing an temporarily increase its permeability while providing an acoustic pressure gradient to move the drug into the clot acoustic pressure gradient to move the drug into the clot to speed its dissolution to speed its dissolution
The EKOS catheter is placed in the proximal portion of the The EKOS catheter is placed in the proximal portion of the clot clot
After a 2-mg bolus of tPA was injected through the After a 2-mg bolus of tPA was injected through the catheter catheter
the patient received a continuous infusion of IA tPA 03 the patient received a continuous infusion of IA tPA 03 mgmin to a maximum of 20 mg and simultaneous mgmin to a maximum of 20 mg and simultaneous ultrasound transmission for as long as 60 minutes ultrasound transmission for as long as 60 minutes
One patient was treated with a total of 4 units of One patient was treated with a total of 4 units of recombinant reteplase (Retavase) hand-injected over 60 recombinant reteplase (Retavase) hand-injected over 60 minutes minutes
Penumbra system Penumbra system The Penumbra system (Penumbra Inc) provides a dual The Penumbra system (Penumbra Inc) provides a dual
approach to clot extraction using aspiration followed by approach to clot extraction using aspiration followed by clot retrieval with a ring device if needed clot retrieval with a ring device if needed
Mechanical Embolus Removal in Cerebral Ischemia Mechanical Embolus Removal in Cerebral Ischemia (MERCI)(MERCI)
a corkscrew-like apparatus to remove blood clots from a corkscrew-like apparatus to remove blood clots from the brain in patients experiencing an ischemic stroke the brain in patients experiencing an ischemic stroke
The corkscrew itself resides in the catheter tip which The corkscrew itself resides in the catheter tip which shields it from the wall of the vessel until it is ready to be shields it from the wall of the vessel until it is ready to be burrowed into the clot Once lodged in the clot the device burrowed into the clot Once lodged in the clot the device and clot are withdrawn from the vessel and clot are withdrawn from the vessel
Snarelike devicesSnarelike devices Snares such as the Neuronet snare (Guidant Snares such as the Neuronet snare (Guidant
Endovascular Santa Clara CA) have been developed Endovascular Santa Clara CA) have been developed specifically for use in the treatment of strokes specifically for use in the treatment of strokes
These devices are simple in design and do not require the These devices are simple in design and do not require the clot to be amenable to emulsification clot to be amenable to emulsification
X-Sizer deviceX-Sizer device a device with small moving blades at the a device with small moving blades at the
catheter tip catheter tip This device the X-Sizer device (EndiCor Medical This device the X-Sizer device (EndiCor Medical
San Clemente CA) can be used to excise the San Clemente CA) can be used to excise the thrombus and aspirate it thrombus and aspirate it
The device was being evaluated in randomized The device was being evaluated in randomized studies of coronary vessels and in a registry of studies of coronary vessels and in a registry of patients with acute myocardial infarctionpatients with acute myocardial infarction
Although the manufacturer had modified the Although the manufacturer had modified the device for use in cerebral vessels a safety and device for use in cerebral vessels a safety and feasibility study was indefinitely suspended after feasibility study was indefinitely suspended after only 1 patient was treated with the device in only 1 patient was treated with the device in Europe Europe
Suction thrombectomySuction thrombectomy This method of mechanical thrombolysis is one of the This method of mechanical thrombolysis is one of the
simplestsimplest In this readily available technique suction is applied with In this readily available technique suction is applied with
a syringe to remove thrombus in the ICA a syringe to remove thrombus in the ICA It requires no other devicesIt requires no other devices A catheter with a large inner diameter (Brite Tip Cordis A catheter with a large inner diameter (Brite Tip Cordis
Corporation Miami FL) was placed in the symptomatic Corporation Miami FL) was placed in the symptomatic vessel and navigated over a guidewire into the thrombusvessel and navigated over a guidewire into the thrombus
A 60-mL syringe was used to aspirate the thrombus A 60-mL syringe was used to aspirate the thrombus Each patient required angioplasty and stenting of carotid Each patient required angioplasty and stenting of carotid
bifurcation stenosis and received daily aspirin and bifurcation stenosis and received daily aspirin and ticlopidine after the procedure No complications ticlopidine after the procedure No complications occurred occurred
Summary Acute Stroke Summary Acute Stroke ImagingImaging
PhysiologyPhysiology importance collaterals importance collaterals
ndash ndashGrowing role for perfusion Growing role for perfusion assessmentassessment
tPAtPA guidelines amp limitations guidelines amp limitations Signs on CT amp MRSigns on CT amp MR follow physiology follow physiology Stroke trialsStroke trials PWI-DWI mismatch PWI-DWI mismatch
ndash ndashTreat based on physiology not timeTreat based on physiology not time ProtocolsProtocols should be fast and should be fast and
comprehensivecomprehensive
Anti Platelet DrugsAnti Platelet DrugsDrug Drug Mechanism Mechanism UsesUsesAspirinAspirin Permanently inhibits Permanently inhibits
COX-1 and COX-2COX-1 and COX-2CADCAD
Stroke-TIAsStroke-TIAs
NSAIDsNSAIDs Reversibly inhibits Reversibly inhibits COX-1COX-1
LimitedLimited
DipyridamoleDipyridamole Inhibits PDE increases Inhibits PDE increases cAMPcAMP
TIAsTIAs
ThenopyridinesThenopyridines
(Ticlopidine(Ticlopidine
ClopidrgrelClopidrgrel))
Inhibits ADP Inhibits ADP
PlatAg PlatAg
TIAsStrokeTIAsStroke
CAD PVDCAD PVD
Abciximab (ReoPro)Abciximab (ReoPro)
Eptifibatide (Integrilin)Eptifibatide (Integrilin)
TirofibanTirofiban
GP IIBIIIA InhibitorsGP IIBIIIA Inhibitors
Stroke- TIAs Stroke- TIAs
MonitoringMonitoring
Bleeding timeBleeding time
Optical aggregometryOptical aggregometry
Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay
Bleeding timeBleeding time
Requires a skin incision (usually made on the ear lobe or Requires a skin incision (usually made on the ear lobe or forearm offorearm of
a depth that results in disruption of capillary loops and a depth that results in disruption of capillary loops and small vessels)small vessels)
AdvantagesAdvantages Universally availableUniversally available Relatively simple techniquesRelatively simple techniques Can be performed bedsideCan be performed bedside
DisadvantagesDisadvantages Insensitive inaccurate non-specific techniqueInsensitive inaccurate non-specific technique
Poorly reproducible (as depends on multiple variables)Poorly reproducible (as depends on multiple variables)
Optical aggregometryOptical aggregometry
Gold standard assay for platelet functionGold standard assay for platelet function Agonist induced aggregation is measuredAgonist induced aggregation is measured Different agonist are available for different Different agonist are available for different
agentsagents However require unique expertise and are not However require unique expertise and are not
universally availableuniversally available Aspirin measured with ADP or AA(gt70 Aspirin measured with ADP or AA(gt70
aggregation so resistance)aggregation so resistance) Clopidogrel( ADP gt 90 aggregation means Clopidogrel( ADP gt 90 aggregation means
resistance) resistance)
Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay
Can be performed bed sideCan be performed bed side Different assay devices with different Different assay devices with different
agonist are used for each of different agonist are used for each of different antiplatelet agents antiplatelet agents
For Aspirin AA is used (result is reported as aspirin For Aspirin AA is used (result is reported as aspirin reaction units [ARU] ARUgt 550 indicates non-reaction units [ARU] ARUgt 550 indicates non-responsiveness)responsiveness)
Verify IIbIIIa assay device uses TRAP as agonist for Verify IIbIIIa assay device uses TRAP as agonist for Abciximab and TirofibanAbciximab and Tirofiban
Practical Applications Practical Applications related to specific related to specific
Neurovascular Neurovascular interventionsinterventions
Acute ischemic StrokeAcute ischemic Stroke When an artery occludes neurons are affected When an artery occludes neurons are affected
differently depending upon the amount of residual blood differently depending upon the amount of residual blood flowflow
Normal cerebral blood flow is greater than 50 mL100 Normal cerebral blood flow is greater than 50 mL100 mgminmgmin
Once blood flow decreases to less than 20 mL100 Once blood flow decreases to less than 20 mL100 mgmin infarction occursmgmin infarction occurs
If blood flow decreases to less than 10 mL100 mgmin If blood flow decreases to less than 10 mL100 mgmin irreversible neuronal death occurs rapidly irreversible neuronal death occurs rapidly
Blood flow between 11 and 20 mL100 mgmin is thought Blood flow between 11 and 20 mL100 mgmin is thought to represent the ischemic penumbra an area where the to represent the ischemic penumbra an area where the cells are functionally silent because of ischemia but are cells are functionally silent because of ischemia but are still able to recover if blood flow is restored still able to recover if blood flow is restored
Many acute stroke therapies are targeted toward Many acute stroke therapies are targeted toward restoring flow or function to the ischemic penumbrarestoring flow or function to the ischemic penumbra
Therapeutic window in Therapeutic window in management of acute Ischemic management of acute Ischemic
StrokeStrokeThe early diagnosis of ischemic stroke is critical to the The early diagnosis of ischemic stroke is critical to the
with only a narrow therapeutic window in the first few with only a narrow therapeutic window in the first few hours following stroke ictushours following stroke ictus
Diagnosis in the first 3 hours postictus provides the Diagnosis in the first 3 hours postictus provides the opportunity for intravenous or intraarterial thrombolysis opportunity for intravenous or intraarterial thrombolysis and intra-arterial clot mechanical treatment which and intra-arterial clot mechanical treatment which improve the outcome improve the outcome
Diagnosis in the time period between 3 and 6 hours Diagnosis in the time period between 3 and 6 hours provides an opportunity for intra-arterial thrombolysis provides an opportunity for intra-arterial thrombolysis and mechanical treatment and mechanical treatment
Involvement of the posterior circulation especially the Involvement of the posterior circulation especially the basilar artery is treated by some regardless of time of basilar artery is treated by some regardless of time of onset or up until 12 to 24 hours in some practices This is onset or up until 12 to 24 hours in some practices This is related to the potentially high mortality and morbidity related to the potentially high mortality and morbidity associated with basilar artery thrombosisassociated with basilar artery thrombosis
Infarct evaluation on angiographyInfarct evaluation on angiography(CT angiography and catheter (CT angiography and catheter
angiography)angiography)CTA is an excellent first-line examination for CTA is an excellent first-line examination for
evaluation of the head and neck arteries evaluation of the head and neck arteries In comparison with catheter angiography In comparison with catheter angiography
what it gives up in resolution and dynamic what it gives up in resolution and dynamic properties it makes up for with rapid properties it makes up for with rapid acquisition of a 3-D dataset and the potential acquisition of a 3-D dataset and the potential for assessment of whole-brain perfusion and for assessment of whole-brain perfusion and better parenchymal evaluationbetter parenchymal evaluation
Moreover CTA illustrates not only arterial Moreover CTA illustrates not only arterial stenosis or occlusion but also the vessel wall stenosis or occlusion but also the vessel wall This factor is most important for evaluation of This factor is most important for evaluation of intramural dissection and thrombosed intramural dissection and thrombosed aneurysms which may both complicate aneurysms which may both complicate evaluation of stroke patientsevaluation of stroke patients
Early angiographic signs of strokes Early angiographic signs of strokes both CTA both CTA and DSA and DSA
Vessel occlusion or cutoff related to Vessel occlusion or cutoff related to thromboembolithromboemboli
aneurysms aneurysms arterial dissection arterial dissection Meniscus or flattened shape to clot Meniscus or flattened shape to clot
(recent) versus reverse meniscus (older)(recent) versus reverse meniscus (older) tram track (nonocclusive or recanalized tram track (nonocclusive or recanalized
clot) clot) delayed (antegrade) flow (manifest as delayed (antegrade) flow (manifest as
decreased whole-brain perfusion on CTA)decreased whole-brain perfusion on CTA) retrograde collateral flowretrograde collateral flow
Non-occlusive left MCA thrombus on 3-D imaging performed from CTA source data and was confirmed at catheter angiography
Therapy to be started within a 6-hr Therapy to be started within a 6-hr time to treatment (TTT) window time to treatment (TTT) window (while in case of IV thrombolysis (while in case of IV thrombolysis therapy to be started with in 3hrs)therapy to be started with in 3hrs)
Exclusion criteria Exclusion criteria Rapidly improving neurologic deficit or Rapidly improving neurologic deficit or Sustained blood pressure of gt180100 Sustained blood pressure of gt180100 Hemorrhage is detected on CTHemorrhage is detected on CT Infarct involving gt more than 13 rd Infarct involving gt more than 13 rd
territory of MCAterritory of MCA MRADWI-Perfusion mismatchlt 20MRADWI-Perfusion mismatchlt 20 Definite hypodensity on CTDefinite hypodensity on CT
Intra-arterial Thrombolysis
Fibrinolytics + AntiplateletsFibrinolytics + Antiplatelets
PlasminogenPlasminogen activators through fibrinolysis exposes activators through fibrinolysis exposes free thrombin and paradoxically stimulatesfree thrombin and paradoxically stimulates platelet platelet aggregation which leads to formation of aaggregation which leads to formation of a platelet platelet thrombus (white clot) thrombus (white clot)
This new thrombus is relatively resistant to This new thrombus is relatively resistant to fibrinolyticsfibrinolytics
So new regimen in case of acute stroke isSo new regimen in case of acute stroke is fibrinolytics + antiplatelet drugsfibrinolytics + antiplatelet drugs
rtPA + IIbIIIa inhibitors( tirofiban rtPA + IIbIIIa inhibitors( tirofiban abciximab) orabciximab) or
Urokinase + IIbIIIa Urokinase + IIbIIIa inhibitors( tirofiban abciximab)inhibitors( tirofiban abciximab)
Intra-arterial Thrombolysis Tirofiban (04 microgkgmin bolus for 3 min followed by Tirofiban (04 microgkgmin bolus for 3 min followed by
0125 ugkgmin)0125 ugkgmin)
++
Heparin (2000ndash3000 IU bolus followed by Heparin (2000ndash3000 IU bolus followed by 1000 IUhour infusion 1000 IUhour infusion
with ACT maintained bw 200-300) throughout the with ACT maintained bw 200-300) throughout the interventional procedure and for 24ndash48 hours thereafter when interventional procedure and for 24ndash48 hours thereafter when there is neither intraprocedural bleeding nor suspicion of there is neither intraprocedural bleeding nor suspicion of increased risk of bleeding increased risk of bleeding
Maximum dose of Urokinase Maximum dose of Urokinase Anterior circulation stroke - 500000 IU (mean 400000 Anterior circulation stroke - 500000 IU (mean 400000
IU range 300000ndash500000 IU)IU range 300000ndash500000 IU) Posterior circulation stroke -1000000 IU (mean 837000 Posterior circulation stroke -1000000 IU (mean 837000
IU range 300000ndash1000000 IU)IU range 300000ndash1000000 IU)American Journal of NeuroradiologyAmerican Journal of Neuroradiology 262595-2601 2005262595-2601 2005
Intravenous ThrombolysisIntravenous Thrombolysis
The first method to restore cerebral The first method to restore cerebral perfusion is clot lysis with the goal perfusion is clot lysis with the goal of re-establishing blood flow to the of re-establishing blood flow to the affected tissue affected tissue
IV thrombolysis rt-PA is the only IV thrombolysis rt-PA is the only FDA- approved treatment for AIS FDA- approved treatment for AIS
Fibrinolysis is enhanced powerfully Fibrinolysis is enhanced powerfully by rt-PAby rt-PA
Intravenous rTPA Intravenous rTPA administration administration protocolprotocol
Total dose of rt-PA 09 mgkg (maximum dose Total dose of rt-PA 09 mgkg (maximum dose 90 mg)90 mg)
Give 10 as initial IV bolusGive 10 as initial IV bolus Infuse remainder over 1 hourInfuse remainder over 1 hour Admit patient to an ICU or stroke unit for Admit patient to an ICU or stroke unit for
monitoringmonitoring Neurologic assessments every 15 minutes Neurologic assessments every 15 minutes
during infusion then every 30 minutes for next during infusion then every 30 minutes for next 6 hours then every hour until 24hours after 6 hours then every hour until 24hours after treatmenttreatment
Favorable Outcome vs Treatment Time Favorable Outcome vs Treatment Time with IV rTPAwith IV rTPA
Protocol limit = 3 hrs
Benefit ~ 45 hrs
Thromboembolism During coilingThromboembolism During coiling Most feared and frequent complication Most feared and frequent complication Reported incidence - Approx 7 Reported incidence - Approx 7 SourcesSources of Thromboembolism are of Thromboembolism are
- Clots at the aneurysmal neck during or immediately- Clots at the aneurysmal neck during or immediately after after embolization embolization
- Thrombus forming on catheters during- Thrombus forming on catheters during proceduresprocedures
- Stenosis of an adjacent artery dt coil mass- Stenosis of an adjacent artery dt coil mass or herniationor herniation
- Migration of intraaneurysmal- Migration of intraaneurysmal thrombus during coil thrombus during coil placement placement
- Slow flow dt vasospasm - Slow flow dt vasospasm
- Rare and unlikely causes are hypercoagulable- Rare and unlikely causes are hypercoagulable state such state such as antiphospholipid antibody syndrome or due to HITas antiphospholipid antibody syndrome or due to HIT
Occur more often with wide-necked aneurysms (dt Occur more often with wide-necked aneurysms (dt increased exposed surface area of thrombogenic coil increased exposed surface area of thrombogenic coil material)material)
Current regimen of endovascular Current regimen of endovascular managementmanagement
The The glycoprotein IIbIIIa antagonist tirofiban glycoprotein IIbIIIa antagonist tirofiban (04 (04 microgkgmin bolus for 30 minutes followed by infusion of microgkgmin bolus for 30 minutes followed by infusion of 0125 ugkgmin until the thrombus dissolved) 0125 ugkgmin until the thrombus dissolved)
Intraarterial thrombolysis with Intraarterial thrombolysis with urokinase or r- TPA urokinase or r- TPA increase of intravenous (IV) heparin (measured by increase of intravenous (IV) heparin (measured by
ACT) ACT) Intravenous aspirin Intravenous aspirin
Coil-related platelet aggregation (white clot) is Coil-related platelet aggregation (white clot) is unlikely to respond to fibrinolytics but has a high risk unlikely to respond to fibrinolytics but has a high risk of hemorrhage (In ISAT) all 5 patients who had of hemorrhage (In ISAT) all 5 patients who had received thrombolytic therapy with tPA to treat a received thrombolytic therapy with tPA to treat a thromboembolic complication after endovascular thromboembolic complication after endovascular treatment rebleed and all of these patients died)treatment rebleed and all of these patients died)
IntracranialIntracranial Stenting Stenting Metallic foreign body such as stent will accumulate Metallic foreign body such as stent will accumulate
thrombus in the absence of platelet inhibitionthrombus in the absence of platelet inhibition Antiplatelet drugs are important to prevent peri or Antiplatelet drugs are important to prevent peri or
post-interventional thromboembolic eventspost-interventional thromboembolic events Optimal treatment regimens has not been determined Optimal treatment regimens has not been determined
but usually but usually Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-
procedureprocedureOrOr
Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on
morning of proceduremorning of procedure
If need to use stent is not pre-planned thanIf need to use stent is not pre-planned than
Abciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkgAbciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkg IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)
Glycoprotein IIbIIIa inhibitor are not used routinely during elective Glycoprotein IIbIIIa inhibitor are not used routinely during elective stenting procedure dt increased risk of ICH stenting procedure dt increased risk of ICH
Carotid StentingCarotid Stenting
Pre-procedurePre-procedure
Double Antiplatelet therapy is routinely given Double Antiplatelet therapy is routinely given beginning at least 3beginning at least 3
days before the proceduredays before the procedure
Aspirin 325mgd+Clopidogrel 75mgdAspirin 325mgd+Clopidogrel 75mgd During procedureDuring procedure
Heparin is given with target clotting time of 250-Heparin is given with target clotting time of 250-300sec300sec
Post-procedure Post-procedure
Aspirin 325mg is continued indefinitely and Aspirin 325mg is continued indefinitely and
Clopidogrel 75mgd for at least 6 weeks Clopidogrel 75mgd for at least 6 weeks
Inclusion criteria for Local ThrombolysisInclusion criteria for Local Thrombolysis a)a) Patients in severe clinical grade on admission Patients in severe clinical grade on admission
with evidence of dural venous sinus with evidence of dural venous sinus thrombosis and restrictive venous outflow on thrombosis and restrictive venous outflow on cerebral angiogramcerebral angiogram
b)b) Patients in clinical grade 3 worsening on Patients in clinical grade 3 worsening on heparin therapy Restriction to venous heparin therapy Restriction to venous outflow was defined as an increase in brain outflow was defined as an increase in brain circulation time gt 12 s delay in the drainage circulation time gt 12 s delay in the drainage of cortical veins with cortical veins hanging of cortical veins with cortical veins hanging in spacein space
Treatment Options for Venous Thrombosis
CT Grading for Venous ThrombosisCT Grading for Venous Thrombosis Grade I no parenchymal change Grade I no parenchymal change
(hyperdense (hyperdense sinuses cortical veins empty sinuses cortical veins empty delta sign)delta sign)
Grade II non hemorrhagic venous infarct Grade II non hemorrhagic venous infarct without mass effect without mass effect
Grade III non-hemorrhagic infarct with Grade III non-hemorrhagic infarct with mass effectmass effect
Grade IV hemorrhagic venous infarct (max Grade IV hemorrhagic venous infarct (max diameter lt 3 cm) with no mass effectdiameter lt 3 cm) with no mass effect
Grade V hemorrhagic venous infarct (max Grade V hemorrhagic venous infarct (max diameter gt 3 cm) with mass effect diameter gt 3 cm) with mass effect
Local ThrombolysisLocal Thrombolysis
Femoral Jugular access was secured and a guiding Femoral Jugular access was secured and a guiding catheter was placed in the jugular bulb catheter was placed in the jugular bulb Mechanical Mechanical clot maceration clot maceration was done with the guidewire was done with the guidewire following which a microcatheter (was navigated and following which a microcatheter (was navigated and placed in the thrombosed segment of sinus confirmed placed in the thrombosed segment of sinus confirmed on a selective venogram on a selective venogram
Urokinase infusion Bolus dose of 2-6 lacs followed Urokinase infusion Bolus dose of 2-6 lacs followed by 60000 to 100000 units per hour along with by 60000 to 100000 units per hour along with periodic check venogram Along with maintenance periodic check venogram Along with maintenance systemic infusion of Heparinsystemic infusion of Heparin Other agents such as Other agents such as streptokinase altepase or rTPAstreptokinase altepase or rTPA can be also used can be also used
After thrombolysis patient should subjected to oral After thrombolysis patient should subjected to oral anticoagulation for six monthsanticoagulation for six months
Low-molecular-weight Low-molecular-weight heparinheparin
PharmacologyPharmacologyLMWH as its name suggests is a glycosaminoglycan that is approximatelyLMWH as its name suggests is a glycosaminoglycan that is approximately
one third the molecular weight of UFH It is derived from UFH through one third the molecular weight of UFH It is derived from UFH through variousvarious
depolymerization processes LMWH binds to antithrombin which in turn depolymerization processes LMWH binds to antithrombin which in turn
Neutralizes actors Xa and IIa Because LMWH lacks many of the longer Neutralizes actors Xa and IIa Because LMWH lacks many of the longer chains chains
required for binding to thrombin it has less ability to neutralize thrombin required for binding to thrombin it has less ability to neutralize thrombin
relativeto its ability to neutralize factor Xa LMWH also has less relativeto its ability to neutralize factor Xa LMWH also has less nonspecific nonspecific
binding to other proteins There is greater bioavailability with more binding to other proteins There is greater bioavailability with more predictable predictable
pharmacokinetics that eliminates the need for monitoring The smaller pharmacokinetics that eliminates the need for monitoring The smaller size also size also
allows for enhanced subcutaneous absorption when compared with UFHallows for enhanced subcutaneous absorption when compared with UFH
Three LMWH preparations are Three LMWH preparations are currently approved for use in the currently approved for use in the United States (1) enoxaparin (2) United States (1) enoxaparin (2) dalteparin and (3) tinzaparin dalteparin and (3) tinzaparin
They are all administered They are all administered subcutaneously at intervals of either subcutaneously at intervals of either once or twice daily for both once or twice daily for both prophylaxis and treatment dosesprophylaxis and treatment doses
Few Experiences of Few Experiences of ThrombolysisThrombolysis
Vickey 25 Yrs male patient presented Vickey 25 Yrs male patient presented with 12with 12thth day HO severe headache with day HO severe headache with right sided hemiplegiaright sided hemiplegia
MRI shows thrombosis of the superior MRI shows thrombosis of the superior sagittal left transverse left sigmoid sagittal left transverse left sigmoid sinuses and cortical veins in the fronto-sinuses and cortical veins in the fronto-parietal regions with eo haemorrhagic parietal regions with eo haemorrhagic infarct in the left cerebral hemisphere infarct in the left cerebral hemisphere with mass effect( Grade ndashV)with mass effect( Grade ndashV)
Sashi Srivastava 64 yrs FSashi Srivastava 64 yrs F In a follow up case of MRD with infra-renal In a follow up case of MRD with infra-renal
aortic abdominal and bilateral renal artery aortic abdominal and bilateral renal artery thrombosis renal angiogram shows filling thrombosis renal angiogram shows filling defects in the right Renal artery defects in the right Renal artery
Initially Renal angioplasty was done Initially Renal angioplasty was done Following angioplasty few thrombi are seem Following angioplasty few thrombi are seem to extends into the segmental branches and to extends into the segmental branches and causing blockage So Thrombolysis was causing blockage So Thrombolysis was plane to dissolve the run-out thrombi with plane to dissolve the run-out thrombi with urokinase urokinase
Rakesh 34yrsMRakesh 34yrsM Left SFA pseudoaneurysm with Left SFA pseudoaneurysm with
Covered stent placementCovered stent placement Pre operative antiplatelets with post Pre operative antiplatelets with post
procedure heparin Tirofiban procedure heparin Tirofiban followed by aspirin and clopidogrel followed by aspirin and clopidogrel were usedwere used
IAT may be a treatment option for selected patients IAT may be a treatment option for selected patients Possible selection criteria include Possible selection criteria include
presentation between 3 and 6 hours from symptom onsetpresentation between 3 and 6 hours from symptom onset major cerebral artery occlusion major cerebral artery occlusion severe neurologic deficits severe neurologic deficits high risk of systemic hemorrhage with IV rt-PA (eg recent high risk of systemic hemorrhage with IV rt-PA (eg recent
surgery) surgery) The MERCI (Mechanical Embolus Removal in Cerebral The MERCI (Mechanical Embolus Removal in Cerebral
Ischemia) retrievalIschemia) retrieval system system
Has been FDA-approved for recanalizing acutely occluded Has been FDA-approved for recanalizing acutely occluded cerebral arteries cerebral arteries
In the Multi-MERCI study patients who did not improve In the Multi-MERCI study patients who did not improve immediately after IV rt-PA underwent mechanical immediately after IV rt-PA underwent mechanical embolectomy within 8 hours of symptom onset embolectomy within 8 hours of symptom onset
Partial or complete recanalization occurred in 74 of Partial or complete recanalization occurred in 74 of patientspatients
with a symptomatic intracerebral hemorrhage (sICH) rate of with a symptomatic intracerebral hemorrhage (sICH) rate of 67 67
Mechanical embolectomy with the MERCI retriever may be a Mechanical embolectomy with the MERCI retriever may be a feasible and safe option for patients after IV rt-PAfeasible and safe option for patients after IV rt-PA
Penumbra stroke systemPenumbra stroke system This device combines two methods of clot This device combines two methods of clot
extraction aspiration and mechanical extraction aspiration and mechanical extraction extraction
First the clot is aspirated then a thrombus First the clot is aspirated then a thrombus removal ring can be used if necessary to removal ring can be used if necessary to remove remaining clot remove remaining clot
successful recanalizing 82successful recanalizing 82 Bridging therapyBridging therapy
06 mgkg IV rt-PA followed by IAT with IA rt-06 mgkg IV rt-PA followed by IAT with IA rt-PA (up to 20 mg)PA (up to 20 mg)
achieved a higher recanalization rateachieved a higher recanalization rate
Criteria for thrombolysis with rTPACriteria for thrombolysis with rTPA
Inclusion criteriaInclusion criteria Clinical signs and symptoms consistent with ischemic Clinical signs and symptoms consistent with ischemic
strokestroke Patient last seen normal within 3 hoursPatient last seen normal within 3 hours Measurable neurologic deficitMeasurable neurologic deficit
Exclusion criteriaExclusion criteria Any hemorrhage on neuroimaging (CT or MRI)Any hemorrhage on neuroimaging (CT or MRI) Symptoms suggestive of subarachnoid hemorrhageSymptoms suggestive of subarachnoid hemorrhage Seizure at stroke onset that is thought to contribute to Seizure at stroke onset that is thought to contribute to
neurologic deficitneurologic deficit Hypodensity greater than one third cerebral hemisphere Hypodensity greater than one third cerebral hemisphere
on CTon CT SBP greater than 185 mm Hg or DBP greater than 110 SBP greater than 185 mm Hg or DBP greater than 110
mm Hgmm Hg International normalized ratio (INR) greater than 17International normalized ratio (INR) greater than 17
Ischemic Stroke Ischemic Stroke Treatment ndash 2006Treatment ndash 2006
IV tissue plasminogen activator (tPA)IV tissue plasminogen activator (tPA) ndash ndash Only FDA-approved acute stroke drugOnly FDA-approved acute stroke drug ndash ndash 3 hour treatment window3 hour treatment window
MERCI - Concentric clot retrieval MERCI - Concentric clot retrieval devicedevice ndash ndash Rescue therapy - approved 2004Rescue therapy - approved 2004 ndash ndash Device approval (not outcomes-based)Device approval (not outcomes-based)
Off label approachesOff label approaches ndash ndash IV tPA after 3 hoursIV tPA after 3 hours ndash ndash IV-IA tPA sequential strategiesIV-IA tPA sequential strategies ndash ndash IA tPA clot angioplasty fragmentationIA tPA clot angioplasty fragmentation ndash ndash Ultrasound-assisted tPA lysisUltrasound-assisted tPA lysis
rt-PA Trials NINDSrt-PA Trials NINDS
Acute stroke - 624 patientsAcute stroke - 624 patients Treat within 3 hrsTreat within 3 hrs Intravenous 09 mgkg rt-PA vs placeboIntravenous 09 mgkg rt-PA vs placebo Hemorrhage 64 tPA 06 placeboHemorrhage 64 tPA 06 placebo Neurologic recovery better with tPA 30 Neurologic recovery better with tPA 30
more like to have minimal or no disabilitymore like to have minimal or no disability
First proven approved treatment for First proven approved treatment for strokestroke
Limitations of tPALimitations of tPA Only 4 of acute strokes receive tPAOnly 4 of acute strokes receive tPA (Kleindorfer et al Stroke 2004 35 e27-e29)(Kleindorfer et al Stroke 2004 35 e27-e29)
Only 22 of patients present within 3 hoursOnly 22 of patients present within 3 hours1048707 1048707 51 of these ineligible due to51 of these ineligible due to
bull bull Mild severityMild severity bull bull Medical or surgical historyMedical or surgical history bull bull Blood testsBlood tests
Sustained recanalization only 13Sustained recanalization only 13 (Alexandrov et al NEJM 2004 351 2170-8)(Alexandrov et al NEJM 2004 351 2170-8)
Concern for hemorrhageConcern for hemorrhage tPA potentiates apoptotic injury tPA potentiates apoptotic injury (Liu et al Nature Med 2004 101379-83)(Liu et al Nature Med 2004 101379-83)
PROACT II IA Lysis TrialPROACT II IA Lysis Trial Baseline 24 hours 8 days
Baseline 60 minutes 120 minutes
9mg IAProurokinase
Desmoteplase Trials DEDAS Desmoteplase Trials DEDAS DIASDIAS
Trial OverviewTrial Overview Double blind randomized placebo Double blind randomized placebo
controlled trialscontrolled trials IV delivery 3-9 hour time windowIV delivery 3-9 hour time window Plasminogen activator ndash from Plasminogen activator ndash from vampire bat vampire bat
salivasaliva Selection based on PWI-DWI MismatchSelection based on PWI-DWI Mismatch
MRI InclusionMRI Inclusion PWI defect at least 2 cm AND ~20 larger PWI defect at least 2 cm AND ~20 larger
than DWIthan DWI PWI should be obvious even visible on PWI should be obvious even visible on
raw imagesraw imagesMRI ExclusionMRI Exclusion
DWI gt 13 MCADWI gt 13 MCA MRA ICA occlusionMRA ICA occlusion
Desmoteplase ndash DIAS Desmoteplase ndash DIAS ResultsResults
Mechanical Thrombolysis Mechanical Thrombolysis devicesdevices
mechanical thrombolysis potentially extends the treatment mechanical thrombolysis potentially extends the treatment window because they act promptly at the site of the thrombuswindow because they act promptly at the site of the thrombus
The devices can retrieve large clots that pharmaceutical agents The devices can retrieve large clots that pharmaceutical agents may not successfully lysemay not successfully lyse
Patients treated with IV tPA may be considered for treatment of Patients treated with IV tPA may be considered for treatment of residual clot with some of these devicesresidual clot with some of these devices
suction-creating saline jets suction-creating saline jets laser energy ultrasound laser energy ultrasound a corkscrew apparatus to treat strokesa corkscrew apparatus to treat strokes The AngioJet systemThe AngioJet system uses saline jets that are directed back into the catheter to uses saline jets that are directed back into the catheter to
create a low-pressure zone around the catheter tip inducing create a low-pressure zone around the catheter tip inducing suction suction
The clot is pulled into the exhaust lumen and removed from the The clot is pulled into the exhaust lumen and removed from the vessel Although US Food and Drug Administration (FDA) has vessel Although US Food and Drug Administration (FDA) has approved this device for use in arteriovenous dialysis grafts and approved this device for use in arteriovenous dialysis grafts and fistulae and for the treatment of coronary arteries saphenous fistulae and for the treatment of coronary arteries saphenous vein grafts and peripheral vessels clinical trials for the vein grafts and peripheral vessels clinical trials for the treatment of acute stroke are no longer in progress treatment of acute stroke are no longer in progress
Most devices are used in cerebral vessels that 2-5 mm
The Latis laser device The Latis laser device used laser energy to ablate clots used laser energy to ablate clots Arteries 2-5 mm in diameter could be Arteries 2-5 mm in diameter could be
treated including the ICA M1 or M2 treated including the ICA M1 or M2 branch of the MCA A1 branch of the branch of the MCA A1 branch of the anterior cerebral artery (ACA) basilar anterior cerebral artery (ACA) basilar artery posterior cerebral artery (PCA) artery posterior cerebral artery (PCA) and vertebral and vertebral
Patients could receive treatment as late Patients could receive treatment as late as 8 hours after symptom onset in the as 8 hours after symptom onset in the anterior circulation and within 24 hours in anterior circulation and within 24 hours in the posterior circulation the posterior circulation
Endovascular Photo Acoustic Endovascular Photo Acoustic Recanalization (EPAR) Recanalization (EPAR)
A laser power source generated energy for the A laser power source generated energy for the systemsystem
The energy was delivered by means of The energy was delivered by means of fiberoptics to the tip of the catheter at the fiberoptics to the tip of the catheter at the treatment sitetreatment site
Absorption of laser light by darkly pigmented Absorption of laser light by darkly pigmented materials (ie the clot) occurred inside the 1-mm materials (ie the clot) occurred inside the 1-mm catheter tipcatheter tip
the system was designed to minimize scattering the system was designed to minimize scattering of laser light of laser light
Absorption converted photo energy to acoustic Absorption converted photo energy to acoustic energy which then emulsified the clot inside the energy which then emulsified the clot inside the catheter tip catheter tip
EKOS ultrasound( the EKOS ultrasound( the Ultrasound Thrombolytic Ultrasound Thrombolytic
Infusion Catheter) Infusion Catheter) combines the use of a distal ultrasound transducer with combines the use of a distal ultrasound transducer with
infusion of a thrombolytic agent through the infusion of a thrombolytic agent through the microcathetermicrocatheter
Ultrasound changes the structure of the clot to Ultrasound changes the structure of the clot to temporarily increase its permeability while providing an temporarily increase its permeability while providing an acoustic pressure gradient to move the drug into the clot acoustic pressure gradient to move the drug into the clot to speed its dissolution to speed its dissolution
The EKOS catheter is placed in the proximal portion of the The EKOS catheter is placed in the proximal portion of the clot clot
After a 2-mg bolus of tPA was injected through the After a 2-mg bolus of tPA was injected through the catheter catheter
the patient received a continuous infusion of IA tPA 03 the patient received a continuous infusion of IA tPA 03 mgmin to a maximum of 20 mg and simultaneous mgmin to a maximum of 20 mg and simultaneous ultrasound transmission for as long as 60 minutes ultrasound transmission for as long as 60 minutes
One patient was treated with a total of 4 units of One patient was treated with a total of 4 units of recombinant reteplase (Retavase) hand-injected over 60 recombinant reteplase (Retavase) hand-injected over 60 minutes minutes
Penumbra system Penumbra system The Penumbra system (Penumbra Inc) provides a dual The Penumbra system (Penumbra Inc) provides a dual
approach to clot extraction using aspiration followed by approach to clot extraction using aspiration followed by clot retrieval with a ring device if needed clot retrieval with a ring device if needed
Mechanical Embolus Removal in Cerebral Ischemia Mechanical Embolus Removal in Cerebral Ischemia (MERCI)(MERCI)
a corkscrew-like apparatus to remove blood clots from a corkscrew-like apparatus to remove blood clots from the brain in patients experiencing an ischemic stroke the brain in patients experiencing an ischemic stroke
The corkscrew itself resides in the catheter tip which The corkscrew itself resides in the catheter tip which shields it from the wall of the vessel until it is ready to be shields it from the wall of the vessel until it is ready to be burrowed into the clot Once lodged in the clot the device burrowed into the clot Once lodged in the clot the device and clot are withdrawn from the vessel and clot are withdrawn from the vessel
Snarelike devicesSnarelike devices Snares such as the Neuronet snare (Guidant Snares such as the Neuronet snare (Guidant
Endovascular Santa Clara CA) have been developed Endovascular Santa Clara CA) have been developed specifically for use in the treatment of strokes specifically for use in the treatment of strokes
These devices are simple in design and do not require the These devices are simple in design and do not require the clot to be amenable to emulsification clot to be amenable to emulsification
X-Sizer deviceX-Sizer device a device with small moving blades at the a device with small moving blades at the
catheter tip catheter tip This device the X-Sizer device (EndiCor Medical This device the X-Sizer device (EndiCor Medical
San Clemente CA) can be used to excise the San Clemente CA) can be used to excise the thrombus and aspirate it thrombus and aspirate it
The device was being evaluated in randomized The device was being evaluated in randomized studies of coronary vessels and in a registry of studies of coronary vessels and in a registry of patients with acute myocardial infarctionpatients with acute myocardial infarction
Although the manufacturer had modified the Although the manufacturer had modified the device for use in cerebral vessels a safety and device for use in cerebral vessels a safety and feasibility study was indefinitely suspended after feasibility study was indefinitely suspended after only 1 patient was treated with the device in only 1 patient was treated with the device in Europe Europe
Suction thrombectomySuction thrombectomy This method of mechanical thrombolysis is one of the This method of mechanical thrombolysis is one of the
simplestsimplest In this readily available technique suction is applied with In this readily available technique suction is applied with
a syringe to remove thrombus in the ICA a syringe to remove thrombus in the ICA It requires no other devicesIt requires no other devices A catheter with a large inner diameter (Brite Tip Cordis A catheter with a large inner diameter (Brite Tip Cordis
Corporation Miami FL) was placed in the symptomatic Corporation Miami FL) was placed in the symptomatic vessel and navigated over a guidewire into the thrombusvessel and navigated over a guidewire into the thrombus
A 60-mL syringe was used to aspirate the thrombus A 60-mL syringe was used to aspirate the thrombus Each patient required angioplasty and stenting of carotid Each patient required angioplasty and stenting of carotid
bifurcation stenosis and received daily aspirin and bifurcation stenosis and received daily aspirin and ticlopidine after the procedure No complications ticlopidine after the procedure No complications occurred occurred
Summary Acute Stroke Summary Acute Stroke ImagingImaging
PhysiologyPhysiology importance collaterals importance collaterals
ndash ndashGrowing role for perfusion Growing role for perfusion assessmentassessment
tPAtPA guidelines amp limitations guidelines amp limitations Signs on CT amp MRSigns on CT amp MR follow physiology follow physiology Stroke trialsStroke trials PWI-DWI mismatch PWI-DWI mismatch
ndash ndashTreat based on physiology not timeTreat based on physiology not time ProtocolsProtocols should be fast and should be fast and
comprehensivecomprehensive
MonitoringMonitoring
Bleeding timeBleeding time
Optical aggregometryOptical aggregometry
Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay
Bleeding timeBleeding time
Requires a skin incision (usually made on the ear lobe or Requires a skin incision (usually made on the ear lobe or forearm offorearm of
a depth that results in disruption of capillary loops and a depth that results in disruption of capillary loops and small vessels)small vessels)
AdvantagesAdvantages Universally availableUniversally available Relatively simple techniquesRelatively simple techniques Can be performed bedsideCan be performed bedside
DisadvantagesDisadvantages Insensitive inaccurate non-specific techniqueInsensitive inaccurate non-specific technique
Poorly reproducible (as depends on multiple variables)Poorly reproducible (as depends on multiple variables)
Optical aggregometryOptical aggregometry
Gold standard assay for platelet functionGold standard assay for platelet function Agonist induced aggregation is measuredAgonist induced aggregation is measured Different agonist are available for different Different agonist are available for different
agentsagents However require unique expertise and are not However require unique expertise and are not
universally availableuniversally available Aspirin measured with ADP or AA(gt70 Aspirin measured with ADP or AA(gt70
aggregation so resistance)aggregation so resistance) Clopidogrel( ADP gt 90 aggregation means Clopidogrel( ADP gt 90 aggregation means
resistance) resistance)
Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay
Can be performed bed sideCan be performed bed side Different assay devices with different Different assay devices with different
agonist are used for each of different agonist are used for each of different antiplatelet agents antiplatelet agents
For Aspirin AA is used (result is reported as aspirin For Aspirin AA is used (result is reported as aspirin reaction units [ARU] ARUgt 550 indicates non-reaction units [ARU] ARUgt 550 indicates non-responsiveness)responsiveness)
Verify IIbIIIa assay device uses TRAP as agonist for Verify IIbIIIa assay device uses TRAP as agonist for Abciximab and TirofibanAbciximab and Tirofiban
Practical Applications Practical Applications related to specific related to specific
Neurovascular Neurovascular interventionsinterventions
Acute ischemic StrokeAcute ischemic Stroke When an artery occludes neurons are affected When an artery occludes neurons are affected
differently depending upon the amount of residual blood differently depending upon the amount of residual blood flowflow
Normal cerebral blood flow is greater than 50 mL100 Normal cerebral blood flow is greater than 50 mL100 mgminmgmin
Once blood flow decreases to less than 20 mL100 Once blood flow decreases to less than 20 mL100 mgmin infarction occursmgmin infarction occurs
If blood flow decreases to less than 10 mL100 mgmin If blood flow decreases to less than 10 mL100 mgmin irreversible neuronal death occurs rapidly irreversible neuronal death occurs rapidly
Blood flow between 11 and 20 mL100 mgmin is thought Blood flow between 11 and 20 mL100 mgmin is thought to represent the ischemic penumbra an area where the to represent the ischemic penumbra an area where the cells are functionally silent because of ischemia but are cells are functionally silent because of ischemia but are still able to recover if blood flow is restored still able to recover if blood flow is restored
Many acute stroke therapies are targeted toward Many acute stroke therapies are targeted toward restoring flow or function to the ischemic penumbrarestoring flow or function to the ischemic penumbra
Therapeutic window in Therapeutic window in management of acute Ischemic management of acute Ischemic
StrokeStrokeThe early diagnosis of ischemic stroke is critical to the The early diagnosis of ischemic stroke is critical to the
with only a narrow therapeutic window in the first few with only a narrow therapeutic window in the first few hours following stroke ictushours following stroke ictus
Diagnosis in the first 3 hours postictus provides the Diagnosis in the first 3 hours postictus provides the opportunity for intravenous or intraarterial thrombolysis opportunity for intravenous or intraarterial thrombolysis and intra-arterial clot mechanical treatment which and intra-arterial clot mechanical treatment which improve the outcome improve the outcome
Diagnosis in the time period between 3 and 6 hours Diagnosis in the time period between 3 and 6 hours provides an opportunity for intra-arterial thrombolysis provides an opportunity for intra-arterial thrombolysis and mechanical treatment and mechanical treatment
Involvement of the posterior circulation especially the Involvement of the posterior circulation especially the basilar artery is treated by some regardless of time of basilar artery is treated by some regardless of time of onset or up until 12 to 24 hours in some practices This is onset or up until 12 to 24 hours in some practices This is related to the potentially high mortality and morbidity related to the potentially high mortality and morbidity associated with basilar artery thrombosisassociated with basilar artery thrombosis
Infarct evaluation on angiographyInfarct evaluation on angiography(CT angiography and catheter (CT angiography and catheter
angiography)angiography)CTA is an excellent first-line examination for CTA is an excellent first-line examination for
evaluation of the head and neck arteries evaluation of the head and neck arteries In comparison with catheter angiography In comparison with catheter angiography
what it gives up in resolution and dynamic what it gives up in resolution and dynamic properties it makes up for with rapid properties it makes up for with rapid acquisition of a 3-D dataset and the potential acquisition of a 3-D dataset and the potential for assessment of whole-brain perfusion and for assessment of whole-brain perfusion and better parenchymal evaluationbetter parenchymal evaluation
Moreover CTA illustrates not only arterial Moreover CTA illustrates not only arterial stenosis or occlusion but also the vessel wall stenosis or occlusion but also the vessel wall This factor is most important for evaluation of This factor is most important for evaluation of intramural dissection and thrombosed intramural dissection and thrombosed aneurysms which may both complicate aneurysms which may both complicate evaluation of stroke patientsevaluation of stroke patients
Early angiographic signs of strokes Early angiographic signs of strokes both CTA both CTA and DSA and DSA
Vessel occlusion or cutoff related to Vessel occlusion or cutoff related to thromboembolithromboemboli
aneurysms aneurysms arterial dissection arterial dissection Meniscus or flattened shape to clot Meniscus or flattened shape to clot
(recent) versus reverse meniscus (older)(recent) versus reverse meniscus (older) tram track (nonocclusive or recanalized tram track (nonocclusive or recanalized
clot) clot) delayed (antegrade) flow (manifest as delayed (antegrade) flow (manifest as
decreased whole-brain perfusion on CTA)decreased whole-brain perfusion on CTA) retrograde collateral flowretrograde collateral flow
Non-occlusive left MCA thrombus on 3-D imaging performed from CTA source data and was confirmed at catheter angiography
Therapy to be started within a 6-hr Therapy to be started within a 6-hr time to treatment (TTT) window time to treatment (TTT) window (while in case of IV thrombolysis (while in case of IV thrombolysis therapy to be started with in 3hrs)therapy to be started with in 3hrs)
Exclusion criteria Exclusion criteria Rapidly improving neurologic deficit or Rapidly improving neurologic deficit or Sustained blood pressure of gt180100 Sustained blood pressure of gt180100 Hemorrhage is detected on CTHemorrhage is detected on CT Infarct involving gt more than 13 rd Infarct involving gt more than 13 rd
territory of MCAterritory of MCA MRADWI-Perfusion mismatchlt 20MRADWI-Perfusion mismatchlt 20 Definite hypodensity on CTDefinite hypodensity on CT
Intra-arterial Thrombolysis
Fibrinolytics + AntiplateletsFibrinolytics + Antiplatelets
PlasminogenPlasminogen activators through fibrinolysis exposes activators through fibrinolysis exposes free thrombin and paradoxically stimulatesfree thrombin and paradoxically stimulates platelet platelet aggregation which leads to formation of aaggregation which leads to formation of a platelet platelet thrombus (white clot) thrombus (white clot)
This new thrombus is relatively resistant to This new thrombus is relatively resistant to fibrinolyticsfibrinolytics
So new regimen in case of acute stroke isSo new regimen in case of acute stroke is fibrinolytics + antiplatelet drugsfibrinolytics + antiplatelet drugs
rtPA + IIbIIIa inhibitors( tirofiban rtPA + IIbIIIa inhibitors( tirofiban abciximab) orabciximab) or
Urokinase + IIbIIIa Urokinase + IIbIIIa inhibitors( tirofiban abciximab)inhibitors( tirofiban abciximab)
Intra-arterial Thrombolysis Tirofiban (04 microgkgmin bolus for 3 min followed by Tirofiban (04 microgkgmin bolus for 3 min followed by
0125 ugkgmin)0125 ugkgmin)
++
Heparin (2000ndash3000 IU bolus followed by Heparin (2000ndash3000 IU bolus followed by 1000 IUhour infusion 1000 IUhour infusion
with ACT maintained bw 200-300) throughout the with ACT maintained bw 200-300) throughout the interventional procedure and for 24ndash48 hours thereafter when interventional procedure and for 24ndash48 hours thereafter when there is neither intraprocedural bleeding nor suspicion of there is neither intraprocedural bleeding nor suspicion of increased risk of bleeding increased risk of bleeding
Maximum dose of Urokinase Maximum dose of Urokinase Anterior circulation stroke - 500000 IU (mean 400000 Anterior circulation stroke - 500000 IU (mean 400000
IU range 300000ndash500000 IU)IU range 300000ndash500000 IU) Posterior circulation stroke -1000000 IU (mean 837000 Posterior circulation stroke -1000000 IU (mean 837000
IU range 300000ndash1000000 IU)IU range 300000ndash1000000 IU)American Journal of NeuroradiologyAmerican Journal of Neuroradiology 262595-2601 2005262595-2601 2005
Intravenous ThrombolysisIntravenous Thrombolysis
The first method to restore cerebral The first method to restore cerebral perfusion is clot lysis with the goal perfusion is clot lysis with the goal of re-establishing blood flow to the of re-establishing blood flow to the affected tissue affected tissue
IV thrombolysis rt-PA is the only IV thrombolysis rt-PA is the only FDA- approved treatment for AIS FDA- approved treatment for AIS
Fibrinolysis is enhanced powerfully Fibrinolysis is enhanced powerfully by rt-PAby rt-PA
Intravenous rTPA Intravenous rTPA administration administration protocolprotocol
Total dose of rt-PA 09 mgkg (maximum dose Total dose of rt-PA 09 mgkg (maximum dose 90 mg)90 mg)
Give 10 as initial IV bolusGive 10 as initial IV bolus Infuse remainder over 1 hourInfuse remainder over 1 hour Admit patient to an ICU or stroke unit for Admit patient to an ICU or stroke unit for
monitoringmonitoring Neurologic assessments every 15 minutes Neurologic assessments every 15 minutes
during infusion then every 30 minutes for next during infusion then every 30 minutes for next 6 hours then every hour until 24hours after 6 hours then every hour until 24hours after treatmenttreatment
Favorable Outcome vs Treatment Time Favorable Outcome vs Treatment Time with IV rTPAwith IV rTPA
Protocol limit = 3 hrs
Benefit ~ 45 hrs
Thromboembolism During coilingThromboembolism During coiling Most feared and frequent complication Most feared and frequent complication Reported incidence - Approx 7 Reported incidence - Approx 7 SourcesSources of Thromboembolism are of Thromboembolism are
- Clots at the aneurysmal neck during or immediately- Clots at the aneurysmal neck during or immediately after after embolization embolization
- Thrombus forming on catheters during- Thrombus forming on catheters during proceduresprocedures
- Stenosis of an adjacent artery dt coil mass- Stenosis of an adjacent artery dt coil mass or herniationor herniation
- Migration of intraaneurysmal- Migration of intraaneurysmal thrombus during coil thrombus during coil placement placement
- Slow flow dt vasospasm - Slow flow dt vasospasm
- Rare and unlikely causes are hypercoagulable- Rare and unlikely causes are hypercoagulable state such state such as antiphospholipid antibody syndrome or due to HITas antiphospholipid antibody syndrome or due to HIT
Occur more often with wide-necked aneurysms (dt Occur more often with wide-necked aneurysms (dt increased exposed surface area of thrombogenic coil increased exposed surface area of thrombogenic coil material)material)
Current regimen of endovascular Current regimen of endovascular managementmanagement
The The glycoprotein IIbIIIa antagonist tirofiban glycoprotein IIbIIIa antagonist tirofiban (04 (04 microgkgmin bolus for 30 minutes followed by infusion of microgkgmin bolus for 30 minutes followed by infusion of 0125 ugkgmin until the thrombus dissolved) 0125 ugkgmin until the thrombus dissolved)
Intraarterial thrombolysis with Intraarterial thrombolysis with urokinase or r- TPA urokinase or r- TPA increase of intravenous (IV) heparin (measured by increase of intravenous (IV) heparin (measured by
ACT) ACT) Intravenous aspirin Intravenous aspirin
Coil-related platelet aggregation (white clot) is Coil-related platelet aggregation (white clot) is unlikely to respond to fibrinolytics but has a high risk unlikely to respond to fibrinolytics but has a high risk of hemorrhage (In ISAT) all 5 patients who had of hemorrhage (In ISAT) all 5 patients who had received thrombolytic therapy with tPA to treat a received thrombolytic therapy with tPA to treat a thromboembolic complication after endovascular thromboembolic complication after endovascular treatment rebleed and all of these patients died)treatment rebleed and all of these patients died)
IntracranialIntracranial Stenting Stenting Metallic foreign body such as stent will accumulate Metallic foreign body such as stent will accumulate
thrombus in the absence of platelet inhibitionthrombus in the absence of platelet inhibition Antiplatelet drugs are important to prevent peri or Antiplatelet drugs are important to prevent peri or
post-interventional thromboembolic eventspost-interventional thromboembolic events Optimal treatment regimens has not been determined Optimal treatment regimens has not been determined
but usually but usually Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-
procedureprocedureOrOr
Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on
morning of proceduremorning of procedure
If need to use stent is not pre-planned thanIf need to use stent is not pre-planned than
Abciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkgAbciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkg IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)
Glycoprotein IIbIIIa inhibitor are not used routinely during elective Glycoprotein IIbIIIa inhibitor are not used routinely during elective stenting procedure dt increased risk of ICH stenting procedure dt increased risk of ICH
Carotid StentingCarotid Stenting
Pre-procedurePre-procedure
Double Antiplatelet therapy is routinely given Double Antiplatelet therapy is routinely given beginning at least 3beginning at least 3
days before the proceduredays before the procedure
Aspirin 325mgd+Clopidogrel 75mgdAspirin 325mgd+Clopidogrel 75mgd During procedureDuring procedure
Heparin is given with target clotting time of 250-Heparin is given with target clotting time of 250-300sec300sec
Post-procedure Post-procedure
Aspirin 325mg is continued indefinitely and Aspirin 325mg is continued indefinitely and
Clopidogrel 75mgd for at least 6 weeks Clopidogrel 75mgd for at least 6 weeks
Inclusion criteria for Local ThrombolysisInclusion criteria for Local Thrombolysis a)a) Patients in severe clinical grade on admission Patients in severe clinical grade on admission
with evidence of dural venous sinus with evidence of dural venous sinus thrombosis and restrictive venous outflow on thrombosis and restrictive venous outflow on cerebral angiogramcerebral angiogram
b)b) Patients in clinical grade 3 worsening on Patients in clinical grade 3 worsening on heparin therapy Restriction to venous heparin therapy Restriction to venous outflow was defined as an increase in brain outflow was defined as an increase in brain circulation time gt 12 s delay in the drainage circulation time gt 12 s delay in the drainage of cortical veins with cortical veins hanging of cortical veins with cortical veins hanging in spacein space
Treatment Options for Venous Thrombosis
CT Grading for Venous ThrombosisCT Grading for Venous Thrombosis Grade I no parenchymal change Grade I no parenchymal change
(hyperdense (hyperdense sinuses cortical veins empty sinuses cortical veins empty delta sign)delta sign)
Grade II non hemorrhagic venous infarct Grade II non hemorrhagic venous infarct without mass effect without mass effect
Grade III non-hemorrhagic infarct with Grade III non-hemorrhagic infarct with mass effectmass effect
Grade IV hemorrhagic venous infarct (max Grade IV hemorrhagic venous infarct (max diameter lt 3 cm) with no mass effectdiameter lt 3 cm) with no mass effect
Grade V hemorrhagic venous infarct (max Grade V hemorrhagic venous infarct (max diameter gt 3 cm) with mass effect diameter gt 3 cm) with mass effect
Local ThrombolysisLocal Thrombolysis
Femoral Jugular access was secured and a guiding Femoral Jugular access was secured and a guiding catheter was placed in the jugular bulb catheter was placed in the jugular bulb Mechanical Mechanical clot maceration clot maceration was done with the guidewire was done with the guidewire following which a microcatheter (was navigated and following which a microcatheter (was navigated and placed in the thrombosed segment of sinus confirmed placed in the thrombosed segment of sinus confirmed on a selective venogram on a selective venogram
Urokinase infusion Bolus dose of 2-6 lacs followed Urokinase infusion Bolus dose of 2-6 lacs followed by 60000 to 100000 units per hour along with by 60000 to 100000 units per hour along with periodic check venogram Along with maintenance periodic check venogram Along with maintenance systemic infusion of Heparinsystemic infusion of Heparin Other agents such as Other agents such as streptokinase altepase or rTPAstreptokinase altepase or rTPA can be also used can be also used
After thrombolysis patient should subjected to oral After thrombolysis patient should subjected to oral anticoagulation for six monthsanticoagulation for six months
Low-molecular-weight Low-molecular-weight heparinheparin
PharmacologyPharmacologyLMWH as its name suggests is a glycosaminoglycan that is approximatelyLMWH as its name suggests is a glycosaminoglycan that is approximately
one third the molecular weight of UFH It is derived from UFH through one third the molecular weight of UFH It is derived from UFH through variousvarious
depolymerization processes LMWH binds to antithrombin which in turn depolymerization processes LMWH binds to antithrombin which in turn
Neutralizes actors Xa and IIa Because LMWH lacks many of the longer Neutralizes actors Xa and IIa Because LMWH lacks many of the longer chains chains
required for binding to thrombin it has less ability to neutralize thrombin required for binding to thrombin it has less ability to neutralize thrombin
relativeto its ability to neutralize factor Xa LMWH also has less relativeto its ability to neutralize factor Xa LMWH also has less nonspecific nonspecific
binding to other proteins There is greater bioavailability with more binding to other proteins There is greater bioavailability with more predictable predictable
pharmacokinetics that eliminates the need for monitoring The smaller pharmacokinetics that eliminates the need for monitoring The smaller size also size also
allows for enhanced subcutaneous absorption when compared with UFHallows for enhanced subcutaneous absorption when compared with UFH
Three LMWH preparations are Three LMWH preparations are currently approved for use in the currently approved for use in the United States (1) enoxaparin (2) United States (1) enoxaparin (2) dalteparin and (3) tinzaparin dalteparin and (3) tinzaparin
They are all administered They are all administered subcutaneously at intervals of either subcutaneously at intervals of either once or twice daily for both once or twice daily for both prophylaxis and treatment dosesprophylaxis and treatment doses
Few Experiences of Few Experiences of ThrombolysisThrombolysis
Vickey 25 Yrs male patient presented Vickey 25 Yrs male patient presented with 12with 12thth day HO severe headache with day HO severe headache with right sided hemiplegiaright sided hemiplegia
MRI shows thrombosis of the superior MRI shows thrombosis of the superior sagittal left transverse left sigmoid sagittal left transverse left sigmoid sinuses and cortical veins in the fronto-sinuses and cortical veins in the fronto-parietal regions with eo haemorrhagic parietal regions with eo haemorrhagic infarct in the left cerebral hemisphere infarct in the left cerebral hemisphere with mass effect( Grade ndashV)with mass effect( Grade ndashV)
Sashi Srivastava 64 yrs FSashi Srivastava 64 yrs F In a follow up case of MRD with infra-renal In a follow up case of MRD with infra-renal
aortic abdominal and bilateral renal artery aortic abdominal and bilateral renal artery thrombosis renal angiogram shows filling thrombosis renal angiogram shows filling defects in the right Renal artery defects in the right Renal artery
Initially Renal angioplasty was done Initially Renal angioplasty was done Following angioplasty few thrombi are seem Following angioplasty few thrombi are seem to extends into the segmental branches and to extends into the segmental branches and causing blockage So Thrombolysis was causing blockage So Thrombolysis was plane to dissolve the run-out thrombi with plane to dissolve the run-out thrombi with urokinase urokinase
Rakesh 34yrsMRakesh 34yrsM Left SFA pseudoaneurysm with Left SFA pseudoaneurysm with
Covered stent placementCovered stent placement Pre operative antiplatelets with post Pre operative antiplatelets with post
procedure heparin Tirofiban procedure heparin Tirofiban followed by aspirin and clopidogrel followed by aspirin and clopidogrel were usedwere used
IAT may be a treatment option for selected patients IAT may be a treatment option for selected patients Possible selection criteria include Possible selection criteria include
presentation between 3 and 6 hours from symptom onsetpresentation between 3 and 6 hours from symptom onset major cerebral artery occlusion major cerebral artery occlusion severe neurologic deficits severe neurologic deficits high risk of systemic hemorrhage with IV rt-PA (eg recent high risk of systemic hemorrhage with IV rt-PA (eg recent
surgery) surgery) The MERCI (Mechanical Embolus Removal in Cerebral The MERCI (Mechanical Embolus Removal in Cerebral
Ischemia) retrievalIschemia) retrieval system system
Has been FDA-approved for recanalizing acutely occluded Has been FDA-approved for recanalizing acutely occluded cerebral arteries cerebral arteries
In the Multi-MERCI study patients who did not improve In the Multi-MERCI study patients who did not improve immediately after IV rt-PA underwent mechanical immediately after IV rt-PA underwent mechanical embolectomy within 8 hours of symptom onset embolectomy within 8 hours of symptom onset
Partial or complete recanalization occurred in 74 of Partial or complete recanalization occurred in 74 of patientspatients
with a symptomatic intracerebral hemorrhage (sICH) rate of with a symptomatic intracerebral hemorrhage (sICH) rate of 67 67
Mechanical embolectomy with the MERCI retriever may be a Mechanical embolectomy with the MERCI retriever may be a feasible and safe option for patients after IV rt-PAfeasible and safe option for patients after IV rt-PA
Penumbra stroke systemPenumbra stroke system This device combines two methods of clot This device combines two methods of clot
extraction aspiration and mechanical extraction aspiration and mechanical extraction extraction
First the clot is aspirated then a thrombus First the clot is aspirated then a thrombus removal ring can be used if necessary to removal ring can be used if necessary to remove remaining clot remove remaining clot
successful recanalizing 82successful recanalizing 82 Bridging therapyBridging therapy
06 mgkg IV rt-PA followed by IAT with IA rt-06 mgkg IV rt-PA followed by IAT with IA rt-PA (up to 20 mg)PA (up to 20 mg)
achieved a higher recanalization rateachieved a higher recanalization rate
Criteria for thrombolysis with rTPACriteria for thrombolysis with rTPA
Inclusion criteriaInclusion criteria Clinical signs and symptoms consistent with ischemic Clinical signs and symptoms consistent with ischemic
strokestroke Patient last seen normal within 3 hoursPatient last seen normal within 3 hours Measurable neurologic deficitMeasurable neurologic deficit
Exclusion criteriaExclusion criteria Any hemorrhage on neuroimaging (CT or MRI)Any hemorrhage on neuroimaging (CT or MRI) Symptoms suggestive of subarachnoid hemorrhageSymptoms suggestive of subarachnoid hemorrhage Seizure at stroke onset that is thought to contribute to Seizure at stroke onset that is thought to contribute to
neurologic deficitneurologic deficit Hypodensity greater than one third cerebral hemisphere Hypodensity greater than one third cerebral hemisphere
on CTon CT SBP greater than 185 mm Hg or DBP greater than 110 SBP greater than 185 mm Hg or DBP greater than 110
mm Hgmm Hg International normalized ratio (INR) greater than 17International normalized ratio (INR) greater than 17
Ischemic Stroke Ischemic Stroke Treatment ndash 2006Treatment ndash 2006
IV tissue plasminogen activator (tPA)IV tissue plasminogen activator (tPA) ndash ndash Only FDA-approved acute stroke drugOnly FDA-approved acute stroke drug ndash ndash 3 hour treatment window3 hour treatment window
MERCI - Concentric clot retrieval MERCI - Concentric clot retrieval devicedevice ndash ndash Rescue therapy - approved 2004Rescue therapy - approved 2004 ndash ndash Device approval (not outcomes-based)Device approval (not outcomes-based)
Off label approachesOff label approaches ndash ndash IV tPA after 3 hoursIV tPA after 3 hours ndash ndash IV-IA tPA sequential strategiesIV-IA tPA sequential strategies ndash ndash IA tPA clot angioplasty fragmentationIA tPA clot angioplasty fragmentation ndash ndash Ultrasound-assisted tPA lysisUltrasound-assisted tPA lysis
rt-PA Trials NINDSrt-PA Trials NINDS
Acute stroke - 624 patientsAcute stroke - 624 patients Treat within 3 hrsTreat within 3 hrs Intravenous 09 mgkg rt-PA vs placeboIntravenous 09 mgkg rt-PA vs placebo Hemorrhage 64 tPA 06 placeboHemorrhage 64 tPA 06 placebo Neurologic recovery better with tPA 30 Neurologic recovery better with tPA 30
more like to have minimal or no disabilitymore like to have minimal or no disability
First proven approved treatment for First proven approved treatment for strokestroke
Limitations of tPALimitations of tPA Only 4 of acute strokes receive tPAOnly 4 of acute strokes receive tPA (Kleindorfer et al Stroke 2004 35 e27-e29)(Kleindorfer et al Stroke 2004 35 e27-e29)
Only 22 of patients present within 3 hoursOnly 22 of patients present within 3 hours1048707 1048707 51 of these ineligible due to51 of these ineligible due to
bull bull Mild severityMild severity bull bull Medical or surgical historyMedical or surgical history bull bull Blood testsBlood tests
Sustained recanalization only 13Sustained recanalization only 13 (Alexandrov et al NEJM 2004 351 2170-8)(Alexandrov et al NEJM 2004 351 2170-8)
Concern for hemorrhageConcern for hemorrhage tPA potentiates apoptotic injury tPA potentiates apoptotic injury (Liu et al Nature Med 2004 101379-83)(Liu et al Nature Med 2004 101379-83)
PROACT II IA Lysis TrialPROACT II IA Lysis Trial Baseline 24 hours 8 days
Baseline 60 minutes 120 minutes
9mg IAProurokinase
Desmoteplase Trials DEDAS Desmoteplase Trials DEDAS DIASDIAS
Trial OverviewTrial Overview Double blind randomized placebo Double blind randomized placebo
controlled trialscontrolled trials IV delivery 3-9 hour time windowIV delivery 3-9 hour time window Plasminogen activator ndash from Plasminogen activator ndash from vampire bat vampire bat
salivasaliva Selection based on PWI-DWI MismatchSelection based on PWI-DWI Mismatch
MRI InclusionMRI Inclusion PWI defect at least 2 cm AND ~20 larger PWI defect at least 2 cm AND ~20 larger
than DWIthan DWI PWI should be obvious even visible on PWI should be obvious even visible on
raw imagesraw imagesMRI ExclusionMRI Exclusion
DWI gt 13 MCADWI gt 13 MCA MRA ICA occlusionMRA ICA occlusion
Desmoteplase ndash DIAS Desmoteplase ndash DIAS ResultsResults
Mechanical Thrombolysis Mechanical Thrombolysis devicesdevices
mechanical thrombolysis potentially extends the treatment mechanical thrombolysis potentially extends the treatment window because they act promptly at the site of the thrombuswindow because they act promptly at the site of the thrombus
The devices can retrieve large clots that pharmaceutical agents The devices can retrieve large clots that pharmaceutical agents may not successfully lysemay not successfully lyse
Patients treated with IV tPA may be considered for treatment of Patients treated with IV tPA may be considered for treatment of residual clot with some of these devicesresidual clot with some of these devices
suction-creating saline jets suction-creating saline jets laser energy ultrasound laser energy ultrasound a corkscrew apparatus to treat strokesa corkscrew apparatus to treat strokes The AngioJet systemThe AngioJet system uses saline jets that are directed back into the catheter to uses saline jets that are directed back into the catheter to
create a low-pressure zone around the catheter tip inducing create a low-pressure zone around the catheter tip inducing suction suction
The clot is pulled into the exhaust lumen and removed from the The clot is pulled into the exhaust lumen and removed from the vessel Although US Food and Drug Administration (FDA) has vessel Although US Food and Drug Administration (FDA) has approved this device for use in arteriovenous dialysis grafts and approved this device for use in arteriovenous dialysis grafts and fistulae and for the treatment of coronary arteries saphenous fistulae and for the treatment of coronary arteries saphenous vein grafts and peripheral vessels clinical trials for the vein grafts and peripheral vessels clinical trials for the treatment of acute stroke are no longer in progress treatment of acute stroke are no longer in progress
Most devices are used in cerebral vessels that 2-5 mm
The Latis laser device The Latis laser device used laser energy to ablate clots used laser energy to ablate clots Arteries 2-5 mm in diameter could be Arteries 2-5 mm in diameter could be
treated including the ICA M1 or M2 treated including the ICA M1 or M2 branch of the MCA A1 branch of the branch of the MCA A1 branch of the anterior cerebral artery (ACA) basilar anterior cerebral artery (ACA) basilar artery posterior cerebral artery (PCA) artery posterior cerebral artery (PCA) and vertebral and vertebral
Patients could receive treatment as late Patients could receive treatment as late as 8 hours after symptom onset in the as 8 hours after symptom onset in the anterior circulation and within 24 hours in anterior circulation and within 24 hours in the posterior circulation the posterior circulation
Endovascular Photo Acoustic Endovascular Photo Acoustic Recanalization (EPAR) Recanalization (EPAR)
A laser power source generated energy for the A laser power source generated energy for the systemsystem
The energy was delivered by means of The energy was delivered by means of fiberoptics to the tip of the catheter at the fiberoptics to the tip of the catheter at the treatment sitetreatment site
Absorption of laser light by darkly pigmented Absorption of laser light by darkly pigmented materials (ie the clot) occurred inside the 1-mm materials (ie the clot) occurred inside the 1-mm catheter tipcatheter tip
the system was designed to minimize scattering the system was designed to minimize scattering of laser light of laser light
Absorption converted photo energy to acoustic Absorption converted photo energy to acoustic energy which then emulsified the clot inside the energy which then emulsified the clot inside the catheter tip catheter tip
EKOS ultrasound( the EKOS ultrasound( the Ultrasound Thrombolytic Ultrasound Thrombolytic
Infusion Catheter) Infusion Catheter) combines the use of a distal ultrasound transducer with combines the use of a distal ultrasound transducer with
infusion of a thrombolytic agent through the infusion of a thrombolytic agent through the microcathetermicrocatheter
Ultrasound changes the structure of the clot to Ultrasound changes the structure of the clot to temporarily increase its permeability while providing an temporarily increase its permeability while providing an acoustic pressure gradient to move the drug into the clot acoustic pressure gradient to move the drug into the clot to speed its dissolution to speed its dissolution
The EKOS catheter is placed in the proximal portion of the The EKOS catheter is placed in the proximal portion of the clot clot
After a 2-mg bolus of tPA was injected through the After a 2-mg bolus of tPA was injected through the catheter catheter
the patient received a continuous infusion of IA tPA 03 the patient received a continuous infusion of IA tPA 03 mgmin to a maximum of 20 mg and simultaneous mgmin to a maximum of 20 mg and simultaneous ultrasound transmission for as long as 60 minutes ultrasound transmission for as long as 60 minutes
One patient was treated with a total of 4 units of One patient was treated with a total of 4 units of recombinant reteplase (Retavase) hand-injected over 60 recombinant reteplase (Retavase) hand-injected over 60 minutes minutes
Penumbra system Penumbra system The Penumbra system (Penumbra Inc) provides a dual The Penumbra system (Penumbra Inc) provides a dual
approach to clot extraction using aspiration followed by approach to clot extraction using aspiration followed by clot retrieval with a ring device if needed clot retrieval with a ring device if needed
Mechanical Embolus Removal in Cerebral Ischemia Mechanical Embolus Removal in Cerebral Ischemia (MERCI)(MERCI)
a corkscrew-like apparatus to remove blood clots from a corkscrew-like apparatus to remove blood clots from the brain in patients experiencing an ischemic stroke the brain in patients experiencing an ischemic stroke
The corkscrew itself resides in the catheter tip which The corkscrew itself resides in the catheter tip which shields it from the wall of the vessel until it is ready to be shields it from the wall of the vessel until it is ready to be burrowed into the clot Once lodged in the clot the device burrowed into the clot Once lodged in the clot the device and clot are withdrawn from the vessel and clot are withdrawn from the vessel
Snarelike devicesSnarelike devices Snares such as the Neuronet snare (Guidant Snares such as the Neuronet snare (Guidant
Endovascular Santa Clara CA) have been developed Endovascular Santa Clara CA) have been developed specifically for use in the treatment of strokes specifically for use in the treatment of strokes
These devices are simple in design and do not require the These devices are simple in design and do not require the clot to be amenable to emulsification clot to be amenable to emulsification
X-Sizer deviceX-Sizer device a device with small moving blades at the a device with small moving blades at the
catheter tip catheter tip This device the X-Sizer device (EndiCor Medical This device the X-Sizer device (EndiCor Medical
San Clemente CA) can be used to excise the San Clemente CA) can be used to excise the thrombus and aspirate it thrombus and aspirate it
The device was being evaluated in randomized The device was being evaluated in randomized studies of coronary vessels and in a registry of studies of coronary vessels and in a registry of patients with acute myocardial infarctionpatients with acute myocardial infarction
Although the manufacturer had modified the Although the manufacturer had modified the device for use in cerebral vessels a safety and device for use in cerebral vessels a safety and feasibility study was indefinitely suspended after feasibility study was indefinitely suspended after only 1 patient was treated with the device in only 1 patient was treated with the device in Europe Europe
Suction thrombectomySuction thrombectomy This method of mechanical thrombolysis is one of the This method of mechanical thrombolysis is one of the
simplestsimplest In this readily available technique suction is applied with In this readily available technique suction is applied with
a syringe to remove thrombus in the ICA a syringe to remove thrombus in the ICA It requires no other devicesIt requires no other devices A catheter with a large inner diameter (Brite Tip Cordis A catheter with a large inner diameter (Brite Tip Cordis
Corporation Miami FL) was placed in the symptomatic Corporation Miami FL) was placed in the symptomatic vessel and navigated over a guidewire into the thrombusvessel and navigated over a guidewire into the thrombus
A 60-mL syringe was used to aspirate the thrombus A 60-mL syringe was used to aspirate the thrombus Each patient required angioplasty and stenting of carotid Each patient required angioplasty and stenting of carotid
bifurcation stenosis and received daily aspirin and bifurcation stenosis and received daily aspirin and ticlopidine after the procedure No complications ticlopidine after the procedure No complications occurred occurred
Summary Acute Stroke Summary Acute Stroke ImagingImaging
PhysiologyPhysiology importance collaterals importance collaterals
ndash ndashGrowing role for perfusion Growing role for perfusion assessmentassessment
tPAtPA guidelines amp limitations guidelines amp limitations Signs on CT amp MRSigns on CT amp MR follow physiology follow physiology Stroke trialsStroke trials PWI-DWI mismatch PWI-DWI mismatch
ndash ndashTreat based on physiology not timeTreat based on physiology not time ProtocolsProtocols should be fast and should be fast and
comprehensivecomprehensive
Bleeding timeBleeding time
Requires a skin incision (usually made on the ear lobe or Requires a skin incision (usually made on the ear lobe or forearm offorearm of
a depth that results in disruption of capillary loops and a depth that results in disruption of capillary loops and small vessels)small vessels)
AdvantagesAdvantages Universally availableUniversally available Relatively simple techniquesRelatively simple techniques Can be performed bedsideCan be performed bedside
DisadvantagesDisadvantages Insensitive inaccurate non-specific techniqueInsensitive inaccurate non-specific technique
Poorly reproducible (as depends on multiple variables)Poorly reproducible (as depends on multiple variables)
Optical aggregometryOptical aggregometry
Gold standard assay for platelet functionGold standard assay for platelet function Agonist induced aggregation is measuredAgonist induced aggregation is measured Different agonist are available for different Different agonist are available for different
agentsagents However require unique expertise and are not However require unique expertise and are not
universally availableuniversally available Aspirin measured with ADP or AA(gt70 Aspirin measured with ADP or AA(gt70
aggregation so resistance)aggregation so resistance) Clopidogrel( ADP gt 90 aggregation means Clopidogrel( ADP gt 90 aggregation means
resistance) resistance)
Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay
Can be performed bed sideCan be performed bed side Different assay devices with different Different assay devices with different
agonist are used for each of different agonist are used for each of different antiplatelet agents antiplatelet agents
For Aspirin AA is used (result is reported as aspirin For Aspirin AA is used (result is reported as aspirin reaction units [ARU] ARUgt 550 indicates non-reaction units [ARU] ARUgt 550 indicates non-responsiveness)responsiveness)
Verify IIbIIIa assay device uses TRAP as agonist for Verify IIbIIIa assay device uses TRAP as agonist for Abciximab and TirofibanAbciximab and Tirofiban
Practical Applications Practical Applications related to specific related to specific
Neurovascular Neurovascular interventionsinterventions
Acute ischemic StrokeAcute ischemic Stroke When an artery occludes neurons are affected When an artery occludes neurons are affected
differently depending upon the amount of residual blood differently depending upon the amount of residual blood flowflow
Normal cerebral blood flow is greater than 50 mL100 Normal cerebral blood flow is greater than 50 mL100 mgminmgmin
Once blood flow decreases to less than 20 mL100 Once blood flow decreases to less than 20 mL100 mgmin infarction occursmgmin infarction occurs
If blood flow decreases to less than 10 mL100 mgmin If blood flow decreases to less than 10 mL100 mgmin irreversible neuronal death occurs rapidly irreversible neuronal death occurs rapidly
Blood flow between 11 and 20 mL100 mgmin is thought Blood flow between 11 and 20 mL100 mgmin is thought to represent the ischemic penumbra an area where the to represent the ischemic penumbra an area where the cells are functionally silent because of ischemia but are cells are functionally silent because of ischemia but are still able to recover if blood flow is restored still able to recover if blood flow is restored
Many acute stroke therapies are targeted toward Many acute stroke therapies are targeted toward restoring flow or function to the ischemic penumbrarestoring flow or function to the ischemic penumbra
Therapeutic window in Therapeutic window in management of acute Ischemic management of acute Ischemic
StrokeStrokeThe early diagnosis of ischemic stroke is critical to the The early diagnosis of ischemic stroke is critical to the
with only a narrow therapeutic window in the first few with only a narrow therapeutic window in the first few hours following stroke ictushours following stroke ictus
Diagnosis in the first 3 hours postictus provides the Diagnosis in the first 3 hours postictus provides the opportunity for intravenous or intraarterial thrombolysis opportunity for intravenous or intraarterial thrombolysis and intra-arterial clot mechanical treatment which and intra-arterial clot mechanical treatment which improve the outcome improve the outcome
Diagnosis in the time period between 3 and 6 hours Diagnosis in the time period between 3 and 6 hours provides an opportunity for intra-arterial thrombolysis provides an opportunity for intra-arterial thrombolysis and mechanical treatment and mechanical treatment
Involvement of the posterior circulation especially the Involvement of the posterior circulation especially the basilar artery is treated by some regardless of time of basilar artery is treated by some regardless of time of onset or up until 12 to 24 hours in some practices This is onset or up until 12 to 24 hours in some practices This is related to the potentially high mortality and morbidity related to the potentially high mortality and morbidity associated with basilar artery thrombosisassociated with basilar artery thrombosis
Infarct evaluation on angiographyInfarct evaluation on angiography(CT angiography and catheter (CT angiography and catheter
angiography)angiography)CTA is an excellent first-line examination for CTA is an excellent first-line examination for
evaluation of the head and neck arteries evaluation of the head and neck arteries In comparison with catheter angiography In comparison with catheter angiography
what it gives up in resolution and dynamic what it gives up in resolution and dynamic properties it makes up for with rapid properties it makes up for with rapid acquisition of a 3-D dataset and the potential acquisition of a 3-D dataset and the potential for assessment of whole-brain perfusion and for assessment of whole-brain perfusion and better parenchymal evaluationbetter parenchymal evaluation
Moreover CTA illustrates not only arterial Moreover CTA illustrates not only arterial stenosis or occlusion but also the vessel wall stenosis or occlusion but also the vessel wall This factor is most important for evaluation of This factor is most important for evaluation of intramural dissection and thrombosed intramural dissection and thrombosed aneurysms which may both complicate aneurysms which may both complicate evaluation of stroke patientsevaluation of stroke patients
Early angiographic signs of strokes Early angiographic signs of strokes both CTA both CTA and DSA and DSA
Vessel occlusion or cutoff related to Vessel occlusion or cutoff related to thromboembolithromboemboli
aneurysms aneurysms arterial dissection arterial dissection Meniscus or flattened shape to clot Meniscus or flattened shape to clot
(recent) versus reverse meniscus (older)(recent) versus reverse meniscus (older) tram track (nonocclusive or recanalized tram track (nonocclusive or recanalized
clot) clot) delayed (antegrade) flow (manifest as delayed (antegrade) flow (manifest as
decreased whole-brain perfusion on CTA)decreased whole-brain perfusion on CTA) retrograde collateral flowretrograde collateral flow
Non-occlusive left MCA thrombus on 3-D imaging performed from CTA source data and was confirmed at catheter angiography
Therapy to be started within a 6-hr Therapy to be started within a 6-hr time to treatment (TTT) window time to treatment (TTT) window (while in case of IV thrombolysis (while in case of IV thrombolysis therapy to be started with in 3hrs)therapy to be started with in 3hrs)
Exclusion criteria Exclusion criteria Rapidly improving neurologic deficit or Rapidly improving neurologic deficit or Sustained blood pressure of gt180100 Sustained blood pressure of gt180100 Hemorrhage is detected on CTHemorrhage is detected on CT Infarct involving gt more than 13 rd Infarct involving gt more than 13 rd
territory of MCAterritory of MCA MRADWI-Perfusion mismatchlt 20MRADWI-Perfusion mismatchlt 20 Definite hypodensity on CTDefinite hypodensity on CT
Intra-arterial Thrombolysis
Fibrinolytics + AntiplateletsFibrinolytics + Antiplatelets
PlasminogenPlasminogen activators through fibrinolysis exposes activators through fibrinolysis exposes free thrombin and paradoxically stimulatesfree thrombin and paradoxically stimulates platelet platelet aggregation which leads to formation of aaggregation which leads to formation of a platelet platelet thrombus (white clot) thrombus (white clot)
This new thrombus is relatively resistant to This new thrombus is relatively resistant to fibrinolyticsfibrinolytics
So new regimen in case of acute stroke isSo new regimen in case of acute stroke is fibrinolytics + antiplatelet drugsfibrinolytics + antiplatelet drugs
rtPA + IIbIIIa inhibitors( tirofiban rtPA + IIbIIIa inhibitors( tirofiban abciximab) orabciximab) or
Urokinase + IIbIIIa Urokinase + IIbIIIa inhibitors( tirofiban abciximab)inhibitors( tirofiban abciximab)
Intra-arterial Thrombolysis Tirofiban (04 microgkgmin bolus for 3 min followed by Tirofiban (04 microgkgmin bolus for 3 min followed by
0125 ugkgmin)0125 ugkgmin)
++
Heparin (2000ndash3000 IU bolus followed by Heparin (2000ndash3000 IU bolus followed by 1000 IUhour infusion 1000 IUhour infusion
with ACT maintained bw 200-300) throughout the with ACT maintained bw 200-300) throughout the interventional procedure and for 24ndash48 hours thereafter when interventional procedure and for 24ndash48 hours thereafter when there is neither intraprocedural bleeding nor suspicion of there is neither intraprocedural bleeding nor suspicion of increased risk of bleeding increased risk of bleeding
Maximum dose of Urokinase Maximum dose of Urokinase Anterior circulation stroke - 500000 IU (mean 400000 Anterior circulation stroke - 500000 IU (mean 400000
IU range 300000ndash500000 IU)IU range 300000ndash500000 IU) Posterior circulation stroke -1000000 IU (mean 837000 Posterior circulation stroke -1000000 IU (mean 837000
IU range 300000ndash1000000 IU)IU range 300000ndash1000000 IU)American Journal of NeuroradiologyAmerican Journal of Neuroradiology 262595-2601 2005262595-2601 2005
Intravenous ThrombolysisIntravenous Thrombolysis
The first method to restore cerebral The first method to restore cerebral perfusion is clot lysis with the goal perfusion is clot lysis with the goal of re-establishing blood flow to the of re-establishing blood flow to the affected tissue affected tissue
IV thrombolysis rt-PA is the only IV thrombolysis rt-PA is the only FDA- approved treatment for AIS FDA- approved treatment for AIS
Fibrinolysis is enhanced powerfully Fibrinolysis is enhanced powerfully by rt-PAby rt-PA
Intravenous rTPA Intravenous rTPA administration administration protocolprotocol
Total dose of rt-PA 09 mgkg (maximum dose Total dose of rt-PA 09 mgkg (maximum dose 90 mg)90 mg)
Give 10 as initial IV bolusGive 10 as initial IV bolus Infuse remainder over 1 hourInfuse remainder over 1 hour Admit patient to an ICU or stroke unit for Admit patient to an ICU or stroke unit for
monitoringmonitoring Neurologic assessments every 15 minutes Neurologic assessments every 15 minutes
during infusion then every 30 minutes for next during infusion then every 30 minutes for next 6 hours then every hour until 24hours after 6 hours then every hour until 24hours after treatmenttreatment
Favorable Outcome vs Treatment Time Favorable Outcome vs Treatment Time with IV rTPAwith IV rTPA
Protocol limit = 3 hrs
Benefit ~ 45 hrs
Thromboembolism During coilingThromboembolism During coiling Most feared and frequent complication Most feared and frequent complication Reported incidence - Approx 7 Reported incidence - Approx 7 SourcesSources of Thromboembolism are of Thromboembolism are
- Clots at the aneurysmal neck during or immediately- Clots at the aneurysmal neck during or immediately after after embolization embolization
- Thrombus forming on catheters during- Thrombus forming on catheters during proceduresprocedures
- Stenosis of an adjacent artery dt coil mass- Stenosis of an adjacent artery dt coil mass or herniationor herniation
- Migration of intraaneurysmal- Migration of intraaneurysmal thrombus during coil thrombus during coil placement placement
- Slow flow dt vasospasm - Slow flow dt vasospasm
- Rare and unlikely causes are hypercoagulable- Rare and unlikely causes are hypercoagulable state such state such as antiphospholipid antibody syndrome or due to HITas antiphospholipid antibody syndrome or due to HIT
Occur more often with wide-necked aneurysms (dt Occur more often with wide-necked aneurysms (dt increased exposed surface area of thrombogenic coil increased exposed surface area of thrombogenic coil material)material)
Current regimen of endovascular Current regimen of endovascular managementmanagement
The The glycoprotein IIbIIIa antagonist tirofiban glycoprotein IIbIIIa antagonist tirofiban (04 (04 microgkgmin bolus for 30 minutes followed by infusion of microgkgmin bolus for 30 minutes followed by infusion of 0125 ugkgmin until the thrombus dissolved) 0125 ugkgmin until the thrombus dissolved)
Intraarterial thrombolysis with Intraarterial thrombolysis with urokinase or r- TPA urokinase or r- TPA increase of intravenous (IV) heparin (measured by increase of intravenous (IV) heparin (measured by
ACT) ACT) Intravenous aspirin Intravenous aspirin
Coil-related platelet aggregation (white clot) is Coil-related platelet aggregation (white clot) is unlikely to respond to fibrinolytics but has a high risk unlikely to respond to fibrinolytics but has a high risk of hemorrhage (In ISAT) all 5 patients who had of hemorrhage (In ISAT) all 5 patients who had received thrombolytic therapy with tPA to treat a received thrombolytic therapy with tPA to treat a thromboembolic complication after endovascular thromboembolic complication after endovascular treatment rebleed and all of these patients died)treatment rebleed and all of these patients died)
IntracranialIntracranial Stenting Stenting Metallic foreign body such as stent will accumulate Metallic foreign body such as stent will accumulate
thrombus in the absence of platelet inhibitionthrombus in the absence of platelet inhibition Antiplatelet drugs are important to prevent peri or Antiplatelet drugs are important to prevent peri or
post-interventional thromboembolic eventspost-interventional thromboembolic events Optimal treatment regimens has not been determined Optimal treatment regimens has not been determined
but usually but usually Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-
procedureprocedureOrOr
Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on
morning of proceduremorning of procedure
If need to use stent is not pre-planned thanIf need to use stent is not pre-planned than
Abciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkgAbciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkg IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)
Glycoprotein IIbIIIa inhibitor are not used routinely during elective Glycoprotein IIbIIIa inhibitor are not used routinely during elective stenting procedure dt increased risk of ICH stenting procedure dt increased risk of ICH
Carotid StentingCarotid Stenting
Pre-procedurePre-procedure
Double Antiplatelet therapy is routinely given Double Antiplatelet therapy is routinely given beginning at least 3beginning at least 3
days before the proceduredays before the procedure
Aspirin 325mgd+Clopidogrel 75mgdAspirin 325mgd+Clopidogrel 75mgd During procedureDuring procedure
Heparin is given with target clotting time of 250-Heparin is given with target clotting time of 250-300sec300sec
Post-procedure Post-procedure
Aspirin 325mg is continued indefinitely and Aspirin 325mg is continued indefinitely and
Clopidogrel 75mgd for at least 6 weeks Clopidogrel 75mgd for at least 6 weeks
Inclusion criteria for Local ThrombolysisInclusion criteria for Local Thrombolysis a)a) Patients in severe clinical grade on admission Patients in severe clinical grade on admission
with evidence of dural venous sinus with evidence of dural venous sinus thrombosis and restrictive venous outflow on thrombosis and restrictive venous outflow on cerebral angiogramcerebral angiogram
b)b) Patients in clinical grade 3 worsening on Patients in clinical grade 3 worsening on heparin therapy Restriction to venous heparin therapy Restriction to venous outflow was defined as an increase in brain outflow was defined as an increase in brain circulation time gt 12 s delay in the drainage circulation time gt 12 s delay in the drainage of cortical veins with cortical veins hanging of cortical veins with cortical veins hanging in spacein space
Treatment Options for Venous Thrombosis
CT Grading for Venous ThrombosisCT Grading for Venous Thrombosis Grade I no parenchymal change Grade I no parenchymal change
(hyperdense (hyperdense sinuses cortical veins empty sinuses cortical veins empty delta sign)delta sign)
Grade II non hemorrhagic venous infarct Grade II non hemorrhagic venous infarct without mass effect without mass effect
Grade III non-hemorrhagic infarct with Grade III non-hemorrhagic infarct with mass effectmass effect
Grade IV hemorrhagic venous infarct (max Grade IV hemorrhagic venous infarct (max diameter lt 3 cm) with no mass effectdiameter lt 3 cm) with no mass effect
Grade V hemorrhagic venous infarct (max Grade V hemorrhagic venous infarct (max diameter gt 3 cm) with mass effect diameter gt 3 cm) with mass effect
Local ThrombolysisLocal Thrombolysis
Femoral Jugular access was secured and a guiding Femoral Jugular access was secured and a guiding catheter was placed in the jugular bulb catheter was placed in the jugular bulb Mechanical Mechanical clot maceration clot maceration was done with the guidewire was done with the guidewire following which a microcatheter (was navigated and following which a microcatheter (was navigated and placed in the thrombosed segment of sinus confirmed placed in the thrombosed segment of sinus confirmed on a selective venogram on a selective venogram
Urokinase infusion Bolus dose of 2-6 lacs followed Urokinase infusion Bolus dose of 2-6 lacs followed by 60000 to 100000 units per hour along with by 60000 to 100000 units per hour along with periodic check venogram Along with maintenance periodic check venogram Along with maintenance systemic infusion of Heparinsystemic infusion of Heparin Other agents such as Other agents such as streptokinase altepase or rTPAstreptokinase altepase or rTPA can be also used can be also used
After thrombolysis patient should subjected to oral After thrombolysis patient should subjected to oral anticoagulation for six monthsanticoagulation for six months
Low-molecular-weight Low-molecular-weight heparinheparin
PharmacologyPharmacologyLMWH as its name suggests is a glycosaminoglycan that is approximatelyLMWH as its name suggests is a glycosaminoglycan that is approximately
one third the molecular weight of UFH It is derived from UFH through one third the molecular weight of UFH It is derived from UFH through variousvarious
depolymerization processes LMWH binds to antithrombin which in turn depolymerization processes LMWH binds to antithrombin which in turn
Neutralizes actors Xa and IIa Because LMWH lacks many of the longer Neutralizes actors Xa and IIa Because LMWH lacks many of the longer chains chains
required for binding to thrombin it has less ability to neutralize thrombin required for binding to thrombin it has less ability to neutralize thrombin
relativeto its ability to neutralize factor Xa LMWH also has less relativeto its ability to neutralize factor Xa LMWH also has less nonspecific nonspecific
binding to other proteins There is greater bioavailability with more binding to other proteins There is greater bioavailability with more predictable predictable
pharmacokinetics that eliminates the need for monitoring The smaller pharmacokinetics that eliminates the need for monitoring The smaller size also size also
allows for enhanced subcutaneous absorption when compared with UFHallows for enhanced subcutaneous absorption when compared with UFH
Three LMWH preparations are Three LMWH preparations are currently approved for use in the currently approved for use in the United States (1) enoxaparin (2) United States (1) enoxaparin (2) dalteparin and (3) tinzaparin dalteparin and (3) tinzaparin
They are all administered They are all administered subcutaneously at intervals of either subcutaneously at intervals of either once or twice daily for both once or twice daily for both prophylaxis and treatment dosesprophylaxis and treatment doses
Few Experiences of Few Experiences of ThrombolysisThrombolysis
Vickey 25 Yrs male patient presented Vickey 25 Yrs male patient presented with 12with 12thth day HO severe headache with day HO severe headache with right sided hemiplegiaright sided hemiplegia
MRI shows thrombosis of the superior MRI shows thrombosis of the superior sagittal left transverse left sigmoid sagittal left transverse left sigmoid sinuses and cortical veins in the fronto-sinuses and cortical veins in the fronto-parietal regions with eo haemorrhagic parietal regions with eo haemorrhagic infarct in the left cerebral hemisphere infarct in the left cerebral hemisphere with mass effect( Grade ndashV)with mass effect( Grade ndashV)
Sashi Srivastava 64 yrs FSashi Srivastava 64 yrs F In a follow up case of MRD with infra-renal In a follow up case of MRD with infra-renal
aortic abdominal and bilateral renal artery aortic abdominal and bilateral renal artery thrombosis renal angiogram shows filling thrombosis renal angiogram shows filling defects in the right Renal artery defects in the right Renal artery
Initially Renal angioplasty was done Initially Renal angioplasty was done Following angioplasty few thrombi are seem Following angioplasty few thrombi are seem to extends into the segmental branches and to extends into the segmental branches and causing blockage So Thrombolysis was causing blockage So Thrombolysis was plane to dissolve the run-out thrombi with plane to dissolve the run-out thrombi with urokinase urokinase
Rakesh 34yrsMRakesh 34yrsM Left SFA pseudoaneurysm with Left SFA pseudoaneurysm with
Covered stent placementCovered stent placement Pre operative antiplatelets with post Pre operative antiplatelets with post
procedure heparin Tirofiban procedure heparin Tirofiban followed by aspirin and clopidogrel followed by aspirin and clopidogrel were usedwere used
IAT may be a treatment option for selected patients IAT may be a treatment option for selected patients Possible selection criteria include Possible selection criteria include
presentation between 3 and 6 hours from symptom onsetpresentation between 3 and 6 hours from symptom onset major cerebral artery occlusion major cerebral artery occlusion severe neurologic deficits severe neurologic deficits high risk of systemic hemorrhage with IV rt-PA (eg recent high risk of systemic hemorrhage with IV rt-PA (eg recent
surgery) surgery) The MERCI (Mechanical Embolus Removal in Cerebral The MERCI (Mechanical Embolus Removal in Cerebral
Ischemia) retrievalIschemia) retrieval system system
Has been FDA-approved for recanalizing acutely occluded Has been FDA-approved for recanalizing acutely occluded cerebral arteries cerebral arteries
In the Multi-MERCI study patients who did not improve In the Multi-MERCI study patients who did not improve immediately after IV rt-PA underwent mechanical immediately after IV rt-PA underwent mechanical embolectomy within 8 hours of symptom onset embolectomy within 8 hours of symptom onset
Partial or complete recanalization occurred in 74 of Partial or complete recanalization occurred in 74 of patientspatients
with a symptomatic intracerebral hemorrhage (sICH) rate of with a symptomatic intracerebral hemorrhage (sICH) rate of 67 67
Mechanical embolectomy with the MERCI retriever may be a Mechanical embolectomy with the MERCI retriever may be a feasible and safe option for patients after IV rt-PAfeasible and safe option for patients after IV rt-PA
Penumbra stroke systemPenumbra stroke system This device combines two methods of clot This device combines two methods of clot
extraction aspiration and mechanical extraction aspiration and mechanical extraction extraction
First the clot is aspirated then a thrombus First the clot is aspirated then a thrombus removal ring can be used if necessary to removal ring can be used if necessary to remove remaining clot remove remaining clot
successful recanalizing 82successful recanalizing 82 Bridging therapyBridging therapy
06 mgkg IV rt-PA followed by IAT with IA rt-06 mgkg IV rt-PA followed by IAT with IA rt-PA (up to 20 mg)PA (up to 20 mg)
achieved a higher recanalization rateachieved a higher recanalization rate
Criteria for thrombolysis with rTPACriteria for thrombolysis with rTPA
Inclusion criteriaInclusion criteria Clinical signs and symptoms consistent with ischemic Clinical signs and symptoms consistent with ischemic
strokestroke Patient last seen normal within 3 hoursPatient last seen normal within 3 hours Measurable neurologic deficitMeasurable neurologic deficit
Exclusion criteriaExclusion criteria Any hemorrhage on neuroimaging (CT or MRI)Any hemorrhage on neuroimaging (CT or MRI) Symptoms suggestive of subarachnoid hemorrhageSymptoms suggestive of subarachnoid hemorrhage Seizure at stroke onset that is thought to contribute to Seizure at stroke onset that is thought to contribute to
neurologic deficitneurologic deficit Hypodensity greater than one third cerebral hemisphere Hypodensity greater than one third cerebral hemisphere
on CTon CT SBP greater than 185 mm Hg or DBP greater than 110 SBP greater than 185 mm Hg or DBP greater than 110
mm Hgmm Hg International normalized ratio (INR) greater than 17International normalized ratio (INR) greater than 17
Ischemic Stroke Ischemic Stroke Treatment ndash 2006Treatment ndash 2006
IV tissue plasminogen activator (tPA)IV tissue plasminogen activator (tPA) ndash ndash Only FDA-approved acute stroke drugOnly FDA-approved acute stroke drug ndash ndash 3 hour treatment window3 hour treatment window
MERCI - Concentric clot retrieval MERCI - Concentric clot retrieval devicedevice ndash ndash Rescue therapy - approved 2004Rescue therapy - approved 2004 ndash ndash Device approval (not outcomes-based)Device approval (not outcomes-based)
Off label approachesOff label approaches ndash ndash IV tPA after 3 hoursIV tPA after 3 hours ndash ndash IV-IA tPA sequential strategiesIV-IA tPA sequential strategies ndash ndash IA tPA clot angioplasty fragmentationIA tPA clot angioplasty fragmentation ndash ndash Ultrasound-assisted tPA lysisUltrasound-assisted tPA lysis
rt-PA Trials NINDSrt-PA Trials NINDS
Acute stroke - 624 patientsAcute stroke - 624 patients Treat within 3 hrsTreat within 3 hrs Intravenous 09 mgkg rt-PA vs placeboIntravenous 09 mgkg rt-PA vs placebo Hemorrhage 64 tPA 06 placeboHemorrhage 64 tPA 06 placebo Neurologic recovery better with tPA 30 Neurologic recovery better with tPA 30
more like to have minimal or no disabilitymore like to have minimal or no disability
First proven approved treatment for First proven approved treatment for strokestroke
Limitations of tPALimitations of tPA Only 4 of acute strokes receive tPAOnly 4 of acute strokes receive tPA (Kleindorfer et al Stroke 2004 35 e27-e29)(Kleindorfer et al Stroke 2004 35 e27-e29)
Only 22 of patients present within 3 hoursOnly 22 of patients present within 3 hours1048707 1048707 51 of these ineligible due to51 of these ineligible due to
bull bull Mild severityMild severity bull bull Medical or surgical historyMedical or surgical history bull bull Blood testsBlood tests
Sustained recanalization only 13Sustained recanalization only 13 (Alexandrov et al NEJM 2004 351 2170-8)(Alexandrov et al NEJM 2004 351 2170-8)
Concern for hemorrhageConcern for hemorrhage tPA potentiates apoptotic injury tPA potentiates apoptotic injury (Liu et al Nature Med 2004 101379-83)(Liu et al Nature Med 2004 101379-83)
PROACT II IA Lysis TrialPROACT II IA Lysis Trial Baseline 24 hours 8 days
Baseline 60 minutes 120 minutes
9mg IAProurokinase
Desmoteplase Trials DEDAS Desmoteplase Trials DEDAS DIASDIAS
Trial OverviewTrial Overview Double blind randomized placebo Double blind randomized placebo
controlled trialscontrolled trials IV delivery 3-9 hour time windowIV delivery 3-9 hour time window Plasminogen activator ndash from Plasminogen activator ndash from vampire bat vampire bat
salivasaliva Selection based on PWI-DWI MismatchSelection based on PWI-DWI Mismatch
MRI InclusionMRI Inclusion PWI defect at least 2 cm AND ~20 larger PWI defect at least 2 cm AND ~20 larger
than DWIthan DWI PWI should be obvious even visible on PWI should be obvious even visible on
raw imagesraw imagesMRI ExclusionMRI Exclusion
DWI gt 13 MCADWI gt 13 MCA MRA ICA occlusionMRA ICA occlusion
Desmoteplase ndash DIAS Desmoteplase ndash DIAS ResultsResults
Mechanical Thrombolysis Mechanical Thrombolysis devicesdevices
mechanical thrombolysis potentially extends the treatment mechanical thrombolysis potentially extends the treatment window because they act promptly at the site of the thrombuswindow because they act promptly at the site of the thrombus
The devices can retrieve large clots that pharmaceutical agents The devices can retrieve large clots that pharmaceutical agents may not successfully lysemay not successfully lyse
Patients treated with IV tPA may be considered for treatment of Patients treated with IV tPA may be considered for treatment of residual clot with some of these devicesresidual clot with some of these devices
suction-creating saline jets suction-creating saline jets laser energy ultrasound laser energy ultrasound a corkscrew apparatus to treat strokesa corkscrew apparatus to treat strokes The AngioJet systemThe AngioJet system uses saline jets that are directed back into the catheter to uses saline jets that are directed back into the catheter to
create a low-pressure zone around the catheter tip inducing create a low-pressure zone around the catheter tip inducing suction suction
The clot is pulled into the exhaust lumen and removed from the The clot is pulled into the exhaust lumen and removed from the vessel Although US Food and Drug Administration (FDA) has vessel Although US Food and Drug Administration (FDA) has approved this device for use in arteriovenous dialysis grafts and approved this device for use in arteriovenous dialysis grafts and fistulae and for the treatment of coronary arteries saphenous fistulae and for the treatment of coronary arteries saphenous vein grafts and peripheral vessels clinical trials for the vein grafts and peripheral vessels clinical trials for the treatment of acute stroke are no longer in progress treatment of acute stroke are no longer in progress
Most devices are used in cerebral vessels that 2-5 mm
The Latis laser device The Latis laser device used laser energy to ablate clots used laser energy to ablate clots Arteries 2-5 mm in diameter could be Arteries 2-5 mm in diameter could be
treated including the ICA M1 or M2 treated including the ICA M1 or M2 branch of the MCA A1 branch of the branch of the MCA A1 branch of the anterior cerebral artery (ACA) basilar anterior cerebral artery (ACA) basilar artery posterior cerebral artery (PCA) artery posterior cerebral artery (PCA) and vertebral and vertebral
Patients could receive treatment as late Patients could receive treatment as late as 8 hours after symptom onset in the as 8 hours after symptom onset in the anterior circulation and within 24 hours in anterior circulation and within 24 hours in the posterior circulation the posterior circulation
Endovascular Photo Acoustic Endovascular Photo Acoustic Recanalization (EPAR) Recanalization (EPAR)
A laser power source generated energy for the A laser power source generated energy for the systemsystem
The energy was delivered by means of The energy was delivered by means of fiberoptics to the tip of the catheter at the fiberoptics to the tip of the catheter at the treatment sitetreatment site
Absorption of laser light by darkly pigmented Absorption of laser light by darkly pigmented materials (ie the clot) occurred inside the 1-mm materials (ie the clot) occurred inside the 1-mm catheter tipcatheter tip
the system was designed to minimize scattering the system was designed to minimize scattering of laser light of laser light
Absorption converted photo energy to acoustic Absorption converted photo energy to acoustic energy which then emulsified the clot inside the energy which then emulsified the clot inside the catheter tip catheter tip
EKOS ultrasound( the EKOS ultrasound( the Ultrasound Thrombolytic Ultrasound Thrombolytic
Infusion Catheter) Infusion Catheter) combines the use of a distal ultrasound transducer with combines the use of a distal ultrasound transducer with
infusion of a thrombolytic agent through the infusion of a thrombolytic agent through the microcathetermicrocatheter
Ultrasound changes the structure of the clot to Ultrasound changes the structure of the clot to temporarily increase its permeability while providing an temporarily increase its permeability while providing an acoustic pressure gradient to move the drug into the clot acoustic pressure gradient to move the drug into the clot to speed its dissolution to speed its dissolution
The EKOS catheter is placed in the proximal portion of the The EKOS catheter is placed in the proximal portion of the clot clot
After a 2-mg bolus of tPA was injected through the After a 2-mg bolus of tPA was injected through the catheter catheter
the patient received a continuous infusion of IA tPA 03 the patient received a continuous infusion of IA tPA 03 mgmin to a maximum of 20 mg and simultaneous mgmin to a maximum of 20 mg and simultaneous ultrasound transmission for as long as 60 minutes ultrasound transmission for as long as 60 minutes
One patient was treated with a total of 4 units of One patient was treated with a total of 4 units of recombinant reteplase (Retavase) hand-injected over 60 recombinant reteplase (Retavase) hand-injected over 60 minutes minutes
Penumbra system Penumbra system The Penumbra system (Penumbra Inc) provides a dual The Penumbra system (Penumbra Inc) provides a dual
approach to clot extraction using aspiration followed by approach to clot extraction using aspiration followed by clot retrieval with a ring device if needed clot retrieval with a ring device if needed
Mechanical Embolus Removal in Cerebral Ischemia Mechanical Embolus Removal in Cerebral Ischemia (MERCI)(MERCI)
a corkscrew-like apparatus to remove blood clots from a corkscrew-like apparatus to remove blood clots from the brain in patients experiencing an ischemic stroke the brain in patients experiencing an ischemic stroke
The corkscrew itself resides in the catheter tip which The corkscrew itself resides in the catheter tip which shields it from the wall of the vessel until it is ready to be shields it from the wall of the vessel until it is ready to be burrowed into the clot Once lodged in the clot the device burrowed into the clot Once lodged in the clot the device and clot are withdrawn from the vessel and clot are withdrawn from the vessel
Snarelike devicesSnarelike devices Snares such as the Neuronet snare (Guidant Snares such as the Neuronet snare (Guidant
Endovascular Santa Clara CA) have been developed Endovascular Santa Clara CA) have been developed specifically for use in the treatment of strokes specifically for use in the treatment of strokes
These devices are simple in design and do not require the These devices are simple in design and do not require the clot to be amenable to emulsification clot to be amenable to emulsification
X-Sizer deviceX-Sizer device a device with small moving blades at the a device with small moving blades at the
catheter tip catheter tip This device the X-Sizer device (EndiCor Medical This device the X-Sizer device (EndiCor Medical
San Clemente CA) can be used to excise the San Clemente CA) can be used to excise the thrombus and aspirate it thrombus and aspirate it
The device was being evaluated in randomized The device was being evaluated in randomized studies of coronary vessels and in a registry of studies of coronary vessels and in a registry of patients with acute myocardial infarctionpatients with acute myocardial infarction
Although the manufacturer had modified the Although the manufacturer had modified the device for use in cerebral vessels a safety and device for use in cerebral vessels a safety and feasibility study was indefinitely suspended after feasibility study was indefinitely suspended after only 1 patient was treated with the device in only 1 patient was treated with the device in Europe Europe
Suction thrombectomySuction thrombectomy This method of mechanical thrombolysis is one of the This method of mechanical thrombolysis is one of the
simplestsimplest In this readily available technique suction is applied with In this readily available technique suction is applied with
a syringe to remove thrombus in the ICA a syringe to remove thrombus in the ICA It requires no other devicesIt requires no other devices A catheter with a large inner diameter (Brite Tip Cordis A catheter with a large inner diameter (Brite Tip Cordis
Corporation Miami FL) was placed in the symptomatic Corporation Miami FL) was placed in the symptomatic vessel and navigated over a guidewire into the thrombusvessel and navigated over a guidewire into the thrombus
A 60-mL syringe was used to aspirate the thrombus A 60-mL syringe was used to aspirate the thrombus Each patient required angioplasty and stenting of carotid Each patient required angioplasty and stenting of carotid
bifurcation stenosis and received daily aspirin and bifurcation stenosis and received daily aspirin and ticlopidine after the procedure No complications ticlopidine after the procedure No complications occurred occurred
Summary Acute Stroke Summary Acute Stroke ImagingImaging
PhysiologyPhysiology importance collaterals importance collaterals
ndash ndashGrowing role for perfusion Growing role for perfusion assessmentassessment
tPAtPA guidelines amp limitations guidelines amp limitations Signs on CT amp MRSigns on CT amp MR follow physiology follow physiology Stroke trialsStroke trials PWI-DWI mismatch PWI-DWI mismatch
ndash ndashTreat based on physiology not timeTreat based on physiology not time ProtocolsProtocols should be fast and should be fast and
comprehensivecomprehensive
Optical aggregometryOptical aggregometry
Gold standard assay for platelet functionGold standard assay for platelet function Agonist induced aggregation is measuredAgonist induced aggregation is measured Different agonist are available for different Different agonist are available for different
agentsagents However require unique expertise and are not However require unique expertise and are not
universally availableuniversally available Aspirin measured with ADP or AA(gt70 Aspirin measured with ADP or AA(gt70
aggregation so resistance)aggregation so resistance) Clopidogrel( ADP gt 90 aggregation means Clopidogrel( ADP gt 90 aggregation means
resistance) resistance)
Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay
Can be performed bed sideCan be performed bed side Different assay devices with different Different assay devices with different
agonist are used for each of different agonist are used for each of different antiplatelet agents antiplatelet agents
For Aspirin AA is used (result is reported as aspirin For Aspirin AA is used (result is reported as aspirin reaction units [ARU] ARUgt 550 indicates non-reaction units [ARU] ARUgt 550 indicates non-responsiveness)responsiveness)
Verify IIbIIIa assay device uses TRAP as agonist for Verify IIbIIIa assay device uses TRAP as agonist for Abciximab and TirofibanAbciximab and Tirofiban
Practical Applications Practical Applications related to specific related to specific
Neurovascular Neurovascular interventionsinterventions
Acute ischemic StrokeAcute ischemic Stroke When an artery occludes neurons are affected When an artery occludes neurons are affected
differently depending upon the amount of residual blood differently depending upon the amount of residual blood flowflow
Normal cerebral blood flow is greater than 50 mL100 Normal cerebral blood flow is greater than 50 mL100 mgminmgmin
Once blood flow decreases to less than 20 mL100 Once blood flow decreases to less than 20 mL100 mgmin infarction occursmgmin infarction occurs
If blood flow decreases to less than 10 mL100 mgmin If blood flow decreases to less than 10 mL100 mgmin irreversible neuronal death occurs rapidly irreversible neuronal death occurs rapidly
Blood flow between 11 and 20 mL100 mgmin is thought Blood flow between 11 and 20 mL100 mgmin is thought to represent the ischemic penumbra an area where the to represent the ischemic penumbra an area where the cells are functionally silent because of ischemia but are cells are functionally silent because of ischemia but are still able to recover if blood flow is restored still able to recover if blood flow is restored
Many acute stroke therapies are targeted toward Many acute stroke therapies are targeted toward restoring flow or function to the ischemic penumbrarestoring flow or function to the ischemic penumbra
Therapeutic window in Therapeutic window in management of acute Ischemic management of acute Ischemic
StrokeStrokeThe early diagnosis of ischemic stroke is critical to the The early diagnosis of ischemic stroke is critical to the
with only a narrow therapeutic window in the first few with only a narrow therapeutic window in the first few hours following stroke ictushours following stroke ictus
Diagnosis in the first 3 hours postictus provides the Diagnosis in the first 3 hours postictus provides the opportunity for intravenous or intraarterial thrombolysis opportunity for intravenous or intraarterial thrombolysis and intra-arterial clot mechanical treatment which and intra-arterial clot mechanical treatment which improve the outcome improve the outcome
Diagnosis in the time period between 3 and 6 hours Diagnosis in the time period between 3 and 6 hours provides an opportunity for intra-arterial thrombolysis provides an opportunity for intra-arterial thrombolysis and mechanical treatment and mechanical treatment
Involvement of the posterior circulation especially the Involvement of the posterior circulation especially the basilar artery is treated by some regardless of time of basilar artery is treated by some regardless of time of onset or up until 12 to 24 hours in some practices This is onset or up until 12 to 24 hours in some practices This is related to the potentially high mortality and morbidity related to the potentially high mortality and morbidity associated with basilar artery thrombosisassociated with basilar artery thrombosis
Infarct evaluation on angiographyInfarct evaluation on angiography(CT angiography and catheter (CT angiography and catheter
angiography)angiography)CTA is an excellent first-line examination for CTA is an excellent first-line examination for
evaluation of the head and neck arteries evaluation of the head and neck arteries In comparison with catheter angiography In comparison with catheter angiography
what it gives up in resolution and dynamic what it gives up in resolution and dynamic properties it makes up for with rapid properties it makes up for with rapid acquisition of a 3-D dataset and the potential acquisition of a 3-D dataset and the potential for assessment of whole-brain perfusion and for assessment of whole-brain perfusion and better parenchymal evaluationbetter parenchymal evaluation
Moreover CTA illustrates not only arterial Moreover CTA illustrates not only arterial stenosis or occlusion but also the vessel wall stenosis or occlusion but also the vessel wall This factor is most important for evaluation of This factor is most important for evaluation of intramural dissection and thrombosed intramural dissection and thrombosed aneurysms which may both complicate aneurysms which may both complicate evaluation of stroke patientsevaluation of stroke patients
Early angiographic signs of strokes Early angiographic signs of strokes both CTA both CTA and DSA and DSA
Vessel occlusion or cutoff related to Vessel occlusion or cutoff related to thromboembolithromboemboli
aneurysms aneurysms arterial dissection arterial dissection Meniscus or flattened shape to clot Meniscus or flattened shape to clot
(recent) versus reverse meniscus (older)(recent) versus reverse meniscus (older) tram track (nonocclusive or recanalized tram track (nonocclusive or recanalized
clot) clot) delayed (antegrade) flow (manifest as delayed (antegrade) flow (manifest as
decreased whole-brain perfusion on CTA)decreased whole-brain perfusion on CTA) retrograde collateral flowretrograde collateral flow
Non-occlusive left MCA thrombus on 3-D imaging performed from CTA source data and was confirmed at catheter angiography
Therapy to be started within a 6-hr Therapy to be started within a 6-hr time to treatment (TTT) window time to treatment (TTT) window (while in case of IV thrombolysis (while in case of IV thrombolysis therapy to be started with in 3hrs)therapy to be started with in 3hrs)
Exclusion criteria Exclusion criteria Rapidly improving neurologic deficit or Rapidly improving neurologic deficit or Sustained blood pressure of gt180100 Sustained blood pressure of gt180100 Hemorrhage is detected on CTHemorrhage is detected on CT Infarct involving gt more than 13 rd Infarct involving gt more than 13 rd
territory of MCAterritory of MCA MRADWI-Perfusion mismatchlt 20MRADWI-Perfusion mismatchlt 20 Definite hypodensity on CTDefinite hypodensity on CT
Intra-arterial Thrombolysis
Fibrinolytics + AntiplateletsFibrinolytics + Antiplatelets
PlasminogenPlasminogen activators through fibrinolysis exposes activators through fibrinolysis exposes free thrombin and paradoxically stimulatesfree thrombin and paradoxically stimulates platelet platelet aggregation which leads to formation of aaggregation which leads to formation of a platelet platelet thrombus (white clot) thrombus (white clot)
This new thrombus is relatively resistant to This new thrombus is relatively resistant to fibrinolyticsfibrinolytics
So new regimen in case of acute stroke isSo new regimen in case of acute stroke is fibrinolytics + antiplatelet drugsfibrinolytics + antiplatelet drugs
rtPA + IIbIIIa inhibitors( tirofiban rtPA + IIbIIIa inhibitors( tirofiban abciximab) orabciximab) or
Urokinase + IIbIIIa Urokinase + IIbIIIa inhibitors( tirofiban abciximab)inhibitors( tirofiban abciximab)
Intra-arterial Thrombolysis Tirofiban (04 microgkgmin bolus for 3 min followed by Tirofiban (04 microgkgmin bolus for 3 min followed by
0125 ugkgmin)0125 ugkgmin)
++
Heparin (2000ndash3000 IU bolus followed by Heparin (2000ndash3000 IU bolus followed by 1000 IUhour infusion 1000 IUhour infusion
with ACT maintained bw 200-300) throughout the with ACT maintained bw 200-300) throughout the interventional procedure and for 24ndash48 hours thereafter when interventional procedure and for 24ndash48 hours thereafter when there is neither intraprocedural bleeding nor suspicion of there is neither intraprocedural bleeding nor suspicion of increased risk of bleeding increased risk of bleeding
Maximum dose of Urokinase Maximum dose of Urokinase Anterior circulation stroke - 500000 IU (mean 400000 Anterior circulation stroke - 500000 IU (mean 400000
IU range 300000ndash500000 IU)IU range 300000ndash500000 IU) Posterior circulation stroke -1000000 IU (mean 837000 Posterior circulation stroke -1000000 IU (mean 837000
IU range 300000ndash1000000 IU)IU range 300000ndash1000000 IU)American Journal of NeuroradiologyAmerican Journal of Neuroradiology 262595-2601 2005262595-2601 2005
Intravenous ThrombolysisIntravenous Thrombolysis
The first method to restore cerebral The first method to restore cerebral perfusion is clot lysis with the goal perfusion is clot lysis with the goal of re-establishing blood flow to the of re-establishing blood flow to the affected tissue affected tissue
IV thrombolysis rt-PA is the only IV thrombolysis rt-PA is the only FDA- approved treatment for AIS FDA- approved treatment for AIS
Fibrinolysis is enhanced powerfully Fibrinolysis is enhanced powerfully by rt-PAby rt-PA
Intravenous rTPA Intravenous rTPA administration administration protocolprotocol
Total dose of rt-PA 09 mgkg (maximum dose Total dose of rt-PA 09 mgkg (maximum dose 90 mg)90 mg)
Give 10 as initial IV bolusGive 10 as initial IV bolus Infuse remainder over 1 hourInfuse remainder over 1 hour Admit patient to an ICU or stroke unit for Admit patient to an ICU or stroke unit for
monitoringmonitoring Neurologic assessments every 15 minutes Neurologic assessments every 15 minutes
during infusion then every 30 minutes for next during infusion then every 30 minutes for next 6 hours then every hour until 24hours after 6 hours then every hour until 24hours after treatmenttreatment
Favorable Outcome vs Treatment Time Favorable Outcome vs Treatment Time with IV rTPAwith IV rTPA
Protocol limit = 3 hrs
Benefit ~ 45 hrs
Thromboembolism During coilingThromboembolism During coiling Most feared and frequent complication Most feared and frequent complication Reported incidence - Approx 7 Reported incidence - Approx 7 SourcesSources of Thromboembolism are of Thromboembolism are
- Clots at the aneurysmal neck during or immediately- Clots at the aneurysmal neck during or immediately after after embolization embolization
- Thrombus forming on catheters during- Thrombus forming on catheters during proceduresprocedures
- Stenosis of an adjacent artery dt coil mass- Stenosis of an adjacent artery dt coil mass or herniationor herniation
- Migration of intraaneurysmal- Migration of intraaneurysmal thrombus during coil thrombus during coil placement placement
- Slow flow dt vasospasm - Slow flow dt vasospasm
- Rare and unlikely causes are hypercoagulable- Rare and unlikely causes are hypercoagulable state such state such as antiphospholipid antibody syndrome or due to HITas antiphospholipid antibody syndrome or due to HIT
Occur more often with wide-necked aneurysms (dt Occur more often with wide-necked aneurysms (dt increased exposed surface area of thrombogenic coil increased exposed surface area of thrombogenic coil material)material)
Current regimen of endovascular Current regimen of endovascular managementmanagement
The The glycoprotein IIbIIIa antagonist tirofiban glycoprotein IIbIIIa antagonist tirofiban (04 (04 microgkgmin bolus for 30 minutes followed by infusion of microgkgmin bolus for 30 minutes followed by infusion of 0125 ugkgmin until the thrombus dissolved) 0125 ugkgmin until the thrombus dissolved)
Intraarterial thrombolysis with Intraarterial thrombolysis with urokinase or r- TPA urokinase or r- TPA increase of intravenous (IV) heparin (measured by increase of intravenous (IV) heparin (measured by
ACT) ACT) Intravenous aspirin Intravenous aspirin
Coil-related platelet aggregation (white clot) is Coil-related platelet aggregation (white clot) is unlikely to respond to fibrinolytics but has a high risk unlikely to respond to fibrinolytics but has a high risk of hemorrhage (In ISAT) all 5 patients who had of hemorrhage (In ISAT) all 5 patients who had received thrombolytic therapy with tPA to treat a received thrombolytic therapy with tPA to treat a thromboembolic complication after endovascular thromboembolic complication after endovascular treatment rebleed and all of these patients died)treatment rebleed and all of these patients died)
IntracranialIntracranial Stenting Stenting Metallic foreign body such as stent will accumulate Metallic foreign body such as stent will accumulate
thrombus in the absence of platelet inhibitionthrombus in the absence of platelet inhibition Antiplatelet drugs are important to prevent peri or Antiplatelet drugs are important to prevent peri or
post-interventional thromboembolic eventspost-interventional thromboembolic events Optimal treatment regimens has not been determined Optimal treatment regimens has not been determined
but usually but usually Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-
procedureprocedureOrOr
Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on
morning of proceduremorning of procedure
If need to use stent is not pre-planned thanIf need to use stent is not pre-planned than
Abciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkgAbciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkg IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)
Glycoprotein IIbIIIa inhibitor are not used routinely during elective Glycoprotein IIbIIIa inhibitor are not used routinely during elective stenting procedure dt increased risk of ICH stenting procedure dt increased risk of ICH
Carotid StentingCarotid Stenting
Pre-procedurePre-procedure
Double Antiplatelet therapy is routinely given Double Antiplatelet therapy is routinely given beginning at least 3beginning at least 3
days before the proceduredays before the procedure
Aspirin 325mgd+Clopidogrel 75mgdAspirin 325mgd+Clopidogrel 75mgd During procedureDuring procedure
Heparin is given with target clotting time of 250-Heparin is given with target clotting time of 250-300sec300sec
Post-procedure Post-procedure
Aspirin 325mg is continued indefinitely and Aspirin 325mg is continued indefinitely and
Clopidogrel 75mgd for at least 6 weeks Clopidogrel 75mgd for at least 6 weeks
Inclusion criteria for Local ThrombolysisInclusion criteria for Local Thrombolysis a)a) Patients in severe clinical grade on admission Patients in severe clinical grade on admission
with evidence of dural venous sinus with evidence of dural venous sinus thrombosis and restrictive venous outflow on thrombosis and restrictive venous outflow on cerebral angiogramcerebral angiogram
b)b) Patients in clinical grade 3 worsening on Patients in clinical grade 3 worsening on heparin therapy Restriction to venous heparin therapy Restriction to venous outflow was defined as an increase in brain outflow was defined as an increase in brain circulation time gt 12 s delay in the drainage circulation time gt 12 s delay in the drainage of cortical veins with cortical veins hanging of cortical veins with cortical veins hanging in spacein space
Treatment Options for Venous Thrombosis
CT Grading for Venous ThrombosisCT Grading for Venous Thrombosis Grade I no parenchymal change Grade I no parenchymal change
(hyperdense (hyperdense sinuses cortical veins empty sinuses cortical veins empty delta sign)delta sign)
Grade II non hemorrhagic venous infarct Grade II non hemorrhagic venous infarct without mass effect without mass effect
Grade III non-hemorrhagic infarct with Grade III non-hemorrhagic infarct with mass effectmass effect
Grade IV hemorrhagic venous infarct (max Grade IV hemorrhagic venous infarct (max diameter lt 3 cm) with no mass effectdiameter lt 3 cm) with no mass effect
Grade V hemorrhagic venous infarct (max Grade V hemorrhagic venous infarct (max diameter gt 3 cm) with mass effect diameter gt 3 cm) with mass effect
Local ThrombolysisLocal Thrombolysis
Femoral Jugular access was secured and a guiding Femoral Jugular access was secured and a guiding catheter was placed in the jugular bulb catheter was placed in the jugular bulb Mechanical Mechanical clot maceration clot maceration was done with the guidewire was done with the guidewire following which a microcatheter (was navigated and following which a microcatheter (was navigated and placed in the thrombosed segment of sinus confirmed placed in the thrombosed segment of sinus confirmed on a selective venogram on a selective venogram
Urokinase infusion Bolus dose of 2-6 lacs followed Urokinase infusion Bolus dose of 2-6 lacs followed by 60000 to 100000 units per hour along with by 60000 to 100000 units per hour along with periodic check venogram Along with maintenance periodic check venogram Along with maintenance systemic infusion of Heparinsystemic infusion of Heparin Other agents such as Other agents such as streptokinase altepase or rTPAstreptokinase altepase or rTPA can be also used can be also used
After thrombolysis patient should subjected to oral After thrombolysis patient should subjected to oral anticoagulation for six monthsanticoagulation for six months
Low-molecular-weight Low-molecular-weight heparinheparin
PharmacologyPharmacologyLMWH as its name suggests is a glycosaminoglycan that is approximatelyLMWH as its name suggests is a glycosaminoglycan that is approximately
one third the molecular weight of UFH It is derived from UFH through one third the molecular weight of UFH It is derived from UFH through variousvarious
depolymerization processes LMWH binds to antithrombin which in turn depolymerization processes LMWH binds to antithrombin which in turn
Neutralizes actors Xa and IIa Because LMWH lacks many of the longer Neutralizes actors Xa and IIa Because LMWH lacks many of the longer chains chains
required for binding to thrombin it has less ability to neutralize thrombin required for binding to thrombin it has less ability to neutralize thrombin
relativeto its ability to neutralize factor Xa LMWH also has less relativeto its ability to neutralize factor Xa LMWH also has less nonspecific nonspecific
binding to other proteins There is greater bioavailability with more binding to other proteins There is greater bioavailability with more predictable predictable
pharmacokinetics that eliminates the need for monitoring The smaller pharmacokinetics that eliminates the need for monitoring The smaller size also size also
allows for enhanced subcutaneous absorption when compared with UFHallows for enhanced subcutaneous absorption when compared with UFH
Three LMWH preparations are Three LMWH preparations are currently approved for use in the currently approved for use in the United States (1) enoxaparin (2) United States (1) enoxaparin (2) dalteparin and (3) tinzaparin dalteparin and (3) tinzaparin
They are all administered They are all administered subcutaneously at intervals of either subcutaneously at intervals of either once or twice daily for both once or twice daily for both prophylaxis and treatment dosesprophylaxis and treatment doses
Few Experiences of Few Experiences of ThrombolysisThrombolysis
Vickey 25 Yrs male patient presented Vickey 25 Yrs male patient presented with 12with 12thth day HO severe headache with day HO severe headache with right sided hemiplegiaright sided hemiplegia
MRI shows thrombosis of the superior MRI shows thrombosis of the superior sagittal left transverse left sigmoid sagittal left transverse left sigmoid sinuses and cortical veins in the fronto-sinuses and cortical veins in the fronto-parietal regions with eo haemorrhagic parietal regions with eo haemorrhagic infarct in the left cerebral hemisphere infarct in the left cerebral hemisphere with mass effect( Grade ndashV)with mass effect( Grade ndashV)
Sashi Srivastava 64 yrs FSashi Srivastava 64 yrs F In a follow up case of MRD with infra-renal In a follow up case of MRD with infra-renal
aortic abdominal and bilateral renal artery aortic abdominal and bilateral renal artery thrombosis renal angiogram shows filling thrombosis renal angiogram shows filling defects in the right Renal artery defects in the right Renal artery
Initially Renal angioplasty was done Initially Renal angioplasty was done Following angioplasty few thrombi are seem Following angioplasty few thrombi are seem to extends into the segmental branches and to extends into the segmental branches and causing blockage So Thrombolysis was causing blockage So Thrombolysis was plane to dissolve the run-out thrombi with plane to dissolve the run-out thrombi with urokinase urokinase
Rakesh 34yrsMRakesh 34yrsM Left SFA pseudoaneurysm with Left SFA pseudoaneurysm with
Covered stent placementCovered stent placement Pre operative antiplatelets with post Pre operative antiplatelets with post
procedure heparin Tirofiban procedure heparin Tirofiban followed by aspirin and clopidogrel followed by aspirin and clopidogrel were usedwere used
IAT may be a treatment option for selected patients IAT may be a treatment option for selected patients Possible selection criteria include Possible selection criteria include
presentation between 3 and 6 hours from symptom onsetpresentation between 3 and 6 hours from symptom onset major cerebral artery occlusion major cerebral artery occlusion severe neurologic deficits severe neurologic deficits high risk of systemic hemorrhage with IV rt-PA (eg recent high risk of systemic hemorrhage with IV rt-PA (eg recent
surgery) surgery) The MERCI (Mechanical Embolus Removal in Cerebral The MERCI (Mechanical Embolus Removal in Cerebral
Ischemia) retrievalIschemia) retrieval system system
Has been FDA-approved for recanalizing acutely occluded Has been FDA-approved for recanalizing acutely occluded cerebral arteries cerebral arteries
In the Multi-MERCI study patients who did not improve In the Multi-MERCI study patients who did not improve immediately after IV rt-PA underwent mechanical immediately after IV rt-PA underwent mechanical embolectomy within 8 hours of symptom onset embolectomy within 8 hours of symptom onset
Partial or complete recanalization occurred in 74 of Partial or complete recanalization occurred in 74 of patientspatients
with a symptomatic intracerebral hemorrhage (sICH) rate of with a symptomatic intracerebral hemorrhage (sICH) rate of 67 67
Mechanical embolectomy with the MERCI retriever may be a Mechanical embolectomy with the MERCI retriever may be a feasible and safe option for patients after IV rt-PAfeasible and safe option for patients after IV rt-PA
Penumbra stroke systemPenumbra stroke system This device combines two methods of clot This device combines two methods of clot
extraction aspiration and mechanical extraction aspiration and mechanical extraction extraction
First the clot is aspirated then a thrombus First the clot is aspirated then a thrombus removal ring can be used if necessary to removal ring can be used if necessary to remove remaining clot remove remaining clot
successful recanalizing 82successful recanalizing 82 Bridging therapyBridging therapy
06 mgkg IV rt-PA followed by IAT with IA rt-06 mgkg IV rt-PA followed by IAT with IA rt-PA (up to 20 mg)PA (up to 20 mg)
achieved a higher recanalization rateachieved a higher recanalization rate
Criteria for thrombolysis with rTPACriteria for thrombolysis with rTPA
Inclusion criteriaInclusion criteria Clinical signs and symptoms consistent with ischemic Clinical signs and symptoms consistent with ischemic
strokestroke Patient last seen normal within 3 hoursPatient last seen normal within 3 hours Measurable neurologic deficitMeasurable neurologic deficit
Exclusion criteriaExclusion criteria Any hemorrhage on neuroimaging (CT or MRI)Any hemorrhage on neuroimaging (CT or MRI) Symptoms suggestive of subarachnoid hemorrhageSymptoms suggestive of subarachnoid hemorrhage Seizure at stroke onset that is thought to contribute to Seizure at stroke onset that is thought to contribute to
neurologic deficitneurologic deficit Hypodensity greater than one third cerebral hemisphere Hypodensity greater than one third cerebral hemisphere
on CTon CT SBP greater than 185 mm Hg or DBP greater than 110 SBP greater than 185 mm Hg or DBP greater than 110
mm Hgmm Hg International normalized ratio (INR) greater than 17International normalized ratio (INR) greater than 17
Ischemic Stroke Ischemic Stroke Treatment ndash 2006Treatment ndash 2006
IV tissue plasminogen activator (tPA)IV tissue plasminogen activator (tPA) ndash ndash Only FDA-approved acute stroke drugOnly FDA-approved acute stroke drug ndash ndash 3 hour treatment window3 hour treatment window
MERCI - Concentric clot retrieval MERCI - Concentric clot retrieval devicedevice ndash ndash Rescue therapy - approved 2004Rescue therapy - approved 2004 ndash ndash Device approval (not outcomes-based)Device approval (not outcomes-based)
Off label approachesOff label approaches ndash ndash IV tPA after 3 hoursIV tPA after 3 hours ndash ndash IV-IA tPA sequential strategiesIV-IA tPA sequential strategies ndash ndash IA tPA clot angioplasty fragmentationIA tPA clot angioplasty fragmentation ndash ndash Ultrasound-assisted tPA lysisUltrasound-assisted tPA lysis
rt-PA Trials NINDSrt-PA Trials NINDS
Acute stroke - 624 patientsAcute stroke - 624 patients Treat within 3 hrsTreat within 3 hrs Intravenous 09 mgkg rt-PA vs placeboIntravenous 09 mgkg rt-PA vs placebo Hemorrhage 64 tPA 06 placeboHemorrhage 64 tPA 06 placebo Neurologic recovery better with tPA 30 Neurologic recovery better with tPA 30
more like to have minimal or no disabilitymore like to have minimal or no disability
First proven approved treatment for First proven approved treatment for strokestroke
Limitations of tPALimitations of tPA Only 4 of acute strokes receive tPAOnly 4 of acute strokes receive tPA (Kleindorfer et al Stroke 2004 35 e27-e29)(Kleindorfer et al Stroke 2004 35 e27-e29)
Only 22 of patients present within 3 hoursOnly 22 of patients present within 3 hours1048707 1048707 51 of these ineligible due to51 of these ineligible due to
bull bull Mild severityMild severity bull bull Medical or surgical historyMedical or surgical history bull bull Blood testsBlood tests
Sustained recanalization only 13Sustained recanalization only 13 (Alexandrov et al NEJM 2004 351 2170-8)(Alexandrov et al NEJM 2004 351 2170-8)
Concern for hemorrhageConcern for hemorrhage tPA potentiates apoptotic injury tPA potentiates apoptotic injury (Liu et al Nature Med 2004 101379-83)(Liu et al Nature Med 2004 101379-83)
PROACT II IA Lysis TrialPROACT II IA Lysis Trial Baseline 24 hours 8 days
Baseline 60 minutes 120 minutes
9mg IAProurokinase
Desmoteplase Trials DEDAS Desmoteplase Trials DEDAS DIASDIAS
Trial OverviewTrial Overview Double blind randomized placebo Double blind randomized placebo
controlled trialscontrolled trials IV delivery 3-9 hour time windowIV delivery 3-9 hour time window Plasminogen activator ndash from Plasminogen activator ndash from vampire bat vampire bat
salivasaliva Selection based on PWI-DWI MismatchSelection based on PWI-DWI Mismatch
MRI InclusionMRI Inclusion PWI defect at least 2 cm AND ~20 larger PWI defect at least 2 cm AND ~20 larger
than DWIthan DWI PWI should be obvious even visible on PWI should be obvious even visible on
raw imagesraw imagesMRI ExclusionMRI Exclusion
DWI gt 13 MCADWI gt 13 MCA MRA ICA occlusionMRA ICA occlusion
Desmoteplase ndash DIAS Desmoteplase ndash DIAS ResultsResults
Mechanical Thrombolysis Mechanical Thrombolysis devicesdevices
mechanical thrombolysis potentially extends the treatment mechanical thrombolysis potentially extends the treatment window because they act promptly at the site of the thrombuswindow because they act promptly at the site of the thrombus
The devices can retrieve large clots that pharmaceutical agents The devices can retrieve large clots that pharmaceutical agents may not successfully lysemay not successfully lyse
Patients treated with IV tPA may be considered for treatment of Patients treated with IV tPA may be considered for treatment of residual clot with some of these devicesresidual clot with some of these devices
suction-creating saline jets suction-creating saline jets laser energy ultrasound laser energy ultrasound a corkscrew apparatus to treat strokesa corkscrew apparatus to treat strokes The AngioJet systemThe AngioJet system uses saline jets that are directed back into the catheter to uses saline jets that are directed back into the catheter to
create a low-pressure zone around the catheter tip inducing create a low-pressure zone around the catheter tip inducing suction suction
The clot is pulled into the exhaust lumen and removed from the The clot is pulled into the exhaust lumen and removed from the vessel Although US Food and Drug Administration (FDA) has vessel Although US Food and Drug Administration (FDA) has approved this device for use in arteriovenous dialysis grafts and approved this device for use in arteriovenous dialysis grafts and fistulae and for the treatment of coronary arteries saphenous fistulae and for the treatment of coronary arteries saphenous vein grafts and peripheral vessels clinical trials for the vein grafts and peripheral vessels clinical trials for the treatment of acute stroke are no longer in progress treatment of acute stroke are no longer in progress
Most devices are used in cerebral vessels that 2-5 mm
The Latis laser device The Latis laser device used laser energy to ablate clots used laser energy to ablate clots Arteries 2-5 mm in diameter could be Arteries 2-5 mm in diameter could be
treated including the ICA M1 or M2 treated including the ICA M1 or M2 branch of the MCA A1 branch of the branch of the MCA A1 branch of the anterior cerebral artery (ACA) basilar anterior cerebral artery (ACA) basilar artery posterior cerebral artery (PCA) artery posterior cerebral artery (PCA) and vertebral and vertebral
Patients could receive treatment as late Patients could receive treatment as late as 8 hours after symptom onset in the as 8 hours after symptom onset in the anterior circulation and within 24 hours in anterior circulation and within 24 hours in the posterior circulation the posterior circulation
Endovascular Photo Acoustic Endovascular Photo Acoustic Recanalization (EPAR) Recanalization (EPAR)
A laser power source generated energy for the A laser power source generated energy for the systemsystem
The energy was delivered by means of The energy was delivered by means of fiberoptics to the tip of the catheter at the fiberoptics to the tip of the catheter at the treatment sitetreatment site
Absorption of laser light by darkly pigmented Absorption of laser light by darkly pigmented materials (ie the clot) occurred inside the 1-mm materials (ie the clot) occurred inside the 1-mm catheter tipcatheter tip
the system was designed to minimize scattering the system was designed to minimize scattering of laser light of laser light
Absorption converted photo energy to acoustic Absorption converted photo energy to acoustic energy which then emulsified the clot inside the energy which then emulsified the clot inside the catheter tip catheter tip
EKOS ultrasound( the EKOS ultrasound( the Ultrasound Thrombolytic Ultrasound Thrombolytic
Infusion Catheter) Infusion Catheter) combines the use of a distal ultrasound transducer with combines the use of a distal ultrasound transducer with
infusion of a thrombolytic agent through the infusion of a thrombolytic agent through the microcathetermicrocatheter
Ultrasound changes the structure of the clot to Ultrasound changes the structure of the clot to temporarily increase its permeability while providing an temporarily increase its permeability while providing an acoustic pressure gradient to move the drug into the clot acoustic pressure gradient to move the drug into the clot to speed its dissolution to speed its dissolution
The EKOS catheter is placed in the proximal portion of the The EKOS catheter is placed in the proximal portion of the clot clot
After a 2-mg bolus of tPA was injected through the After a 2-mg bolus of tPA was injected through the catheter catheter
the patient received a continuous infusion of IA tPA 03 the patient received a continuous infusion of IA tPA 03 mgmin to a maximum of 20 mg and simultaneous mgmin to a maximum of 20 mg and simultaneous ultrasound transmission for as long as 60 minutes ultrasound transmission for as long as 60 minutes
One patient was treated with a total of 4 units of One patient was treated with a total of 4 units of recombinant reteplase (Retavase) hand-injected over 60 recombinant reteplase (Retavase) hand-injected over 60 minutes minutes
Penumbra system Penumbra system The Penumbra system (Penumbra Inc) provides a dual The Penumbra system (Penumbra Inc) provides a dual
approach to clot extraction using aspiration followed by approach to clot extraction using aspiration followed by clot retrieval with a ring device if needed clot retrieval with a ring device if needed
Mechanical Embolus Removal in Cerebral Ischemia Mechanical Embolus Removal in Cerebral Ischemia (MERCI)(MERCI)
a corkscrew-like apparatus to remove blood clots from a corkscrew-like apparatus to remove blood clots from the brain in patients experiencing an ischemic stroke the brain in patients experiencing an ischemic stroke
The corkscrew itself resides in the catheter tip which The corkscrew itself resides in the catheter tip which shields it from the wall of the vessel until it is ready to be shields it from the wall of the vessel until it is ready to be burrowed into the clot Once lodged in the clot the device burrowed into the clot Once lodged in the clot the device and clot are withdrawn from the vessel and clot are withdrawn from the vessel
Snarelike devicesSnarelike devices Snares such as the Neuronet snare (Guidant Snares such as the Neuronet snare (Guidant
Endovascular Santa Clara CA) have been developed Endovascular Santa Clara CA) have been developed specifically for use in the treatment of strokes specifically for use in the treatment of strokes
These devices are simple in design and do not require the These devices are simple in design and do not require the clot to be amenable to emulsification clot to be amenable to emulsification
X-Sizer deviceX-Sizer device a device with small moving blades at the a device with small moving blades at the
catheter tip catheter tip This device the X-Sizer device (EndiCor Medical This device the X-Sizer device (EndiCor Medical
San Clemente CA) can be used to excise the San Clemente CA) can be used to excise the thrombus and aspirate it thrombus and aspirate it
The device was being evaluated in randomized The device was being evaluated in randomized studies of coronary vessels and in a registry of studies of coronary vessels and in a registry of patients with acute myocardial infarctionpatients with acute myocardial infarction
Although the manufacturer had modified the Although the manufacturer had modified the device for use in cerebral vessels a safety and device for use in cerebral vessels a safety and feasibility study was indefinitely suspended after feasibility study was indefinitely suspended after only 1 patient was treated with the device in only 1 patient was treated with the device in Europe Europe
Suction thrombectomySuction thrombectomy This method of mechanical thrombolysis is one of the This method of mechanical thrombolysis is one of the
simplestsimplest In this readily available technique suction is applied with In this readily available technique suction is applied with
a syringe to remove thrombus in the ICA a syringe to remove thrombus in the ICA It requires no other devicesIt requires no other devices A catheter with a large inner diameter (Brite Tip Cordis A catheter with a large inner diameter (Brite Tip Cordis
Corporation Miami FL) was placed in the symptomatic Corporation Miami FL) was placed in the symptomatic vessel and navigated over a guidewire into the thrombusvessel and navigated over a guidewire into the thrombus
A 60-mL syringe was used to aspirate the thrombus A 60-mL syringe was used to aspirate the thrombus Each patient required angioplasty and stenting of carotid Each patient required angioplasty and stenting of carotid
bifurcation stenosis and received daily aspirin and bifurcation stenosis and received daily aspirin and ticlopidine after the procedure No complications ticlopidine after the procedure No complications occurred occurred
Summary Acute Stroke Summary Acute Stroke ImagingImaging
PhysiologyPhysiology importance collaterals importance collaterals
ndash ndashGrowing role for perfusion Growing role for perfusion assessmentassessment
tPAtPA guidelines amp limitations guidelines amp limitations Signs on CT amp MRSigns on CT amp MR follow physiology follow physiology Stroke trialsStroke trials PWI-DWI mismatch PWI-DWI mismatch
ndash ndashTreat based on physiology not timeTreat based on physiology not time ProtocolsProtocols should be fast and should be fast and
comprehensivecomprehensive
Point-of-care rapid platelet function Point-of-care rapid platelet function assayassay
Can be performed bed sideCan be performed bed side Different assay devices with different Different assay devices with different
agonist are used for each of different agonist are used for each of different antiplatelet agents antiplatelet agents
For Aspirin AA is used (result is reported as aspirin For Aspirin AA is used (result is reported as aspirin reaction units [ARU] ARUgt 550 indicates non-reaction units [ARU] ARUgt 550 indicates non-responsiveness)responsiveness)
Verify IIbIIIa assay device uses TRAP as agonist for Verify IIbIIIa assay device uses TRAP as agonist for Abciximab and TirofibanAbciximab and Tirofiban
Practical Applications Practical Applications related to specific related to specific
Neurovascular Neurovascular interventionsinterventions
Acute ischemic StrokeAcute ischemic Stroke When an artery occludes neurons are affected When an artery occludes neurons are affected
differently depending upon the amount of residual blood differently depending upon the amount of residual blood flowflow
Normal cerebral blood flow is greater than 50 mL100 Normal cerebral blood flow is greater than 50 mL100 mgminmgmin
Once blood flow decreases to less than 20 mL100 Once blood flow decreases to less than 20 mL100 mgmin infarction occursmgmin infarction occurs
If blood flow decreases to less than 10 mL100 mgmin If blood flow decreases to less than 10 mL100 mgmin irreversible neuronal death occurs rapidly irreversible neuronal death occurs rapidly
Blood flow between 11 and 20 mL100 mgmin is thought Blood flow between 11 and 20 mL100 mgmin is thought to represent the ischemic penumbra an area where the to represent the ischemic penumbra an area where the cells are functionally silent because of ischemia but are cells are functionally silent because of ischemia but are still able to recover if blood flow is restored still able to recover if blood flow is restored
Many acute stroke therapies are targeted toward Many acute stroke therapies are targeted toward restoring flow or function to the ischemic penumbrarestoring flow or function to the ischemic penumbra
Therapeutic window in Therapeutic window in management of acute Ischemic management of acute Ischemic
StrokeStrokeThe early diagnosis of ischemic stroke is critical to the The early diagnosis of ischemic stroke is critical to the
with only a narrow therapeutic window in the first few with only a narrow therapeutic window in the first few hours following stroke ictushours following stroke ictus
Diagnosis in the first 3 hours postictus provides the Diagnosis in the first 3 hours postictus provides the opportunity for intravenous or intraarterial thrombolysis opportunity for intravenous or intraarterial thrombolysis and intra-arterial clot mechanical treatment which and intra-arterial clot mechanical treatment which improve the outcome improve the outcome
Diagnosis in the time period between 3 and 6 hours Diagnosis in the time period between 3 and 6 hours provides an opportunity for intra-arterial thrombolysis provides an opportunity for intra-arterial thrombolysis and mechanical treatment and mechanical treatment
Involvement of the posterior circulation especially the Involvement of the posterior circulation especially the basilar artery is treated by some regardless of time of basilar artery is treated by some regardless of time of onset or up until 12 to 24 hours in some practices This is onset or up until 12 to 24 hours in some practices This is related to the potentially high mortality and morbidity related to the potentially high mortality and morbidity associated with basilar artery thrombosisassociated with basilar artery thrombosis
Infarct evaluation on angiographyInfarct evaluation on angiography(CT angiography and catheter (CT angiography and catheter
angiography)angiography)CTA is an excellent first-line examination for CTA is an excellent first-line examination for
evaluation of the head and neck arteries evaluation of the head and neck arteries In comparison with catheter angiography In comparison with catheter angiography
what it gives up in resolution and dynamic what it gives up in resolution and dynamic properties it makes up for with rapid properties it makes up for with rapid acquisition of a 3-D dataset and the potential acquisition of a 3-D dataset and the potential for assessment of whole-brain perfusion and for assessment of whole-brain perfusion and better parenchymal evaluationbetter parenchymal evaluation
Moreover CTA illustrates not only arterial Moreover CTA illustrates not only arterial stenosis or occlusion but also the vessel wall stenosis or occlusion but also the vessel wall This factor is most important for evaluation of This factor is most important for evaluation of intramural dissection and thrombosed intramural dissection and thrombosed aneurysms which may both complicate aneurysms which may both complicate evaluation of stroke patientsevaluation of stroke patients
Early angiographic signs of strokes Early angiographic signs of strokes both CTA both CTA and DSA and DSA
Vessel occlusion or cutoff related to Vessel occlusion or cutoff related to thromboembolithromboemboli
aneurysms aneurysms arterial dissection arterial dissection Meniscus or flattened shape to clot Meniscus or flattened shape to clot
(recent) versus reverse meniscus (older)(recent) versus reverse meniscus (older) tram track (nonocclusive or recanalized tram track (nonocclusive or recanalized
clot) clot) delayed (antegrade) flow (manifest as delayed (antegrade) flow (manifest as
decreased whole-brain perfusion on CTA)decreased whole-brain perfusion on CTA) retrograde collateral flowretrograde collateral flow
Non-occlusive left MCA thrombus on 3-D imaging performed from CTA source data and was confirmed at catheter angiography
Therapy to be started within a 6-hr Therapy to be started within a 6-hr time to treatment (TTT) window time to treatment (TTT) window (while in case of IV thrombolysis (while in case of IV thrombolysis therapy to be started with in 3hrs)therapy to be started with in 3hrs)
Exclusion criteria Exclusion criteria Rapidly improving neurologic deficit or Rapidly improving neurologic deficit or Sustained blood pressure of gt180100 Sustained blood pressure of gt180100 Hemorrhage is detected on CTHemorrhage is detected on CT Infarct involving gt more than 13 rd Infarct involving gt more than 13 rd
territory of MCAterritory of MCA MRADWI-Perfusion mismatchlt 20MRADWI-Perfusion mismatchlt 20 Definite hypodensity on CTDefinite hypodensity on CT
Intra-arterial Thrombolysis
Fibrinolytics + AntiplateletsFibrinolytics + Antiplatelets
PlasminogenPlasminogen activators through fibrinolysis exposes activators through fibrinolysis exposes free thrombin and paradoxically stimulatesfree thrombin and paradoxically stimulates platelet platelet aggregation which leads to formation of aaggregation which leads to formation of a platelet platelet thrombus (white clot) thrombus (white clot)
This new thrombus is relatively resistant to This new thrombus is relatively resistant to fibrinolyticsfibrinolytics
So new regimen in case of acute stroke isSo new regimen in case of acute stroke is fibrinolytics + antiplatelet drugsfibrinolytics + antiplatelet drugs
rtPA + IIbIIIa inhibitors( tirofiban rtPA + IIbIIIa inhibitors( tirofiban abciximab) orabciximab) or
Urokinase + IIbIIIa Urokinase + IIbIIIa inhibitors( tirofiban abciximab)inhibitors( tirofiban abciximab)
Intra-arterial Thrombolysis Tirofiban (04 microgkgmin bolus for 3 min followed by Tirofiban (04 microgkgmin bolus for 3 min followed by
0125 ugkgmin)0125 ugkgmin)
++
Heparin (2000ndash3000 IU bolus followed by Heparin (2000ndash3000 IU bolus followed by 1000 IUhour infusion 1000 IUhour infusion
with ACT maintained bw 200-300) throughout the with ACT maintained bw 200-300) throughout the interventional procedure and for 24ndash48 hours thereafter when interventional procedure and for 24ndash48 hours thereafter when there is neither intraprocedural bleeding nor suspicion of there is neither intraprocedural bleeding nor suspicion of increased risk of bleeding increased risk of bleeding
Maximum dose of Urokinase Maximum dose of Urokinase Anterior circulation stroke - 500000 IU (mean 400000 Anterior circulation stroke - 500000 IU (mean 400000
IU range 300000ndash500000 IU)IU range 300000ndash500000 IU) Posterior circulation stroke -1000000 IU (mean 837000 Posterior circulation stroke -1000000 IU (mean 837000
IU range 300000ndash1000000 IU)IU range 300000ndash1000000 IU)American Journal of NeuroradiologyAmerican Journal of Neuroradiology 262595-2601 2005262595-2601 2005
Intravenous ThrombolysisIntravenous Thrombolysis
The first method to restore cerebral The first method to restore cerebral perfusion is clot lysis with the goal perfusion is clot lysis with the goal of re-establishing blood flow to the of re-establishing blood flow to the affected tissue affected tissue
IV thrombolysis rt-PA is the only IV thrombolysis rt-PA is the only FDA- approved treatment for AIS FDA- approved treatment for AIS
Fibrinolysis is enhanced powerfully Fibrinolysis is enhanced powerfully by rt-PAby rt-PA
Intravenous rTPA Intravenous rTPA administration administration protocolprotocol
Total dose of rt-PA 09 mgkg (maximum dose Total dose of rt-PA 09 mgkg (maximum dose 90 mg)90 mg)
Give 10 as initial IV bolusGive 10 as initial IV bolus Infuse remainder over 1 hourInfuse remainder over 1 hour Admit patient to an ICU or stroke unit for Admit patient to an ICU or stroke unit for
monitoringmonitoring Neurologic assessments every 15 minutes Neurologic assessments every 15 minutes
during infusion then every 30 minutes for next during infusion then every 30 minutes for next 6 hours then every hour until 24hours after 6 hours then every hour until 24hours after treatmenttreatment
Favorable Outcome vs Treatment Time Favorable Outcome vs Treatment Time with IV rTPAwith IV rTPA
Protocol limit = 3 hrs
Benefit ~ 45 hrs
Thromboembolism During coilingThromboembolism During coiling Most feared and frequent complication Most feared and frequent complication Reported incidence - Approx 7 Reported incidence - Approx 7 SourcesSources of Thromboembolism are of Thromboembolism are
- Clots at the aneurysmal neck during or immediately- Clots at the aneurysmal neck during or immediately after after embolization embolization
- Thrombus forming on catheters during- Thrombus forming on catheters during proceduresprocedures
- Stenosis of an adjacent artery dt coil mass- Stenosis of an adjacent artery dt coil mass or herniationor herniation
- Migration of intraaneurysmal- Migration of intraaneurysmal thrombus during coil thrombus during coil placement placement
- Slow flow dt vasospasm - Slow flow dt vasospasm
- Rare and unlikely causes are hypercoagulable- Rare and unlikely causes are hypercoagulable state such state such as antiphospholipid antibody syndrome or due to HITas antiphospholipid antibody syndrome or due to HIT
Occur more often with wide-necked aneurysms (dt Occur more often with wide-necked aneurysms (dt increased exposed surface area of thrombogenic coil increased exposed surface area of thrombogenic coil material)material)
Current regimen of endovascular Current regimen of endovascular managementmanagement
The The glycoprotein IIbIIIa antagonist tirofiban glycoprotein IIbIIIa antagonist tirofiban (04 (04 microgkgmin bolus for 30 minutes followed by infusion of microgkgmin bolus for 30 minutes followed by infusion of 0125 ugkgmin until the thrombus dissolved) 0125 ugkgmin until the thrombus dissolved)
Intraarterial thrombolysis with Intraarterial thrombolysis with urokinase or r- TPA urokinase or r- TPA increase of intravenous (IV) heparin (measured by increase of intravenous (IV) heparin (measured by
ACT) ACT) Intravenous aspirin Intravenous aspirin
Coil-related platelet aggregation (white clot) is Coil-related platelet aggregation (white clot) is unlikely to respond to fibrinolytics but has a high risk unlikely to respond to fibrinolytics but has a high risk of hemorrhage (In ISAT) all 5 patients who had of hemorrhage (In ISAT) all 5 patients who had received thrombolytic therapy with tPA to treat a received thrombolytic therapy with tPA to treat a thromboembolic complication after endovascular thromboembolic complication after endovascular treatment rebleed and all of these patients died)treatment rebleed and all of these patients died)
IntracranialIntracranial Stenting Stenting Metallic foreign body such as stent will accumulate Metallic foreign body such as stent will accumulate
thrombus in the absence of platelet inhibitionthrombus in the absence of platelet inhibition Antiplatelet drugs are important to prevent peri or Antiplatelet drugs are important to prevent peri or
post-interventional thromboembolic eventspost-interventional thromboembolic events Optimal treatment regimens has not been determined Optimal treatment regimens has not been determined
but usually but usually Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-
procedureprocedureOrOr
Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on
morning of proceduremorning of procedure
If need to use stent is not pre-planned thanIf need to use stent is not pre-planned than
Abciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkgAbciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkg IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)
Glycoprotein IIbIIIa inhibitor are not used routinely during elective Glycoprotein IIbIIIa inhibitor are not used routinely during elective stenting procedure dt increased risk of ICH stenting procedure dt increased risk of ICH
Carotid StentingCarotid Stenting
Pre-procedurePre-procedure
Double Antiplatelet therapy is routinely given Double Antiplatelet therapy is routinely given beginning at least 3beginning at least 3
days before the proceduredays before the procedure
Aspirin 325mgd+Clopidogrel 75mgdAspirin 325mgd+Clopidogrel 75mgd During procedureDuring procedure
Heparin is given with target clotting time of 250-Heparin is given with target clotting time of 250-300sec300sec
Post-procedure Post-procedure
Aspirin 325mg is continued indefinitely and Aspirin 325mg is continued indefinitely and
Clopidogrel 75mgd for at least 6 weeks Clopidogrel 75mgd for at least 6 weeks
Inclusion criteria for Local ThrombolysisInclusion criteria for Local Thrombolysis a)a) Patients in severe clinical grade on admission Patients in severe clinical grade on admission
with evidence of dural venous sinus with evidence of dural venous sinus thrombosis and restrictive venous outflow on thrombosis and restrictive venous outflow on cerebral angiogramcerebral angiogram
b)b) Patients in clinical grade 3 worsening on Patients in clinical grade 3 worsening on heparin therapy Restriction to venous heparin therapy Restriction to venous outflow was defined as an increase in brain outflow was defined as an increase in brain circulation time gt 12 s delay in the drainage circulation time gt 12 s delay in the drainage of cortical veins with cortical veins hanging of cortical veins with cortical veins hanging in spacein space
Treatment Options for Venous Thrombosis
CT Grading for Venous ThrombosisCT Grading for Venous Thrombosis Grade I no parenchymal change Grade I no parenchymal change
(hyperdense (hyperdense sinuses cortical veins empty sinuses cortical veins empty delta sign)delta sign)
Grade II non hemorrhagic venous infarct Grade II non hemorrhagic venous infarct without mass effect without mass effect
Grade III non-hemorrhagic infarct with Grade III non-hemorrhagic infarct with mass effectmass effect
Grade IV hemorrhagic venous infarct (max Grade IV hemorrhagic venous infarct (max diameter lt 3 cm) with no mass effectdiameter lt 3 cm) with no mass effect
Grade V hemorrhagic venous infarct (max Grade V hemorrhagic venous infarct (max diameter gt 3 cm) with mass effect diameter gt 3 cm) with mass effect
Local ThrombolysisLocal Thrombolysis
Femoral Jugular access was secured and a guiding Femoral Jugular access was secured and a guiding catheter was placed in the jugular bulb catheter was placed in the jugular bulb Mechanical Mechanical clot maceration clot maceration was done with the guidewire was done with the guidewire following which a microcatheter (was navigated and following which a microcatheter (was navigated and placed in the thrombosed segment of sinus confirmed placed in the thrombosed segment of sinus confirmed on a selective venogram on a selective venogram
Urokinase infusion Bolus dose of 2-6 lacs followed Urokinase infusion Bolus dose of 2-6 lacs followed by 60000 to 100000 units per hour along with by 60000 to 100000 units per hour along with periodic check venogram Along with maintenance periodic check venogram Along with maintenance systemic infusion of Heparinsystemic infusion of Heparin Other agents such as Other agents such as streptokinase altepase or rTPAstreptokinase altepase or rTPA can be also used can be also used
After thrombolysis patient should subjected to oral After thrombolysis patient should subjected to oral anticoagulation for six monthsanticoagulation for six months
Low-molecular-weight Low-molecular-weight heparinheparin
PharmacologyPharmacologyLMWH as its name suggests is a glycosaminoglycan that is approximatelyLMWH as its name suggests is a glycosaminoglycan that is approximately
one third the molecular weight of UFH It is derived from UFH through one third the molecular weight of UFH It is derived from UFH through variousvarious
depolymerization processes LMWH binds to antithrombin which in turn depolymerization processes LMWH binds to antithrombin which in turn
Neutralizes actors Xa and IIa Because LMWH lacks many of the longer Neutralizes actors Xa and IIa Because LMWH lacks many of the longer chains chains
required for binding to thrombin it has less ability to neutralize thrombin required for binding to thrombin it has less ability to neutralize thrombin
relativeto its ability to neutralize factor Xa LMWH also has less relativeto its ability to neutralize factor Xa LMWH also has less nonspecific nonspecific
binding to other proteins There is greater bioavailability with more binding to other proteins There is greater bioavailability with more predictable predictable
pharmacokinetics that eliminates the need for monitoring The smaller pharmacokinetics that eliminates the need for monitoring The smaller size also size also
allows for enhanced subcutaneous absorption when compared with UFHallows for enhanced subcutaneous absorption when compared with UFH
Three LMWH preparations are Three LMWH preparations are currently approved for use in the currently approved for use in the United States (1) enoxaparin (2) United States (1) enoxaparin (2) dalteparin and (3) tinzaparin dalteparin and (3) tinzaparin
They are all administered They are all administered subcutaneously at intervals of either subcutaneously at intervals of either once or twice daily for both once or twice daily for both prophylaxis and treatment dosesprophylaxis and treatment doses
Few Experiences of Few Experiences of ThrombolysisThrombolysis
Vickey 25 Yrs male patient presented Vickey 25 Yrs male patient presented with 12with 12thth day HO severe headache with day HO severe headache with right sided hemiplegiaright sided hemiplegia
MRI shows thrombosis of the superior MRI shows thrombosis of the superior sagittal left transverse left sigmoid sagittal left transverse left sigmoid sinuses and cortical veins in the fronto-sinuses and cortical veins in the fronto-parietal regions with eo haemorrhagic parietal regions with eo haemorrhagic infarct in the left cerebral hemisphere infarct in the left cerebral hemisphere with mass effect( Grade ndashV)with mass effect( Grade ndashV)
Sashi Srivastava 64 yrs FSashi Srivastava 64 yrs F In a follow up case of MRD with infra-renal In a follow up case of MRD with infra-renal
aortic abdominal and bilateral renal artery aortic abdominal and bilateral renal artery thrombosis renal angiogram shows filling thrombosis renal angiogram shows filling defects in the right Renal artery defects in the right Renal artery
Initially Renal angioplasty was done Initially Renal angioplasty was done Following angioplasty few thrombi are seem Following angioplasty few thrombi are seem to extends into the segmental branches and to extends into the segmental branches and causing blockage So Thrombolysis was causing blockage So Thrombolysis was plane to dissolve the run-out thrombi with plane to dissolve the run-out thrombi with urokinase urokinase
Rakesh 34yrsMRakesh 34yrsM Left SFA pseudoaneurysm with Left SFA pseudoaneurysm with
Covered stent placementCovered stent placement Pre operative antiplatelets with post Pre operative antiplatelets with post
procedure heparin Tirofiban procedure heparin Tirofiban followed by aspirin and clopidogrel followed by aspirin and clopidogrel were usedwere used
IAT may be a treatment option for selected patients IAT may be a treatment option for selected patients Possible selection criteria include Possible selection criteria include
presentation between 3 and 6 hours from symptom onsetpresentation between 3 and 6 hours from symptom onset major cerebral artery occlusion major cerebral artery occlusion severe neurologic deficits severe neurologic deficits high risk of systemic hemorrhage with IV rt-PA (eg recent high risk of systemic hemorrhage with IV rt-PA (eg recent
surgery) surgery) The MERCI (Mechanical Embolus Removal in Cerebral The MERCI (Mechanical Embolus Removal in Cerebral
Ischemia) retrievalIschemia) retrieval system system
Has been FDA-approved for recanalizing acutely occluded Has been FDA-approved for recanalizing acutely occluded cerebral arteries cerebral arteries
In the Multi-MERCI study patients who did not improve In the Multi-MERCI study patients who did not improve immediately after IV rt-PA underwent mechanical immediately after IV rt-PA underwent mechanical embolectomy within 8 hours of symptom onset embolectomy within 8 hours of symptom onset
Partial or complete recanalization occurred in 74 of Partial or complete recanalization occurred in 74 of patientspatients
with a symptomatic intracerebral hemorrhage (sICH) rate of with a symptomatic intracerebral hemorrhage (sICH) rate of 67 67
Mechanical embolectomy with the MERCI retriever may be a Mechanical embolectomy with the MERCI retriever may be a feasible and safe option for patients after IV rt-PAfeasible and safe option for patients after IV rt-PA
Penumbra stroke systemPenumbra stroke system This device combines two methods of clot This device combines two methods of clot
extraction aspiration and mechanical extraction aspiration and mechanical extraction extraction
First the clot is aspirated then a thrombus First the clot is aspirated then a thrombus removal ring can be used if necessary to removal ring can be used if necessary to remove remaining clot remove remaining clot
successful recanalizing 82successful recanalizing 82 Bridging therapyBridging therapy
06 mgkg IV rt-PA followed by IAT with IA rt-06 mgkg IV rt-PA followed by IAT with IA rt-PA (up to 20 mg)PA (up to 20 mg)
achieved a higher recanalization rateachieved a higher recanalization rate
Criteria for thrombolysis with rTPACriteria for thrombolysis with rTPA
Inclusion criteriaInclusion criteria Clinical signs and symptoms consistent with ischemic Clinical signs and symptoms consistent with ischemic
strokestroke Patient last seen normal within 3 hoursPatient last seen normal within 3 hours Measurable neurologic deficitMeasurable neurologic deficit
Exclusion criteriaExclusion criteria Any hemorrhage on neuroimaging (CT or MRI)Any hemorrhage on neuroimaging (CT or MRI) Symptoms suggestive of subarachnoid hemorrhageSymptoms suggestive of subarachnoid hemorrhage Seizure at stroke onset that is thought to contribute to Seizure at stroke onset that is thought to contribute to
neurologic deficitneurologic deficit Hypodensity greater than one third cerebral hemisphere Hypodensity greater than one third cerebral hemisphere
on CTon CT SBP greater than 185 mm Hg or DBP greater than 110 SBP greater than 185 mm Hg or DBP greater than 110
mm Hgmm Hg International normalized ratio (INR) greater than 17International normalized ratio (INR) greater than 17
Ischemic Stroke Ischemic Stroke Treatment ndash 2006Treatment ndash 2006
IV tissue plasminogen activator (tPA)IV tissue plasminogen activator (tPA) ndash ndash Only FDA-approved acute stroke drugOnly FDA-approved acute stroke drug ndash ndash 3 hour treatment window3 hour treatment window
MERCI - Concentric clot retrieval MERCI - Concentric clot retrieval devicedevice ndash ndash Rescue therapy - approved 2004Rescue therapy - approved 2004 ndash ndash Device approval (not outcomes-based)Device approval (not outcomes-based)
Off label approachesOff label approaches ndash ndash IV tPA after 3 hoursIV tPA after 3 hours ndash ndash IV-IA tPA sequential strategiesIV-IA tPA sequential strategies ndash ndash IA tPA clot angioplasty fragmentationIA tPA clot angioplasty fragmentation ndash ndash Ultrasound-assisted tPA lysisUltrasound-assisted tPA lysis
rt-PA Trials NINDSrt-PA Trials NINDS
Acute stroke - 624 patientsAcute stroke - 624 patients Treat within 3 hrsTreat within 3 hrs Intravenous 09 mgkg rt-PA vs placeboIntravenous 09 mgkg rt-PA vs placebo Hemorrhage 64 tPA 06 placeboHemorrhage 64 tPA 06 placebo Neurologic recovery better with tPA 30 Neurologic recovery better with tPA 30
more like to have minimal or no disabilitymore like to have minimal or no disability
First proven approved treatment for First proven approved treatment for strokestroke
Limitations of tPALimitations of tPA Only 4 of acute strokes receive tPAOnly 4 of acute strokes receive tPA (Kleindorfer et al Stroke 2004 35 e27-e29)(Kleindorfer et al Stroke 2004 35 e27-e29)
Only 22 of patients present within 3 hoursOnly 22 of patients present within 3 hours1048707 1048707 51 of these ineligible due to51 of these ineligible due to
bull bull Mild severityMild severity bull bull Medical or surgical historyMedical or surgical history bull bull Blood testsBlood tests
Sustained recanalization only 13Sustained recanalization only 13 (Alexandrov et al NEJM 2004 351 2170-8)(Alexandrov et al NEJM 2004 351 2170-8)
Concern for hemorrhageConcern for hemorrhage tPA potentiates apoptotic injury tPA potentiates apoptotic injury (Liu et al Nature Med 2004 101379-83)(Liu et al Nature Med 2004 101379-83)
PROACT II IA Lysis TrialPROACT II IA Lysis Trial Baseline 24 hours 8 days
Baseline 60 minutes 120 minutes
9mg IAProurokinase
Desmoteplase Trials DEDAS Desmoteplase Trials DEDAS DIASDIAS
Trial OverviewTrial Overview Double blind randomized placebo Double blind randomized placebo
controlled trialscontrolled trials IV delivery 3-9 hour time windowIV delivery 3-9 hour time window Plasminogen activator ndash from Plasminogen activator ndash from vampire bat vampire bat
salivasaliva Selection based on PWI-DWI MismatchSelection based on PWI-DWI Mismatch
MRI InclusionMRI Inclusion PWI defect at least 2 cm AND ~20 larger PWI defect at least 2 cm AND ~20 larger
than DWIthan DWI PWI should be obvious even visible on PWI should be obvious even visible on
raw imagesraw imagesMRI ExclusionMRI Exclusion
DWI gt 13 MCADWI gt 13 MCA MRA ICA occlusionMRA ICA occlusion
Desmoteplase ndash DIAS Desmoteplase ndash DIAS ResultsResults
Mechanical Thrombolysis Mechanical Thrombolysis devicesdevices
mechanical thrombolysis potentially extends the treatment mechanical thrombolysis potentially extends the treatment window because they act promptly at the site of the thrombuswindow because they act promptly at the site of the thrombus
The devices can retrieve large clots that pharmaceutical agents The devices can retrieve large clots that pharmaceutical agents may not successfully lysemay not successfully lyse
Patients treated with IV tPA may be considered for treatment of Patients treated with IV tPA may be considered for treatment of residual clot with some of these devicesresidual clot with some of these devices
suction-creating saline jets suction-creating saline jets laser energy ultrasound laser energy ultrasound a corkscrew apparatus to treat strokesa corkscrew apparatus to treat strokes The AngioJet systemThe AngioJet system uses saline jets that are directed back into the catheter to uses saline jets that are directed back into the catheter to
create a low-pressure zone around the catheter tip inducing create a low-pressure zone around the catheter tip inducing suction suction
The clot is pulled into the exhaust lumen and removed from the The clot is pulled into the exhaust lumen and removed from the vessel Although US Food and Drug Administration (FDA) has vessel Although US Food and Drug Administration (FDA) has approved this device for use in arteriovenous dialysis grafts and approved this device for use in arteriovenous dialysis grafts and fistulae and for the treatment of coronary arteries saphenous fistulae and for the treatment of coronary arteries saphenous vein grafts and peripheral vessels clinical trials for the vein grafts and peripheral vessels clinical trials for the treatment of acute stroke are no longer in progress treatment of acute stroke are no longer in progress
Most devices are used in cerebral vessels that 2-5 mm
The Latis laser device The Latis laser device used laser energy to ablate clots used laser energy to ablate clots Arteries 2-5 mm in diameter could be Arteries 2-5 mm in diameter could be
treated including the ICA M1 or M2 treated including the ICA M1 or M2 branch of the MCA A1 branch of the branch of the MCA A1 branch of the anterior cerebral artery (ACA) basilar anterior cerebral artery (ACA) basilar artery posterior cerebral artery (PCA) artery posterior cerebral artery (PCA) and vertebral and vertebral
Patients could receive treatment as late Patients could receive treatment as late as 8 hours after symptom onset in the as 8 hours after symptom onset in the anterior circulation and within 24 hours in anterior circulation and within 24 hours in the posterior circulation the posterior circulation
Endovascular Photo Acoustic Endovascular Photo Acoustic Recanalization (EPAR) Recanalization (EPAR)
A laser power source generated energy for the A laser power source generated energy for the systemsystem
The energy was delivered by means of The energy was delivered by means of fiberoptics to the tip of the catheter at the fiberoptics to the tip of the catheter at the treatment sitetreatment site
Absorption of laser light by darkly pigmented Absorption of laser light by darkly pigmented materials (ie the clot) occurred inside the 1-mm materials (ie the clot) occurred inside the 1-mm catheter tipcatheter tip
the system was designed to minimize scattering the system was designed to minimize scattering of laser light of laser light
Absorption converted photo energy to acoustic Absorption converted photo energy to acoustic energy which then emulsified the clot inside the energy which then emulsified the clot inside the catheter tip catheter tip
EKOS ultrasound( the EKOS ultrasound( the Ultrasound Thrombolytic Ultrasound Thrombolytic
Infusion Catheter) Infusion Catheter) combines the use of a distal ultrasound transducer with combines the use of a distal ultrasound transducer with
infusion of a thrombolytic agent through the infusion of a thrombolytic agent through the microcathetermicrocatheter
Ultrasound changes the structure of the clot to Ultrasound changes the structure of the clot to temporarily increase its permeability while providing an temporarily increase its permeability while providing an acoustic pressure gradient to move the drug into the clot acoustic pressure gradient to move the drug into the clot to speed its dissolution to speed its dissolution
The EKOS catheter is placed in the proximal portion of the The EKOS catheter is placed in the proximal portion of the clot clot
After a 2-mg bolus of tPA was injected through the After a 2-mg bolus of tPA was injected through the catheter catheter
the patient received a continuous infusion of IA tPA 03 the patient received a continuous infusion of IA tPA 03 mgmin to a maximum of 20 mg and simultaneous mgmin to a maximum of 20 mg and simultaneous ultrasound transmission for as long as 60 minutes ultrasound transmission for as long as 60 minutes
One patient was treated with a total of 4 units of One patient was treated with a total of 4 units of recombinant reteplase (Retavase) hand-injected over 60 recombinant reteplase (Retavase) hand-injected over 60 minutes minutes
Penumbra system Penumbra system The Penumbra system (Penumbra Inc) provides a dual The Penumbra system (Penumbra Inc) provides a dual
approach to clot extraction using aspiration followed by approach to clot extraction using aspiration followed by clot retrieval with a ring device if needed clot retrieval with a ring device if needed
Mechanical Embolus Removal in Cerebral Ischemia Mechanical Embolus Removal in Cerebral Ischemia (MERCI)(MERCI)
a corkscrew-like apparatus to remove blood clots from a corkscrew-like apparatus to remove blood clots from the brain in patients experiencing an ischemic stroke the brain in patients experiencing an ischemic stroke
The corkscrew itself resides in the catheter tip which The corkscrew itself resides in the catheter tip which shields it from the wall of the vessel until it is ready to be shields it from the wall of the vessel until it is ready to be burrowed into the clot Once lodged in the clot the device burrowed into the clot Once lodged in the clot the device and clot are withdrawn from the vessel and clot are withdrawn from the vessel
Snarelike devicesSnarelike devices Snares such as the Neuronet snare (Guidant Snares such as the Neuronet snare (Guidant
Endovascular Santa Clara CA) have been developed Endovascular Santa Clara CA) have been developed specifically for use in the treatment of strokes specifically for use in the treatment of strokes
These devices are simple in design and do not require the These devices are simple in design and do not require the clot to be amenable to emulsification clot to be amenable to emulsification
X-Sizer deviceX-Sizer device a device with small moving blades at the a device with small moving blades at the
catheter tip catheter tip This device the X-Sizer device (EndiCor Medical This device the X-Sizer device (EndiCor Medical
San Clemente CA) can be used to excise the San Clemente CA) can be used to excise the thrombus and aspirate it thrombus and aspirate it
The device was being evaluated in randomized The device was being evaluated in randomized studies of coronary vessels and in a registry of studies of coronary vessels and in a registry of patients with acute myocardial infarctionpatients with acute myocardial infarction
Although the manufacturer had modified the Although the manufacturer had modified the device for use in cerebral vessels a safety and device for use in cerebral vessels a safety and feasibility study was indefinitely suspended after feasibility study was indefinitely suspended after only 1 patient was treated with the device in only 1 patient was treated with the device in Europe Europe
Suction thrombectomySuction thrombectomy This method of mechanical thrombolysis is one of the This method of mechanical thrombolysis is one of the
simplestsimplest In this readily available technique suction is applied with In this readily available technique suction is applied with
a syringe to remove thrombus in the ICA a syringe to remove thrombus in the ICA It requires no other devicesIt requires no other devices A catheter with a large inner diameter (Brite Tip Cordis A catheter with a large inner diameter (Brite Tip Cordis
Corporation Miami FL) was placed in the symptomatic Corporation Miami FL) was placed in the symptomatic vessel and navigated over a guidewire into the thrombusvessel and navigated over a guidewire into the thrombus
A 60-mL syringe was used to aspirate the thrombus A 60-mL syringe was used to aspirate the thrombus Each patient required angioplasty and stenting of carotid Each patient required angioplasty and stenting of carotid
bifurcation stenosis and received daily aspirin and bifurcation stenosis and received daily aspirin and ticlopidine after the procedure No complications ticlopidine after the procedure No complications occurred occurred
Summary Acute Stroke Summary Acute Stroke ImagingImaging
PhysiologyPhysiology importance collaterals importance collaterals
ndash ndashGrowing role for perfusion Growing role for perfusion assessmentassessment
tPAtPA guidelines amp limitations guidelines amp limitations Signs on CT amp MRSigns on CT amp MR follow physiology follow physiology Stroke trialsStroke trials PWI-DWI mismatch PWI-DWI mismatch
ndash ndashTreat based on physiology not timeTreat based on physiology not time ProtocolsProtocols should be fast and should be fast and
comprehensivecomprehensive
Practical Applications Practical Applications related to specific related to specific
Neurovascular Neurovascular interventionsinterventions
Acute ischemic StrokeAcute ischemic Stroke When an artery occludes neurons are affected When an artery occludes neurons are affected
differently depending upon the amount of residual blood differently depending upon the amount of residual blood flowflow
Normal cerebral blood flow is greater than 50 mL100 Normal cerebral blood flow is greater than 50 mL100 mgminmgmin
Once blood flow decreases to less than 20 mL100 Once blood flow decreases to less than 20 mL100 mgmin infarction occursmgmin infarction occurs
If blood flow decreases to less than 10 mL100 mgmin If blood flow decreases to less than 10 mL100 mgmin irreversible neuronal death occurs rapidly irreversible neuronal death occurs rapidly
Blood flow between 11 and 20 mL100 mgmin is thought Blood flow between 11 and 20 mL100 mgmin is thought to represent the ischemic penumbra an area where the to represent the ischemic penumbra an area where the cells are functionally silent because of ischemia but are cells are functionally silent because of ischemia but are still able to recover if blood flow is restored still able to recover if blood flow is restored
Many acute stroke therapies are targeted toward Many acute stroke therapies are targeted toward restoring flow or function to the ischemic penumbrarestoring flow or function to the ischemic penumbra
Therapeutic window in Therapeutic window in management of acute Ischemic management of acute Ischemic
StrokeStrokeThe early diagnosis of ischemic stroke is critical to the The early diagnosis of ischemic stroke is critical to the
with only a narrow therapeutic window in the first few with only a narrow therapeutic window in the first few hours following stroke ictushours following stroke ictus
Diagnosis in the first 3 hours postictus provides the Diagnosis in the first 3 hours postictus provides the opportunity for intravenous or intraarterial thrombolysis opportunity for intravenous or intraarterial thrombolysis and intra-arterial clot mechanical treatment which and intra-arterial clot mechanical treatment which improve the outcome improve the outcome
Diagnosis in the time period between 3 and 6 hours Diagnosis in the time period between 3 and 6 hours provides an opportunity for intra-arterial thrombolysis provides an opportunity for intra-arterial thrombolysis and mechanical treatment and mechanical treatment
Involvement of the posterior circulation especially the Involvement of the posterior circulation especially the basilar artery is treated by some regardless of time of basilar artery is treated by some regardless of time of onset or up until 12 to 24 hours in some practices This is onset or up until 12 to 24 hours in some practices This is related to the potentially high mortality and morbidity related to the potentially high mortality and morbidity associated with basilar artery thrombosisassociated with basilar artery thrombosis
Infarct evaluation on angiographyInfarct evaluation on angiography(CT angiography and catheter (CT angiography and catheter
angiography)angiography)CTA is an excellent first-line examination for CTA is an excellent first-line examination for
evaluation of the head and neck arteries evaluation of the head and neck arteries In comparison with catheter angiography In comparison with catheter angiography
what it gives up in resolution and dynamic what it gives up in resolution and dynamic properties it makes up for with rapid properties it makes up for with rapid acquisition of a 3-D dataset and the potential acquisition of a 3-D dataset and the potential for assessment of whole-brain perfusion and for assessment of whole-brain perfusion and better parenchymal evaluationbetter parenchymal evaluation
Moreover CTA illustrates not only arterial Moreover CTA illustrates not only arterial stenosis or occlusion but also the vessel wall stenosis or occlusion but also the vessel wall This factor is most important for evaluation of This factor is most important for evaluation of intramural dissection and thrombosed intramural dissection and thrombosed aneurysms which may both complicate aneurysms which may both complicate evaluation of stroke patientsevaluation of stroke patients
Early angiographic signs of strokes Early angiographic signs of strokes both CTA both CTA and DSA and DSA
Vessel occlusion or cutoff related to Vessel occlusion or cutoff related to thromboembolithromboemboli
aneurysms aneurysms arterial dissection arterial dissection Meniscus or flattened shape to clot Meniscus or flattened shape to clot
(recent) versus reverse meniscus (older)(recent) versus reverse meniscus (older) tram track (nonocclusive or recanalized tram track (nonocclusive or recanalized
clot) clot) delayed (antegrade) flow (manifest as delayed (antegrade) flow (manifest as
decreased whole-brain perfusion on CTA)decreased whole-brain perfusion on CTA) retrograde collateral flowretrograde collateral flow
Non-occlusive left MCA thrombus on 3-D imaging performed from CTA source data and was confirmed at catheter angiography
Therapy to be started within a 6-hr Therapy to be started within a 6-hr time to treatment (TTT) window time to treatment (TTT) window (while in case of IV thrombolysis (while in case of IV thrombolysis therapy to be started with in 3hrs)therapy to be started with in 3hrs)
Exclusion criteria Exclusion criteria Rapidly improving neurologic deficit or Rapidly improving neurologic deficit or Sustained blood pressure of gt180100 Sustained blood pressure of gt180100 Hemorrhage is detected on CTHemorrhage is detected on CT Infarct involving gt more than 13 rd Infarct involving gt more than 13 rd
territory of MCAterritory of MCA MRADWI-Perfusion mismatchlt 20MRADWI-Perfusion mismatchlt 20 Definite hypodensity on CTDefinite hypodensity on CT
Intra-arterial Thrombolysis
Fibrinolytics + AntiplateletsFibrinolytics + Antiplatelets
PlasminogenPlasminogen activators through fibrinolysis exposes activators through fibrinolysis exposes free thrombin and paradoxically stimulatesfree thrombin and paradoxically stimulates platelet platelet aggregation which leads to formation of aaggregation which leads to formation of a platelet platelet thrombus (white clot) thrombus (white clot)
This new thrombus is relatively resistant to This new thrombus is relatively resistant to fibrinolyticsfibrinolytics
So new regimen in case of acute stroke isSo new regimen in case of acute stroke is fibrinolytics + antiplatelet drugsfibrinolytics + antiplatelet drugs
rtPA + IIbIIIa inhibitors( tirofiban rtPA + IIbIIIa inhibitors( tirofiban abciximab) orabciximab) or
Urokinase + IIbIIIa Urokinase + IIbIIIa inhibitors( tirofiban abciximab)inhibitors( tirofiban abciximab)
Intra-arterial Thrombolysis Tirofiban (04 microgkgmin bolus for 3 min followed by Tirofiban (04 microgkgmin bolus for 3 min followed by
0125 ugkgmin)0125 ugkgmin)
++
Heparin (2000ndash3000 IU bolus followed by Heparin (2000ndash3000 IU bolus followed by 1000 IUhour infusion 1000 IUhour infusion
with ACT maintained bw 200-300) throughout the with ACT maintained bw 200-300) throughout the interventional procedure and for 24ndash48 hours thereafter when interventional procedure and for 24ndash48 hours thereafter when there is neither intraprocedural bleeding nor suspicion of there is neither intraprocedural bleeding nor suspicion of increased risk of bleeding increased risk of bleeding
Maximum dose of Urokinase Maximum dose of Urokinase Anterior circulation stroke - 500000 IU (mean 400000 Anterior circulation stroke - 500000 IU (mean 400000
IU range 300000ndash500000 IU)IU range 300000ndash500000 IU) Posterior circulation stroke -1000000 IU (mean 837000 Posterior circulation stroke -1000000 IU (mean 837000
IU range 300000ndash1000000 IU)IU range 300000ndash1000000 IU)American Journal of NeuroradiologyAmerican Journal of Neuroradiology 262595-2601 2005262595-2601 2005
Intravenous ThrombolysisIntravenous Thrombolysis
The first method to restore cerebral The first method to restore cerebral perfusion is clot lysis with the goal perfusion is clot lysis with the goal of re-establishing blood flow to the of re-establishing blood flow to the affected tissue affected tissue
IV thrombolysis rt-PA is the only IV thrombolysis rt-PA is the only FDA- approved treatment for AIS FDA- approved treatment for AIS
Fibrinolysis is enhanced powerfully Fibrinolysis is enhanced powerfully by rt-PAby rt-PA
Intravenous rTPA Intravenous rTPA administration administration protocolprotocol
Total dose of rt-PA 09 mgkg (maximum dose Total dose of rt-PA 09 mgkg (maximum dose 90 mg)90 mg)
Give 10 as initial IV bolusGive 10 as initial IV bolus Infuse remainder over 1 hourInfuse remainder over 1 hour Admit patient to an ICU or stroke unit for Admit patient to an ICU or stroke unit for
monitoringmonitoring Neurologic assessments every 15 minutes Neurologic assessments every 15 minutes
during infusion then every 30 minutes for next during infusion then every 30 minutes for next 6 hours then every hour until 24hours after 6 hours then every hour until 24hours after treatmenttreatment
Favorable Outcome vs Treatment Time Favorable Outcome vs Treatment Time with IV rTPAwith IV rTPA
Protocol limit = 3 hrs
Benefit ~ 45 hrs
Thromboembolism During coilingThromboembolism During coiling Most feared and frequent complication Most feared and frequent complication Reported incidence - Approx 7 Reported incidence - Approx 7 SourcesSources of Thromboembolism are of Thromboembolism are
- Clots at the aneurysmal neck during or immediately- Clots at the aneurysmal neck during or immediately after after embolization embolization
- Thrombus forming on catheters during- Thrombus forming on catheters during proceduresprocedures
- Stenosis of an adjacent artery dt coil mass- Stenosis of an adjacent artery dt coil mass or herniationor herniation
- Migration of intraaneurysmal- Migration of intraaneurysmal thrombus during coil thrombus during coil placement placement
- Slow flow dt vasospasm - Slow flow dt vasospasm
- Rare and unlikely causes are hypercoagulable- Rare and unlikely causes are hypercoagulable state such state such as antiphospholipid antibody syndrome or due to HITas antiphospholipid antibody syndrome or due to HIT
Occur more often with wide-necked aneurysms (dt Occur more often with wide-necked aneurysms (dt increased exposed surface area of thrombogenic coil increased exposed surface area of thrombogenic coil material)material)
Current regimen of endovascular Current regimen of endovascular managementmanagement
The The glycoprotein IIbIIIa antagonist tirofiban glycoprotein IIbIIIa antagonist tirofiban (04 (04 microgkgmin bolus for 30 minutes followed by infusion of microgkgmin bolus for 30 minutes followed by infusion of 0125 ugkgmin until the thrombus dissolved) 0125 ugkgmin until the thrombus dissolved)
Intraarterial thrombolysis with Intraarterial thrombolysis with urokinase or r- TPA urokinase or r- TPA increase of intravenous (IV) heparin (measured by increase of intravenous (IV) heparin (measured by
ACT) ACT) Intravenous aspirin Intravenous aspirin
Coil-related platelet aggregation (white clot) is Coil-related platelet aggregation (white clot) is unlikely to respond to fibrinolytics but has a high risk unlikely to respond to fibrinolytics but has a high risk of hemorrhage (In ISAT) all 5 patients who had of hemorrhage (In ISAT) all 5 patients who had received thrombolytic therapy with tPA to treat a received thrombolytic therapy with tPA to treat a thromboembolic complication after endovascular thromboembolic complication after endovascular treatment rebleed and all of these patients died)treatment rebleed and all of these patients died)
IntracranialIntracranial Stenting Stenting Metallic foreign body such as stent will accumulate Metallic foreign body such as stent will accumulate
thrombus in the absence of platelet inhibitionthrombus in the absence of platelet inhibition Antiplatelet drugs are important to prevent peri or Antiplatelet drugs are important to prevent peri or
post-interventional thromboembolic eventspost-interventional thromboembolic events Optimal treatment regimens has not been determined Optimal treatment regimens has not been determined
but usually but usually Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-
procedureprocedureOrOr
Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on
morning of proceduremorning of procedure
If need to use stent is not pre-planned thanIf need to use stent is not pre-planned than
Abciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkgAbciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkg IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)
Glycoprotein IIbIIIa inhibitor are not used routinely during elective Glycoprotein IIbIIIa inhibitor are not used routinely during elective stenting procedure dt increased risk of ICH stenting procedure dt increased risk of ICH
Carotid StentingCarotid Stenting
Pre-procedurePre-procedure
Double Antiplatelet therapy is routinely given Double Antiplatelet therapy is routinely given beginning at least 3beginning at least 3
days before the proceduredays before the procedure
Aspirin 325mgd+Clopidogrel 75mgdAspirin 325mgd+Clopidogrel 75mgd During procedureDuring procedure
Heparin is given with target clotting time of 250-Heparin is given with target clotting time of 250-300sec300sec
Post-procedure Post-procedure
Aspirin 325mg is continued indefinitely and Aspirin 325mg is continued indefinitely and
Clopidogrel 75mgd for at least 6 weeks Clopidogrel 75mgd for at least 6 weeks
Inclusion criteria for Local ThrombolysisInclusion criteria for Local Thrombolysis a)a) Patients in severe clinical grade on admission Patients in severe clinical grade on admission
with evidence of dural venous sinus with evidence of dural venous sinus thrombosis and restrictive venous outflow on thrombosis and restrictive venous outflow on cerebral angiogramcerebral angiogram
b)b) Patients in clinical grade 3 worsening on Patients in clinical grade 3 worsening on heparin therapy Restriction to venous heparin therapy Restriction to venous outflow was defined as an increase in brain outflow was defined as an increase in brain circulation time gt 12 s delay in the drainage circulation time gt 12 s delay in the drainage of cortical veins with cortical veins hanging of cortical veins with cortical veins hanging in spacein space
Treatment Options for Venous Thrombosis
CT Grading for Venous ThrombosisCT Grading for Venous Thrombosis Grade I no parenchymal change Grade I no parenchymal change
(hyperdense (hyperdense sinuses cortical veins empty sinuses cortical veins empty delta sign)delta sign)
Grade II non hemorrhagic venous infarct Grade II non hemorrhagic venous infarct without mass effect without mass effect
Grade III non-hemorrhagic infarct with Grade III non-hemorrhagic infarct with mass effectmass effect
Grade IV hemorrhagic venous infarct (max Grade IV hemorrhagic venous infarct (max diameter lt 3 cm) with no mass effectdiameter lt 3 cm) with no mass effect
Grade V hemorrhagic venous infarct (max Grade V hemorrhagic venous infarct (max diameter gt 3 cm) with mass effect diameter gt 3 cm) with mass effect
Local ThrombolysisLocal Thrombolysis
Femoral Jugular access was secured and a guiding Femoral Jugular access was secured and a guiding catheter was placed in the jugular bulb catheter was placed in the jugular bulb Mechanical Mechanical clot maceration clot maceration was done with the guidewire was done with the guidewire following which a microcatheter (was navigated and following which a microcatheter (was navigated and placed in the thrombosed segment of sinus confirmed placed in the thrombosed segment of sinus confirmed on a selective venogram on a selective venogram
Urokinase infusion Bolus dose of 2-6 lacs followed Urokinase infusion Bolus dose of 2-6 lacs followed by 60000 to 100000 units per hour along with by 60000 to 100000 units per hour along with periodic check venogram Along with maintenance periodic check venogram Along with maintenance systemic infusion of Heparinsystemic infusion of Heparin Other agents such as Other agents such as streptokinase altepase or rTPAstreptokinase altepase or rTPA can be also used can be also used
After thrombolysis patient should subjected to oral After thrombolysis patient should subjected to oral anticoagulation for six monthsanticoagulation for six months
Low-molecular-weight Low-molecular-weight heparinheparin
PharmacologyPharmacologyLMWH as its name suggests is a glycosaminoglycan that is approximatelyLMWH as its name suggests is a glycosaminoglycan that is approximately
one third the molecular weight of UFH It is derived from UFH through one third the molecular weight of UFH It is derived from UFH through variousvarious
depolymerization processes LMWH binds to antithrombin which in turn depolymerization processes LMWH binds to antithrombin which in turn
Neutralizes actors Xa and IIa Because LMWH lacks many of the longer Neutralizes actors Xa and IIa Because LMWH lacks many of the longer chains chains
required for binding to thrombin it has less ability to neutralize thrombin required for binding to thrombin it has less ability to neutralize thrombin
relativeto its ability to neutralize factor Xa LMWH also has less relativeto its ability to neutralize factor Xa LMWH also has less nonspecific nonspecific
binding to other proteins There is greater bioavailability with more binding to other proteins There is greater bioavailability with more predictable predictable
pharmacokinetics that eliminates the need for monitoring The smaller pharmacokinetics that eliminates the need for monitoring The smaller size also size also
allows for enhanced subcutaneous absorption when compared with UFHallows for enhanced subcutaneous absorption when compared with UFH
Three LMWH preparations are Three LMWH preparations are currently approved for use in the currently approved for use in the United States (1) enoxaparin (2) United States (1) enoxaparin (2) dalteparin and (3) tinzaparin dalteparin and (3) tinzaparin
They are all administered They are all administered subcutaneously at intervals of either subcutaneously at intervals of either once or twice daily for both once or twice daily for both prophylaxis and treatment dosesprophylaxis and treatment doses
Few Experiences of Few Experiences of ThrombolysisThrombolysis
Vickey 25 Yrs male patient presented Vickey 25 Yrs male patient presented with 12with 12thth day HO severe headache with day HO severe headache with right sided hemiplegiaright sided hemiplegia
MRI shows thrombosis of the superior MRI shows thrombosis of the superior sagittal left transverse left sigmoid sagittal left transverse left sigmoid sinuses and cortical veins in the fronto-sinuses and cortical veins in the fronto-parietal regions with eo haemorrhagic parietal regions with eo haemorrhagic infarct in the left cerebral hemisphere infarct in the left cerebral hemisphere with mass effect( Grade ndashV)with mass effect( Grade ndashV)
Sashi Srivastava 64 yrs FSashi Srivastava 64 yrs F In a follow up case of MRD with infra-renal In a follow up case of MRD with infra-renal
aortic abdominal and bilateral renal artery aortic abdominal and bilateral renal artery thrombosis renal angiogram shows filling thrombosis renal angiogram shows filling defects in the right Renal artery defects in the right Renal artery
Initially Renal angioplasty was done Initially Renal angioplasty was done Following angioplasty few thrombi are seem Following angioplasty few thrombi are seem to extends into the segmental branches and to extends into the segmental branches and causing blockage So Thrombolysis was causing blockage So Thrombolysis was plane to dissolve the run-out thrombi with plane to dissolve the run-out thrombi with urokinase urokinase
Rakesh 34yrsMRakesh 34yrsM Left SFA pseudoaneurysm with Left SFA pseudoaneurysm with
Covered stent placementCovered stent placement Pre operative antiplatelets with post Pre operative antiplatelets with post
procedure heparin Tirofiban procedure heparin Tirofiban followed by aspirin and clopidogrel followed by aspirin and clopidogrel were usedwere used
IAT may be a treatment option for selected patients IAT may be a treatment option for selected patients Possible selection criteria include Possible selection criteria include
presentation between 3 and 6 hours from symptom onsetpresentation between 3 and 6 hours from symptom onset major cerebral artery occlusion major cerebral artery occlusion severe neurologic deficits severe neurologic deficits high risk of systemic hemorrhage with IV rt-PA (eg recent high risk of systemic hemorrhage with IV rt-PA (eg recent
surgery) surgery) The MERCI (Mechanical Embolus Removal in Cerebral The MERCI (Mechanical Embolus Removal in Cerebral
Ischemia) retrievalIschemia) retrieval system system
Has been FDA-approved for recanalizing acutely occluded Has been FDA-approved for recanalizing acutely occluded cerebral arteries cerebral arteries
In the Multi-MERCI study patients who did not improve In the Multi-MERCI study patients who did not improve immediately after IV rt-PA underwent mechanical immediately after IV rt-PA underwent mechanical embolectomy within 8 hours of symptom onset embolectomy within 8 hours of symptom onset
Partial or complete recanalization occurred in 74 of Partial or complete recanalization occurred in 74 of patientspatients
with a symptomatic intracerebral hemorrhage (sICH) rate of with a symptomatic intracerebral hemorrhage (sICH) rate of 67 67
Mechanical embolectomy with the MERCI retriever may be a Mechanical embolectomy with the MERCI retriever may be a feasible and safe option for patients after IV rt-PAfeasible and safe option for patients after IV rt-PA
Penumbra stroke systemPenumbra stroke system This device combines two methods of clot This device combines two methods of clot
extraction aspiration and mechanical extraction aspiration and mechanical extraction extraction
First the clot is aspirated then a thrombus First the clot is aspirated then a thrombus removal ring can be used if necessary to removal ring can be used if necessary to remove remaining clot remove remaining clot
successful recanalizing 82successful recanalizing 82 Bridging therapyBridging therapy
06 mgkg IV rt-PA followed by IAT with IA rt-06 mgkg IV rt-PA followed by IAT with IA rt-PA (up to 20 mg)PA (up to 20 mg)
achieved a higher recanalization rateachieved a higher recanalization rate
Criteria for thrombolysis with rTPACriteria for thrombolysis with rTPA
Inclusion criteriaInclusion criteria Clinical signs and symptoms consistent with ischemic Clinical signs and symptoms consistent with ischemic
strokestroke Patient last seen normal within 3 hoursPatient last seen normal within 3 hours Measurable neurologic deficitMeasurable neurologic deficit
Exclusion criteriaExclusion criteria Any hemorrhage on neuroimaging (CT or MRI)Any hemorrhage on neuroimaging (CT or MRI) Symptoms suggestive of subarachnoid hemorrhageSymptoms suggestive of subarachnoid hemorrhage Seizure at stroke onset that is thought to contribute to Seizure at stroke onset that is thought to contribute to
neurologic deficitneurologic deficit Hypodensity greater than one third cerebral hemisphere Hypodensity greater than one third cerebral hemisphere
on CTon CT SBP greater than 185 mm Hg or DBP greater than 110 SBP greater than 185 mm Hg or DBP greater than 110
mm Hgmm Hg International normalized ratio (INR) greater than 17International normalized ratio (INR) greater than 17
Ischemic Stroke Ischemic Stroke Treatment ndash 2006Treatment ndash 2006
IV tissue plasminogen activator (tPA)IV tissue plasminogen activator (tPA) ndash ndash Only FDA-approved acute stroke drugOnly FDA-approved acute stroke drug ndash ndash 3 hour treatment window3 hour treatment window
MERCI - Concentric clot retrieval MERCI - Concentric clot retrieval devicedevice ndash ndash Rescue therapy - approved 2004Rescue therapy - approved 2004 ndash ndash Device approval (not outcomes-based)Device approval (not outcomes-based)
Off label approachesOff label approaches ndash ndash IV tPA after 3 hoursIV tPA after 3 hours ndash ndash IV-IA tPA sequential strategiesIV-IA tPA sequential strategies ndash ndash IA tPA clot angioplasty fragmentationIA tPA clot angioplasty fragmentation ndash ndash Ultrasound-assisted tPA lysisUltrasound-assisted tPA lysis
rt-PA Trials NINDSrt-PA Trials NINDS
Acute stroke - 624 patientsAcute stroke - 624 patients Treat within 3 hrsTreat within 3 hrs Intravenous 09 mgkg rt-PA vs placeboIntravenous 09 mgkg rt-PA vs placebo Hemorrhage 64 tPA 06 placeboHemorrhage 64 tPA 06 placebo Neurologic recovery better with tPA 30 Neurologic recovery better with tPA 30
more like to have minimal or no disabilitymore like to have minimal or no disability
First proven approved treatment for First proven approved treatment for strokestroke
Limitations of tPALimitations of tPA Only 4 of acute strokes receive tPAOnly 4 of acute strokes receive tPA (Kleindorfer et al Stroke 2004 35 e27-e29)(Kleindorfer et al Stroke 2004 35 e27-e29)
Only 22 of patients present within 3 hoursOnly 22 of patients present within 3 hours1048707 1048707 51 of these ineligible due to51 of these ineligible due to
bull bull Mild severityMild severity bull bull Medical or surgical historyMedical or surgical history bull bull Blood testsBlood tests
Sustained recanalization only 13Sustained recanalization only 13 (Alexandrov et al NEJM 2004 351 2170-8)(Alexandrov et al NEJM 2004 351 2170-8)
Concern for hemorrhageConcern for hemorrhage tPA potentiates apoptotic injury tPA potentiates apoptotic injury (Liu et al Nature Med 2004 101379-83)(Liu et al Nature Med 2004 101379-83)
PROACT II IA Lysis TrialPROACT II IA Lysis Trial Baseline 24 hours 8 days
Baseline 60 minutes 120 minutes
9mg IAProurokinase
Desmoteplase Trials DEDAS Desmoteplase Trials DEDAS DIASDIAS
Trial OverviewTrial Overview Double blind randomized placebo Double blind randomized placebo
controlled trialscontrolled trials IV delivery 3-9 hour time windowIV delivery 3-9 hour time window Plasminogen activator ndash from Plasminogen activator ndash from vampire bat vampire bat
salivasaliva Selection based on PWI-DWI MismatchSelection based on PWI-DWI Mismatch
MRI InclusionMRI Inclusion PWI defect at least 2 cm AND ~20 larger PWI defect at least 2 cm AND ~20 larger
than DWIthan DWI PWI should be obvious even visible on PWI should be obvious even visible on
raw imagesraw imagesMRI ExclusionMRI Exclusion
DWI gt 13 MCADWI gt 13 MCA MRA ICA occlusionMRA ICA occlusion
Desmoteplase ndash DIAS Desmoteplase ndash DIAS ResultsResults
Mechanical Thrombolysis Mechanical Thrombolysis devicesdevices
mechanical thrombolysis potentially extends the treatment mechanical thrombolysis potentially extends the treatment window because they act promptly at the site of the thrombuswindow because they act promptly at the site of the thrombus
The devices can retrieve large clots that pharmaceutical agents The devices can retrieve large clots that pharmaceutical agents may not successfully lysemay not successfully lyse
Patients treated with IV tPA may be considered for treatment of Patients treated with IV tPA may be considered for treatment of residual clot with some of these devicesresidual clot with some of these devices
suction-creating saline jets suction-creating saline jets laser energy ultrasound laser energy ultrasound a corkscrew apparatus to treat strokesa corkscrew apparatus to treat strokes The AngioJet systemThe AngioJet system uses saline jets that are directed back into the catheter to uses saline jets that are directed back into the catheter to
create a low-pressure zone around the catheter tip inducing create a low-pressure zone around the catheter tip inducing suction suction
The clot is pulled into the exhaust lumen and removed from the The clot is pulled into the exhaust lumen and removed from the vessel Although US Food and Drug Administration (FDA) has vessel Although US Food and Drug Administration (FDA) has approved this device for use in arteriovenous dialysis grafts and approved this device for use in arteriovenous dialysis grafts and fistulae and for the treatment of coronary arteries saphenous fistulae and for the treatment of coronary arteries saphenous vein grafts and peripheral vessels clinical trials for the vein grafts and peripheral vessels clinical trials for the treatment of acute stroke are no longer in progress treatment of acute stroke are no longer in progress
Most devices are used in cerebral vessels that 2-5 mm
The Latis laser device The Latis laser device used laser energy to ablate clots used laser energy to ablate clots Arteries 2-5 mm in diameter could be Arteries 2-5 mm in diameter could be
treated including the ICA M1 or M2 treated including the ICA M1 or M2 branch of the MCA A1 branch of the branch of the MCA A1 branch of the anterior cerebral artery (ACA) basilar anterior cerebral artery (ACA) basilar artery posterior cerebral artery (PCA) artery posterior cerebral artery (PCA) and vertebral and vertebral
Patients could receive treatment as late Patients could receive treatment as late as 8 hours after symptom onset in the as 8 hours after symptom onset in the anterior circulation and within 24 hours in anterior circulation and within 24 hours in the posterior circulation the posterior circulation
Endovascular Photo Acoustic Endovascular Photo Acoustic Recanalization (EPAR) Recanalization (EPAR)
A laser power source generated energy for the A laser power source generated energy for the systemsystem
The energy was delivered by means of The energy was delivered by means of fiberoptics to the tip of the catheter at the fiberoptics to the tip of the catheter at the treatment sitetreatment site
Absorption of laser light by darkly pigmented Absorption of laser light by darkly pigmented materials (ie the clot) occurred inside the 1-mm materials (ie the clot) occurred inside the 1-mm catheter tipcatheter tip
the system was designed to minimize scattering the system was designed to minimize scattering of laser light of laser light
Absorption converted photo energy to acoustic Absorption converted photo energy to acoustic energy which then emulsified the clot inside the energy which then emulsified the clot inside the catheter tip catheter tip
EKOS ultrasound( the EKOS ultrasound( the Ultrasound Thrombolytic Ultrasound Thrombolytic
Infusion Catheter) Infusion Catheter) combines the use of a distal ultrasound transducer with combines the use of a distal ultrasound transducer with
infusion of a thrombolytic agent through the infusion of a thrombolytic agent through the microcathetermicrocatheter
Ultrasound changes the structure of the clot to Ultrasound changes the structure of the clot to temporarily increase its permeability while providing an temporarily increase its permeability while providing an acoustic pressure gradient to move the drug into the clot acoustic pressure gradient to move the drug into the clot to speed its dissolution to speed its dissolution
The EKOS catheter is placed in the proximal portion of the The EKOS catheter is placed in the proximal portion of the clot clot
After a 2-mg bolus of tPA was injected through the After a 2-mg bolus of tPA was injected through the catheter catheter
the patient received a continuous infusion of IA tPA 03 the patient received a continuous infusion of IA tPA 03 mgmin to a maximum of 20 mg and simultaneous mgmin to a maximum of 20 mg and simultaneous ultrasound transmission for as long as 60 minutes ultrasound transmission for as long as 60 minutes
One patient was treated with a total of 4 units of One patient was treated with a total of 4 units of recombinant reteplase (Retavase) hand-injected over 60 recombinant reteplase (Retavase) hand-injected over 60 minutes minutes
Penumbra system Penumbra system The Penumbra system (Penumbra Inc) provides a dual The Penumbra system (Penumbra Inc) provides a dual
approach to clot extraction using aspiration followed by approach to clot extraction using aspiration followed by clot retrieval with a ring device if needed clot retrieval with a ring device if needed
Mechanical Embolus Removal in Cerebral Ischemia Mechanical Embolus Removal in Cerebral Ischemia (MERCI)(MERCI)
a corkscrew-like apparatus to remove blood clots from a corkscrew-like apparatus to remove blood clots from the brain in patients experiencing an ischemic stroke the brain in patients experiencing an ischemic stroke
The corkscrew itself resides in the catheter tip which The corkscrew itself resides in the catheter tip which shields it from the wall of the vessel until it is ready to be shields it from the wall of the vessel until it is ready to be burrowed into the clot Once lodged in the clot the device burrowed into the clot Once lodged in the clot the device and clot are withdrawn from the vessel and clot are withdrawn from the vessel
Snarelike devicesSnarelike devices Snares such as the Neuronet snare (Guidant Snares such as the Neuronet snare (Guidant
Endovascular Santa Clara CA) have been developed Endovascular Santa Clara CA) have been developed specifically for use in the treatment of strokes specifically for use in the treatment of strokes
These devices are simple in design and do not require the These devices are simple in design and do not require the clot to be amenable to emulsification clot to be amenable to emulsification
X-Sizer deviceX-Sizer device a device with small moving blades at the a device with small moving blades at the
catheter tip catheter tip This device the X-Sizer device (EndiCor Medical This device the X-Sizer device (EndiCor Medical
San Clemente CA) can be used to excise the San Clemente CA) can be used to excise the thrombus and aspirate it thrombus and aspirate it
The device was being evaluated in randomized The device was being evaluated in randomized studies of coronary vessels and in a registry of studies of coronary vessels and in a registry of patients with acute myocardial infarctionpatients with acute myocardial infarction
Although the manufacturer had modified the Although the manufacturer had modified the device for use in cerebral vessels a safety and device for use in cerebral vessels a safety and feasibility study was indefinitely suspended after feasibility study was indefinitely suspended after only 1 patient was treated with the device in only 1 patient was treated with the device in Europe Europe
Suction thrombectomySuction thrombectomy This method of mechanical thrombolysis is one of the This method of mechanical thrombolysis is one of the
simplestsimplest In this readily available technique suction is applied with In this readily available technique suction is applied with
a syringe to remove thrombus in the ICA a syringe to remove thrombus in the ICA It requires no other devicesIt requires no other devices A catheter with a large inner diameter (Brite Tip Cordis A catheter with a large inner diameter (Brite Tip Cordis
Corporation Miami FL) was placed in the symptomatic Corporation Miami FL) was placed in the symptomatic vessel and navigated over a guidewire into the thrombusvessel and navigated over a guidewire into the thrombus
A 60-mL syringe was used to aspirate the thrombus A 60-mL syringe was used to aspirate the thrombus Each patient required angioplasty and stenting of carotid Each patient required angioplasty and stenting of carotid
bifurcation stenosis and received daily aspirin and bifurcation stenosis and received daily aspirin and ticlopidine after the procedure No complications ticlopidine after the procedure No complications occurred occurred
Summary Acute Stroke Summary Acute Stroke ImagingImaging
PhysiologyPhysiology importance collaterals importance collaterals
ndash ndashGrowing role for perfusion Growing role for perfusion assessmentassessment
tPAtPA guidelines amp limitations guidelines amp limitations Signs on CT amp MRSigns on CT amp MR follow physiology follow physiology Stroke trialsStroke trials PWI-DWI mismatch PWI-DWI mismatch
ndash ndashTreat based on physiology not timeTreat based on physiology not time ProtocolsProtocols should be fast and should be fast and
comprehensivecomprehensive
Acute ischemic StrokeAcute ischemic Stroke When an artery occludes neurons are affected When an artery occludes neurons are affected
differently depending upon the amount of residual blood differently depending upon the amount of residual blood flowflow
Normal cerebral blood flow is greater than 50 mL100 Normal cerebral blood flow is greater than 50 mL100 mgminmgmin
Once blood flow decreases to less than 20 mL100 Once blood flow decreases to less than 20 mL100 mgmin infarction occursmgmin infarction occurs
If blood flow decreases to less than 10 mL100 mgmin If blood flow decreases to less than 10 mL100 mgmin irreversible neuronal death occurs rapidly irreversible neuronal death occurs rapidly
Blood flow between 11 and 20 mL100 mgmin is thought Blood flow between 11 and 20 mL100 mgmin is thought to represent the ischemic penumbra an area where the to represent the ischemic penumbra an area where the cells are functionally silent because of ischemia but are cells are functionally silent because of ischemia but are still able to recover if blood flow is restored still able to recover if blood flow is restored
Many acute stroke therapies are targeted toward Many acute stroke therapies are targeted toward restoring flow or function to the ischemic penumbrarestoring flow or function to the ischemic penumbra
Therapeutic window in Therapeutic window in management of acute Ischemic management of acute Ischemic
StrokeStrokeThe early diagnosis of ischemic stroke is critical to the The early diagnosis of ischemic stroke is critical to the
with only a narrow therapeutic window in the first few with only a narrow therapeutic window in the first few hours following stroke ictushours following stroke ictus
Diagnosis in the first 3 hours postictus provides the Diagnosis in the first 3 hours postictus provides the opportunity for intravenous or intraarterial thrombolysis opportunity for intravenous or intraarterial thrombolysis and intra-arterial clot mechanical treatment which and intra-arterial clot mechanical treatment which improve the outcome improve the outcome
Diagnosis in the time period between 3 and 6 hours Diagnosis in the time period between 3 and 6 hours provides an opportunity for intra-arterial thrombolysis provides an opportunity for intra-arterial thrombolysis and mechanical treatment and mechanical treatment
Involvement of the posterior circulation especially the Involvement of the posterior circulation especially the basilar artery is treated by some regardless of time of basilar artery is treated by some regardless of time of onset or up until 12 to 24 hours in some practices This is onset or up until 12 to 24 hours in some practices This is related to the potentially high mortality and morbidity related to the potentially high mortality and morbidity associated with basilar artery thrombosisassociated with basilar artery thrombosis
Infarct evaluation on angiographyInfarct evaluation on angiography(CT angiography and catheter (CT angiography and catheter
angiography)angiography)CTA is an excellent first-line examination for CTA is an excellent first-line examination for
evaluation of the head and neck arteries evaluation of the head and neck arteries In comparison with catheter angiography In comparison with catheter angiography
what it gives up in resolution and dynamic what it gives up in resolution and dynamic properties it makes up for with rapid properties it makes up for with rapid acquisition of a 3-D dataset and the potential acquisition of a 3-D dataset and the potential for assessment of whole-brain perfusion and for assessment of whole-brain perfusion and better parenchymal evaluationbetter parenchymal evaluation
Moreover CTA illustrates not only arterial Moreover CTA illustrates not only arterial stenosis or occlusion but also the vessel wall stenosis or occlusion but also the vessel wall This factor is most important for evaluation of This factor is most important for evaluation of intramural dissection and thrombosed intramural dissection and thrombosed aneurysms which may both complicate aneurysms which may both complicate evaluation of stroke patientsevaluation of stroke patients
Early angiographic signs of strokes Early angiographic signs of strokes both CTA both CTA and DSA and DSA
Vessel occlusion or cutoff related to Vessel occlusion or cutoff related to thromboembolithromboemboli
aneurysms aneurysms arterial dissection arterial dissection Meniscus or flattened shape to clot Meniscus or flattened shape to clot
(recent) versus reverse meniscus (older)(recent) versus reverse meniscus (older) tram track (nonocclusive or recanalized tram track (nonocclusive or recanalized
clot) clot) delayed (antegrade) flow (manifest as delayed (antegrade) flow (manifest as
decreased whole-brain perfusion on CTA)decreased whole-brain perfusion on CTA) retrograde collateral flowretrograde collateral flow
Non-occlusive left MCA thrombus on 3-D imaging performed from CTA source data and was confirmed at catheter angiography
Therapy to be started within a 6-hr Therapy to be started within a 6-hr time to treatment (TTT) window time to treatment (TTT) window (while in case of IV thrombolysis (while in case of IV thrombolysis therapy to be started with in 3hrs)therapy to be started with in 3hrs)
Exclusion criteria Exclusion criteria Rapidly improving neurologic deficit or Rapidly improving neurologic deficit or Sustained blood pressure of gt180100 Sustained blood pressure of gt180100 Hemorrhage is detected on CTHemorrhage is detected on CT Infarct involving gt more than 13 rd Infarct involving gt more than 13 rd
territory of MCAterritory of MCA MRADWI-Perfusion mismatchlt 20MRADWI-Perfusion mismatchlt 20 Definite hypodensity on CTDefinite hypodensity on CT
Intra-arterial Thrombolysis
Fibrinolytics + AntiplateletsFibrinolytics + Antiplatelets
PlasminogenPlasminogen activators through fibrinolysis exposes activators through fibrinolysis exposes free thrombin and paradoxically stimulatesfree thrombin and paradoxically stimulates platelet platelet aggregation which leads to formation of aaggregation which leads to formation of a platelet platelet thrombus (white clot) thrombus (white clot)
This new thrombus is relatively resistant to This new thrombus is relatively resistant to fibrinolyticsfibrinolytics
So new regimen in case of acute stroke isSo new regimen in case of acute stroke is fibrinolytics + antiplatelet drugsfibrinolytics + antiplatelet drugs
rtPA + IIbIIIa inhibitors( tirofiban rtPA + IIbIIIa inhibitors( tirofiban abciximab) orabciximab) or
Urokinase + IIbIIIa Urokinase + IIbIIIa inhibitors( tirofiban abciximab)inhibitors( tirofiban abciximab)
Intra-arterial Thrombolysis Tirofiban (04 microgkgmin bolus for 3 min followed by Tirofiban (04 microgkgmin bolus for 3 min followed by
0125 ugkgmin)0125 ugkgmin)
++
Heparin (2000ndash3000 IU bolus followed by Heparin (2000ndash3000 IU bolus followed by 1000 IUhour infusion 1000 IUhour infusion
with ACT maintained bw 200-300) throughout the with ACT maintained bw 200-300) throughout the interventional procedure and for 24ndash48 hours thereafter when interventional procedure and for 24ndash48 hours thereafter when there is neither intraprocedural bleeding nor suspicion of there is neither intraprocedural bleeding nor suspicion of increased risk of bleeding increased risk of bleeding
Maximum dose of Urokinase Maximum dose of Urokinase Anterior circulation stroke - 500000 IU (mean 400000 Anterior circulation stroke - 500000 IU (mean 400000
IU range 300000ndash500000 IU)IU range 300000ndash500000 IU) Posterior circulation stroke -1000000 IU (mean 837000 Posterior circulation stroke -1000000 IU (mean 837000
IU range 300000ndash1000000 IU)IU range 300000ndash1000000 IU)American Journal of NeuroradiologyAmerican Journal of Neuroradiology 262595-2601 2005262595-2601 2005
Intravenous ThrombolysisIntravenous Thrombolysis
The first method to restore cerebral The first method to restore cerebral perfusion is clot lysis with the goal perfusion is clot lysis with the goal of re-establishing blood flow to the of re-establishing blood flow to the affected tissue affected tissue
IV thrombolysis rt-PA is the only IV thrombolysis rt-PA is the only FDA- approved treatment for AIS FDA- approved treatment for AIS
Fibrinolysis is enhanced powerfully Fibrinolysis is enhanced powerfully by rt-PAby rt-PA
Intravenous rTPA Intravenous rTPA administration administration protocolprotocol
Total dose of rt-PA 09 mgkg (maximum dose Total dose of rt-PA 09 mgkg (maximum dose 90 mg)90 mg)
Give 10 as initial IV bolusGive 10 as initial IV bolus Infuse remainder over 1 hourInfuse remainder over 1 hour Admit patient to an ICU or stroke unit for Admit patient to an ICU or stroke unit for
monitoringmonitoring Neurologic assessments every 15 minutes Neurologic assessments every 15 minutes
during infusion then every 30 minutes for next during infusion then every 30 minutes for next 6 hours then every hour until 24hours after 6 hours then every hour until 24hours after treatmenttreatment
Favorable Outcome vs Treatment Time Favorable Outcome vs Treatment Time with IV rTPAwith IV rTPA
Protocol limit = 3 hrs
Benefit ~ 45 hrs
Thromboembolism During coilingThromboembolism During coiling Most feared and frequent complication Most feared and frequent complication Reported incidence - Approx 7 Reported incidence - Approx 7 SourcesSources of Thromboembolism are of Thromboembolism are
- Clots at the aneurysmal neck during or immediately- Clots at the aneurysmal neck during or immediately after after embolization embolization
- Thrombus forming on catheters during- Thrombus forming on catheters during proceduresprocedures
- Stenosis of an adjacent artery dt coil mass- Stenosis of an adjacent artery dt coil mass or herniationor herniation
- Migration of intraaneurysmal- Migration of intraaneurysmal thrombus during coil thrombus during coil placement placement
- Slow flow dt vasospasm - Slow flow dt vasospasm
- Rare and unlikely causes are hypercoagulable- Rare and unlikely causes are hypercoagulable state such state such as antiphospholipid antibody syndrome or due to HITas antiphospholipid antibody syndrome or due to HIT
Occur more often with wide-necked aneurysms (dt Occur more often with wide-necked aneurysms (dt increased exposed surface area of thrombogenic coil increased exposed surface area of thrombogenic coil material)material)
Current regimen of endovascular Current regimen of endovascular managementmanagement
The The glycoprotein IIbIIIa antagonist tirofiban glycoprotein IIbIIIa antagonist tirofiban (04 (04 microgkgmin bolus for 30 minutes followed by infusion of microgkgmin bolus for 30 minutes followed by infusion of 0125 ugkgmin until the thrombus dissolved) 0125 ugkgmin until the thrombus dissolved)
Intraarterial thrombolysis with Intraarterial thrombolysis with urokinase or r- TPA urokinase or r- TPA increase of intravenous (IV) heparin (measured by increase of intravenous (IV) heparin (measured by
ACT) ACT) Intravenous aspirin Intravenous aspirin
Coil-related platelet aggregation (white clot) is Coil-related platelet aggregation (white clot) is unlikely to respond to fibrinolytics but has a high risk unlikely to respond to fibrinolytics but has a high risk of hemorrhage (In ISAT) all 5 patients who had of hemorrhage (In ISAT) all 5 patients who had received thrombolytic therapy with tPA to treat a received thrombolytic therapy with tPA to treat a thromboembolic complication after endovascular thromboembolic complication after endovascular treatment rebleed and all of these patients died)treatment rebleed and all of these patients died)
IntracranialIntracranial Stenting Stenting Metallic foreign body such as stent will accumulate Metallic foreign body such as stent will accumulate
thrombus in the absence of platelet inhibitionthrombus in the absence of platelet inhibition Antiplatelet drugs are important to prevent peri or Antiplatelet drugs are important to prevent peri or
post-interventional thromboembolic eventspost-interventional thromboembolic events Optimal treatment regimens has not been determined Optimal treatment regimens has not been determined
but usually but usually Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-
procedureprocedureOrOr
Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on
morning of proceduremorning of procedure
If need to use stent is not pre-planned thanIf need to use stent is not pre-planned than
Abciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkgAbciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkg IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)
Glycoprotein IIbIIIa inhibitor are not used routinely during elective Glycoprotein IIbIIIa inhibitor are not used routinely during elective stenting procedure dt increased risk of ICH stenting procedure dt increased risk of ICH
Carotid StentingCarotid Stenting
Pre-procedurePre-procedure
Double Antiplatelet therapy is routinely given Double Antiplatelet therapy is routinely given beginning at least 3beginning at least 3
days before the proceduredays before the procedure
Aspirin 325mgd+Clopidogrel 75mgdAspirin 325mgd+Clopidogrel 75mgd During procedureDuring procedure
Heparin is given with target clotting time of 250-Heparin is given with target clotting time of 250-300sec300sec
Post-procedure Post-procedure
Aspirin 325mg is continued indefinitely and Aspirin 325mg is continued indefinitely and
Clopidogrel 75mgd for at least 6 weeks Clopidogrel 75mgd for at least 6 weeks
Inclusion criteria for Local ThrombolysisInclusion criteria for Local Thrombolysis a)a) Patients in severe clinical grade on admission Patients in severe clinical grade on admission
with evidence of dural venous sinus with evidence of dural venous sinus thrombosis and restrictive venous outflow on thrombosis and restrictive venous outflow on cerebral angiogramcerebral angiogram
b)b) Patients in clinical grade 3 worsening on Patients in clinical grade 3 worsening on heparin therapy Restriction to venous heparin therapy Restriction to venous outflow was defined as an increase in brain outflow was defined as an increase in brain circulation time gt 12 s delay in the drainage circulation time gt 12 s delay in the drainage of cortical veins with cortical veins hanging of cortical veins with cortical veins hanging in spacein space
Treatment Options for Venous Thrombosis
CT Grading for Venous ThrombosisCT Grading for Venous Thrombosis Grade I no parenchymal change Grade I no parenchymal change
(hyperdense (hyperdense sinuses cortical veins empty sinuses cortical veins empty delta sign)delta sign)
Grade II non hemorrhagic venous infarct Grade II non hemorrhagic venous infarct without mass effect without mass effect
Grade III non-hemorrhagic infarct with Grade III non-hemorrhagic infarct with mass effectmass effect
Grade IV hemorrhagic venous infarct (max Grade IV hemorrhagic venous infarct (max diameter lt 3 cm) with no mass effectdiameter lt 3 cm) with no mass effect
Grade V hemorrhagic venous infarct (max Grade V hemorrhagic venous infarct (max diameter gt 3 cm) with mass effect diameter gt 3 cm) with mass effect
Local ThrombolysisLocal Thrombolysis
Femoral Jugular access was secured and a guiding Femoral Jugular access was secured and a guiding catheter was placed in the jugular bulb catheter was placed in the jugular bulb Mechanical Mechanical clot maceration clot maceration was done with the guidewire was done with the guidewire following which a microcatheter (was navigated and following which a microcatheter (was navigated and placed in the thrombosed segment of sinus confirmed placed in the thrombosed segment of sinus confirmed on a selective venogram on a selective venogram
Urokinase infusion Bolus dose of 2-6 lacs followed Urokinase infusion Bolus dose of 2-6 lacs followed by 60000 to 100000 units per hour along with by 60000 to 100000 units per hour along with periodic check venogram Along with maintenance periodic check venogram Along with maintenance systemic infusion of Heparinsystemic infusion of Heparin Other agents such as Other agents such as streptokinase altepase or rTPAstreptokinase altepase or rTPA can be also used can be also used
After thrombolysis patient should subjected to oral After thrombolysis patient should subjected to oral anticoagulation for six monthsanticoagulation for six months
Low-molecular-weight Low-molecular-weight heparinheparin
PharmacologyPharmacologyLMWH as its name suggests is a glycosaminoglycan that is approximatelyLMWH as its name suggests is a glycosaminoglycan that is approximately
one third the molecular weight of UFH It is derived from UFH through one third the molecular weight of UFH It is derived from UFH through variousvarious
depolymerization processes LMWH binds to antithrombin which in turn depolymerization processes LMWH binds to antithrombin which in turn
Neutralizes actors Xa and IIa Because LMWH lacks many of the longer Neutralizes actors Xa and IIa Because LMWH lacks many of the longer chains chains
required for binding to thrombin it has less ability to neutralize thrombin required for binding to thrombin it has less ability to neutralize thrombin
relativeto its ability to neutralize factor Xa LMWH also has less relativeto its ability to neutralize factor Xa LMWH also has less nonspecific nonspecific
binding to other proteins There is greater bioavailability with more binding to other proteins There is greater bioavailability with more predictable predictable
pharmacokinetics that eliminates the need for monitoring The smaller pharmacokinetics that eliminates the need for monitoring The smaller size also size also
allows for enhanced subcutaneous absorption when compared with UFHallows for enhanced subcutaneous absorption when compared with UFH
Three LMWH preparations are Three LMWH preparations are currently approved for use in the currently approved for use in the United States (1) enoxaparin (2) United States (1) enoxaparin (2) dalteparin and (3) tinzaparin dalteparin and (3) tinzaparin
They are all administered They are all administered subcutaneously at intervals of either subcutaneously at intervals of either once or twice daily for both once or twice daily for both prophylaxis and treatment dosesprophylaxis and treatment doses
Few Experiences of Few Experiences of ThrombolysisThrombolysis
Vickey 25 Yrs male patient presented Vickey 25 Yrs male patient presented with 12with 12thth day HO severe headache with day HO severe headache with right sided hemiplegiaright sided hemiplegia
MRI shows thrombosis of the superior MRI shows thrombosis of the superior sagittal left transverse left sigmoid sagittal left transverse left sigmoid sinuses and cortical veins in the fronto-sinuses and cortical veins in the fronto-parietal regions with eo haemorrhagic parietal regions with eo haemorrhagic infarct in the left cerebral hemisphere infarct in the left cerebral hemisphere with mass effect( Grade ndashV)with mass effect( Grade ndashV)
Sashi Srivastava 64 yrs FSashi Srivastava 64 yrs F In a follow up case of MRD with infra-renal In a follow up case of MRD with infra-renal
aortic abdominal and bilateral renal artery aortic abdominal and bilateral renal artery thrombosis renal angiogram shows filling thrombosis renal angiogram shows filling defects in the right Renal artery defects in the right Renal artery
Initially Renal angioplasty was done Initially Renal angioplasty was done Following angioplasty few thrombi are seem Following angioplasty few thrombi are seem to extends into the segmental branches and to extends into the segmental branches and causing blockage So Thrombolysis was causing blockage So Thrombolysis was plane to dissolve the run-out thrombi with plane to dissolve the run-out thrombi with urokinase urokinase
Rakesh 34yrsMRakesh 34yrsM Left SFA pseudoaneurysm with Left SFA pseudoaneurysm with
Covered stent placementCovered stent placement Pre operative antiplatelets with post Pre operative antiplatelets with post
procedure heparin Tirofiban procedure heparin Tirofiban followed by aspirin and clopidogrel followed by aspirin and clopidogrel were usedwere used
IAT may be a treatment option for selected patients IAT may be a treatment option for selected patients Possible selection criteria include Possible selection criteria include
presentation between 3 and 6 hours from symptom onsetpresentation between 3 and 6 hours from symptom onset major cerebral artery occlusion major cerebral artery occlusion severe neurologic deficits severe neurologic deficits high risk of systemic hemorrhage with IV rt-PA (eg recent high risk of systemic hemorrhage with IV rt-PA (eg recent
surgery) surgery) The MERCI (Mechanical Embolus Removal in Cerebral The MERCI (Mechanical Embolus Removal in Cerebral
Ischemia) retrievalIschemia) retrieval system system
Has been FDA-approved for recanalizing acutely occluded Has been FDA-approved for recanalizing acutely occluded cerebral arteries cerebral arteries
In the Multi-MERCI study patients who did not improve In the Multi-MERCI study patients who did not improve immediately after IV rt-PA underwent mechanical immediately after IV rt-PA underwent mechanical embolectomy within 8 hours of symptom onset embolectomy within 8 hours of symptom onset
Partial or complete recanalization occurred in 74 of Partial or complete recanalization occurred in 74 of patientspatients
with a symptomatic intracerebral hemorrhage (sICH) rate of with a symptomatic intracerebral hemorrhage (sICH) rate of 67 67
Mechanical embolectomy with the MERCI retriever may be a Mechanical embolectomy with the MERCI retriever may be a feasible and safe option for patients after IV rt-PAfeasible and safe option for patients after IV rt-PA
Penumbra stroke systemPenumbra stroke system This device combines two methods of clot This device combines two methods of clot
extraction aspiration and mechanical extraction aspiration and mechanical extraction extraction
First the clot is aspirated then a thrombus First the clot is aspirated then a thrombus removal ring can be used if necessary to removal ring can be used if necessary to remove remaining clot remove remaining clot
successful recanalizing 82successful recanalizing 82 Bridging therapyBridging therapy
06 mgkg IV rt-PA followed by IAT with IA rt-06 mgkg IV rt-PA followed by IAT with IA rt-PA (up to 20 mg)PA (up to 20 mg)
achieved a higher recanalization rateachieved a higher recanalization rate
Criteria for thrombolysis with rTPACriteria for thrombolysis with rTPA
Inclusion criteriaInclusion criteria Clinical signs and symptoms consistent with ischemic Clinical signs and symptoms consistent with ischemic
strokestroke Patient last seen normal within 3 hoursPatient last seen normal within 3 hours Measurable neurologic deficitMeasurable neurologic deficit
Exclusion criteriaExclusion criteria Any hemorrhage on neuroimaging (CT or MRI)Any hemorrhage on neuroimaging (CT or MRI) Symptoms suggestive of subarachnoid hemorrhageSymptoms suggestive of subarachnoid hemorrhage Seizure at stroke onset that is thought to contribute to Seizure at stroke onset that is thought to contribute to
neurologic deficitneurologic deficit Hypodensity greater than one third cerebral hemisphere Hypodensity greater than one third cerebral hemisphere
on CTon CT SBP greater than 185 mm Hg or DBP greater than 110 SBP greater than 185 mm Hg or DBP greater than 110
mm Hgmm Hg International normalized ratio (INR) greater than 17International normalized ratio (INR) greater than 17
Ischemic Stroke Ischemic Stroke Treatment ndash 2006Treatment ndash 2006
IV tissue plasminogen activator (tPA)IV tissue plasminogen activator (tPA) ndash ndash Only FDA-approved acute stroke drugOnly FDA-approved acute stroke drug ndash ndash 3 hour treatment window3 hour treatment window
MERCI - Concentric clot retrieval MERCI - Concentric clot retrieval devicedevice ndash ndash Rescue therapy - approved 2004Rescue therapy - approved 2004 ndash ndash Device approval (not outcomes-based)Device approval (not outcomes-based)
Off label approachesOff label approaches ndash ndash IV tPA after 3 hoursIV tPA after 3 hours ndash ndash IV-IA tPA sequential strategiesIV-IA tPA sequential strategies ndash ndash IA tPA clot angioplasty fragmentationIA tPA clot angioplasty fragmentation ndash ndash Ultrasound-assisted tPA lysisUltrasound-assisted tPA lysis
rt-PA Trials NINDSrt-PA Trials NINDS
Acute stroke - 624 patientsAcute stroke - 624 patients Treat within 3 hrsTreat within 3 hrs Intravenous 09 mgkg rt-PA vs placeboIntravenous 09 mgkg rt-PA vs placebo Hemorrhage 64 tPA 06 placeboHemorrhage 64 tPA 06 placebo Neurologic recovery better with tPA 30 Neurologic recovery better with tPA 30
more like to have minimal or no disabilitymore like to have minimal or no disability
First proven approved treatment for First proven approved treatment for strokestroke
Limitations of tPALimitations of tPA Only 4 of acute strokes receive tPAOnly 4 of acute strokes receive tPA (Kleindorfer et al Stroke 2004 35 e27-e29)(Kleindorfer et al Stroke 2004 35 e27-e29)
Only 22 of patients present within 3 hoursOnly 22 of patients present within 3 hours1048707 1048707 51 of these ineligible due to51 of these ineligible due to
bull bull Mild severityMild severity bull bull Medical or surgical historyMedical or surgical history bull bull Blood testsBlood tests
Sustained recanalization only 13Sustained recanalization only 13 (Alexandrov et al NEJM 2004 351 2170-8)(Alexandrov et al NEJM 2004 351 2170-8)
Concern for hemorrhageConcern for hemorrhage tPA potentiates apoptotic injury tPA potentiates apoptotic injury (Liu et al Nature Med 2004 101379-83)(Liu et al Nature Med 2004 101379-83)
PROACT II IA Lysis TrialPROACT II IA Lysis Trial Baseline 24 hours 8 days
Baseline 60 minutes 120 minutes
9mg IAProurokinase
Desmoteplase Trials DEDAS Desmoteplase Trials DEDAS DIASDIAS
Trial OverviewTrial Overview Double blind randomized placebo Double blind randomized placebo
controlled trialscontrolled trials IV delivery 3-9 hour time windowIV delivery 3-9 hour time window Plasminogen activator ndash from Plasminogen activator ndash from vampire bat vampire bat
salivasaliva Selection based on PWI-DWI MismatchSelection based on PWI-DWI Mismatch
MRI InclusionMRI Inclusion PWI defect at least 2 cm AND ~20 larger PWI defect at least 2 cm AND ~20 larger
than DWIthan DWI PWI should be obvious even visible on PWI should be obvious even visible on
raw imagesraw imagesMRI ExclusionMRI Exclusion
DWI gt 13 MCADWI gt 13 MCA MRA ICA occlusionMRA ICA occlusion
Desmoteplase ndash DIAS Desmoteplase ndash DIAS ResultsResults
Mechanical Thrombolysis Mechanical Thrombolysis devicesdevices
mechanical thrombolysis potentially extends the treatment mechanical thrombolysis potentially extends the treatment window because they act promptly at the site of the thrombuswindow because they act promptly at the site of the thrombus
The devices can retrieve large clots that pharmaceutical agents The devices can retrieve large clots that pharmaceutical agents may not successfully lysemay not successfully lyse
Patients treated with IV tPA may be considered for treatment of Patients treated with IV tPA may be considered for treatment of residual clot with some of these devicesresidual clot with some of these devices
suction-creating saline jets suction-creating saline jets laser energy ultrasound laser energy ultrasound a corkscrew apparatus to treat strokesa corkscrew apparatus to treat strokes The AngioJet systemThe AngioJet system uses saline jets that are directed back into the catheter to uses saline jets that are directed back into the catheter to
create a low-pressure zone around the catheter tip inducing create a low-pressure zone around the catheter tip inducing suction suction
The clot is pulled into the exhaust lumen and removed from the The clot is pulled into the exhaust lumen and removed from the vessel Although US Food and Drug Administration (FDA) has vessel Although US Food and Drug Administration (FDA) has approved this device for use in arteriovenous dialysis grafts and approved this device for use in arteriovenous dialysis grafts and fistulae and for the treatment of coronary arteries saphenous fistulae and for the treatment of coronary arteries saphenous vein grafts and peripheral vessels clinical trials for the vein grafts and peripheral vessels clinical trials for the treatment of acute stroke are no longer in progress treatment of acute stroke are no longer in progress
Most devices are used in cerebral vessels that 2-5 mm
The Latis laser device The Latis laser device used laser energy to ablate clots used laser energy to ablate clots Arteries 2-5 mm in diameter could be Arteries 2-5 mm in diameter could be
treated including the ICA M1 or M2 treated including the ICA M1 or M2 branch of the MCA A1 branch of the branch of the MCA A1 branch of the anterior cerebral artery (ACA) basilar anterior cerebral artery (ACA) basilar artery posterior cerebral artery (PCA) artery posterior cerebral artery (PCA) and vertebral and vertebral
Patients could receive treatment as late Patients could receive treatment as late as 8 hours after symptom onset in the as 8 hours after symptom onset in the anterior circulation and within 24 hours in anterior circulation and within 24 hours in the posterior circulation the posterior circulation
Endovascular Photo Acoustic Endovascular Photo Acoustic Recanalization (EPAR) Recanalization (EPAR)
A laser power source generated energy for the A laser power source generated energy for the systemsystem
The energy was delivered by means of The energy was delivered by means of fiberoptics to the tip of the catheter at the fiberoptics to the tip of the catheter at the treatment sitetreatment site
Absorption of laser light by darkly pigmented Absorption of laser light by darkly pigmented materials (ie the clot) occurred inside the 1-mm materials (ie the clot) occurred inside the 1-mm catheter tipcatheter tip
the system was designed to minimize scattering the system was designed to minimize scattering of laser light of laser light
Absorption converted photo energy to acoustic Absorption converted photo energy to acoustic energy which then emulsified the clot inside the energy which then emulsified the clot inside the catheter tip catheter tip
EKOS ultrasound( the EKOS ultrasound( the Ultrasound Thrombolytic Ultrasound Thrombolytic
Infusion Catheter) Infusion Catheter) combines the use of a distal ultrasound transducer with combines the use of a distal ultrasound transducer with
infusion of a thrombolytic agent through the infusion of a thrombolytic agent through the microcathetermicrocatheter
Ultrasound changes the structure of the clot to Ultrasound changes the structure of the clot to temporarily increase its permeability while providing an temporarily increase its permeability while providing an acoustic pressure gradient to move the drug into the clot acoustic pressure gradient to move the drug into the clot to speed its dissolution to speed its dissolution
The EKOS catheter is placed in the proximal portion of the The EKOS catheter is placed in the proximal portion of the clot clot
After a 2-mg bolus of tPA was injected through the After a 2-mg bolus of tPA was injected through the catheter catheter
the patient received a continuous infusion of IA tPA 03 the patient received a continuous infusion of IA tPA 03 mgmin to a maximum of 20 mg and simultaneous mgmin to a maximum of 20 mg and simultaneous ultrasound transmission for as long as 60 minutes ultrasound transmission for as long as 60 minutes
One patient was treated with a total of 4 units of One patient was treated with a total of 4 units of recombinant reteplase (Retavase) hand-injected over 60 recombinant reteplase (Retavase) hand-injected over 60 minutes minutes
Penumbra system Penumbra system The Penumbra system (Penumbra Inc) provides a dual The Penumbra system (Penumbra Inc) provides a dual
approach to clot extraction using aspiration followed by approach to clot extraction using aspiration followed by clot retrieval with a ring device if needed clot retrieval with a ring device if needed
Mechanical Embolus Removal in Cerebral Ischemia Mechanical Embolus Removal in Cerebral Ischemia (MERCI)(MERCI)
a corkscrew-like apparatus to remove blood clots from a corkscrew-like apparatus to remove blood clots from the brain in patients experiencing an ischemic stroke the brain in patients experiencing an ischemic stroke
The corkscrew itself resides in the catheter tip which The corkscrew itself resides in the catheter tip which shields it from the wall of the vessel until it is ready to be shields it from the wall of the vessel until it is ready to be burrowed into the clot Once lodged in the clot the device burrowed into the clot Once lodged in the clot the device and clot are withdrawn from the vessel and clot are withdrawn from the vessel
Snarelike devicesSnarelike devices Snares such as the Neuronet snare (Guidant Snares such as the Neuronet snare (Guidant
Endovascular Santa Clara CA) have been developed Endovascular Santa Clara CA) have been developed specifically for use in the treatment of strokes specifically for use in the treatment of strokes
These devices are simple in design and do not require the These devices are simple in design and do not require the clot to be amenable to emulsification clot to be amenable to emulsification
X-Sizer deviceX-Sizer device a device with small moving blades at the a device with small moving blades at the
catheter tip catheter tip This device the X-Sizer device (EndiCor Medical This device the X-Sizer device (EndiCor Medical
San Clemente CA) can be used to excise the San Clemente CA) can be used to excise the thrombus and aspirate it thrombus and aspirate it
The device was being evaluated in randomized The device was being evaluated in randomized studies of coronary vessels and in a registry of studies of coronary vessels and in a registry of patients with acute myocardial infarctionpatients with acute myocardial infarction
Although the manufacturer had modified the Although the manufacturer had modified the device for use in cerebral vessels a safety and device for use in cerebral vessels a safety and feasibility study was indefinitely suspended after feasibility study was indefinitely suspended after only 1 patient was treated with the device in only 1 patient was treated with the device in Europe Europe
Suction thrombectomySuction thrombectomy This method of mechanical thrombolysis is one of the This method of mechanical thrombolysis is one of the
simplestsimplest In this readily available technique suction is applied with In this readily available technique suction is applied with
a syringe to remove thrombus in the ICA a syringe to remove thrombus in the ICA It requires no other devicesIt requires no other devices A catheter with a large inner diameter (Brite Tip Cordis A catheter with a large inner diameter (Brite Tip Cordis
Corporation Miami FL) was placed in the symptomatic Corporation Miami FL) was placed in the symptomatic vessel and navigated over a guidewire into the thrombusvessel and navigated over a guidewire into the thrombus
A 60-mL syringe was used to aspirate the thrombus A 60-mL syringe was used to aspirate the thrombus Each patient required angioplasty and stenting of carotid Each patient required angioplasty and stenting of carotid
bifurcation stenosis and received daily aspirin and bifurcation stenosis and received daily aspirin and ticlopidine after the procedure No complications ticlopidine after the procedure No complications occurred occurred
Summary Acute Stroke Summary Acute Stroke ImagingImaging
PhysiologyPhysiology importance collaterals importance collaterals
ndash ndashGrowing role for perfusion Growing role for perfusion assessmentassessment
tPAtPA guidelines amp limitations guidelines amp limitations Signs on CT amp MRSigns on CT amp MR follow physiology follow physiology Stroke trialsStroke trials PWI-DWI mismatch PWI-DWI mismatch
ndash ndashTreat based on physiology not timeTreat based on physiology not time ProtocolsProtocols should be fast and should be fast and
comprehensivecomprehensive
Therapeutic window in Therapeutic window in management of acute Ischemic management of acute Ischemic
StrokeStrokeThe early diagnosis of ischemic stroke is critical to the The early diagnosis of ischemic stroke is critical to the
with only a narrow therapeutic window in the first few with only a narrow therapeutic window in the first few hours following stroke ictushours following stroke ictus
Diagnosis in the first 3 hours postictus provides the Diagnosis in the first 3 hours postictus provides the opportunity for intravenous or intraarterial thrombolysis opportunity for intravenous or intraarterial thrombolysis and intra-arterial clot mechanical treatment which and intra-arterial clot mechanical treatment which improve the outcome improve the outcome
Diagnosis in the time period between 3 and 6 hours Diagnosis in the time period between 3 and 6 hours provides an opportunity for intra-arterial thrombolysis provides an opportunity for intra-arterial thrombolysis and mechanical treatment and mechanical treatment
Involvement of the posterior circulation especially the Involvement of the posterior circulation especially the basilar artery is treated by some regardless of time of basilar artery is treated by some regardless of time of onset or up until 12 to 24 hours in some practices This is onset or up until 12 to 24 hours in some practices This is related to the potentially high mortality and morbidity related to the potentially high mortality and morbidity associated with basilar artery thrombosisassociated with basilar artery thrombosis
Infarct evaluation on angiographyInfarct evaluation on angiography(CT angiography and catheter (CT angiography and catheter
angiography)angiography)CTA is an excellent first-line examination for CTA is an excellent first-line examination for
evaluation of the head and neck arteries evaluation of the head and neck arteries In comparison with catheter angiography In comparison with catheter angiography
what it gives up in resolution and dynamic what it gives up in resolution and dynamic properties it makes up for with rapid properties it makes up for with rapid acquisition of a 3-D dataset and the potential acquisition of a 3-D dataset and the potential for assessment of whole-brain perfusion and for assessment of whole-brain perfusion and better parenchymal evaluationbetter parenchymal evaluation
Moreover CTA illustrates not only arterial Moreover CTA illustrates not only arterial stenosis or occlusion but also the vessel wall stenosis or occlusion but also the vessel wall This factor is most important for evaluation of This factor is most important for evaluation of intramural dissection and thrombosed intramural dissection and thrombosed aneurysms which may both complicate aneurysms which may both complicate evaluation of stroke patientsevaluation of stroke patients
Early angiographic signs of strokes Early angiographic signs of strokes both CTA both CTA and DSA and DSA
Vessel occlusion or cutoff related to Vessel occlusion or cutoff related to thromboembolithromboemboli
aneurysms aneurysms arterial dissection arterial dissection Meniscus or flattened shape to clot Meniscus or flattened shape to clot
(recent) versus reverse meniscus (older)(recent) versus reverse meniscus (older) tram track (nonocclusive or recanalized tram track (nonocclusive or recanalized
clot) clot) delayed (antegrade) flow (manifest as delayed (antegrade) flow (manifest as
decreased whole-brain perfusion on CTA)decreased whole-brain perfusion on CTA) retrograde collateral flowretrograde collateral flow
Non-occlusive left MCA thrombus on 3-D imaging performed from CTA source data and was confirmed at catheter angiography
Therapy to be started within a 6-hr Therapy to be started within a 6-hr time to treatment (TTT) window time to treatment (TTT) window (while in case of IV thrombolysis (while in case of IV thrombolysis therapy to be started with in 3hrs)therapy to be started with in 3hrs)
Exclusion criteria Exclusion criteria Rapidly improving neurologic deficit or Rapidly improving neurologic deficit or Sustained blood pressure of gt180100 Sustained blood pressure of gt180100 Hemorrhage is detected on CTHemorrhage is detected on CT Infarct involving gt more than 13 rd Infarct involving gt more than 13 rd
territory of MCAterritory of MCA MRADWI-Perfusion mismatchlt 20MRADWI-Perfusion mismatchlt 20 Definite hypodensity on CTDefinite hypodensity on CT
Intra-arterial Thrombolysis
Fibrinolytics + AntiplateletsFibrinolytics + Antiplatelets
PlasminogenPlasminogen activators through fibrinolysis exposes activators through fibrinolysis exposes free thrombin and paradoxically stimulatesfree thrombin and paradoxically stimulates platelet platelet aggregation which leads to formation of aaggregation which leads to formation of a platelet platelet thrombus (white clot) thrombus (white clot)
This new thrombus is relatively resistant to This new thrombus is relatively resistant to fibrinolyticsfibrinolytics
So new regimen in case of acute stroke isSo new regimen in case of acute stroke is fibrinolytics + antiplatelet drugsfibrinolytics + antiplatelet drugs
rtPA + IIbIIIa inhibitors( tirofiban rtPA + IIbIIIa inhibitors( tirofiban abciximab) orabciximab) or
Urokinase + IIbIIIa Urokinase + IIbIIIa inhibitors( tirofiban abciximab)inhibitors( tirofiban abciximab)
Intra-arterial Thrombolysis Tirofiban (04 microgkgmin bolus for 3 min followed by Tirofiban (04 microgkgmin bolus for 3 min followed by
0125 ugkgmin)0125 ugkgmin)
++
Heparin (2000ndash3000 IU bolus followed by Heparin (2000ndash3000 IU bolus followed by 1000 IUhour infusion 1000 IUhour infusion
with ACT maintained bw 200-300) throughout the with ACT maintained bw 200-300) throughout the interventional procedure and for 24ndash48 hours thereafter when interventional procedure and for 24ndash48 hours thereafter when there is neither intraprocedural bleeding nor suspicion of there is neither intraprocedural bleeding nor suspicion of increased risk of bleeding increased risk of bleeding
Maximum dose of Urokinase Maximum dose of Urokinase Anterior circulation stroke - 500000 IU (mean 400000 Anterior circulation stroke - 500000 IU (mean 400000
IU range 300000ndash500000 IU)IU range 300000ndash500000 IU) Posterior circulation stroke -1000000 IU (mean 837000 Posterior circulation stroke -1000000 IU (mean 837000
IU range 300000ndash1000000 IU)IU range 300000ndash1000000 IU)American Journal of NeuroradiologyAmerican Journal of Neuroradiology 262595-2601 2005262595-2601 2005
Intravenous ThrombolysisIntravenous Thrombolysis
The first method to restore cerebral The first method to restore cerebral perfusion is clot lysis with the goal perfusion is clot lysis with the goal of re-establishing blood flow to the of re-establishing blood flow to the affected tissue affected tissue
IV thrombolysis rt-PA is the only IV thrombolysis rt-PA is the only FDA- approved treatment for AIS FDA- approved treatment for AIS
Fibrinolysis is enhanced powerfully Fibrinolysis is enhanced powerfully by rt-PAby rt-PA
Intravenous rTPA Intravenous rTPA administration administration protocolprotocol
Total dose of rt-PA 09 mgkg (maximum dose Total dose of rt-PA 09 mgkg (maximum dose 90 mg)90 mg)
Give 10 as initial IV bolusGive 10 as initial IV bolus Infuse remainder over 1 hourInfuse remainder over 1 hour Admit patient to an ICU or stroke unit for Admit patient to an ICU or stroke unit for
monitoringmonitoring Neurologic assessments every 15 minutes Neurologic assessments every 15 minutes
during infusion then every 30 minutes for next during infusion then every 30 minutes for next 6 hours then every hour until 24hours after 6 hours then every hour until 24hours after treatmenttreatment
Favorable Outcome vs Treatment Time Favorable Outcome vs Treatment Time with IV rTPAwith IV rTPA
Protocol limit = 3 hrs
Benefit ~ 45 hrs
Thromboembolism During coilingThromboembolism During coiling Most feared and frequent complication Most feared and frequent complication Reported incidence - Approx 7 Reported incidence - Approx 7 SourcesSources of Thromboembolism are of Thromboembolism are
- Clots at the aneurysmal neck during or immediately- Clots at the aneurysmal neck during or immediately after after embolization embolization
- Thrombus forming on catheters during- Thrombus forming on catheters during proceduresprocedures
- Stenosis of an adjacent artery dt coil mass- Stenosis of an adjacent artery dt coil mass or herniationor herniation
- Migration of intraaneurysmal- Migration of intraaneurysmal thrombus during coil thrombus during coil placement placement
- Slow flow dt vasospasm - Slow flow dt vasospasm
- Rare and unlikely causes are hypercoagulable- Rare and unlikely causes are hypercoagulable state such state such as antiphospholipid antibody syndrome or due to HITas antiphospholipid antibody syndrome or due to HIT
Occur more often with wide-necked aneurysms (dt Occur more often with wide-necked aneurysms (dt increased exposed surface area of thrombogenic coil increased exposed surface area of thrombogenic coil material)material)
Current regimen of endovascular Current regimen of endovascular managementmanagement
The The glycoprotein IIbIIIa antagonist tirofiban glycoprotein IIbIIIa antagonist tirofiban (04 (04 microgkgmin bolus for 30 minutes followed by infusion of microgkgmin bolus for 30 minutes followed by infusion of 0125 ugkgmin until the thrombus dissolved) 0125 ugkgmin until the thrombus dissolved)
Intraarterial thrombolysis with Intraarterial thrombolysis with urokinase or r- TPA urokinase or r- TPA increase of intravenous (IV) heparin (measured by increase of intravenous (IV) heparin (measured by
ACT) ACT) Intravenous aspirin Intravenous aspirin
Coil-related platelet aggregation (white clot) is Coil-related platelet aggregation (white clot) is unlikely to respond to fibrinolytics but has a high risk unlikely to respond to fibrinolytics but has a high risk of hemorrhage (In ISAT) all 5 patients who had of hemorrhage (In ISAT) all 5 patients who had received thrombolytic therapy with tPA to treat a received thrombolytic therapy with tPA to treat a thromboembolic complication after endovascular thromboembolic complication after endovascular treatment rebleed and all of these patients died)treatment rebleed and all of these patients died)
IntracranialIntracranial Stenting Stenting Metallic foreign body such as stent will accumulate Metallic foreign body such as stent will accumulate
thrombus in the absence of platelet inhibitionthrombus in the absence of platelet inhibition Antiplatelet drugs are important to prevent peri or Antiplatelet drugs are important to prevent peri or
post-interventional thromboembolic eventspost-interventional thromboembolic events Optimal treatment regimens has not been determined Optimal treatment regimens has not been determined
but usually but usually Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-
procedureprocedureOrOr
Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on
morning of proceduremorning of procedure
If need to use stent is not pre-planned thanIf need to use stent is not pre-planned than
Abciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkgAbciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkg IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)
Glycoprotein IIbIIIa inhibitor are not used routinely during elective Glycoprotein IIbIIIa inhibitor are not used routinely during elective stenting procedure dt increased risk of ICH stenting procedure dt increased risk of ICH
Carotid StentingCarotid Stenting
Pre-procedurePre-procedure
Double Antiplatelet therapy is routinely given Double Antiplatelet therapy is routinely given beginning at least 3beginning at least 3
days before the proceduredays before the procedure
Aspirin 325mgd+Clopidogrel 75mgdAspirin 325mgd+Clopidogrel 75mgd During procedureDuring procedure
Heparin is given with target clotting time of 250-Heparin is given with target clotting time of 250-300sec300sec
Post-procedure Post-procedure
Aspirin 325mg is continued indefinitely and Aspirin 325mg is continued indefinitely and
Clopidogrel 75mgd for at least 6 weeks Clopidogrel 75mgd for at least 6 weeks
Inclusion criteria for Local ThrombolysisInclusion criteria for Local Thrombolysis a)a) Patients in severe clinical grade on admission Patients in severe clinical grade on admission
with evidence of dural venous sinus with evidence of dural venous sinus thrombosis and restrictive venous outflow on thrombosis and restrictive venous outflow on cerebral angiogramcerebral angiogram
b)b) Patients in clinical grade 3 worsening on Patients in clinical grade 3 worsening on heparin therapy Restriction to venous heparin therapy Restriction to venous outflow was defined as an increase in brain outflow was defined as an increase in brain circulation time gt 12 s delay in the drainage circulation time gt 12 s delay in the drainage of cortical veins with cortical veins hanging of cortical veins with cortical veins hanging in spacein space
Treatment Options for Venous Thrombosis
CT Grading for Venous ThrombosisCT Grading for Venous Thrombosis Grade I no parenchymal change Grade I no parenchymal change
(hyperdense (hyperdense sinuses cortical veins empty sinuses cortical veins empty delta sign)delta sign)
Grade II non hemorrhagic venous infarct Grade II non hemorrhagic venous infarct without mass effect without mass effect
Grade III non-hemorrhagic infarct with Grade III non-hemorrhagic infarct with mass effectmass effect
Grade IV hemorrhagic venous infarct (max Grade IV hemorrhagic venous infarct (max diameter lt 3 cm) with no mass effectdiameter lt 3 cm) with no mass effect
Grade V hemorrhagic venous infarct (max Grade V hemorrhagic venous infarct (max diameter gt 3 cm) with mass effect diameter gt 3 cm) with mass effect
Local ThrombolysisLocal Thrombolysis
Femoral Jugular access was secured and a guiding Femoral Jugular access was secured and a guiding catheter was placed in the jugular bulb catheter was placed in the jugular bulb Mechanical Mechanical clot maceration clot maceration was done with the guidewire was done with the guidewire following which a microcatheter (was navigated and following which a microcatheter (was navigated and placed in the thrombosed segment of sinus confirmed placed in the thrombosed segment of sinus confirmed on a selective venogram on a selective venogram
Urokinase infusion Bolus dose of 2-6 lacs followed Urokinase infusion Bolus dose of 2-6 lacs followed by 60000 to 100000 units per hour along with by 60000 to 100000 units per hour along with periodic check venogram Along with maintenance periodic check venogram Along with maintenance systemic infusion of Heparinsystemic infusion of Heparin Other agents such as Other agents such as streptokinase altepase or rTPAstreptokinase altepase or rTPA can be also used can be also used
After thrombolysis patient should subjected to oral After thrombolysis patient should subjected to oral anticoagulation for six monthsanticoagulation for six months
Low-molecular-weight Low-molecular-weight heparinheparin
PharmacologyPharmacologyLMWH as its name suggests is a glycosaminoglycan that is approximatelyLMWH as its name suggests is a glycosaminoglycan that is approximately
one third the molecular weight of UFH It is derived from UFH through one third the molecular weight of UFH It is derived from UFH through variousvarious
depolymerization processes LMWH binds to antithrombin which in turn depolymerization processes LMWH binds to antithrombin which in turn
Neutralizes actors Xa and IIa Because LMWH lacks many of the longer Neutralizes actors Xa and IIa Because LMWH lacks many of the longer chains chains
required for binding to thrombin it has less ability to neutralize thrombin required for binding to thrombin it has less ability to neutralize thrombin
relativeto its ability to neutralize factor Xa LMWH also has less relativeto its ability to neutralize factor Xa LMWH also has less nonspecific nonspecific
binding to other proteins There is greater bioavailability with more binding to other proteins There is greater bioavailability with more predictable predictable
pharmacokinetics that eliminates the need for monitoring The smaller pharmacokinetics that eliminates the need for monitoring The smaller size also size also
allows for enhanced subcutaneous absorption when compared with UFHallows for enhanced subcutaneous absorption when compared with UFH
Three LMWH preparations are Three LMWH preparations are currently approved for use in the currently approved for use in the United States (1) enoxaparin (2) United States (1) enoxaparin (2) dalteparin and (3) tinzaparin dalteparin and (3) tinzaparin
They are all administered They are all administered subcutaneously at intervals of either subcutaneously at intervals of either once or twice daily for both once or twice daily for both prophylaxis and treatment dosesprophylaxis and treatment doses
Few Experiences of Few Experiences of ThrombolysisThrombolysis
Vickey 25 Yrs male patient presented Vickey 25 Yrs male patient presented with 12with 12thth day HO severe headache with day HO severe headache with right sided hemiplegiaright sided hemiplegia
MRI shows thrombosis of the superior MRI shows thrombosis of the superior sagittal left transverse left sigmoid sagittal left transverse left sigmoid sinuses and cortical veins in the fronto-sinuses and cortical veins in the fronto-parietal regions with eo haemorrhagic parietal regions with eo haemorrhagic infarct in the left cerebral hemisphere infarct in the left cerebral hemisphere with mass effect( Grade ndashV)with mass effect( Grade ndashV)
Sashi Srivastava 64 yrs FSashi Srivastava 64 yrs F In a follow up case of MRD with infra-renal In a follow up case of MRD with infra-renal
aortic abdominal and bilateral renal artery aortic abdominal and bilateral renal artery thrombosis renal angiogram shows filling thrombosis renal angiogram shows filling defects in the right Renal artery defects in the right Renal artery
Initially Renal angioplasty was done Initially Renal angioplasty was done Following angioplasty few thrombi are seem Following angioplasty few thrombi are seem to extends into the segmental branches and to extends into the segmental branches and causing blockage So Thrombolysis was causing blockage So Thrombolysis was plane to dissolve the run-out thrombi with plane to dissolve the run-out thrombi with urokinase urokinase
Rakesh 34yrsMRakesh 34yrsM Left SFA pseudoaneurysm with Left SFA pseudoaneurysm with
Covered stent placementCovered stent placement Pre operative antiplatelets with post Pre operative antiplatelets with post
procedure heparin Tirofiban procedure heparin Tirofiban followed by aspirin and clopidogrel followed by aspirin and clopidogrel were usedwere used
IAT may be a treatment option for selected patients IAT may be a treatment option for selected patients Possible selection criteria include Possible selection criteria include
presentation between 3 and 6 hours from symptom onsetpresentation between 3 and 6 hours from symptom onset major cerebral artery occlusion major cerebral artery occlusion severe neurologic deficits severe neurologic deficits high risk of systemic hemorrhage with IV rt-PA (eg recent high risk of systemic hemorrhage with IV rt-PA (eg recent
surgery) surgery) The MERCI (Mechanical Embolus Removal in Cerebral The MERCI (Mechanical Embolus Removal in Cerebral
Ischemia) retrievalIschemia) retrieval system system
Has been FDA-approved for recanalizing acutely occluded Has been FDA-approved for recanalizing acutely occluded cerebral arteries cerebral arteries
In the Multi-MERCI study patients who did not improve In the Multi-MERCI study patients who did not improve immediately after IV rt-PA underwent mechanical immediately after IV rt-PA underwent mechanical embolectomy within 8 hours of symptom onset embolectomy within 8 hours of symptom onset
Partial or complete recanalization occurred in 74 of Partial or complete recanalization occurred in 74 of patientspatients
with a symptomatic intracerebral hemorrhage (sICH) rate of with a symptomatic intracerebral hemorrhage (sICH) rate of 67 67
Mechanical embolectomy with the MERCI retriever may be a Mechanical embolectomy with the MERCI retriever may be a feasible and safe option for patients after IV rt-PAfeasible and safe option for patients after IV rt-PA
Penumbra stroke systemPenumbra stroke system This device combines two methods of clot This device combines two methods of clot
extraction aspiration and mechanical extraction aspiration and mechanical extraction extraction
First the clot is aspirated then a thrombus First the clot is aspirated then a thrombus removal ring can be used if necessary to removal ring can be used if necessary to remove remaining clot remove remaining clot
successful recanalizing 82successful recanalizing 82 Bridging therapyBridging therapy
06 mgkg IV rt-PA followed by IAT with IA rt-06 mgkg IV rt-PA followed by IAT with IA rt-PA (up to 20 mg)PA (up to 20 mg)
achieved a higher recanalization rateachieved a higher recanalization rate
Criteria for thrombolysis with rTPACriteria for thrombolysis with rTPA
Inclusion criteriaInclusion criteria Clinical signs and symptoms consistent with ischemic Clinical signs and symptoms consistent with ischemic
strokestroke Patient last seen normal within 3 hoursPatient last seen normal within 3 hours Measurable neurologic deficitMeasurable neurologic deficit
Exclusion criteriaExclusion criteria Any hemorrhage on neuroimaging (CT or MRI)Any hemorrhage on neuroimaging (CT or MRI) Symptoms suggestive of subarachnoid hemorrhageSymptoms suggestive of subarachnoid hemorrhage Seizure at stroke onset that is thought to contribute to Seizure at stroke onset that is thought to contribute to
neurologic deficitneurologic deficit Hypodensity greater than one third cerebral hemisphere Hypodensity greater than one third cerebral hemisphere
on CTon CT SBP greater than 185 mm Hg or DBP greater than 110 SBP greater than 185 mm Hg or DBP greater than 110
mm Hgmm Hg International normalized ratio (INR) greater than 17International normalized ratio (INR) greater than 17
Ischemic Stroke Ischemic Stroke Treatment ndash 2006Treatment ndash 2006
IV tissue plasminogen activator (tPA)IV tissue plasminogen activator (tPA) ndash ndash Only FDA-approved acute stroke drugOnly FDA-approved acute stroke drug ndash ndash 3 hour treatment window3 hour treatment window
MERCI - Concentric clot retrieval MERCI - Concentric clot retrieval devicedevice ndash ndash Rescue therapy - approved 2004Rescue therapy - approved 2004 ndash ndash Device approval (not outcomes-based)Device approval (not outcomes-based)
Off label approachesOff label approaches ndash ndash IV tPA after 3 hoursIV tPA after 3 hours ndash ndash IV-IA tPA sequential strategiesIV-IA tPA sequential strategies ndash ndash IA tPA clot angioplasty fragmentationIA tPA clot angioplasty fragmentation ndash ndash Ultrasound-assisted tPA lysisUltrasound-assisted tPA lysis
rt-PA Trials NINDSrt-PA Trials NINDS
Acute stroke - 624 patientsAcute stroke - 624 patients Treat within 3 hrsTreat within 3 hrs Intravenous 09 mgkg rt-PA vs placeboIntravenous 09 mgkg rt-PA vs placebo Hemorrhage 64 tPA 06 placeboHemorrhage 64 tPA 06 placebo Neurologic recovery better with tPA 30 Neurologic recovery better with tPA 30
more like to have minimal or no disabilitymore like to have minimal or no disability
First proven approved treatment for First proven approved treatment for strokestroke
Limitations of tPALimitations of tPA Only 4 of acute strokes receive tPAOnly 4 of acute strokes receive tPA (Kleindorfer et al Stroke 2004 35 e27-e29)(Kleindorfer et al Stroke 2004 35 e27-e29)
Only 22 of patients present within 3 hoursOnly 22 of patients present within 3 hours1048707 1048707 51 of these ineligible due to51 of these ineligible due to
bull bull Mild severityMild severity bull bull Medical or surgical historyMedical or surgical history bull bull Blood testsBlood tests
Sustained recanalization only 13Sustained recanalization only 13 (Alexandrov et al NEJM 2004 351 2170-8)(Alexandrov et al NEJM 2004 351 2170-8)
Concern for hemorrhageConcern for hemorrhage tPA potentiates apoptotic injury tPA potentiates apoptotic injury (Liu et al Nature Med 2004 101379-83)(Liu et al Nature Med 2004 101379-83)
PROACT II IA Lysis TrialPROACT II IA Lysis Trial Baseline 24 hours 8 days
Baseline 60 minutes 120 minutes
9mg IAProurokinase
Desmoteplase Trials DEDAS Desmoteplase Trials DEDAS DIASDIAS
Trial OverviewTrial Overview Double blind randomized placebo Double blind randomized placebo
controlled trialscontrolled trials IV delivery 3-9 hour time windowIV delivery 3-9 hour time window Plasminogen activator ndash from Plasminogen activator ndash from vampire bat vampire bat
salivasaliva Selection based on PWI-DWI MismatchSelection based on PWI-DWI Mismatch
MRI InclusionMRI Inclusion PWI defect at least 2 cm AND ~20 larger PWI defect at least 2 cm AND ~20 larger
than DWIthan DWI PWI should be obvious even visible on PWI should be obvious even visible on
raw imagesraw imagesMRI ExclusionMRI Exclusion
DWI gt 13 MCADWI gt 13 MCA MRA ICA occlusionMRA ICA occlusion
Desmoteplase ndash DIAS Desmoteplase ndash DIAS ResultsResults
Mechanical Thrombolysis Mechanical Thrombolysis devicesdevices
mechanical thrombolysis potentially extends the treatment mechanical thrombolysis potentially extends the treatment window because they act promptly at the site of the thrombuswindow because they act promptly at the site of the thrombus
The devices can retrieve large clots that pharmaceutical agents The devices can retrieve large clots that pharmaceutical agents may not successfully lysemay not successfully lyse
Patients treated with IV tPA may be considered for treatment of Patients treated with IV tPA may be considered for treatment of residual clot with some of these devicesresidual clot with some of these devices
suction-creating saline jets suction-creating saline jets laser energy ultrasound laser energy ultrasound a corkscrew apparatus to treat strokesa corkscrew apparatus to treat strokes The AngioJet systemThe AngioJet system uses saline jets that are directed back into the catheter to uses saline jets that are directed back into the catheter to
create a low-pressure zone around the catheter tip inducing create a low-pressure zone around the catheter tip inducing suction suction
The clot is pulled into the exhaust lumen and removed from the The clot is pulled into the exhaust lumen and removed from the vessel Although US Food and Drug Administration (FDA) has vessel Although US Food and Drug Administration (FDA) has approved this device for use in arteriovenous dialysis grafts and approved this device for use in arteriovenous dialysis grafts and fistulae and for the treatment of coronary arteries saphenous fistulae and for the treatment of coronary arteries saphenous vein grafts and peripheral vessels clinical trials for the vein grafts and peripheral vessels clinical trials for the treatment of acute stroke are no longer in progress treatment of acute stroke are no longer in progress
Most devices are used in cerebral vessels that 2-5 mm
The Latis laser device The Latis laser device used laser energy to ablate clots used laser energy to ablate clots Arteries 2-5 mm in diameter could be Arteries 2-5 mm in diameter could be
treated including the ICA M1 or M2 treated including the ICA M1 or M2 branch of the MCA A1 branch of the branch of the MCA A1 branch of the anterior cerebral artery (ACA) basilar anterior cerebral artery (ACA) basilar artery posterior cerebral artery (PCA) artery posterior cerebral artery (PCA) and vertebral and vertebral
Patients could receive treatment as late Patients could receive treatment as late as 8 hours after symptom onset in the as 8 hours after symptom onset in the anterior circulation and within 24 hours in anterior circulation and within 24 hours in the posterior circulation the posterior circulation
Endovascular Photo Acoustic Endovascular Photo Acoustic Recanalization (EPAR) Recanalization (EPAR)
A laser power source generated energy for the A laser power source generated energy for the systemsystem
The energy was delivered by means of The energy was delivered by means of fiberoptics to the tip of the catheter at the fiberoptics to the tip of the catheter at the treatment sitetreatment site
Absorption of laser light by darkly pigmented Absorption of laser light by darkly pigmented materials (ie the clot) occurred inside the 1-mm materials (ie the clot) occurred inside the 1-mm catheter tipcatheter tip
the system was designed to minimize scattering the system was designed to minimize scattering of laser light of laser light
Absorption converted photo energy to acoustic Absorption converted photo energy to acoustic energy which then emulsified the clot inside the energy which then emulsified the clot inside the catheter tip catheter tip
EKOS ultrasound( the EKOS ultrasound( the Ultrasound Thrombolytic Ultrasound Thrombolytic
Infusion Catheter) Infusion Catheter) combines the use of a distal ultrasound transducer with combines the use of a distal ultrasound transducer with
infusion of a thrombolytic agent through the infusion of a thrombolytic agent through the microcathetermicrocatheter
Ultrasound changes the structure of the clot to Ultrasound changes the structure of the clot to temporarily increase its permeability while providing an temporarily increase its permeability while providing an acoustic pressure gradient to move the drug into the clot acoustic pressure gradient to move the drug into the clot to speed its dissolution to speed its dissolution
The EKOS catheter is placed in the proximal portion of the The EKOS catheter is placed in the proximal portion of the clot clot
After a 2-mg bolus of tPA was injected through the After a 2-mg bolus of tPA was injected through the catheter catheter
the patient received a continuous infusion of IA tPA 03 the patient received a continuous infusion of IA tPA 03 mgmin to a maximum of 20 mg and simultaneous mgmin to a maximum of 20 mg and simultaneous ultrasound transmission for as long as 60 minutes ultrasound transmission for as long as 60 minutes
One patient was treated with a total of 4 units of One patient was treated with a total of 4 units of recombinant reteplase (Retavase) hand-injected over 60 recombinant reteplase (Retavase) hand-injected over 60 minutes minutes
Penumbra system Penumbra system The Penumbra system (Penumbra Inc) provides a dual The Penumbra system (Penumbra Inc) provides a dual
approach to clot extraction using aspiration followed by approach to clot extraction using aspiration followed by clot retrieval with a ring device if needed clot retrieval with a ring device if needed
Mechanical Embolus Removal in Cerebral Ischemia Mechanical Embolus Removal in Cerebral Ischemia (MERCI)(MERCI)
a corkscrew-like apparatus to remove blood clots from a corkscrew-like apparatus to remove blood clots from the brain in patients experiencing an ischemic stroke the brain in patients experiencing an ischemic stroke
The corkscrew itself resides in the catheter tip which The corkscrew itself resides in the catheter tip which shields it from the wall of the vessel until it is ready to be shields it from the wall of the vessel until it is ready to be burrowed into the clot Once lodged in the clot the device burrowed into the clot Once lodged in the clot the device and clot are withdrawn from the vessel and clot are withdrawn from the vessel
Snarelike devicesSnarelike devices Snares such as the Neuronet snare (Guidant Snares such as the Neuronet snare (Guidant
Endovascular Santa Clara CA) have been developed Endovascular Santa Clara CA) have been developed specifically for use in the treatment of strokes specifically for use in the treatment of strokes
These devices are simple in design and do not require the These devices are simple in design and do not require the clot to be amenable to emulsification clot to be amenable to emulsification
X-Sizer deviceX-Sizer device a device with small moving blades at the a device with small moving blades at the
catheter tip catheter tip This device the X-Sizer device (EndiCor Medical This device the X-Sizer device (EndiCor Medical
San Clemente CA) can be used to excise the San Clemente CA) can be used to excise the thrombus and aspirate it thrombus and aspirate it
The device was being evaluated in randomized The device was being evaluated in randomized studies of coronary vessels and in a registry of studies of coronary vessels and in a registry of patients with acute myocardial infarctionpatients with acute myocardial infarction
Although the manufacturer had modified the Although the manufacturer had modified the device for use in cerebral vessels a safety and device for use in cerebral vessels a safety and feasibility study was indefinitely suspended after feasibility study was indefinitely suspended after only 1 patient was treated with the device in only 1 patient was treated with the device in Europe Europe
Suction thrombectomySuction thrombectomy This method of mechanical thrombolysis is one of the This method of mechanical thrombolysis is one of the
simplestsimplest In this readily available technique suction is applied with In this readily available technique suction is applied with
a syringe to remove thrombus in the ICA a syringe to remove thrombus in the ICA It requires no other devicesIt requires no other devices A catheter with a large inner diameter (Brite Tip Cordis A catheter with a large inner diameter (Brite Tip Cordis
Corporation Miami FL) was placed in the symptomatic Corporation Miami FL) was placed in the symptomatic vessel and navigated over a guidewire into the thrombusvessel and navigated over a guidewire into the thrombus
A 60-mL syringe was used to aspirate the thrombus A 60-mL syringe was used to aspirate the thrombus Each patient required angioplasty and stenting of carotid Each patient required angioplasty and stenting of carotid
bifurcation stenosis and received daily aspirin and bifurcation stenosis and received daily aspirin and ticlopidine after the procedure No complications ticlopidine after the procedure No complications occurred occurred
Summary Acute Stroke Summary Acute Stroke ImagingImaging
PhysiologyPhysiology importance collaterals importance collaterals
ndash ndashGrowing role for perfusion Growing role for perfusion assessmentassessment
tPAtPA guidelines amp limitations guidelines amp limitations Signs on CT amp MRSigns on CT amp MR follow physiology follow physiology Stroke trialsStroke trials PWI-DWI mismatch PWI-DWI mismatch
ndash ndashTreat based on physiology not timeTreat based on physiology not time ProtocolsProtocols should be fast and should be fast and
comprehensivecomprehensive
Infarct evaluation on angiographyInfarct evaluation on angiography(CT angiography and catheter (CT angiography and catheter
angiography)angiography)CTA is an excellent first-line examination for CTA is an excellent first-line examination for
evaluation of the head and neck arteries evaluation of the head and neck arteries In comparison with catheter angiography In comparison with catheter angiography
what it gives up in resolution and dynamic what it gives up in resolution and dynamic properties it makes up for with rapid properties it makes up for with rapid acquisition of a 3-D dataset and the potential acquisition of a 3-D dataset and the potential for assessment of whole-brain perfusion and for assessment of whole-brain perfusion and better parenchymal evaluationbetter parenchymal evaluation
Moreover CTA illustrates not only arterial Moreover CTA illustrates not only arterial stenosis or occlusion but also the vessel wall stenosis or occlusion but also the vessel wall This factor is most important for evaluation of This factor is most important for evaluation of intramural dissection and thrombosed intramural dissection and thrombosed aneurysms which may both complicate aneurysms which may both complicate evaluation of stroke patientsevaluation of stroke patients
Early angiographic signs of strokes Early angiographic signs of strokes both CTA both CTA and DSA and DSA
Vessel occlusion or cutoff related to Vessel occlusion or cutoff related to thromboembolithromboemboli
aneurysms aneurysms arterial dissection arterial dissection Meniscus or flattened shape to clot Meniscus or flattened shape to clot
(recent) versus reverse meniscus (older)(recent) versus reverse meniscus (older) tram track (nonocclusive or recanalized tram track (nonocclusive or recanalized
clot) clot) delayed (antegrade) flow (manifest as delayed (antegrade) flow (manifest as
decreased whole-brain perfusion on CTA)decreased whole-brain perfusion on CTA) retrograde collateral flowretrograde collateral flow
Non-occlusive left MCA thrombus on 3-D imaging performed from CTA source data and was confirmed at catheter angiography
Therapy to be started within a 6-hr Therapy to be started within a 6-hr time to treatment (TTT) window time to treatment (TTT) window (while in case of IV thrombolysis (while in case of IV thrombolysis therapy to be started with in 3hrs)therapy to be started with in 3hrs)
Exclusion criteria Exclusion criteria Rapidly improving neurologic deficit or Rapidly improving neurologic deficit or Sustained blood pressure of gt180100 Sustained blood pressure of gt180100 Hemorrhage is detected on CTHemorrhage is detected on CT Infarct involving gt more than 13 rd Infarct involving gt more than 13 rd
territory of MCAterritory of MCA MRADWI-Perfusion mismatchlt 20MRADWI-Perfusion mismatchlt 20 Definite hypodensity on CTDefinite hypodensity on CT
Intra-arterial Thrombolysis
Fibrinolytics + AntiplateletsFibrinolytics + Antiplatelets
PlasminogenPlasminogen activators through fibrinolysis exposes activators through fibrinolysis exposes free thrombin and paradoxically stimulatesfree thrombin and paradoxically stimulates platelet platelet aggregation which leads to formation of aaggregation which leads to formation of a platelet platelet thrombus (white clot) thrombus (white clot)
This new thrombus is relatively resistant to This new thrombus is relatively resistant to fibrinolyticsfibrinolytics
So new regimen in case of acute stroke isSo new regimen in case of acute stroke is fibrinolytics + antiplatelet drugsfibrinolytics + antiplatelet drugs
rtPA + IIbIIIa inhibitors( tirofiban rtPA + IIbIIIa inhibitors( tirofiban abciximab) orabciximab) or
Urokinase + IIbIIIa Urokinase + IIbIIIa inhibitors( tirofiban abciximab)inhibitors( tirofiban abciximab)
Intra-arterial Thrombolysis Tirofiban (04 microgkgmin bolus for 3 min followed by Tirofiban (04 microgkgmin bolus for 3 min followed by
0125 ugkgmin)0125 ugkgmin)
++
Heparin (2000ndash3000 IU bolus followed by Heparin (2000ndash3000 IU bolus followed by 1000 IUhour infusion 1000 IUhour infusion
with ACT maintained bw 200-300) throughout the with ACT maintained bw 200-300) throughout the interventional procedure and for 24ndash48 hours thereafter when interventional procedure and for 24ndash48 hours thereafter when there is neither intraprocedural bleeding nor suspicion of there is neither intraprocedural bleeding nor suspicion of increased risk of bleeding increased risk of bleeding
Maximum dose of Urokinase Maximum dose of Urokinase Anterior circulation stroke - 500000 IU (mean 400000 Anterior circulation stroke - 500000 IU (mean 400000
IU range 300000ndash500000 IU)IU range 300000ndash500000 IU) Posterior circulation stroke -1000000 IU (mean 837000 Posterior circulation stroke -1000000 IU (mean 837000
IU range 300000ndash1000000 IU)IU range 300000ndash1000000 IU)American Journal of NeuroradiologyAmerican Journal of Neuroradiology 262595-2601 2005262595-2601 2005
Intravenous ThrombolysisIntravenous Thrombolysis
The first method to restore cerebral The first method to restore cerebral perfusion is clot lysis with the goal perfusion is clot lysis with the goal of re-establishing blood flow to the of re-establishing blood flow to the affected tissue affected tissue
IV thrombolysis rt-PA is the only IV thrombolysis rt-PA is the only FDA- approved treatment for AIS FDA- approved treatment for AIS
Fibrinolysis is enhanced powerfully Fibrinolysis is enhanced powerfully by rt-PAby rt-PA
Intravenous rTPA Intravenous rTPA administration administration protocolprotocol
Total dose of rt-PA 09 mgkg (maximum dose Total dose of rt-PA 09 mgkg (maximum dose 90 mg)90 mg)
Give 10 as initial IV bolusGive 10 as initial IV bolus Infuse remainder over 1 hourInfuse remainder over 1 hour Admit patient to an ICU or stroke unit for Admit patient to an ICU or stroke unit for
monitoringmonitoring Neurologic assessments every 15 minutes Neurologic assessments every 15 minutes
during infusion then every 30 minutes for next during infusion then every 30 minutes for next 6 hours then every hour until 24hours after 6 hours then every hour until 24hours after treatmenttreatment
Favorable Outcome vs Treatment Time Favorable Outcome vs Treatment Time with IV rTPAwith IV rTPA
Protocol limit = 3 hrs
Benefit ~ 45 hrs
Thromboembolism During coilingThromboembolism During coiling Most feared and frequent complication Most feared and frequent complication Reported incidence - Approx 7 Reported incidence - Approx 7 SourcesSources of Thromboembolism are of Thromboembolism are
- Clots at the aneurysmal neck during or immediately- Clots at the aneurysmal neck during or immediately after after embolization embolization
- Thrombus forming on catheters during- Thrombus forming on catheters during proceduresprocedures
- Stenosis of an adjacent artery dt coil mass- Stenosis of an adjacent artery dt coil mass or herniationor herniation
- Migration of intraaneurysmal- Migration of intraaneurysmal thrombus during coil thrombus during coil placement placement
- Slow flow dt vasospasm - Slow flow dt vasospasm
- Rare and unlikely causes are hypercoagulable- Rare and unlikely causes are hypercoagulable state such state such as antiphospholipid antibody syndrome or due to HITas antiphospholipid antibody syndrome or due to HIT
Occur more often with wide-necked aneurysms (dt Occur more often with wide-necked aneurysms (dt increased exposed surface area of thrombogenic coil increased exposed surface area of thrombogenic coil material)material)
Current regimen of endovascular Current regimen of endovascular managementmanagement
The The glycoprotein IIbIIIa antagonist tirofiban glycoprotein IIbIIIa antagonist tirofiban (04 (04 microgkgmin bolus for 30 minutes followed by infusion of microgkgmin bolus for 30 minutes followed by infusion of 0125 ugkgmin until the thrombus dissolved) 0125 ugkgmin until the thrombus dissolved)
Intraarterial thrombolysis with Intraarterial thrombolysis with urokinase or r- TPA urokinase or r- TPA increase of intravenous (IV) heparin (measured by increase of intravenous (IV) heparin (measured by
ACT) ACT) Intravenous aspirin Intravenous aspirin
Coil-related platelet aggregation (white clot) is Coil-related platelet aggregation (white clot) is unlikely to respond to fibrinolytics but has a high risk unlikely to respond to fibrinolytics but has a high risk of hemorrhage (In ISAT) all 5 patients who had of hemorrhage (In ISAT) all 5 patients who had received thrombolytic therapy with tPA to treat a received thrombolytic therapy with tPA to treat a thromboembolic complication after endovascular thromboembolic complication after endovascular treatment rebleed and all of these patients died)treatment rebleed and all of these patients died)
IntracranialIntracranial Stenting Stenting Metallic foreign body such as stent will accumulate Metallic foreign body such as stent will accumulate
thrombus in the absence of platelet inhibitionthrombus in the absence of platelet inhibition Antiplatelet drugs are important to prevent peri or Antiplatelet drugs are important to prevent peri or
post-interventional thromboembolic eventspost-interventional thromboembolic events Optimal treatment regimens has not been determined Optimal treatment regimens has not been determined
but usually but usually Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-
procedureprocedureOrOr
Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on
morning of proceduremorning of procedure
If need to use stent is not pre-planned thanIf need to use stent is not pre-planned than
Abciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkgAbciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkg IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)
Glycoprotein IIbIIIa inhibitor are not used routinely during elective Glycoprotein IIbIIIa inhibitor are not used routinely during elective stenting procedure dt increased risk of ICH stenting procedure dt increased risk of ICH
Carotid StentingCarotid Stenting
Pre-procedurePre-procedure
Double Antiplatelet therapy is routinely given Double Antiplatelet therapy is routinely given beginning at least 3beginning at least 3
days before the proceduredays before the procedure
Aspirin 325mgd+Clopidogrel 75mgdAspirin 325mgd+Clopidogrel 75mgd During procedureDuring procedure
Heparin is given with target clotting time of 250-Heparin is given with target clotting time of 250-300sec300sec
Post-procedure Post-procedure
Aspirin 325mg is continued indefinitely and Aspirin 325mg is continued indefinitely and
Clopidogrel 75mgd for at least 6 weeks Clopidogrel 75mgd for at least 6 weeks
Inclusion criteria for Local ThrombolysisInclusion criteria for Local Thrombolysis a)a) Patients in severe clinical grade on admission Patients in severe clinical grade on admission
with evidence of dural venous sinus with evidence of dural venous sinus thrombosis and restrictive venous outflow on thrombosis and restrictive venous outflow on cerebral angiogramcerebral angiogram
b)b) Patients in clinical grade 3 worsening on Patients in clinical grade 3 worsening on heparin therapy Restriction to venous heparin therapy Restriction to venous outflow was defined as an increase in brain outflow was defined as an increase in brain circulation time gt 12 s delay in the drainage circulation time gt 12 s delay in the drainage of cortical veins with cortical veins hanging of cortical veins with cortical veins hanging in spacein space
Treatment Options for Venous Thrombosis
CT Grading for Venous ThrombosisCT Grading for Venous Thrombosis Grade I no parenchymal change Grade I no parenchymal change
(hyperdense (hyperdense sinuses cortical veins empty sinuses cortical veins empty delta sign)delta sign)
Grade II non hemorrhagic venous infarct Grade II non hemorrhagic venous infarct without mass effect without mass effect
Grade III non-hemorrhagic infarct with Grade III non-hemorrhagic infarct with mass effectmass effect
Grade IV hemorrhagic venous infarct (max Grade IV hemorrhagic venous infarct (max diameter lt 3 cm) with no mass effectdiameter lt 3 cm) with no mass effect
Grade V hemorrhagic venous infarct (max Grade V hemorrhagic venous infarct (max diameter gt 3 cm) with mass effect diameter gt 3 cm) with mass effect
Local ThrombolysisLocal Thrombolysis
Femoral Jugular access was secured and a guiding Femoral Jugular access was secured and a guiding catheter was placed in the jugular bulb catheter was placed in the jugular bulb Mechanical Mechanical clot maceration clot maceration was done with the guidewire was done with the guidewire following which a microcatheter (was navigated and following which a microcatheter (was navigated and placed in the thrombosed segment of sinus confirmed placed in the thrombosed segment of sinus confirmed on a selective venogram on a selective venogram
Urokinase infusion Bolus dose of 2-6 lacs followed Urokinase infusion Bolus dose of 2-6 lacs followed by 60000 to 100000 units per hour along with by 60000 to 100000 units per hour along with periodic check venogram Along with maintenance periodic check venogram Along with maintenance systemic infusion of Heparinsystemic infusion of Heparin Other agents such as Other agents such as streptokinase altepase or rTPAstreptokinase altepase or rTPA can be also used can be also used
After thrombolysis patient should subjected to oral After thrombolysis patient should subjected to oral anticoagulation for six monthsanticoagulation for six months
Low-molecular-weight Low-molecular-weight heparinheparin
PharmacologyPharmacologyLMWH as its name suggests is a glycosaminoglycan that is approximatelyLMWH as its name suggests is a glycosaminoglycan that is approximately
one third the molecular weight of UFH It is derived from UFH through one third the molecular weight of UFH It is derived from UFH through variousvarious
depolymerization processes LMWH binds to antithrombin which in turn depolymerization processes LMWH binds to antithrombin which in turn
Neutralizes actors Xa and IIa Because LMWH lacks many of the longer Neutralizes actors Xa and IIa Because LMWH lacks many of the longer chains chains
required for binding to thrombin it has less ability to neutralize thrombin required for binding to thrombin it has less ability to neutralize thrombin
relativeto its ability to neutralize factor Xa LMWH also has less relativeto its ability to neutralize factor Xa LMWH also has less nonspecific nonspecific
binding to other proteins There is greater bioavailability with more binding to other proteins There is greater bioavailability with more predictable predictable
pharmacokinetics that eliminates the need for monitoring The smaller pharmacokinetics that eliminates the need for monitoring The smaller size also size also
allows for enhanced subcutaneous absorption when compared with UFHallows for enhanced subcutaneous absorption when compared with UFH
Three LMWH preparations are Three LMWH preparations are currently approved for use in the currently approved for use in the United States (1) enoxaparin (2) United States (1) enoxaparin (2) dalteparin and (3) tinzaparin dalteparin and (3) tinzaparin
They are all administered They are all administered subcutaneously at intervals of either subcutaneously at intervals of either once or twice daily for both once or twice daily for both prophylaxis and treatment dosesprophylaxis and treatment doses
Few Experiences of Few Experiences of ThrombolysisThrombolysis
Vickey 25 Yrs male patient presented Vickey 25 Yrs male patient presented with 12with 12thth day HO severe headache with day HO severe headache with right sided hemiplegiaright sided hemiplegia
MRI shows thrombosis of the superior MRI shows thrombosis of the superior sagittal left transverse left sigmoid sagittal left transverse left sigmoid sinuses and cortical veins in the fronto-sinuses and cortical veins in the fronto-parietal regions with eo haemorrhagic parietal regions with eo haemorrhagic infarct in the left cerebral hemisphere infarct in the left cerebral hemisphere with mass effect( Grade ndashV)with mass effect( Grade ndashV)
Sashi Srivastava 64 yrs FSashi Srivastava 64 yrs F In a follow up case of MRD with infra-renal In a follow up case of MRD with infra-renal
aortic abdominal and bilateral renal artery aortic abdominal and bilateral renal artery thrombosis renal angiogram shows filling thrombosis renal angiogram shows filling defects in the right Renal artery defects in the right Renal artery
Initially Renal angioplasty was done Initially Renal angioplasty was done Following angioplasty few thrombi are seem Following angioplasty few thrombi are seem to extends into the segmental branches and to extends into the segmental branches and causing blockage So Thrombolysis was causing blockage So Thrombolysis was plane to dissolve the run-out thrombi with plane to dissolve the run-out thrombi with urokinase urokinase
Rakesh 34yrsMRakesh 34yrsM Left SFA pseudoaneurysm with Left SFA pseudoaneurysm with
Covered stent placementCovered stent placement Pre operative antiplatelets with post Pre operative antiplatelets with post
procedure heparin Tirofiban procedure heparin Tirofiban followed by aspirin and clopidogrel followed by aspirin and clopidogrel were usedwere used
IAT may be a treatment option for selected patients IAT may be a treatment option for selected patients Possible selection criteria include Possible selection criteria include
presentation between 3 and 6 hours from symptom onsetpresentation between 3 and 6 hours from symptom onset major cerebral artery occlusion major cerebral artery occlusion severe neurologic deficits severe neurologic deficits high risk of systemic hemorrhage with IV rt-PA (eg recent high risk of systemic hemorrhage with IV rt-PA (eg recent
surgery) surgery) The MERCI (Mechanical Embolus Removal in Cerebral The MERCI (Mechanical Embolus Removal in Cerebral
Ischemia) retrievalIschemia) retrieval system system
Has been FDA-approved for recanalizing acutely occluded Has been FDA-approved for recanalizing acutely occluded cerebral arteries cerebral arteries
In the Multi-MERCI study patients who did not improve In the Multi-MERCI study patients who did not improve immediately after IV rt-PA underwent mechanical immediately after IV rt-PA underwent mechanical embolectomy within 8 hours of symptom onset embolectomy within 8 hours of symptom onset
Partial or complete recanalization occurred in 74 of Partial or complete recanalization occurred in 74 of patientspatients
with a symptomatic intracerebral hemorrhage (sICH) rate of with a symptomatic intracerebral hemorrhage (sICH) rate of 67 67
Mechanical embolectomy with the MERCI retriever may be a Mechanical embolectomy with the MERCI retriever may be a feasible and safe option for patients after IV rt-PAfeasible and safe option for patients after IV rt-PA
Penumbra stroke systemPenumbra stroke system This device combines two methods of clot This device combines two methods of clot
extraction aspiration and mechanical extraction aspiration and mechanical extraction extraction
First the clot is aspirated then a thrombus First the clot is aspirated then a thrombus removal ring can be used if necessary to removal ring can be used if necessary to remove remaining clot remove remaining clot
successful recanalizing 82successful recanalizing 82 Bridging therapyBridging therapy
06 mgkg IV rt-PA followed by IAT with IA rt-06 mgkg IV rt-PA followed by IAT with IA rt-PA (up to 20 mg)PA (up to 20 mg)
achieved a higher recanalization rateachieved a higher recanalization rate
Criteria for thrombolysis with rTPACriteria for thrombolysis with rTPA
Inclusion criteriaInclusion criteria Clinical signs and symptoms consistent with ischemic Clinical signs and symptoms consistent with ischemic
strokestroke Patient last seen normal within 3 hoursPatient last seen normal within 3 hours Measurable neurologic deficitMeasurable neurologic deficit
Exclusion criteriaExclusion criteria Any hemorrhage on neuroimaging (CT or MRI)Any hemorrhage on neuroimaging (CT or MRI) Symptoms suggestive of subarachnoid hemorrhageSymptoms suggestive of subarachnoid hemorrhage Seizure at stroke onset that is thought to contribute to Seizure at stroke onset that is thought to contribute to
neurologic deficitneurologic deficit Hypodensity greater than one third cerebral hemisphere Hypodensity greater than one third cerebral hemisphere
on CTon CT SBP greater than 185 mm Hg or DBP greater than 110 SBP greater than 185 mm Hg or DBP greater than 110
mm Hgmm Hg International normalized ratio (INR) greater than 17International normalized ratio (INR) greater than 17
Ischemic Stroke Ischemic Stroke Treatment ndash 2006Treatment ndash 2006
IV tissue plasminogen activator (tPA)IV tissue plasminogen activator (tPA) ndash ndash Only FDA-approved acute stroke drugOnly FDA-approved acute stroke drug ndash ndash 3 hour treatment window3 hour treatment window
MERCI - Concentric clot retrieval MERCI - Concentric clot retrieval devicedevice ndash ndash Rescue therapy - approved 2004Rescue therapy - approved 2004 ndash ndash Device approval (not outcomes-based)Device approval (not outcomes-based)
Off label approachesOff label approaches ndash ndash IV tPA after 3 hoursIV tPA after 3 hours ndash ndash IV-IA tPA sequential strategiesIV-IA tPA sequential strategies ndash ndash IA tPA clot angioplasty fragmentationIA tPA clot angioplasty fragmentation ndash ndash Ultrasound-assisted tPA lysisUltrasound-assisted tPA lysis
rt-PA Trials NINDSrt-PA Trials NINDS
Acute stroke - 624 patientsAcute stroke - 624 patients Treat within 3 hrsTreat within 3 hrs Intravenous 09 mgkg rt-PA vs placeboIntravenous 09 mgkg rt-PA vs placebo Hemorrhage 64 tPA 06 placeboHemorrhage 64 tPA 06 placebo Neurologic recovery better with tPA 30 Neurologic recovery better with tPA 30
more like to have minimal or no disabilitymore like to have minimal or no disability
First proven approved treatment for First proven approved treatment for strokestroke
Limitations of tPALimitations of tPA Only 4 of acute strokes receive tPAOnly 4 of acute strokes receive tPA (Kleindorfer et al Stroke 2004 35 e27-e29)(Kleindorfer et al Stroke 2004 35 e27-e29)
Only 22 of patients present within 3 hoursOnly 22 of patients present within 3 hours1048707 1048707 51 of these ineligible due to51 of these ineligible due to
bull bull Mild severityMild severity bull bull Medical or surgical historyMedical or surgical history bull bull Blood testsBlood tests
Sustained recanalization only 13Sustained recanalization only 13 (Alexandrov et al NEJM 2004 351 2170-8)(Alexandrov et al NEJM 2004 351 2170-8)
Concern for hemorrhageConcern for hemorrhage tPA potentiates apoptotic injury tPA potentiates apoptotic injury (Liu et al Nature Med 2004 101379-83)(Liu et al Nature Med 2004 101379-83)
PROACT II IA Lysis TrialPROACT II IA Lysis Trial Baseline 24 hours 8 days
Baseline 60 minutes 120 minutes
9mg IAProurokinase
Desmoteplase Trials DEDAS Desmoteplase Trials DEDAS DIASDIAS
Trial OverviewTrial Overview Double blind randomized placebo Double blind randomized placebo
controlled trialscontrolled trials IV delivery 3-9 hour time windowIV delivery 3-9 hour time window Plasminogen activator ndash from Plasminogen activator ndash from vampire bat vampire bat
salivasaliva Selection based on PWI-DWI MismatchSelection based on PWI-DWI Mismatch
MRI InclusionMRI Inclusion PWI defect at least 2 cm AND ~20 larger PWI defect at least 2 cm AND ~20 larger
than DWIthan DWI PWI should be obvious even visible on PWI should be obvious even visible on
raw imagesraw imagesMRI ExclusionMRI Exclusion
DWI gt 13 MCADWI gt 13 MCA MRA ICA occlusionMRA ICA occlusion
Desmoteplase ndash DIAS Desmoteplase ndash DIAS ResultsResults
Mechanical Thrombolysis Mechanical Thrombolysis devicesdevices
mechanical thrombolysis potentially extends the treatment mechanical thrombolysis potentially extends the treatment window because they act promptly at the site of the thrombuswindow because they act promptly at the site of the thrombus
The devices can retrieve large clots that pharmaceutical agents The devices can retrieve large clots that pharmaceutical agents may not successfully lysemay not successfully lyse
Patients treated with IV tPA may be considered for treatment of Patients treated with IV tPA may be considered for treatment of residual clot with some of these devicesresidual clot with some of these devices
suction-creating saline jets suction-creating saline jets laser energy ultrasound laser energy ultrasound a corkscrew apparatus to treat strokesa corkscrew apparatus to treat strokes The AngioJet systemThe AngioJet system uses saline jets that are directed back into the catheter to uses saline jets that are directed back into the catheter to
create a low-pressure zone around the catheter tip inducing create a low-pressure zone around the catheter tip inducing suction suction
The clot is pulled into the exhaust lumen and removed from the The clot is pulled into the exhaust lumen and removed from the vessel Although US Food and Drug Administration (FDA) has vessel Although US Food and Drug Administration (FDA) has approved this device for use in arteriovenous dialysis grafts and approved this device for use in arteriovenous dialysis grafts and fistulae and for the treatment of coronary arteries saphenous fistulae and for the treatment of coronary arteries saphenous vein grafts and peripheral vessels clinical trials for the vein grafts and peripheral vessels clinical trials for the treatment of acute stroke are no longer in progress treatment of acute stroke are no longer in progress
Most devices are used in cerebral vessels that 2-5 mm
The Latis laser device The Latis laser device used laser energy to ablate clots used laser energy to ablate clots Arteries 2-5 mm in diameter could be Arteries 2-5 mm in diameter could be
treated including the ICA M1 or M2 treated including the ICA M1 or M2 branch of the MCA A1 branch of the branch of the MCA A1 branch of the anterior cerebral artery (ACA) basilar anterior cerebral artery (ACA) basilar artery posterior cerebral artery (PCA) artery posterior cerebral artery (PCA) and vertebral and vertebral
Patients could receive treatment as late Patients could receive treatment as late as 8 hours after symptom onset in the as 8 hours after symptom onset in the anterior circulation and within 24 hours in anterior circulation and within 24 hours in the posterior circulation the posterior circulation
Endovascular Photo Acoustic Endovascular Photo Acoustic Recanalization (EPAR) Recanalization (EPAR)
A laser power source generated energy for the A laser power source generated energy for the systemsystem
The energy was delivered by means of The energy was delivered by means of fiberoptics to the tip of the catheter at the fiberoptics to the tip of the catheter at the treatment sitetreatment site
Absorption of laser light by darkly pigmented Absorption of laser light by darkly pigmented materials (ie the clot) occurred inside the 1-mm materials (ie the clot) occurred inside the 1-mm catheter tipcatheter tip
the system was designed to minimize scattering the system was designed to minimize scattering of laser light of laser light
Absorption converted photo energy to acoustic Absorption converted photo energy to acoustic energy which then emulsified the clot inside the energy which then emulsified the clot inside the catheter tip catheter tip
EKOS ultrasound( the EKOS ultrasound( the Ultrasound Thrombolytic Ultrasound Thrombolytic
Infusion Catheter) Infusion Catheter) combines the use of a distal ultrasound transducer with combines the use of a distal ultrasound transducer with
infusion of a thrombolytic agent through the infusion of a thrombolytic agent through the microcathetermicrocatheter
Ultrasound changes the structure of the clot to Ultrasound changes the structure of the clot to temporarily increase its permeability while providing an temporarily increase its permeability while providing an acoustic pressure gradient to move the drug into the clot acoustic pressure gradient to move the drug into the clot to speed its dissolution to speed its dissolution
The EKOS catheter is placed in the proximal portion of the The EKOS catheter is placed in the proximal portion of the clot clot
After a 2-mg bolus of tPA was injected through the After a 2-mg bolus of tPA was injected through the catheter catheter
the patient received a continuous infusion of IA tPA 03 the patient received a continuous infusion of IA tPA 03 mgmin to a maximum of 20 mg and simultaneous mgmin to a maximum of 20 mg and simultaneous ultrasound transmission for as long as 60 minutes ultrasound transmission for as long as 60 minutes
One patient was treated with a total of 4 units of One patient was treated with a total of 4 units of recombinant reteplase (Retavase) hand-injected over 60 recombinant reteplase (Retavase) hand-injected over 60 minutes minutes
Penumbra system Penumbra system The Penumbra system (Penumbra Inc) provides a dual The Penumbra system (Penumbra Inc) provides a dual
approach to clot extraction using aspiration followed by approach to clot extraction using aspiration followed by clot retrieval with a ring device if needed clot retrieval with a ring device if needed
Mechanical Embolus Removal in Cerebral Ischemia Mechanical Embolus Removal in Cerebral Ischemia (MERCI)(MERCI)
a corkscrew-like apparatus to remove blood clots from a corkscrew-like apparatus to remove blood clots from the brain in patients experiencing an ischemic stroke the brain in patients experiencing an ischemic stroke
The corkscrew itself resides in the catheter tip which The corkscrew itself resides in the catheter tip which shields it from the wall of the vessel until it is ready to be shields it from the wall of the vessel until it is ready to be burrowed into the clot Once lodged in the clot the device burrowed into the clot Once lodged in the clot the device and clot are withdrawn from the vessel and clot are withdrawn from the vessel
Snarelike devicesSnarelike devices Snares such as the Neuronet snare (Guidant Snares such as the Neuronet snare (Guidant
Endovascular Santa Clara CA) have been developed Endovascular Santa Clara CA) have been developed specifically for use in the treatment of strokes specifically for use in the treatment of strokes
These devices are simple in design and do not require the These devices are simple in design and do not require the clot to be amenable to emulsification clot to be amenable to emulsification
X-Sizer deviceX-Sizer device a device with small moving blades at the a device with small moving blades at the
catheter tip catheter tip This device the X-Sizer device (EndiCor Medical This device the X-Sizer device (EndiCor Medical
San Clemente CA) can be used to excise the San Clemente CA) can be used to excise the thrombus and aspirate it thrombus and aspirate it
The device was being evaluated in randomized The device was being evaluated in randomized studies of coronary vessels and in a registry of studies of coronary vessels and in a registry of patients with acute myocardial infarctionpatients with acute myocardial infarction
Although the manufacturer had modified the Although the manufacturer had modified the device for use in cerebral vessels a safety and device for use in cerebral vessels a safety and feasibility study was indefinitely suspended after feasibility study was indefinitely suspended after only 1 patient was treated with the device in only 1 patient was treated with the device in Europe Europe
Suction thrombectomySuction thrombectomy This method of mechanical thrombolysis is one of the This method of mechanical thrombolysis is one of the
simplestsimplest In this readily available technique suction is applied with In this readily available technique suction is applied with
a syringe to remove thrombus in the ICA a syringe to remove thrombus in the ICA It requires no other devicesIt requires no other devices A catheter with a large inner diameter (Brite Tip Cordis A catheter with a large inner diameter (Brite Tip Cordis
Corporation Miami FL) was placed in the symptomatic Corporation Miami FL) was placed in the symptomatic vessel and navigated over a guidewire into the thrombusvessel and navigated over a guidewire into the thrombus
A 60-mL syringe was used to aspirate the thrombus A 60-mL syringe was used to aspirate the thrombus Each patient required angioplasty and stenting of carotid Each patient required angioplasty and stenting of carotid
bifurcation stenosis and received daily aspirin and bifurcation stenosis and received daily aspirin and ticlopidine after the procedure No complications ticlopidine after the procedure No complications occurred occurred
Summary Acute Stroke Summary Acute Stroke ImagingImaging
PhysiologyPhysiology importance collaterals importance collaterals
ndash ndashGrowing role for perfusion Growing role for perfusion assessmentassessment
tPAtPA guidelines amp limitations guidelines amp limitations Signs on CT amp MRSigns on CT amp MR follow physiology follow physiology Stroke trialsStroke trials PWI-DWI mismatch PWI-DWI mismatch
ndash ndashTreat based on physiology not timeTreat based on physiology not time ProtocolsProtocols should be fast and should be fast and
comprehensivecomprehensive
Early angiographic signs of strokes Early angiographic signs of strokes both CTA both CTA and DSA and DSA
Vessel occlusion or cutoff related to Vessel occlusion or cutoff related to thromboembolithromboemboli
aneurysms aneurysms arterial dissection arterial dissection Meniscus or flattened shape to clot Meniscus or flattened shape to clot
(recent) versus reverse meniscus (older)(recent) versus reverse meniscus (older) tram track (nonocclusive or recanalized tram track (nonocclusive or recanalized
clot) clot) delayed (antegrade) flow (manifest as delayed (antegrade) flow (manifest as
decreased whole-brain perfusion on CTA)decreased whole-brain perfusion on CTA) retrograde collateral flowretrograde collateral flow
Non-occlusive left MCA thrombus on 3-D imaging performed from CTA source data and was confirmed at catheter angiography
Therapy to be started within a 6-hr Therapy to be started within a 6-hr time to treatment (TTT) window time to treatment (TTT) window (while in case of IV thrombolysis (while in case of IV thrombolysis therapy to be started with in 3hrs)therapy to be started with in 3hrs)
Exclusion criteria Exclusion criteria Rapidly improving neurologic deficit or Rapidly improving neurologic deficit or Sustained blood pressure of gt180100 Sustained blood pressure of gt180100 Hemorrhage is detected on CTHemorrhage is detected on CT Infarct involving gt more than 13 rd Infarct involving gt more than 13 rd
territory of MCAterritory of MCA MRADWI-Perfusion mismatchlt 20MRADWI-Perfusion mismatchlt 20 Definite hypodensity on CTDefinite hypodensity on CT
Intra-arterial Thrombolysis
Fibrinolytics + AntiplateletsFibrinolytics + Antiplatelets
PlasminogenPlasminogen activators through fibrinolysis exposes activators through fibrinolysis exposes free thrombin and paradoxically stimulatesfree thrombin and paradoxically stimulates platelet platelet aggregation which leads to formation of aaggregation which leads to formation of a platelet platelet thrombus (white clot) thrombus (white clot)
This new thrombus is relatively resistant to This new thrombus is relatively resistant to fibrinolyticsfibrinolytics
So new regimen in case of acute stroke isSo new regimen in case of acute stroke is fibrinolytics + antiplatelet drugsfibrinolytics + antiplatelet drugs
rtPA + IIbIIIa inhibitors( tirofiban rtPA + IIbIIIa inhibitors( tirofiban abciximab) orabciximab) or
Urokinase + IIbIIIa Urokinase + IIbIIIa inhibitors( tirofiban abciximab)inhibitors( tirofiban abciximab)
Intra-arterial Thrombolysis Tirofiban (04 microgkgmin bolus for 3 min followed by Tirofiban (04 microgkgmin bolus for 3 min followed by
0125 ugkgmin)0125 ugkgmin)
++
Heparin (2000ndash3000 IU bolus followed by Heparin (2000ndash3000 IU bolus followed by 1000 IUhour infusion 1000 IUhour infusion
with ACT maintained bw 200-300) throughout the with ACT maintained bw 200-300) throughout the interventional procedure and for 24ndash48 hours thereafter when interventional procedure and for 24ndash48 hours thereafter when there is neither intraprocedural bleeding nor suspicion of there is neither intraprocedural bleeding nor suspicion of increased risk of bleeding increased risk of bleeding
Maximum dose of Urokinase Maximum dose of Urokinase Anterior circulation stroke - 500000 IU (mean 400000 Anterior circulation stroke - 500000 IU (mean 400000
IU range 300000ndash500000 IU)IU range 300000ndash500000 IU) Posterior circulation stroke -1000000 IU (mean 837000 Posterior circulation stroke -1000000 IU (mean 837000
IU range 300000ndash1000000 IU)IU range 300000ndash1000000 IU)American Journal of NeuroradiologyAmerican Journal of Neuroradiology 262595-2601 2005262595-2601 2005
Intravenous ThrombolysisIntravenous Thrombolysis
The first method to restore cerebral The first method to restore cerebral perfusion is clot lysis with the goal perfusion is clot lysis with the goal of re-establishing blood flow to the of re-establishing blood flow to the affected tissue affected tissue
IV thrombolysis rt-PA is the only IV thrombolysis rt-PA is the only FDA- approved treatment for AIS FDA- approved treatment for AIS
Fibrinolysis is enhanced powerfully Fibrinolysis is enhanced powerfully by rt-PAby rt-PA
Intravenous rTPA Intravenous rTPA administration administration protocolprotocol
Total dose of rt-PA 09 mgkg (maximum dose Total dose of rt-PA 09 mgkg (maximum dose 90 mg)90 mg)
Give 10 as initial IV bolusGive 10 as initial IV bolus Infuse remainder over 1 hourInfuse remainder over 1 hour Admit patient to an ICU or stroke unit for Admit patient to an ICU or stroke unit for
monitoringmonitoring Neurologic assessments every 15 minutes Neurologic assessments every 15 minutes
during infusion then every 30 minutes for next during infusion then every 30 minutes for next 6 hours then every hour until 24hours after 6 hours then every hour until 24hours after treatmenttreatment
Favorable Outcome vs Treatment Time Favorable Outcome vs Treatment Time with IV rTPAwith IV rTPA
Protocol limit = 3 hrs
Benefit ~ 45 hrs
Thromboembolism During coilingThromboembolism During coiling Most feared and frequent complication Most feared and frequent complication Reported incidence - Approx 7 Reported incidence - Approx 7 SourcesSources of Thromboembolism are of Thromboembolism are
- Clots at the aneurysmal neck during or immediately- Clots at the aneurysmal neck during or immediately after after embolization embolization
- Thrombus forming on catheters during- Thrombus forming on catheters during proceduresprocedures
- Stenosis of an adjacent artery dt coil mass- Stenosis of an adjacent artery dt coil mass or herniationor herniation
- Migration of intraaneurysmal- Migration of intraaneurysmal thrombus during coil thrombus during coil placement placement
- Slow flow dt vasospasm - Slow flow dt vasospasm
- Rare and unlikely causes are hypercoagulable- Rare and unlikely causes are hypercoagulable state such state such as antiphospholipid antibody syndrome or due to HITas antiphospholipid antibody syndrome or due to HIT
Occur more often with wide-necked aneurysms (dt Occur more often with wide-necked aneurysms (dt increased exposed surface area of thrombogenic coil increased exposed surface area of thrombogenic coil material)material)
Current regimen of endovascular Current regimen of endovascular managementmanagement
The The glycoprotein IIbIIIa antagonist tirofiban glycoprotein IIbIIIa antagonist tirofiban (04 (04 microgkgmin bolus for 30 minutes followed by infusion of microgkgmin bolus for 30 minutes followed by infusion of 0125 ugkgmin until the thrombus dissolved) 0125 ugkgmin until the thrombus dissolved)
Intraarterial thrombolysis with Intraarterial thrombolysis with urokinase or r- TPA urokinase or r- TPA increase of intravenous (IV) heparin (measured by increase of intravenous (IV) heparin (measured by
ACT) ACT) Intravenous aspirin Intravenous aspirin
Coil-related platelet aggregation (white clot) is Coil-related platelet aggregation (white clot) is unlikely to respond to fibrinolytics but has a high risk unlikely to respond to fibrinolytics but has a high risk of hemorrhage (In ISAT) all 5 patients who had of hemorrhage (In ISAT) all 5 patients who had received thrombolytic therapy with tPA to treat a received thrombolytic therapy with tPA to treat a thromboembolic complication after endovascular thromboembolic complication after endovascular treatment rebleed and all of these patients died)treatment rebleed and all of these patients died)
IntracranialIntracranial Stenting Stenting Metallic foreign body such as stent will accumulate Metallic foreign body such as stent will accumulate
thrombus in the absence of platelet inhibitionthrombus in the absence of platelet inhibition Antiplatelet drugs are important to prevent peri or Antiplatelet drugs are important to prevent peri or
post-interventional thromboembolic eventspost-interventional thromboembolic events Optimal treatment regimens has not been determined Optimal treatment regimens has not been determined
but usually but usually Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-
procedureprocedureOrOr
Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on
morning of proceduremorning of procedure
If need to use stent is not pre-planned thanIf need to use stent is not pre-planned than
Abciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkgAbciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkg IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)
Glycoprotein IIbIIIa inhibitor are not used routinely during elective Glycoprotein IIbIIIa inhibitor are not used routinely during elective stenting procedure dt increased risk of ICH stenting procedure dt increased risk of ICH
Carotid StentingCarotid Stenting
Pre-procedurePre-procedure
Double Antiplatelet therapy is routinely given Double Antiplatelet therapy is routinely given beginning at least 3beginning at least 3
days before the proceduredays before the procedure
Aspirin 325mgd+Clopidogrel 75mgdAspirin 325mgd+Clopidogrel 75mgd During procedureDuring procedure
Heparin is given with target clotting time of 250-Heparin is given with target clotting time of 250-300sec300sec
Post-procedure Post-procedure
Aspirin 325mg is continued indefinitely and Aspirin 325mg is continued indefinitely and
Clopidogrel 75mgd for at least 6 weeks Clopidogrel 75mgd for at least 6 weeks
Inclusion criteria for Local ThrombolysisInclusion criteria for Local Thrombolysis a)a) Patients in severe clinical grade on admission Patients in severe clinical grade on admission
with evidence of dural venous sinus with evidence of dural venous sinus thrombosis and restrictive venous outflow on thrombosis and restrictive venous outflow on cerebral angiogramcerebral angiogram
b)b) Patients in clinical grade 3 worsening on Patients in clinical grade 3 worsening on heparin therapy Restriction to venous heparin therapy Restriction to venous outflow was defined as an increase in brain outflow was defined as an increase in brain circulation time gt 12 s delay in the drainage circulation time gt 12 s delay in the drainage of cortical veins with cortical veins hanging of cortical veins with cortical veins hanging in spacein space
Treatment Options for Venous Thrombosis
CT Grading for Venous ThrombosisCT Grading for Venous Thrombosis Grade I no parenchymal change Grade I no parenchymal change
(hyperdense (hyperdense sinuses cortical veins empty sinuses cortical veins empty delta sign)delta sign)
Grade II non hemorrhagic venous infarct Grade II non hemorrhagic venous infarct without mass effect without mass effect
Grade III non-hemorrhagic infarct with Grade III non-hemorrhagic infarct with mass effectmass effect
Grade IV hemorrhagic venous infarct (max Grade IV hemorrhagic venous infarct (max diameter lt 3 cm) with no mass effectdiameter lt 3 cm) with no mass effect
Grade V hemorrhagic venous infarct (max Grade V hemorrhagic venous infarct (max diameter gt 3 cm) with mass effect diameter gt 3 cm) with mass effect
Local ThrombolysisLocal Thrombolysis
Femoral Jugular access was secured and a guiding Femoral Jugular access was secured and a guiding catheter was placed in the jugular bulb catheter was placed in the jugular bulb Mechanical Mechanical clot maceration clot maceration was done with the guidewire was done with the guidewire following which a microcatheter (was navigated and following which a microcatheter (was navigated and placed in the thrombosed segment of sinus confirmed placed in the thrombosed segment of sinus confirmed on a selective venogram on a selective venogram
Urokinase infusion Bolus dose of 2-6 lacs followed Urokinase infusion Bolus dose of 2-6 lacs followed by 60000 to 100000 units per hour along with by 60000 to 100000 units per hour along with periodic check venogram Along with maintenance periodic check venogram Along with maintenance systemic infusion of Heparinsystemic infusion of Heparin Other agents such as Other agents such as streptokinase altepase or rTPAstreptokinase altepase or rTPA can be also used can be also used
After thrombolysis patient should subjected to oral After thrombolysis patient should subjected to oral anticoagulation for six monthsanticoagulation for six months
Low-molecular-weight Low-molecular-weight heparinheparin
PharmacologyPharmacologyLMWH as its name suggests is a glycosaminoglycan that is approximatelyLMWH as its name suggests is a glycosaminoglycan that is approximately
one third the molecular weight of UFH It is derived from UFH through one third the molecular weight of UFH It is derived from UFH through variousvarious
depolymerization processes LMWH binds to antithrombin which in turn depolymerization processes LMWH binds to antithrombin which in turn
Neutralizes actors Xa and IIa Because LMWH lacks many of the longer Neutralizes actors Xa and IIa Because LMWH lacks many of the longer chains chains
required for binding to thrombin it has less ability to neutralize thrombin required for binding to thrombin it has less ability to neutralize thrombin
relativeto its ability to neutralize factor Xa LMWH also has less relativeto its ability to neutralize factor Xa LMWH also has less nonspecific nonspecific
binding to other proteins There is greater bioavailability with more binding to other proteins There is greater bioavailability with more predictable predictable
pharmacokinetics that eliminates the need for monitoring The smaller pharmacokinetics that eliminates the need for monitoring The smaller size also size also
allows for enhanced subcutaneous absorption when compared with UFHallows for enhanced subcutaneous absorption when compared with UFH
Three LMWH preparations are Three LMWH preparations are currently approved for use in the currently approved for use in the United States (1) enoxaparin (2) United States (1) enoxaparin (2) dalteparin and (3) tinzaparin dalteparin and (3) tinzaparin
They are all administered They are all administered subcutaneously at intervals of either subcutaneously at intervals of either once or twice daily for both once or twice daily for both prophylaxis and treatment dosesprophylaxis and treatment doses
Few Experiences of Few Experiences of ThrombolysisThrombolysis
Vickey 25 Yrs male patient presented Vickey 25 Yrs male patient presented with 12with 12thth day HO severe headache with day HO severe headache with right sided hemiplegiaright sided hemiplegia
MRI shows thrombosis of the superior MRI shows thrombosis of the superior sagittal left transverse left sigmoid sagittal left transverse left sigmoid sinuses and cortical veins in the fronto-sinuses and cortical veins in the fronto-parietal regions with eo haemorrhagic parietal regions with eo haemorrhagic infarct in the left cerebral hemisphere infarct in the left cerebral hemisphere with mass effect( Grade ndashV)with mass effect( Grade ndashV)
Sashi Srivastava 64 yrs FSashi Srivastava 64 yrs F In a follow up case of MRD with infra-renal In a follow up case of MRD with infra-renal
aortic abdominal and bilateral renal artery aortic abdominal and bilateral renal artery thrombosis renal angiogram shows filling thrombosis renal angiogram shows filling defects in the right Renal artery defects in the right Renal artery
Initially Renal angioplasty was done Initially Renal angioplasty was done Following angioplasty few thrombi are seem Following angioplasty few thrombi are seem to extends into the segmental branches and to extends into the segmental branches and causing blockage So Thrombolysis was causing blockage So Thrombolysis was plane to dissolve the run-out thrombi with plane to dissolve the run-out thrombi with urokinase urokinase
Rakesh 34yrsMRakesh 34yrsM Left SFA pseudoaneurysm with Left SFA pseudoaneurysm with
Covered stent placementCovered stent placement Pre operative antiplatelets with post Pre operative antiplatelets with post
procedure heparin Tirofiban procedure heparin Tirofiban followed by aspirin and clopidogrel followed by aspirin and clopidogrel were usedwere used
IAT may be a treatment option for selected patients IAT may be a treatment option for selected patients Possible selection criteria include Possible selection criteria include
presentation between 3 and 6 hours from symptom onsetpresentation between 3 and 6 hours from symptom onset major cerebral artery occlusion major cerebral artery occlusion severe neurologic deficits severe neurologic deficits high risk of systemic hemorrhage with IV rt-PA (eg recent high risk of systemic hemorrhage with IV rt-PA (eg recent
surgery) surgery) The MERCI (Mechanical Embolus Removal in Cerebral The MERCI (Mechanical Embolus Removal in Cerebral
Ischemia) retrievalIschemia) retrieval system system
Has been FDA-approved for recanalizing acutely occluded Has been FDA-approved for recanalizing acutely occluded cerebral arteries cerebral arteries
In the Multi-MERCI study patients who did not improve In the Multi-MERCI study patients who did not improve immediately after IV rt-PA underwent mechanical immediately after IV rt-PA underwent mechanical embolectomy within 8 hours of symptom onset embolectomy within 8 hours of symptom onset
Partial or complete recanalization occurred in 74 of Partial or complete recanalization occurred in 74 of patientspatients
with a symptomatic intracerebral hemorrhage (sICH) rate of with a symptomatic intracerebral hemorrhage (sICH) rate of 67 67
Mechanical embolectomy with the MERCI retriever may be a Mechanical embolectomy with the MERCI retriever may be a feasible and safe option for patients after IV rt-PAfeasible and safe option for patients after IV rt-PA
Penumbra stroke systemPenumbra stroke system This device combines two methods of clot This device combines two methods of clot
extraction aspiration and mechanical extraction aspiration and mechanical extraction extraction
First the clot is aspirated then a thrombus First the clot is aspirated then a thrombus removal ring can be used if necessary to removal ring can be used if necessary to remove remaining clot remove remaining clot
successful recanalizing 82successful recanalizing 82 Bridging therapyBridging therapy
06 mgkg IV rt-PA followed by IAT with IA rt-06 mgkg IV rt-PA followed by IAT with IA rt-PA (up to 20 mg)PA (up to 20 mg)
achieved a higher recanalization rateachieved a higher recanalization rate
Criteria for thrombolysis with rTPACriteria for thrombolysis with rTPA
Inclusion criteriaInclusion criteria Clinical signs and symptoms consistent with ischemic Clinical signs and symptoms consistent with ischemic
strokestroke Patient last seen normal within 3 hoursPatient last seen normal within 3 hours Measurable neurologic deficitMeasurable neurologic deficit
Exclusion criteriaExclusion criteria Any hemorrhage on neuroimaging (CT or MRI)Any hemorrhage on neuroimaging (CT or MRI) Symptoms suggestive of subarachnoid hemorrhageSymptoms suggestive of subarachnoid hemorrhage Seizure at stroke onset that is thought to contribute to Seizure at stroke onset that is thought to contribute to
neurologic deficitneurologic deficit Hypodensity greater than one third cerebral hemisphere Hypodensity greater than one third cerebral hemisphere
on CTon CT SBP greater than 185 mm Hg or DBP greater than 110 SBP greater than 185 mm Hg or DBP greater than 110
mm Hgmm Hg International normalized ratio (INR) greater than 17International normalized ratio (INR) greater than 17
Ischemic Stroke Ischemic Stroke Treatment ndash 2006Treatment ndash 2006
IV tissue plasminogen activator (tPA)IV tissue plasminogen activator (tPA) ndash ndash Only FDA-approved acute stroke drugOnly FDA-approved acute stroke drug ndash ndash 3 hour treatment window3 hour treatment window
MERCI - Concentric clot retrieval MERCI - Concentric clot retrieval devicedevice ndash ndash Rescue therapy - approved 2004Rescue therapy - approved 2004 ndash ndash Device approval (not outcomes-based)Device approval (not outcomes-based)
Off label approachesOff label approaches ndash ndash IV tPA after 3 hoursIV tPA after 3 hours ndash ndash IV-IA tPA sequential strategiesIV-IA tPA sequential strategies ndash ndash IA tPA clot angioplasty fragmentationIA tPA clot angioplasty fragmentation ndash ndash Ultrasound-assisted tPA lysisUltrasound-assisted tPA lysis
rt-PA Trials NINDSrt-PA Trials NINDS
Acute stroke - 624 patientsAcute stroke - 624 patients Treat within 3 hrsTreat within 3 hrs Intravenous 09 mgkg rt-PA vs placeboIntravenous 09 mgkg rt-PA vs placebo Hemorrhage 64 tPA 06 placeboHemorrhage 64 tPA 06 placebo Neurologic recovery better with tPA 30 Neurologic recovery better with tPA 30
more like to have minimal or no disabilitymore like to have minimal or no disability
First proven approved treatment for First proven approved treatment for strokestroke
Limitations of tPALimitations of tPA Only 4 of acute strokes receive tPAOnly 4 of acute strokes receive tPA (Kleindorfer et al Stroke 2004 35 e27-e29)(Kleindorfer et al Stroke 2004 35 e27-e29)
Only 22 of patients present within 3 hoursOnly 22 of patients present within 3 hours1048707 1048707 51 of these ineligible due to51 of these ineligible due to
bull bull Mild severityMild severity bull bull Medical or surgical historyMedical or surgical history bull bull Blood testsBlood tests
Sustained recanalization only 13Sustained recanalization only 13 (Alexandrov et al NEJM 2004 351 2170-8)(Alexandrov et al NEJM 2004 351 2170-8)
Concern for hemorrhageConcern for hemorrhage tPA potentiates apoptotic injury tPA potentiates apoptotic injury (Liu et al Nature Med 2004 101379-83)(Liu et al Nature Med 2004 101379-83)
PROACT II IA Lysis TrialPROACT II IA Lysis Trial Baseline 24 hours 8 days
Baseline 60 minutes 120 minutes
9mg IAProurokinase
Desmoteplase Trials DEDAS Desmoteplase Trials DEDAS DIASDIAS
Trial OverviewTrial Overview Double blind randomized placebo Double blind randomized placebo
controlled trialscontrolled trials IV delivery 3-9 hour time windowIV delivery 3-9 hour time window Plasminogen activator ndash from Plasminogen activator ndash from vampire bat vampire bat
salivasaliva Selection based on PWI-DWI MismatchSelection based on PWI-DWI Mismatch
MRI InclusionMRI Inclusion PWI defect at least 2 cm AND ~20 larger PWI defect at least 2 cm AND ~20 larger
than DWIthan DWI PWI should be obvious even visible on PWI should be obvious even visible on
raw imagesraw imagesMRI ExclusionMRI Exclusion
DWI gt 13 MCADWI gt 13 MCA MRA ICA occlusionMRA ICA occlusion
Desmoteplase ndash DIAS Desmoteplase ndash DIAS ResultsResults
Mechanical Thrombolysis Mechanical Thrombolysis devicesdevices
mechanical thrombolysis potentially extends the treatment mechanical thrombolysis potentially extends the treatment window because they act promptly at the site of the thrombuswindow because they act promptly at the site of the thrombus
The devices can retrieve large clots that pharmaceutical agents The devices can retrieve large clots that pharmaceutical agents may not successfully lysemay not successfully lyse
Patients treated with IV tPA may be considered for treatment of Patients treated with IV tPA may be considered for treatment of residual clot with some of these devicesresidual clot with some of these devices
suction-creating saline jets suction-creating saline jets laser energy ultrasound laser energy ultrasound a corkscrew apparatus to treat strokesa corkscrew apparatus to treat strokes The AngioJet systemThe AngioJet system uses saline jets that are directed back into the catheter to uses saline jets that are directed back into the catheter to
create a low-pressure zone around the catheter tip inducing create a low-pressure zone around the catheter tip inducing suction suction
The clot is pulled into the exhaust lumen and removed from the The clot is pulled into the exhaust lumen and removed from the vessel Although US Food and Drug Administration (FDA) has vessel Although US Food and Drug Administration (FDA) has approved this device for use in arteriovenous dialysis grafts and approved this device for use in arteriovenous dialysis grafts and fistulae and for the treatment of coronary arteries saphenous fistulae and for the treatment of coronary arteries saphenous vein grafts and peripheral vessels clinical trials for the vein grafts and peripheral vessels clinical trials for the treatment of acute stroke are no longer in progress treatment of acute stroke are no longer in progress
Most devices are used in cerebral vessels that 2-5 mm
The Latis laser device The Latis laser device used laser energy to ablate clots used laser energy to ablate clots Arteries 2-5 mm in diameter could be Arteries 2-5 mm in diameter could be
treated including the ICA M1 or M2 treated including the ICA M1 or M2 branch of the MCA A1 branch of the branch of the MCA A1 branch of the anterior cerebral artery (ACA) basilar anterior cerebral artery (ACA) basilar artery posterior cerebral artery (PCA) artery posterior cerebral artery (PCA) and vertebral and vertebral
Patients could receive treatment as late Patients could receive treatment as late as 8 hours after symptom onset in the as 8 hours after symptom onset in the anterior circulation and within 24 hours in anterior circulation and within 24 hours in the posterior circulation the posterior circulation
Endovascular Photo Acoustic Endovascular Photo Acoustic Recanalization (EPAR) Recanalization (EPAR)
A laser power source generated energy for the A laser power source generated energy for the systemsystem
The energy was delivered by means of The energy was delivered by means of fiberoptics to the tip of the catheter at the fiberoptics to the tip of the catheter at the treatment sitetreatment site
Absorption of laser light by darkly pigmented Absorption of laser light by darkly pigmented materials (ie the clot) occurred inside the 1-mm materials (ie the clot) occurred inside the 1-mm catheter tipcatheter tip
the system was designed to minimize scattering the system was designed to minimize scattering of laser light of laser light
Absorption converted photo energy to acoustic Absorption converted photo energy to acoustic energy which then emulsified the clot inside the energy which then emulsified the clot inside the catheter tip catheter tip
EKOS ultrasound( the EKOS ultrasound( the Ultrasound Thrombolytic Ultrasound Thrombolytic
Infusion Catheter) Infusion Catheter) combines the use of a distal ultrasound transducer with combines the use of a distal ultrasound transducer with
infusion of a thrombolytic agent through the infusion of a thrombolytic agent through the microcathetermicrocatheter
Ultrasound changes the structure of the clot to Ultrasound changes the structure of the clot to temporarily increase its permeability while providing an temporarily increase its permeability while providing an acoustic pressure gradient to move the drug into the clot acoustic pressure gradient to move the drug into the clot to speed its dissolution to speed its dissolution
The EKOS catheter is placed in the proximal portion of the The EKOS catheter is placed in the proximal portion of the clot clot
After a 2-mg bolus of tPA was injected through the After a 2-mg bolus of tPA was injected through the catheter catheter
the patient received a continuous infusion of IA tPA 03 the patient received a continuous infusion of IA tPA 03 mgmin to a maximum of 20 mg and simultaneous mgmin to a maximum of 20 mg and simultaneous ultrasound transmission for as long as 60 minutes ultrasound transmission for as long as 60 minutes
One patient was treated with a total of 4 units of One patient was treated with a total of 4 units of recombinant reteplase (Retavase) hand-injected over 60 recombinant reteplase (Retavase) hand-injected over 60 minutes minutes
Penumbra system Penumbra system The Penumbra system (Penumbra Inc) provides a dual The Penumbra system (Penumbra Inc) provides a dual
approach to clot extraction using aspiration followed by approach to clot extraction using aspiration followed by clot retrieval with a ring device if needed clot retrieval with a ring device if needed
Mechanical Embolus Removal in Cerebral Ischemia Mechanical Embolus Removal in Cerebral Ischemia (MERCI)(MERCI)
a corkscrew-like apparatus to remove blood clots from a corkscrew-like apparatus to remove blood clots from the brain in patients experiencing an ischemic stroke the brain in patients experiencing an ischemic stroke
The corkscrew itself resides in the catheter tip which The corkscrew itself resides in the catheter tip which shields it from the wall of the vessel until it is ready to be shields it from the wall of the vessel until it is ready to be burrowed into the clot Once lodged in the clot the device burrowed into the clot Once lodged in the clot the device and clot are withdrawn from the vessel and clot are withdrawn from the vessel
Snarelike devicesSnarelike devices Snares such as the Neuronet snare (Guidant Snares such as the Neuronet snare (Guidant
Endovascular Santa Clara CA) have been developed Endovascular Santa Clara CA) have been developed specifically for use in the treatment of strokes specifically for use in the treatment of strokes
These devices are simple in design and do not require the These devices are simple in design and do not require the clot to be amenable to emulsification clot to be amenable to emulsification
X-Sizer deviceX-Sizer device a device with small moving blades at the a device with small moving blades at the
catheter tip catheter tip This device the X-Sizer device (EndiCor Medical This device the X-Sizer device (EndiCor Medical
San Clemente CA) can be used to excise the San Clemente CA) can be used to excise the thrombus and aspirate it thrombus and aspirate it
The device was being evaluated in randomized The device was being evaluated in randomized studies of coronary vessels and in a registry of studies of coronary vessels and in a registry of patients with acute myocardial infarctionpatients with acute myocardial infarction
Although the manufacturer had modified the Although the manufacturer had modified the device for use in cerebral vessels a safety and device for use in cerebral vessels a safety and feasibility study was indefinitely suspended after feasibility study was indefinitely suspended after only 1 patient was treated with the device in only 1 patient was treated with the device in Europe Europe
Suction thrombectomySuction thrombectomy This method of mechanical thrombolysis is one of the This method of mechanical thrombolysis is one of the
simplestsimplest In this readily available technique suction is applied with In this readily available technique suction is applied with
a syringe to remove thrombus in the ICA a syringe to remove thrombus in the ICA It requires no other devicesIt requires no other devices A catheter with a large inner diameter (Brite Tip Cordis A catheter with a large inner diameter (Brite Tip Cordis
Corporation Miami FL) was placed in the symptomatic Corporation Miami FL) was placed in the symptomatic vessel and navigated over a guidewire into the thrombusvessel and navigated over a guidewire into the thrombus
A 60-mL syringe was used to aspirate the thrombus A 60-mL syringe was used to aspirate the thrombus Each patient required angioplasty and stenting of carotid Each patient required angioplasty and stenting of carotid
bifurcation stenosis and received daily aspirin and bifurcation stenosis and received daily aspirin and ticlopidine after the procedure No complications ticlopidine after the procedure No complications occurred occurred
Summary Acute Stroke Summary Acute Stroke ImagingImaging
PhysiologyPhysiology importance collaterals importance collaterals
ndash ndashGrowing role for perfusion Growing role for perfusion assessmentassessment
tPAtPA guidelines amp limitations guidelines amp limitations Signs on CT amp MRSigns on CT amp MR follow physiology follow physiology Stroke trialsStroke trials PWI-DWI mismatch PWI-DWI mismatch
ndash ndashTreat based on physiology not timeTreat based on physiology not time ProtocolsProtocols should be fast and should be fast and
comprehensivecomprehensive
Non-occlusive left MCA thrombus on 3-D imaging performed from CTA source data and was confirmed at catheter angiography
Therapy to be started within a 6-hr Therapy to be started within a 6-hr time to treatment (TTT) window time to treatment (TTT) window (while in case of IV thrombolysis (while in case of IV thrombolysis therapy to be started with in 3hrs)therapy to be started with in 3hrs)
Exclusion criteria Exclusion criteria Rapidly improving neurologic deficit or Rapidly improving neurologic deficit or Sustained blood pressure of gt180100 Sustained blood pressure of gt180100 Hemorrhage is detected on CTHemorrhage is detected on CT Infarct involving gt more than 13 rd Infarct involving gt more than 13 rd
territory of MCAterritory of MCA MRADWI-Perfusion mismatchlt 20MRADWI-Perfusion mismatchlt 20 Definite hypodensity on CTDefinite hypodensity on CT
Intra-arterial Thrombolysis
Fibrinolytics + AntiplateletsFibrinolytics + Antiplatelets
PlasminogenPlasminogen activators through fibrinolysis exposes activators through fibrinolysis exposes free thrombin and paradoxically stimulatesfree thrombin and paradoxically stimulates platelet platelet aggregation which leads to formation of aaggregation which leads to formation of a platelet platelet thrombus (white clot) thrombus (white clot)
This new thrombus is relatively resistant to This new thrombus is relatively resistant to fibrinolyticsfibrinolytics
So new regimen in case of acute stroke isSo new regimen in case of acute stroke is fibrinolytics + antiplatelet drugsfibrinolytics + antiplatelet drugs
rtPA + IIbIIIa inhibitors( tirofiban rtPA + IIbIIIa inhibitors( tirofiban abciximab) orabciximab) or
Urokinase + IIbIIIa Urokinase + IIbIIIa inhibitors( tirofiban abciximab)inhibitors( tirofiban abciximab)
Intra-arterial Thrombolysis Tirofiban (04 microgkgmin bolus for 3 min followed by Tirofiban (04 microgkgmin bolus for 3 min followed by
0125 ugkgmin)0125 ugkgmin)
++
Heparin (2000ndash3000 IU bolus followed by Heparin (2000ndash3000 IU bolus followed by 1000 IUhour infusion 1000 IUhour infusion
with ACT maintained bw 200-300) throughout the with ACT maintained bw 200-300) throughout the interventional procedure and for 24ndash48 hours thereafter when interventional procedure and for 24ndash48 hours thereafter when there is neither intraprocedural bleeding nor suspicion of there is neither intraprocedural bleeding nor suspicion of increased risk of bleeding increased risk of bleeding
Maximum dose of Urokinase Maximum dose of Urokinase Anterior circulation stroke - 500000 IU (mean 400000 Anterior circulation stroke - 500000 IU (mean 400000
IU range 300000ndash500000 IU)IU range 300000ndash500000 IU) Posterior circulation stroke -1000000 IU (mean 837000 Posterior circulation stroke -1000000 IU (mean 837000
IU range 300000ndash1000000 IU)IU range 300000ndash1000000 IU)American Journal of NeuroradiologyAmerican Journal of Neuroradiology 262595-2601 2005262595-2601 2005
Intravenous ThrombolysisIntravenous Thrombolysis
The first method to restore cerebral The first method to restore cerebral perfusion is clot lysis with the goal perfusion is clot lysis with the goal of re-establishing blood flow to the of re-establishing blood flow to the affected tissue affected tissue
IV thrombolysis rt-PA is the only IV thrombolysis rt-PA is the only FDA- approved treatment for AIS FDA- approved treatment for AIS
Fibrinolysis is enhanced powerfully Fibrinolysis is enhanced powerfully by rt-PAby rt-PA
Intravenous rTPA Intravenous rTPA administration administration protocolprotocol
Total dose of rt-PA 09 mgkg (maximum dose Total dose of rt-PA 09 mgkg (maximum dose 90 mg)90 mg)
Give 10 as initial IV bolusGive 10 as initial IV bolus Infuse remainder over 1 hourInfuse remainder over 1 hour Admit patient to an ICU or stroke unit for Admit patient to an ICU or stroke unit for
monitoringmonitoring Neurologic assessments every 15 minutes Neurologic assessments every 15 minutes
during infusion then every 30 minutes for next during infusion then every 30 minutes for next 6 hours then every hour until 24hours after 6 hours then every hour until 24hours after treatmenttreatment
Favorable Outcome vs Treatment Time Favorable Outcome vs Treatment Time with IV rTPAwith IV rTPA
Protocol limit = 3 hrs
Benefit ~ 45 hrs
Thromboembolism During coilingThromboembolism During coiling Most feared and frequent complication Most feared and frequent complication Reported incidence - Approx 7 Reported incidence - Approx 7 SourcesSources of Thromboembolism are of Thromboembolism are
- Clots at the aneurysmal neck during or immediately- Clots at the aneurysmal neck during or immediately after after embolization embolization
- Thrombus forming on catheters during- Thrombus forming on catheters during proceduresprocedures
- Stenosis of an adjacent artery dt coil mass- Stenosis of an adjacent artery dt coil mass or herniationor herniation
- Migration of intraaneurysmal- Migration of intraaneurysmal thrombus during coil thrombus during coil placement placement
- Slow flow dt vasospasm - Slow flow dt vasospasm
- Rare and unlikely causes are hypercoagulable- Rare and unlikely causes are hypercoagulable state such state such as antiphospholipid antibody syndrome or due to HITas antiphospholipid antibody syndrome or due to HIT
Occur more often with wide-necked aneurysms (dt Occur more often with wide-necked aneurysms (dt increased exposed surface area of thrombogenic coil increased exposed surface area of thrombogenic coil material)material)
Current regimen of endovascular Current regimen of endovascular managementmanagement
The The glycoprotein IIbIIIa antagonist tirofiban glycoprotein IIbIIIa antagonist tirofiban (04 (04 microgkgmin bolus for 30 minutes followed by infusion of microgkgmin bolus for 30 minutes followed by infusion of 0125 ugkgmin until the thrombus dissolved) 0125 ugkgmin until the thrombus dissolved)
Intraarterial thrombolysis with Intraarterial thrombolysis with urokinase or r- TPA urokinase or r- TPA increase of intravenous (IV) heparin (measured by increase of intravenous (IV) heparin (measured by
ACT) ACT) Intravenous aspirin Intravenous aspirin
Coil-related platelet aggregation (white clot) is Coil-related platelet aggregation (white clot) is unlikely to respond to fibrinolytics but has a high risk unlikely to respond to fibrinolytics but has a high risk of hemorrhage (In ISAT) all 5 patients who had of hemorrhage (In ISAT) all 5 patients who had received thrombolytic therapy with tPA to treat a received thrombolytic therapy with tPA to treat a thromboembolic complication after endovascular thromboembolic complication after endovascular treatment rebleed and all of these patients died)treatment rebleed and all of these patients died)
IntracranialIntracranial Stenting Stenting Metallic foreign body such as stent will accumulate Metallic foreign body such as stent will accumulate
thrombus in the absence of platelet inhibitionthrombus in the absence of platelet inhibition Antiplatelet drugs are important to prevent peri or Antiplatelet drugs are important to prevent peri or
post-interventional thromboembolic eventspost-interventional thromboembolic events Optimal treatment regimens has not been determined Optimal treatment regimens has not been determined
but usually but usually Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-
procedureprocedureOrOr
Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on
morning of proceduremorning of procedure
If need to use stent is not pre-planned thanIf need to use stent is not pre-planned than
Abciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkgAbciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkg IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)
Glycoprotein IIbIIIa inhibitor are not used routinely during elective Glycoprotein IIbIIIa inhibitor are not used routinely during elective stenting procedure dt increased risk of ICH stenting procedure dt increased risk of ICH
Carotid StentingCarotid Stenting
Pre-procedurePre-procedure
Double Antiplatelet therapy is routinely given Double Antiplatelet therapy is routinely given beginning at least 3beginning at least 3
days before the proceduredays before the procedure
Aspirin 325mgd+Clopidogrel 75mgdAspirin 325mgd+Clopidogrel 75mgd During procedureDuring procedure
Heparin is given with target clotting time of 250-Heparin is given with target clotting time of 250-300sec300sec
Post-procedure Post-procedure
Aspirin 325mg is continued indefinitely and Aspirin 325mg is continued indefinitely and
Clopidogrel 75mgd for at least 6 weeks Clopidogrel 75mgd for at least 6 weeks
Inclusion criteria for Local ThrombolysisInclusion criteria for Local Thrombolysis a)a) Patients in severe clinical grade on admission Patients in severe clinical grade on admission
with evidence of dural venous sinus with evidence of dural venous sinus thrombosis and restrictive venous outflow on thrombosis and restrictive venous outflow on cerebral angiogramcerebral angiogram
b)b) Patients in clinical grade 3 worsening on Patients in clinical grade 3 worsening on heparin therapy Restriction to venous heparin therapy Restriction to venous outflow was defined as an increase in brain outflow was defined as an increase in brain circulation time gt 12 s delay in the drainage circulation time gt 12 s delay in the drainage of cortical veins with cortical veins hanging of cortical veins with cortical veins hanging in spacein space
Treatment Options for Venous Thrombosis
CT Grading for Venous ThrombosisCT Grading for Venous Thrombosis Grade I no parenchymal change Grade I no parenchymal change
(hyperdense (hyperdense sinuses cortical veins empty sinuses cortical veins empty delta sign)delta sign)
Grade II non hemorrhagic venous infarct Grade II non hemorrhagic venous infarct without mass effect without mass effect
Grade III non-hemorrhagic infarct with Grade III non-hemorrhagic infarct with mass effectmass effect
Grade IV hemorrhagic venous infarct (max Grade IV hemorrhagic venous infarct (max diameter lt 3 cm) with no mass effectdiameter lt 3 cm) with no mass effect
Grade V hemorrhagic venous infarct (max Grade V hemorrhagic venous infarct (max diameter gt 3 cm) with mass effect diameter gt 3 cm) with mass effect
Local ThrombolysisLocal Thrombolysis
Femoral Jugular access was secured and a guiding Femoral Jugular access was secured and a guiding catheter was placed in the jugular bulb catheter was placed in the jugular bulb Mechanical Mechanical clot maceration clot maceration was done with the guidewire was done with the guidewire following which a microcatheter (was navigated and following which a microcatheter (was navigated and placed in the thrombosed segment of sinus confirmed placed in the thrombosed segment of sinus confirmed on a selective venogram on a selective venogram
Urokinase infusion Bolus dose of 2-6 lacs followed Urokinase infusion Bolus dose of 2-6 lacs followed by 60000 to 100000 units per hour along with by 60000 to 100000 units per hour along with periodic check venogram Along with maintenance periodic check venogram Along with maintenance systemic infusion of Heparinsystemic infusion of Heparin Other agents such as Other agents such as streptokinase altepase or rTPAstreptokinase altepase or rTPA can be also used can be also used
After thrombolysis patient should subjected to oral After thrombolysis patient should subjected to oral anticoagulation for six monthsanticoagulation for six months
Low-molecular-weight Low-molecular-weight heparinheparin
PharmacologyPharmacologyLMWH as its name suggests is a glycosaminoglycan that is approximatelyLMWH as its name suggests is a glycosaminoglycan that is approximately
one third the molecular weight of UFH It is derived from UFH through one third the molecular weight of UFH It is derived from UFH through variousvarious
depolymerization processes LMWH binds to antithrombin which in turn depolymerization processes LMWH binds to antithrombin which in turn
Neutralizes actors Xa and IIa Because LMWH lacks many of the longer Neutralizes actors Xa and IIa Because LMWH lacks many of the longer chains chains
required for binding to thrombin it has less ability to neutralize thrombin required for binding to thrombin it has less ability to neutralize thrombin
relativeto its ability to neutralize factor Xa LMWH also has less relativeto its ability to neutralize factor Xa LMWH also has less nonspecific nonspecific
binding to other proteins There is greater bioavailability with more binding to other proteins There is greater bioavailability with more predictable predictable
pharmacokinetics that eliminates the need for monitoring The smaller pharmacokinetics that eliminates the need for monitoring The smaller size also size also
allows for enhanced subcutaneous absorption when compared with UFHallows for enhanced subcutaneous absorption when compared with UFH
Three LMWH preparations are Three LMWH preparations are currently approved for use in the currently approved for use in the United States (1) enoxaparin (2) United States (1) enoxaparin (2) dalteparin and (3) tinzaparin dalteparin and (3) tinzaparin
They are all administered They are all administered subcutaneously at intervals of either subcutaneously at intervals of either once or twice daily for both once or twice daily for both prophylaxis and treatment dosesprophylaxis and treatment doses
Few Experiences of Few Experiences of ThrombolysisThrombolysis
Vickey 25 Yrs male patient presented Vickey 25 Yrs male patient presented with 12with 12thth day HO severe headache with day HO severe headache with right sided hemiplegiaright sided hemiplegia
MRI shows thrombosis of the superior MRI shows thrombosis of the superior sagittal left transverse left sigmoid sagittal left transverse left sigmoid sinuses and cortical veins in the fronto-sinuses and cortical veins in the fronto-parietal regions with eo haemorrhagic parietal regions with eo haemorrhagic infarct in the left cerebral hemisphere infarct in the left cerebral hemisphere with mass effect( Grade ndashV)with mass effect( Grade ndashV)
Sashi Srivastava 64 yrs FSashi Srivastava 64 yrs F In a follow up case of MRD with infra-renal In a follow up case of MRD with infra-renal
aortic abdominal and bilateral renal artery aortic abdominal and bilateral renal artery thrombosis renal angiogram shows filling thrombosis renal angiogram shows filling defects in the right Renal artery defects in the right Renal artery
Initially Renal angioplasty was done Initially Renal angioplasty was done Following angioplasty few thrombi are seem Following angioplasty few thrombi are seem to extends into the segmental branches and to extends into the segmental branches and causing blockage So Thrombolysis was causing blockage So Thrombolysis was plane to dissolve the run-out thrombi with plane to dissolve the run-out thrombi with urokinase urokinase
Rakesh 34yrsMRakesh 34yrsM Left SFA pseudoaneurysm with Left SFA pseudoaneurysm with
Covered stent placementCovered stent placement Pre operative antiplatelets with post Pre operative antiplatelets with post
procedure heparin Tirofiban procedure heparin Tirofiban followed by aspirin and clopidogrel followed by aspirin and clopidogrel were usedwere used
IAT may be a treatment option for selected patients IAT may be a treatment option for selected patients Possible selection criteria include Possible selection criteria include
presentation between 3 and 6 hours from symptom onsetpresentation between 3 and 6 hours from symptom onset major cerebral artery occlusion major cerebral artery occlusion severe neurologic deficits severe neurologic deficits high risk of systemic hemorrhage with IV rt-PA (eg recent high risk of systemic hemorrhage with IV rt-PA (eg recent
surgery) surgery) The MERCI (Mechanical Embolus Removal in Cerebral The MERCI (Mechanical Embolus Removal in Cerebral
Ischemia) retrievalIschemia) retrieval system system
Has been FDA-approved for recanalizing acutely occluded Has been FDA-approved for recanalizing acutely occluded cerebral arteries cerebral arteries
In the Multi-MERCI study patients who did not improve In the Multi-MERCI study patients who did not improve immediately after IV rt-PA underwent mechanical immediately after IV rt-PA underwent mechanical embolectomy within 8 hours of symptom onset embolectomy within 8 hours of symptom onset
Partial or complete recanalization occurred in 74 of Partial or complete recanalization occurred in 74 of patientspatients
with a symptomatic intracerebral hemorrhage (sICH) rate of with a symptomatic intracerebral hemorrhage (sICH) rate of 67 67
Mechanical embolectomy with the MERCI retriever may be a Mechanical embolectomy with the MERCI retriever may be a feasible and safe option for patients after IV rt-PAfeasible and safe option for patients after IV rt-PA
Penumbra stroke systemPenumbra stroke system This device combines two methods of clot This device combines two methods of clot
extraction aspiration and mechanical extraction aspiration and mechanical extraction extraction
First the clot is aspirated then a thrombus First the clot is aspirated then a thrombus removal ring can be used if necessary to removal ring can be used if necessary to remove remaining clot remove remaining clot
successful recanalizing 82successful recanalizing 82 Bridging therapyBridging therapy
06 mgkg IV rt-PA followed by IAT with IA rt-06 mgkg IV rt-PA followed by IAT with IA rt-PA (up to 20 mg)PA (up to 20 mg)
achieved a higher recanalization rateachieved a higher recanalization rate
Criteria for thrombolysis with rTPACriteria for thrombolysis with rTPA
Inclusion criteriaInclusion criteria Clinical signs and symptoms consistent with ischemic Clinical signs and symptoms consistent with ischemic
strokestroke Patient last seen normal within 3 hoursPatient last seen normal within 3 hours Measurable neurologic deficitMeasurable neurologic deficit
Exclusion criteriaExclusion criteria Any hemorrhage on neuroimaging (CT or MRI)Any hemorrhage on neuroimaging (CT or MRI) Symptoms suggestive of subarachnoid hemorrhageSymptoms suggestive of subarachnoid hemorrhage Seizure at stroke onset that is thought to contribute to Seizure at stroke onset that is thought to contribute to
neurologic deficitneurologic deficit Hypodensity greater than one third cerebral hemisphere Hypodensity greater than one third cerebral hemisphere
on CTon CT SBP greater than 185 mm Hg or DBP greater than 110 SBP greater than 185 mm Hg or DBP greater than 110
mm Hgmm Hg International normalized ratio (INR) greater than 17International normalized ratio (INR) greater than 17
Ischemic Stroke Ischemic Stroke Treatment ndash 2006Treatment ndash 2006
IV tissue plasminogen activator (tPA)IV tissue plasminogen activator (tPA) ndash ndash Only FDA-approved acute stroke drugOnly FDA-approved acute stroke drug ndash ndash 3 hour treatment window3 hour treatment window
MERCI - Concentric clot retrieval MERCI - Concentric clot retrieval devicedevice ndash ndash Rescue therapy - approved 2004Rescue therapy - approved 2004 ndash ndash Device approval (not outcomes-based)Device approval (not outcomes-based)
Off label approachesOff label approaches ndash ndash IV tPA after 3 hoursIV tPA after 3 hours ndash ndash IV-IA tPA sequential strategiesIV-IA tPA sequential strategies ndash ndash IA tPA clot angioplasty fragmentationIA tPA clot angioplasty fragmentation ndash ndash Ultrasound-assisted tPA lysisUltrasound-assisted tPA lysis
rt-PA Trials NINDSrt-PA Trials NINDS
Acute stroke - 624 patientsAcute stroke - 624 patients Treat within 3 hrsTreat within 3 hrs Intravenous 09 mgkg rt-PA vs placeboIntravenous 09 mgkg rt-PA vs placebo Hemorrhage 64 tPA 06 placeboHemorrhage 64 tPA 06 placebo Neurologic recovery better with tPA 30 Neurologic recovery better with tPA 30
more like to have minimal or no disabilitymore like to have minimal or no disability
First proven approved treatment for First proven approved treatment for strokestroke
Limitations of tPALimitations of tPA Only 4 of acute strokes receive tPAOnly 4 of acute strokes receive tPA (Kleindorfer et al Stroke 2004 35 e27-e29)(Kleindorfer et al Stroke 2004 35 e27-e29)
Only 22 of patients present within 3 hoursOnly 22 of patients present within 3 hours1048707 1048707 51 of these ineligible due to51 of these ineligible due to
bull bull Mild severityMild severity bull bull Medical or surgical historyMedical or surgical history bull bull Blood testsBlood tests
Sustained recanalization only 13Sustained recanalization only 13 (Alexandrov et al NEJM 2004 351 2170-8)(Alexandrov et al NEJM 2004 351 2170-8)
Concern for hemorrhageConcern for hemorrhage tPA potentiates apoptotic injury tPA potentiates apoptotic injury (Liu et al Nature Med 2004 101379-83)(Liu et al Nature Med 2004 101379-83)
PROACT II IA Lysis TrialPROACT II IA Lysis Trial Baseline 24 hours 8 days
Baseline 60 minutes 120 minutes
9mg IAProurokinase
Desmoteplase Trials DEDAS Desmoteplase Trials DEDAS DIASDIAS
Trial OverviewTrial Overview Double blind randomized placebo Double blind randomized placebo
controlled trialscontrolled trials IV delivery 3-9 hour time windowIV delivery 3-9 hour time window Plasminogen activator ndash from Plasminogen activator ndash from vampire bat vampire bat
salivasaliva Selection based on PWI-DWI MismatchSelection based on PWI-DWI Mismatch
MRI InclusionMRI Inclusion PWI defect at least 2 cm AND ~20 larger PWI defect at least 2 cm AND ~20 larger
than DWIthan DWI PWI should be obvious even visible on PWI should be obvious even visible on
raw imagesraw imagesMRI ExclusionMRI Exclusion
DWI gt 13 MCADWI gt 13 MCA MRA ICA occlusionMRA ICA occlusion
Desmoteplase ndash DIAS Desmoteplase ndash DIAS ResultsResults
Mechanical Thrombolysis Mechanical Thrombolysis devicesdevices
mechanical thrombolysis potentially extends the treatment mechanical thrombolysis potentially extends the treatment window because they act promptly at the site of the thrombuswindow because they act promptly at the site of the thrombus
The devices can retrieve large clots that pharmaceutical agents The devices can retrieve large clots that pharmaceutical agents may not successfully lysemay not successfully lyse
Patients treated with IV tPA may be considered for treatment of Patients treated with IV tPA may be considered for treatment of residual clot with some of these devicesresidual clot with some of these devices
suction-creating saline jets suction-creating saline jets laser energy ultrasound laser energy ultrasound a corkscrew apparatus to treat strokesa corkscrew apparatus to treat strokes The AngioJet systemThe AngioJet system uses saline jets that are directed back into the catheter to uses saline jets that are directed back into the catheter to
create a low-pressure zone around the catheter tip inducing create a low-pressure zone around the catheter tip inducing suction suction
The clot is pulled into the exhaust lumen and removed from the The clot is pulled into the exhaust lumen and removed from the vessel Although US Food and Drug Administration (FDA) has vessel Although US Food and Drug Administration (FDA) has approved this device for use in arteriovenous dialysis grafts and approved this device for use in arteriovenous dialysis grafts and fistulae and for the treatment of coronary arteries saphenous fistulae and for the treatment of coronary arteries saphenous vein grafts and peripheral vessels clinical trials for the vein grafts and peripheral vessels clinical trials for the treatment of acute stroke are no longer in progress treatment of acute stroke are no longer in progress
Most devices are used in cerebral vessels that 2-5 mm
The Latis laser device The Latis laser device used laser energy to ablate clots used laser energy to ablate clots Arteries 2-5 mm in diameter could be Arteries 2-5 mm in diameter could be
treated including the ICA M1 or M2 treated including the ICA M1 or M2 branch of the MCA A1 branch of the branch of the MCA A1 branch of the anterior cerebral artery (ACA) basilar anterior cerebral artery (ACA) basilar artery posterior cerebral artery (PCA) artery posterior cerebral artery (PCA) and vertebral and vertebral
Patients could receive treatment as late Patients could receive treatment as late as 8 hours after symptom onset in the as 8 hours after symptom onset in the anterior circulation and within 24 hours in anterior circulation and within 24 hours in the posterior circulation the posterior circulation
Endovascular Photo Acoustic Endovascular Photo Acoustic Recanalization (EPAR) Recanalization (EPAR)
A laser power source generated energy for the A laser power source generated energy for the systemsystem
The energy was delivered by means of The energy was delivered by means of fiberoptics to the tip of the catheter at the fiberoptics to the tip of the catheter at the treatment sitetreatment site
Absorption of laser light by darkly pigmented Absorption of laser light by darkly pigmented materials (ie the clot) occurred inside the 1-mm materials (ie the clot) occurred inside the 1-mm catheter tipcatheter tip
the system was designed to minimize scattering the system was designed to minimize scattering of laser light of laser light
Absorption converted photo energy to acoustic Absorption converted photo energy to acoustic energy which then emulsified the clot inside the energy which then emulsified the clot inside the catheter tip catheter tip
EKOS ultrasound( the EKOS ultrasound( the Ultrasound Thrombolytic Ultrasound Thrombolytic
Infusion Catheter) Infusion Catheter) combines the use of a distal ultrasound transducer with combines the use of a distal ultrasound transducer with
infusion of a thrombolytic agent through the infusion of a thrombolytic agent through the microcathetermicrocatheter
Ultrasound changes the structure of the clot to Ultrasound changes the structure of the clot to temporarily increase its permeability while providing an temporarily increase its permeability while providing an acoustic pressure gradient to move the drug into the clot acoustic pressure gradient to move the drug into the clot to speed its dissolution to speed its dissolution
The EKOS catheter is placed in the proximal portion of the The EKOS catheter is placed in the proximal portion of the clot clot
After a 2-mg bolus of tPA was injected through the After a 2-mg bolus of tPA was injected through the catheter catheter
the patient received a continuous infusion of IA tPA 03 the patient received a continuous infusion of IA tPA 03 mgmin to a maximum of 20 mg and simultaneous mgmin to a maximum of 20 mg and simultaneous ultrasound transmission for as long as 60 minutes ultrasound transmission for as long as 60 minutes
One patient was treated with a total of 4 units of One patient was treated with a total of 4 units of recombinant reteplase (Retavase) hand-injected over 60 recombinant reteplase (Retavase) hand-injected over 60 minutes minutes
Penumbra system Penumbra system The Penumbra system (Penumbra Inc) provides a dual The Penumbra system (Penumbra Inc) provides a dual
approach to clot extraction using aspiration followed by approach to clot extraction using aspiration followed by clot retrieval with a ring device if needed clot retrieval with a ring device if needed
Mechanical Embolus Removal in Cerebral Ischemia Mechanical Embolus Removal in Cerebral Ischemia (MERCI)(MERCI)
a corkscrew-like apparatus to remove blood clots from a corkscrew-like apparatus to remove blood clots from the brain in patients experiencing an ischemic stroke the brain in patients experiencing an ischemic stroke
The corkscrew itself resides in the catheter tip which The corkscrew itself resides in the catheter tip which shields it from the wall of the vessel until it is ready to be shields it from the wall of the vessel until it is ready to be burrowed into the clot Once lodged in the clot the device burrowed into the clot Once lodged in the clot the device and clot are withdrawn from the vessel and clot are withdrawn from the vessel
Snarelike devicesSnarelike devices Snares such as the Neuronet snare (Guidant Snares such as the Neuronet snare (Guidant
Endovascular Santa Clara CA) have been developed Endovascular Santa Clara CA) have been developed specifically for use in the treatment of strokes specifically for use in the treatment of strokes
These devices are simple in design and do not require the These devices are simple in design and do not require the clot to be amenable to emulsification clot to be amenable to emulsification
X-Sizer deviceX-Sizer device a device with small moving blades at the a device with small moving blades at the
catheter tip catheter tip This device the X-Sizer device (EndiCor Medical This device the X-Sizer device (EndiCor Medical
San Clemente CA) can be used to excise the San Clemente CA) can be used to excise the thrombus and aspirate it thrombus and aspirate it
The device was being evaluated in randomized The device was being evaluated in randomized studies of coronary vessels and in a registry of studies of coronary vessels and in a registry of patients with acute myocardial infarctionpatients with acute myocardial infarction
Although the manufacturer had modified the Although the manufacturer had modified the device for use in cerebral vessels a safety and device for use in cerebral vessels a safety and feasibility study was indefinitely suspended after feasibility study was indefinitely suspended after only 1 patient was treated with the device in only 1 patient was treated with the device in Europe Europe
Suction thrombectomySuction thrombectomy This method of mechanical thrombolysis is one of the This method of mechanical thrombolysis is one of the
simplestsimplest In this readily available technique suction is applied with In this readily available technique suction is applied with
a syringe to remove thrombus in the ICA a syringe to remove thrombus in the ICA It requires no other devicesIt requires no other devices A catheter with a large inner diameter (Brite Tip Cordis A catheter with a large inner diameter (Brite Tip Cordis
Corporation Miami FL) was placed in the symptomatic Corporation Miami FL) was placed in the symptomatic vessel and navigated over a guidewire into the thrombusvessel and navigated over a guidewire into the thrombus
A 60-mL syringe was used to aspirate the thrombus A 60-mL syringe was used to aspirate the thrombus Each patient required angioplasty and stenting of carotid Each patient required angioplasty and stenting of carotid
bifurcation stenosis and received daily aspirin and bifurcation stenosis and received daily aspirin and ticlopidine after the procedure No complications ticlopidine after the procedure No complications occurred occurred
Summary Acute Stroke Summary Acute Stroke ImagingImaging
PhysiologyPhysiology importance collaterals importance collaterals
ndash ndashGrowing role for perfusion Growing role for perfusion assessmentassessment
tPAtPA guidelines amp limitations guidelines amp limitations Signs on CT amp MRSigns on CT amp MR follow physiology follow physiology Stroke trialsStroke trials PWI-DWI mismatch PWI-DWI mismatch
ndash ndashTreat based on physiology not timeTreat based on physiology not time ProtocolsProtocols should be fast and should be fast and
comprehensivecomprehensive
Therapy to be started within a 6-hr Therapy to be started within a 6-hr time to treatment (TTT) window time to treatment (TTT) window (while in case of IV thrombolysis (while in case of IV thrombolysis therapy to be started with in 3hrs)therapy to be started with in 3hrs)
Exclusion criteria Exclusion criteria Rapidly improving neurologic deficit or Rapidly improving neurologic deficit or Sustained blood pressure of gt180100 Sustained blood pressure of gt180100 Hemorrhage is detected on CTHemorrhage is detected on CT Infarct involving gt more than 13 rd Infarct involving gt more than 13 rd
territory of MCAterritory of MCA MRADWI-Perfusion mismatchlt 20MRADWI-Perfusion mismatchlt 20 Definite hypodensity on CTDefinite hypodensity on CT
Intra-arterial Thrombolysis
Fibrinolytics + AntiplateletsFibrinolytics + Antiplatelets
PlasminogenPlasminogen activators through fibrinolysis exposes activators through fibrinolysis exposes free thrombin and paradoxically stimulatesfree thrombin and paradoxically stimulates platelet platelet aggregation which leads to formation of aaggregation which leads to formation of a platelet platelet thrombus (white clot) thrombus (white clot)
This new thrombus is relatively resistant to This new thrombus is relatively resistant to fibrinolyticsfibrinolytics
So new regimen in case of acute stroke isSo new regimen in case of acute stroke is fibrinolytics + antiplatelet drugsfibrinolytics + antiplatelet drugs
rtPA + IIbIIIa inhibitors( tirofiban rtPA + IIbIIIa inhibitors( tirofiban abciximab) orabciximab) or
Urokinase + IIbIIIa Urokinase + IIbIIIa inhibitors( tirofiban abciximab)inhibitors( tirofiban abciximab)
Intra-arterial Thrombolysis Tirofiban (04 microgkgmin bolus for 3 min followed by Tirofiban (04 microgkgmin bolus for 3 min followed by
0125 ugkgmin)0125 ugkgmin)
++
Heparin (2000ndash3000 IU bolus followed by Heparin (2000ndash3000 IU bolus followed by 1000 IUhour infusion 1000 IUhour infusion
with ACT maintained bw 200-300) throughout the with ACT maintained bw 200-300) throughout the interventional procedure and for 24ndash48 hours thereafter when interventional procedure and for 24ndash48 hours thereafter when there is neither intraprocedural bleeding nor suspicion of there is neither intraprocedural bleeding nor suspicion of increased risk of bleeding increased risk of bleeding
Maximum dose of Urokinase Maximum dose of Urokinase Anterior circulation stroke - 500000 IU (mean 400000 Anterior circulation stroke - 500000 IU (mean 400000
IU range 300000ndash500000 IU)IU range 300000ndash500000 IU) Posterior circulation stroke -1000000 IU (mean 837000 Posterior circulation stroke -1000000 IU (mean 837000
IU range 300000ndash1000000 IU)IU range 300000ndash1000000 IU)American Journal of NeuroradiologyAmerican Journal of Neuroradiology 262595-2601 2005262595-2601 2005
Intravenous ThrombolysisIntravenous Thrombolysis
The first method to restore cerebral The first method to restore cerebral perfusion is clot lysis with the goal perfusion is clot lysis with the goal of re-establishing blood flow to the of re-establishing blood flow to the affected tissue affected tissue
IV thrombolysis rt-PA is the only IV thrombolysis rt-PA is the only FDA- approved treatment for AIS FDA- approved treatment for AIS
Fibrinolysis is enhanced powerfully Fibrinolysis is enhanced powerfully by rt-PAby rt-PA
Intravenous rTPA Intravenous rTPA administration administration protocolprotocol
Total dose of rt-PA 09 mgkg (maximum dose Total dose of rt-PA 09 mgkg (maximum dose 90 mg)90 mg)
Give 10 as initial IV bolusGive 10 as initial IV bolus Infuse remainder over 1 hourInfuse remainder over 1 hour Admit patient to an ICU or stroke unit for Admit patient to an ICU or stroke unit for
monitoringmonitoring Neurologic assessments every 15 minutes Neurologic assessments every 15 minutes
during infusion then every 30 minutes for next during infusion then every 30 minutes for next 6 hours then every hour until 24hours after 6 hours then every hour until 24hours after treatmenttreatment
Favorable Outcome vs Treatment Time Favorable Outcome vs Treatment Time with IV rTPAwith IV rTPA
Protocol limit = 3 hrs
Benefit ~ 45 hrs
Thromboembolism During coilingThromboembolism During coiling Most feared and frequent complication Most feared and frequent complication Reported incidence - Approx 7 Reported incidence - Approx 7 SourcesSources of Thromboembolism are of Thromboembolism are
- Clots at the aneurysmal neck during or immediately- Clots at the aneurysmal neck during or immediately after after embolization embolization
- Thrombus forming on catheters during- Thrombus forming on catheters during proceduresprocedures
- Stenosis of an adjacent artery dt coil mass- Stenosis of an adjacent artery dt coil mass or herniationor herniation
- Migration of intraaneurysmal- Migration of intraaneurysmal thrombus during coil thrombus during coil placement placement
- Slow flow dt vasospasm - Slow flow dt vasospasm
- Rare and unlikely causes are hypercoagulable- Rare and unlikely causes are hypercoagulable state such state such as antiphospholipid antibody syndrome or due to HITas antiphospholipid antibody syndrome or due to HIT
Occur more often with wide-necked aneurysms (dt Occur more often with wide-necked aneurysms (dt increased exposed surface area of thrombogenic coil increased exposed surface area of thrombogenic coil material)material)
Current regimen of endovascular Current regimen of endovascular managementmanagement
The The glycoprotein IIbIIIa antagonist tirofiban glycoprotein IIbIIIa antagonist tirofiban (04 (04 microgkgmin bolus for 30 minutes followed by infusion of microgkgmin bolus for 30 minutes followed by infusion of 0125 ugkgmin until the thrombus dissolved) 0125 ugkgmin until the thrombus dissolved)
Intraarterial thrombolysis with Intraarterial thrombolysis with urokinase or r- TPA urokinase or r- TPA increase of intravenous (IV) heparin (measured by increase of intravenous (IV) heparin (measured by
ACT) ACT) Intravenous aspirin Intravenous aspirin
Coil-related platelet aggregation (white clot) is Coil-related platelet aggregation (white clot) is unlikely to respond to fibrinolytics but has a high risk unlikely to respond to fibrinolytics but has a high risk of hemorrhage (In ISAT) all 5 patients who had of hemorrhage (In ISAT) all 5 patients who had received thrombolytic therapy with tPA to treat a received thrombolytic therapy with tPA to treat a thromboembolic complication after endovascular thromboembolic complication after endovascular treatment rebleed and all of these patients died)treatment rebleed and all of these patients died)
IntracranialIntracranial Stenting Stenting Metallic foreign body such as stent will accumulate Metallic foreign body such as stent will accumulate
thrombus in the absence of platelet inhibitionthrombus in the absence of platelet inhibition Antiplatelet drugs are important to prevent peri or Antiplatelet drugs are important to prevent peri or
post-interventional thromboembolic eventspost-interventional thromboembolic events Optimal treatment regimens has not been determined Optimal treatment regimens has not been determined
but usually but usually Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-
procedureprocedureOrOr
Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on
morning of proceduremorning of procedure
If need to use stent is not pre-planned thanIf need to use stent is not pre-planned than
Abciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkgAbciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkg IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)
Glycoprotein IIbIIIa inhibitor are not used routinely during elective Glycoprotein IIbIIIa inhibitor are not used routinely during elective stenting procedure dt increased risk of ICH stenting procedure dt increased risk of ICH
Carotid StentingCarotid Stenting
Pre-procedurePre-procedure
Double Antiplatelet therapy is routinely given Double Antiplatelet therapy is routinely given beginning at least 3beginning at least 3
days before the proceduredays before the procedure
Aspirin 325mgd+Clopidogrel 75mgdAspirin 325mgd+Clopidogrel 75mgd During procedureDuring procedure
Heparin is given with target clotting time of 250-Heparin is given with target clotting time of 250-300sec300sec
Post-procedure Post-procedure
Aspirin 325mg is continued indefinitely and Aspirin 325mg is continued indefinitely and
Clopidogrel 75mgd for at least 6 weeks Clopidogrel 75mgd for at least 6 weeks
Inclusion criteria for Local ThrombolysisInclusion criteria for Local Thrombolysis a)a) Patients in severe clinical grade on admission Patients in severe clinical grade on admission
with evidence of dural venous sinus with evidence of dural venous sinus thrombosis and restrictive venous outflow on thrombosis and restrictive venous outflow on cerebral angiogramcerebral angiogram
b)b) Patients in clinical grade 3 worsening on Patients in clinical grade 3 worsening on heparin therapy Restriction to venous heparin therapy Restriction to venous outflow was defined as an increase in brain outflow was defined as an increase in brain circulation time gt 12 s delay in the drainage circulation time gt 12 s delay in the drainage of cortical veins with cortical veins hanging of cortical veins with cortical veins hanging in spacein space
Treatment Options for Venous Thrombosis
CT Grading for Venous ThrombosisCT Grading for Venous Thrombosis Grade I no parenchymal change Grade I no parenchymal change
(hyperdense (hyperdense sinuses cortical veins empty sinuses cortical veins empty delta sign)delta sign)
Grade II non hemorrhagic venous infarct Grade II non hemorrhagic venous infarct without mass effect without mass effect
Grade III non-hemorrhagic infarct with Grade III non-hemorrhagic infarct with mass effectmass effect
Grade IV hemorrhagic venous infarct (max Grade IV hemorrhagic venous infarct (max diameter lt 3 cm) with no mass effectdiameter lt 3 cm) with no mass effect
Grade V hemorrhagic venous infarct (max Grade V hemorrhagic venous infarct (max diameter gt 3 cm) with mass effect diameter gt 3 cm) with mass effect
Local ThrombolysisLocal Thrombolysis
Femoral Jugular access was secured and a guiding Femoral Jugular access was secured and a guiding catheter was placed in the jugular bulb catheter was placed in the jugular bulb Mechanical Mechanical clot maceration clot maceration was done with the guidewire was done with the guidewire following which a microcatheter (was navigated and following which a microcatheter (was navigated and placed in the thrombosed segment of sinus confirmed placed in the thrombosed segment of sinus confirmed on a selective venogram on a selective venogram
Urokinase infusion Bolus dose of 2-6 lacs followed Urokinase infusion Bolus dose of 2-6 lacs followed by 60000 to 100000 units per hour along with by 60000 to 100000 units per hour along with periodic check venogram Along with maintenance periodic check venogram Along with maintenance systemic infusion of Heparinsystemic infusion of Heparin Other agents such as Other agents such as streptokinase altepase or rTPAstreptokinase altepase or rTPA can be also used can be also used
After thrombolysis patient should subjected to oral After thrombolysis patient should subjected to oral anticoagulation for six monthsanticoagulation for six months
Low-molecular-weight Low-molecular-weight heparinheparin
PharmacologyPharmacologyLMWH as its name suggests is a glycosaminoglycan that is approximatelyLMWH as its name suggests is a glycosaminoglycan that is approximately
one third the molecular weight of UFH It is derived from UFH through one third the molecular weight of UFH It is derived from UFH through variousvarious
depolymerization processes LMWH binds to antithrombin which in turn depolymerization processes LMWH binds to antithrombin which in turn
Neutralizes actors Xa and IIa Because LMWH lacks many of the longer Neutralizes actors Xa and IIa Because LMWH lacks many of the longer chains chains
required for binding to thrombin it has less ability to neutralize thrombin required for binding to thrombin it has less ability to neutralize thrombin
relativeto its ability to neutralize factor Xa LMWH also has less relativeto its ability to neutralize factor Xa LMWH also has less nonspecific nonspecific
binding to other proteins There is greater bioavailability with more binding to other proteins There is greater bioavailability with more predictable predictable
pharmacokinetics that eliminates the need for monitoring The smaller pharmacokinetics that eliminates the need for monitoring The smaller size also size also
allows for enhanced subcutaneous absorption when compared with UFHallows for enhanced subcutaneous absorption when compared with UFH
Three LMWH preparations are Three LMWH preparations are currently approved for use in the currently approved for use in the United States (1) enoxaparin (2) United States (1) enoxaparin (2) dalteparin and (3) tinzaparin dalteparin and (3) tinzaparin
They are all administered They are all administered subcutaneously at intervals of either subcutaneously at intervals of either once or twice daily for both once or twice daily for both prophylaxis and treatment dosesprophylaxis and treatment doses
Few Experiences of Few Experiences of ThrombolysisThrombolysis
Vickey 25 Yrs male patient presented Vickey 25 Yrs male patient presented with 12with 12thth day HO severe headache with day HO severe headache with right sided hemiplegiaright sided hemiplegia
MRI shows thrombosis of the superior MRI shows thrombosis of the superior sagittal left transverse left sigmoid sagittal left transverse left sigmoid sinuses and cortical veins in the fronto-sinuses and cortical veins in the fronto-parietal regions with eo haemorrhagic parietal regions with eo haemorrhagic infarct in the left cerebral hemisphere infarct in the left cerebral hemisphere with mass effect( Grade ndashV)with mass effect( Grade ndashV)
Sashi Srivastava 64 yrs FSashi Srivastava 64 yrs F In a follow up case of MRD with infra-renal In a follow up case of MRD with infra-renal
aortic abdominal and bilateral renal artery aortic abdominal and bilateral renal artery thrombosis renal angiogram shows filling thrombosis renal angiogram shows filling defects in the right Renal artery defects in the right Renal artery
Initially Renal angioplasty was done Initially Renal angioplasty was done Following angioplasty few thrombi are seem Following angioplasty few thrombi are seem to extends into the segmental branches and to extends into the segmental branches and causing blockage So Thrombolysis was causing blockage So Thrombolysis was plane to dissolve the run-out thrombi with plane to dissolve the run-out thrombi with urokinase urokinase
Rakesh 34yrsMRakesh 34yrsM Left SFA pseudoaneurysm with Left SFA pseudoaneurysm with
Covered stent placementCovered stent placement Pre operative antiplatelets with post Pre operative antiplatelets with post
procedure heparin Tirofiban procedure heparin Tirofiban followed by aspirin and clopidogrel followed by aspirin and clopidogrel were usedwere used
IAT may be a treatment option for selected patients IAT may be a treatment option for selected patients Possible selection criteria include Possible selection criteria include
presentation between 3 and 6 hours from symptom onsetpresentation between 3 and 6 hours from symptom onset major cerebral artery occlusion major cerebral artery occlusion severe neurologic deficits severe neurologic deficits high risk of systemic hemorrhage with IV rt-PA (eg recent high risk of systemic hemorrhage with IV rt-PA (eg recent
surgery) surgery) The MERCI (Mechanical Embolus Removal in Cerebral The MERCI (Mechanical Embolus Removal in Cerebral
Ischemia) retrievalIschemia) retrieval system system
Has been FDA-approved for recanalizing acutely occluded Has been FDA-approved for recanalizing acutely occluded cerebral arteries cerebral arteries
In the Multi-MERCI study patients who did not improve In the Multi-MERCI study patients who did not improve immediately after IV rt-PA underwent mechanical immediately after IV rt-PA underwent mechanical embolectomy within 8 hours of symptom onset embolectomy within 8 hours of symptom onset
Partial or complete recanalization occurred in 74 of Partial or complete recanalization occurred in 74 of patientspatients
with a symptomatic intracerebral hemorrhage (sICH) rate of with a symptomatic intracerebral hemorrhage (sICH) rate of 67 67
Mechanical embolectomy with the MERCI retriever may be a Mechanical embolectomy with the MERCI retriever may be a feasible and safe option for patients after IV rt-PAfeasible and safe option for patients after IV rt-PA
Penumbra stroke systemPenumbra stroke system This device combines two methods of clot This device combines two methods of clot
extraction aspiration and mechanical extraction aspiration and mechanical extraction extraction
First the clot is aspirated then a thrombus First the clot is aspirated then a thrombus removal ring can be used if necessary to removal ring can be used if necessary to remove remaining clot remove remaining clot
successful recanalizing 82successful recanalizing 82 Bridging therapyBridging therapy
06 mgkg IV rt-PA followed by IAT with IA rt-06 mgkg IV rt-PA followed by IAT with IA rt-PA (up to 20 mg)PA (up to 20 mg)
achieved a higher recanalization rateachieved a higher recanalization rate
Criteria for thrombolysis with rTPACriteria for thrombolysis with rTPA
Inclusion criteriaInclusion criteria Clinical signs and symptoms consistent with ischemic Clinical signs and symptoms consistent with ischemic
strokestroke Patient last seen normal within 3 hoursPatient last seen normal within 3 hours Measurable neurologic deficitMeasurable neurologic deficit
Exclusion criteriaExclusion criteria Any hemorrhage on neuroimaging (CT or MRI)Any hemorrhage on neuroimaging (CT or MRI) Symptoms suggestive of subarachnoid hemorrhageSymptoms suggestive of subarachnoid hemorrhage Seizure at stroke onset that is thought to contribute to Seizure at stroke onset that is thought to contribute to
neurologic deficitneurologic deficit Hypodensity greater than one third cerebral hemisphere Hypodensity greater than one third cerebral hemisphere
on CTon CT SBP greater than 185 mm Hg or DBP greater than 110 SBP greater than 185 mm Hg or DBP greater than 110
mm Hgmm Hg International normalized ratio (INR) greater than 17International normalized ratio (INR) greater than 17
Ischemic Stroke Ischemic Stroke Treatment ndash 2006Treatment ndash 2006
IV tissue plasminogen activator (tPA)IV tissue plasminogen activator (tPA) ndash ndash Only FDA-approved acute stroke drugOnly FDA-approved acute stroke drug ndash ndash 3 hour treatment window3 hour treatment window
MERCI - Concentric clot retrieval MERCI - Concentric clot retrieval devicedevice ndash ndash Rescue therapy - approved 2004Rescue therapy - approved 2004 ndash ndash Device approval (not outcomes-based)Device approval (not outcomes-based)
Off label approachesOff label approaches ndash ndash IV tPA after 3 hoursIV tPA after 3 hours ndash ndash IV-IA tPA sequential strategiesIV-IA tPA sequential strategies ndash ndash IA tPA clot angioplasty fragmentationIA tPA clot angioplasty fragmentation ndash ndash Ultrasound-assisted tPA lysisUltrasound-assisted tPA lysis
rt-PA Trials NINDSrt-PA Trials NINDS
Acute stroke - 624 patientsAcute stroke - 624 patients Treat within 3 hrsTreat within 3 hrs Intravenous 09 mgkg rt-PA vs placeboIntravenous 09 mgkg rt-PA vs placebo Hemorrhage 64 tPA 06 placeboHemorrhage 64 tPA 06 placebo Neurologic recovery better with tPA 30 Neurologic recovery better with tPA 30
more like to have minimal or no disabilitymore like to have minimal or no disability
First proven approved treatment for First proven approved treatment for strokestroke
Limitations of tPALimitations of tPA Only 4 of acute strokes receive tPAOnly 4 of acute strokes receive tPA (Kleindorfer et al Stroke 2004 35 e27-e29)(Kleindorfer et al Stroke 2004 35 e27-e29)
Only 22 of patients present within 3 hoursOnly 22 of patients present within 3 hours1048707 1048707 51 of these ineligible due to51 of these ineligible due to
bull bull Mild severityMild severity bull bull Medical or surgical historyMedical or surgical history bull bull Blood testsBlood tests
Sustained recanalization only 13Sustained recanalization only 13 (Alexandrov et al NEJM 2004 351 2170-8)(Alexandrov et al NEJM 2004 351 2170-8)
Concern for hemorrhageConcern for hemorrhage tPA potentiates apoptotic injury tPA potentiates apoptotic injury (Liu et al Nature Med 2004 101379-83)(Liu et al Nature Med 2004 101379-83)
PROACT II IA Lysis TrialPROACT II IA Lysis Trial Baseline 24 hours 8 days
Baseline 60 minutes 120 minutes
9mg IAProurokinase
Desmoteplase Trials DEDAS Desmoteplase Trials DEDAS DIASDIAS
Trial OverviewTrial Overview Double blind randomized placebo Double blind randomized placebo
controlled trialscontrolled trials IV delivery 3-9 hour time windowIV delivery 3-9 hour time window Plasminogen activator ndash from Plasminogen activator ndash from vampire bat vampire bat
salivasaliva Selection based on PWI-DWI MismatchSelection based on PWI-DWI Mismatch
MRI InclusionMRI Inclusion PWI defect at least 2 cm AND ~20 larger PWI defect at least 2 cm AND ~20 larger
than DWIthan DWI PWI should be obvious even visible on PWI should be obvious even visible on
raw imagesraw imagesMRI ExclusionMRI Exclusion
DWI gt 13 MCADWI gt 13 MCA MRA ICA occlusionMRA ICA occlusion
Desmoteplase ndash DIAS Desmoteplase ndash DIAS ResultsResults
Mechanical Thrombolysis Mechanical Thrombolysis devicesdevices
mechanical thrombolysis potentially extends the treatment mechanical thrombolysis potentially extends the treatment window because they act promptly at the site of the thrombuswindow because they act promptly at the site of the thrombus
The devices can retrieve large clots that pharmaceutical agents The devices can retrieve large clots that pharmaceutical agents may not successfully lysemay not successfully lyse
Patients treated with IV tPA may be considered for treatment of Patients treated with IV tPA may be considered for treatment of residual clot with some of these devicesresidual clot with some of these devices
suction-creating saline jets suction-creating saline jets laser energy ultrasound laser energy ultrasound a corkscrew apparatus to treat strokesa corkscrew apparatus to treat strokes The AngioJet systemThe AngioJet system uses saline jets that are directed back into the catheter to uses saline jets that are directed back into the catheter to
create a low-pressure zone around the catheter tip inducing create a low-pressure zone around the catheter tip inducing suction suction
The clot is pulled into the exhaust lumen and removed from the The clot is pulled into the exhaust lumen and removed from the vessel Although US Food and Drug Administration (FDA) has vessel Although US Food and Drug Administration (FDA) has approved this device for use in arteriovenous dialysis grafts and approved this device for use in arteriovenous dialysis grafts and fistulae and for the treatment of coronary arteries saphenous fistulae and for the treatment of coronary arteries saphenous vein grafts and peripheral vessels clinical trials for the vein grafts and peripheral vessels clinical trials for the treatment of acute stroke are no longer in progress treatment of acute stroke are no longer in progress
Most devices are used in cerebral vessels that 2-5 mm
The Latis laser device The Latis laser device used laser energy to ablate clots used laser energy to ablate clots Arteries 2-5 mm in diameter could be Arteries 2-5 mm in diameter could be
treated including the ICA M1 or M2 treated including the ICA M1 or M2 branch of the MCA A1 branch of the branch of the MCA A1 branch of the anterior cerebral artery (ACA) basilar anterior cerebral artery (ACA) basilar artery posterior cerebral artery (PCA) artery posterior cerebral artery (PCA) and vertebral and vertebral
Patients could receive treatment as late Patients could receive treatment as late as 8 hours after symptom onset in the as 8 hours after symptom onset in the anterior circulation and within 24 hours in anterior circulation and within 24 hours in the posterior circulation the posterior circulation
Endovascular Photo Acoustic Endovascular Photo Acoustic Recanalization (EPAR) Recanalization (EPAR)
A laser power source generated energy for the A laser power source generated energy for the systemsystem
The energy was delivered by means of The energy was delivered by means of fiberoptics to the tip of the catheter at the fiberoptics to the tip of the catheter at the treatment sitetreatment site
Absorption of laser light by darkly pigmented Absorption of laser light by darkly pigmented materials (ie the clot) occurred inside the 1-mm materials (ie the clot) occurred inside the 1-mm catheter tipcatheter tip
the system was designed to minimize scattering the system was designed to minimize scattering of laser light of laser light
Absorption converted photo energy to acoustic Absorption converted photo energy to acoustic energy which then emulsified the clot inside the energy which then emulsified the clot inside the catheter tip catheter tip
EKOS ultrasound( the EKOS ultrasound( the Ultrasound Thrombolytic Ultrasound Thrombolytic
Infusion Catheter) Infusion Catheter) combines the use of a distal ultrasound transducer with combines the use of a distal ultrasound transducer with
infusion of a thrombolytic agent through the infusion of a thrombolytic agent through the microcathetermicrocatheter
Ultrasound changes the structure of the clot to Ultrasound changes the structure of the clot to temporarily increase its permeability while providing an temporarily increase its permeability while providing an acoustic pressure gradient to move the drug into the clot acoustic pressure gradient to move the drug into the clot to speed its dissolution to speed its dissolution
The EKOS catheter is placed in the proximal portion of the The EKOS catheter is placed in the proximal portion of the clot clot
After a 2-mg bolus of tPA was injected through the After a 2-mg bolus of tPA was injected through the catheter catheter
the patient received a continuous infusion of IA tPA 03 the patient received a continuous infusion of IA tPA 03 mgmin to a maximum of 20 mg and simultaneous mgmin to a maximum of 20 mg and simultaneous ultrasound transmission for as long as 60 minutes ultrasound transmission for as long as 60 minutes
One patient was treated with a total of 4 units of One patient was treated with a total of 4 units of recombinant reteplase (Retavase) hand-injected over 60 recombinant reteplase (Retavase) hand-injected over 60 minutes minutes
Penumbra system Penumbra system The Penumbra system (Penumbra Inc) provides a dual The Penumbra system (Penumbra Inc) provides a dual
approach to clot extraction using aspiration followed by approach to clot extraction using aspiration followed by clot retrieval with a ring device if needed clot retrieval with a ring device if needed
Mechanical Embolus Removal in Cerebral Ischemia Mechanical Embolus Removal in Cerebral Ischemia (MERCI)(MERCI)
a corkscrew-like apparatus to remove blood clots from a corkscrew-like apparatus to remove blood clots from the brain in patients experiencing an ischemic stroke the brain in patients experiencing an ischemic stroke
The corkscrew itself resides in the catheter tip which The corkscrew itself resides in the catheter tip which shields it from the wall of the vessel until it is ready to be shields it from the wall of the vessel until it is ready to be burrowed into the clot Once lodged in the clot the device burrowed into the clot Once lodged in the clot the device and clot are withdrawn from the vessel and clot are withdrawn from the vessel
Snarelike devicesSnarelike devices Snares such as the Neuronet snare (Guidant Snares such as the Neuronet snare (Guidant
Endovascular Santa Clara CA) have been developed Endovascular Santa Clara CA) have been developed specifically for use in the treatment of strokes specifically for use in the treatment of strokes
These devices are simple in design and do not require the These devices are simple in design and do not require the clot to be amenable to emulsification clot to be amenable to emulsification
X-Sizer deviceX-Sizer device a device with small moving blades at the a device with small moving blades at the
catheter tip catheter tip This device the X-Sizer device (EndiCor Medical This device the X-Sizer device (EndiCor Medical
San Clemente CA) can be used to excise the San Clemente CA) can be used to excise the thrombus and aspirate it thrombus and aspirate it
The device was being evaluated in randomized The device was being evaluated in randomized studies of coronary vessels and in a registry of studies of coronary vessels and in a registry of patients with acute myocardial infarctionpatients with acute myocardial infarction
Although the manufacturer had modified the Although the manufacturer had modified the device for use in cerebral vessels a safety and device for use in cerebral vessels a safety and feasibility study was indefinitely suspended after feasibility study was indefinitely suspended after only 1 patient was treated with the device in only 1 patient was treated with the device in Europe Europe
Suction thrombectomySuction thrombectomy This method of mechanical thrombolysis is one of the This method of mechanical thrombolysis is one of the
simplestsimplest In this readily available technique suction is applied with In this readily available technique suction is applied with
a syringe to remove thrombus in the ICA a syringe to remove thrombus in the ICA It requires no other devicesIt requires no other devices A catheter with a large inner diameter (Brite Tip Cordis A catheter with a large inner diameter (Brite Tip Cordis
Corporation Miami FL) was placed in the symptomatic Corporation Miami FL) was placed in the symptomatic vessel and navigated over a guidewire into the thrombusvessel and navigated over a guidewire into the thrombus
A 60-mL syringe was used to aspirate the thrombus A 60-mL syringe was used to aspirate the thrombus Each patient required angioplasty and stenting of carotid Each patient required angioplasty and stenting of carotid
bifurcation stenosis and received daily aspirin and bifurcation stenosis and received daily aspirin and ticlopidine after the procedure No complications ticlopidine after the procedure No complications occurred occurred
Summary Acute Stroke Summary Acute Stroke ImagingImaging
PhysiologyPhysiology importance collaterals importance collaterals
ndash ndashGrowing role for perfusion Growing role for perfusion assessmentassessment
tPAtPA guidelines amp limitations guidelines amp limitations Signs on CT amp MRSigns on CT amp MR follow physiology follow physiology Stroke trialsStroke trials PWI-DWI mismatch PWI-DWI mismatch
ndash ndashTreat based on physiology not timeTreat based on physiology not time ProtocolsProtocols should be fast and should be fast and
comprehensivecomprehensive
Fibrinolytics + AntiplateletsFibrinolytics + Antiplatelets
PlasminogenPlasminogen activators through fibrinolysis exposes activators through fibrinolysis exposes free thrombin and paradoxically stimulatesfree thrombin and paradoxically stimulates platelet platelet aggregation which leads to formation of aaggregation which leads to formation of a platelet platelet thrombus (white clot) thrombus (white clot)
This new thrombus is relatively resistant to This new thrombus is relatively resistant to fibrinolyticsfibrinolytics
So new regimen in case of acute stroke isSo new regimen in case of acute stroke is fibrinolytics + antiplatelet drugsfibrinolytics + antiplatelet drugs
rtPA + IIbIIIa inhibitors( tirofiban rtPA + IIbIIIa inhibitors( tirofiban abciximab) orabciximab) or
Urokinase + IIbIIIa Urokinase + IIbIIIa inhibitors( tirofiban abciximab)inhibitors( tirofiban abciximab)
Intra-arterial Thrombolysis Tirofiban (04 microgkgmin bolus for 3 min followed by Tirofiban (04 microgkgmin bolus for 3 min followed by
0125 ugkgmin)0125 ugkgmin)
++
Heparin (2000ndash3000 IU bolus followed by Heparin (2000ndash3000 IU bolus followed by 1000 IUhour infusion 1000 IUhour infusion
with ACT maintained bw 200-300) throughout the with ACT maintained bw 200-300) throughout the interventional procedure and for 24ndash48 hours thereafter when interventional procedure and for 24ndash48 hours thereafter when there is neither intraprocedural bleeding nor suspicion of there is neither intraprocedural bleeding nor suspicion of increased risk of bleeding increased risk of bleeding
Maximum dose of Urokinase Maximum dose of Urokinase Anterior circulation stroke - 500000 IU (mean 400000 Anterior circulation stroke - 500000 IU (mean 400000
IU range 300000ndash500000 IU)IU range 300000ndash500000 IU) Posterior circulation stroke -1000000 IU (mean 837000 Posterior circulation stroke -1000000 IU (mean 837000
IU range 300000ndash1000000 IU)IU range 300000ndash1000000 IU)American Journal of NeuroradiologyAmerican Journal of Neuroradiology 262595-2601 2005262595-2601 2005
Intravenous ThrombolysisIntravenous Thrombolysis
The first method to restore cerebral The first method to restore cerebral perfusion is clot lysis with the goal perfusion is clot lysis with the goal of re-establishing blood flow to the of re-establishing blood flow to the affected tissue affected tissue
IV thrombolysis rt-PA is the only IV thrombolysis rt-PA is the only FDA- approved treatment for AIS FDA- approved treatment for AIS
Fibrinolysis is enhanced powerfully Fibrinolysis is enhanced powerfully by rt-PAby rt-PA
Intravenous rTPA Intravenous rTPA administration administration protocolprotocol
Total dose of rt-PA 09 mgkg (maximum dose Total dose of rt-PA 09 mgkg (maximum dose 90 mg)90 mg)
Give 10 as initial IV bolusGive 10 as initial IV bolus Infuse remainder over 1 hourInfuse remainder over 1 hour Admit patient to an ICU or stroke unit for Admit patient to an ICU or stroke unit for
monitoringmonitoring Neurologic assessments every 15 minutes Neurologic assessments every 15 minutes
during infusion then every 30 minutes for next during infusion then every 30 minutes for next 6 hours then every hour until 24hours after 6 hours then every hour until 24hours after treatmenttreatment
Favorable Outcome vs Treatment Time Favorable Outcome vs Treatment Time with IV rTPAwith IV rTPA
Protocol limit = 3 hrs
Benefit ~ 45 hrs
Thromboembolism During coilingThromboembolism During coiling Most feared and frequent complication Most feared and frequent complication Reported incidence - Approx 7 Reported incidence - Approx 7 SourcesSources of Thromboembolism are of Thromboembolism are
- Clots at the aneurysmal neck during or immediately- Clots at the aneurysmal neck during or immediately after after embolization embolization
- Thrombus forming on catheters during- Thrombus forming on catheters during proceduresprocedures
- Stenosis of an adjacent artery dt coil mass- Stenosis of an adjacent artery dt coil mass or herniationor herniation
- Migration of intraaneurysmal- Migration of intraaneurysmal thrombus during coil thrombus during coil placement placement
- Slow flow dt vasospasm - Slow flow dt vasospasm
- Rare and unlikely causes are hypercoagulable- Rare and unlikely causes are hypercoagulable state such state such as antiphospholipid antibody syndrome or due to HITas antiphospholipid antibody syndrome or due to HIT
Occur more often with wide-necked aneurysms (dt Occur more often with wide-necked aneurysms (dt increased exposed surface area of thrombogenic coil increased exposed surface area of thrombogenic coil material)material)
Current regimen of endovascular Current regimen of endovascular managementmanagement
The The glycoprotein IIbIIIa antagonist tirofiban glycoprotein IIbIIIa antagonist tirofiban (04 (04 microgkgmin bolus for 30 minutes followed by infusion of microgkgmin bolus for 30 minutes followed by infusion of 0125 ugkgmin until the thrombus dissolved) 0125 ugkgmin until the thrombus dissolved)
Intraarterial thrombolysis with Intraarterial thrombolysis with urokinase or r- TPA urokinase or r- TPA increase of intravenous (IV) heparin (measured by increase of intravenous (IV) heparin (measured by
ACT) ACT) Intravenous aspirin Intravenous aspirin
Coil-related platelet aggregation (white clot) is Coil-related platelet aggregation (white clot) is unlikely to respond to fibrinolytics but has a high risk unlikely to respond to fibrinolytics but has a high risk of hemorrhage (In ISAT) all 5 patients who had of hemorrhage (In ISAT) all 5 patients who had received thrombolytic therapy with tPA to treat a received thrombolytic therapy with tPA to treat a thromboembolic complication after endovascular thromboembolic complication after endovascular treatment rebleed and all of these patients died)treatment rebleed and all of these patients died)
IntracranialIntracranial Stenting Stenting Metallic foreign body such as stent will accumulate Metallic foreign body such as stent will accumulate
thrombus in the absence of platelet inhibitionthrombus in the absence of platelet inhibition Antiplatelet drugs are important to prevent peri or Antiplatelet drugs are important to prevent peri or
post-interventional thromboembolic eventspost-interventional thromboembolic events Optimal treatment regimens has not been determined Optimal treatment regimens has not been determined
but usually but usually Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-
procedureprocedureOrOr
Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on
morning of proceduremorning of procedure
If need to use stent is not pre-planned thanIf need to use stent is not pre-planned than
Abciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkgAbciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkg IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)
Glycoprotein IIbIIIa inhibitor are not used routinely during elective Glycoprotein IIbIIIa inhibitor are not used routinely during elective stenting procedure dt increased risk of ICH stenting procedure dt increased risk of ICH
Carotid StentingCarotid Stenting
Pre-procedurePre-procedure
Double Antiplatelet therapy is routinely given Double Antiplatelet therapy is routinely given beginning at least 3beginning at least 3
days before the proceduredays before the procedure
Aspirin 325mgd+Clopidogrel 75mgdAspirin 325mgd+Clopidogrel 75mgd During procedureDuring procedure
Heparin is given with target clotting time of 250-Heparin is given with target clotting time of 250-300sec300sec
Post-procedure Post-procedure
Aspirin 325mg is continued indefinitely and Aspirin 325mg is continued indefinitely and
Clopidogrel 75mgd for at least 6 weeks Clopidogrel 75mgd for at least 6 weeks
Inclusion criteria for Local ThrombolysisInclusion criteria for Local Thrombolysis a)a) Patients in severe clinical grade on admission Patients in severe clinical grade on admission
with evidence of dural venous sinus with evidence of dural venous sinus thrombosis and restrictive venous outflow on thrombosis and restrictive venous outflow on cerebral angiogramcerebral angiogram
b)b) Patients in clinical grade 3 worsening on Patients in clinical grade 3 worsening on heparin therapy Restriction to venous heparin therapy Restriction to venous outflow was defined as an increase in brain outflow was defined as an increase in brain circulation time gt 12 s delay in the drainage circulation time gt 12 s delay in the drainage of cortical veins with cortical veins hanging of cortical veins with cortical veins hanging in spacein space
Treatment Options for Venous Thrombosis
CT Grading for Venous ThrombosisCT Grading for Venous Thrombosis Grade I no parenchymal change Grade I no parenchymal change
(hyperdense (hyperdense sinuses cortical veins empty sinuses cortical veins empty delta sign)delta sign)
Grade II non hemorrhagic venous infarct Grade II non hemorrhagic venous infarct without mass effect without mass effect
Grade III non-hemorrhagic infarct with Grade III non-hemorrhagic infarct with mass effectmass effect
Grade IV hemorrhagic venous infarct (max Grade IV hemorrhagic venous infarct (max diameter lt 3 cm) with no mass effectdiameter lt 3 cm) with no mass effect
Grade V hemorrhagic venous infarct (max Grade V hemorrhagic venous infarct (max diameter gt 3 cm) with mass effect diameter gt 3 cm) with mass effect
Local ThrombolysisLocal Thrombolysis
Femoral Jugular access was secured and a guiding Femoral Jugular access was secured and a guiding catheter was placed in the jugular bulb catheter was placed in the jugular bulb Mechanical Mechanical clot maceration clot maceration was done with the guidewire was done with the guidewire following which a microcatheter (was navigated and following which a microcatheter (was navigated and placed in the thrombosed segment of sinus confirmed placed in the thrombosed segment of sinus confirmed on a selective venogram on a selective venogram
Urokinase infusion Bolus dose of 2-6 lacs followed Urokinase infusion Bolus dose of 2-6 lacs followed by 60000 to 100000 units per hour along with by 60000 to 100000 units per hour along with periodic check venogram Along with maintenance periodic check venogram Along with maintenance systemic infusion of Heparinsystemic infusion of Heparin Other agents such as Other agents such as streptokinase altepase or rTPAstreptokinase altepase or rTPA can be also used can be also used
After thrombolysis patient should subjected to oral After thrombolysis patient should subjected to oral anticoagulation for six monthsanticoagulation for six months
Low-molecular-weight Low-molecular-weight heparinheparin
PharmacologyPharmacologyLMWH as its name suggests is a glycosaminoglycan that is approximatelyLMWH as its name suggests is a glycosaminoglycan that is approximately
one third the molecular weight of UFH It is derived from UFH through one third the molecular weight of UFH It is derived from UFH through variousvarious
depolymerization processes LMWH binds to antithrombin which in turn depolymerization processes LMWH binds to antithrombin which in turn
Neutralizes actors Xa and IIa Because LMWH lacks many of the longer Neutralizes actors Xa and IIa Because LMWH lacks many of the longer chains chains
required for binding to thrombin it has less ability to neutralize thrombin required for binding to thrombin it has less ability to neutralize thrombin
relativeto its ability to neutralize factor Xa LMWH also has less relativeto its ability to neutralize factor Xa LMWH also has less nonspecific nonspecific
binding to other proteins There is greater bioavailability with more binding to other proteins There is greater bioavailability with more predictable predictable
pharmacokinetics that eliminates the need for monitoring The smaller pharmacokinetics that eliminates the need for monitoring The smaller size also size also
allows for enhanced subcutaneous absorption when compared with UFHallows for enhanced subcutaneous absorption when compared with UFH
Three LMWH preparations are Three LMWH preparations are currently approved for use in the currently approved for use in the United States (1) enoxaparin (2) United States (1) enoxaparin (2) dalteparin and (3) tinzaparin dalteparin and (3) tinzaparin
They are all administered They are all administered subcutaneously at intervals of either subcutaneously at intervals of either once or twice daily for both once or twice daily for both prophylaxis and treatment dosesprophylaxis and treatment doses
Few Experiences of Few Experiences of ThrombolysisThrombolysis
Vickey 25 Yrs male patient presented Vickey 25 Yrs male patient presented with 12with 12thth day HO severe headache with day HO severe headache with right sided hemiplegiaright sided hemiplegia
MRI shows thrombosis of the superior MRI shows thrombosis of the superior sagittal left transverse left sigmoid sagittal left transverse left sigmoid sinuses and cortical veins in the fronto-sinuses and cortical veins in the fronto-parietal regions with eo haemorrhagic parietal regions with eo haemorrhagic infarct in the left cerebral hemisphere infarct in the left cerebral hemisphere with mass effect( Grade ndashV)with mass effect( Grade ndashV)
Sashi Srivastava 64 yrs FSashi Srivastava 64 yrs F In a follow up case of MRD with infra-renal In a follow up case of MRD with infra-renal
aortic abdominal and bilateral renal artery aortic abdominal and bilateral renal artery thrombosis renal angiogram shows filling thrombosis renal angiogram shows filling defects in the right Renal artery defects in the right Renal artery
Initially Renal angioplasty was done Initially Renal angioplasty was done Following angioplasty few thrombi are seem Following angioplasty few thrombi are seem to extends into the segmental branches and to extends into the segmental branches and causing blockage So Thrombolysis was causing blockage So Thrombolysis was plane to dissolve the run-out thrombi with plane to dissolve the run-out thrombi with urokinase urokinase
Rakesh 34yrsMRakesh 34yrsM Left SFA pseudoaneurysm with Left SFA pseudoaneurysm with
Covered stent placementCovered stent placement Pre operative antiplatelets with post Pre operative antiplatelets with post
procedure heparin Tirofiban procedure heparin Tirofiban followed by aspirin and clopidogrel followed by aspirin and clopidogrel were usedwere used
IAT may be a treatment option for selected patients IAT may be a treatment option for selected patients Possible selection criteria include Possible selection criteria include
presentation between 3 and 6 hours from symptom onsetpresentation between 3 and 6 hours from symptom onset major cerebral artery occlusion major cerebral artery occlusion severe neurologic deficits severe neurologic deficits high risk of systemic hemorrhage with IV rt-PA (eg recent high risk of systemic hemorrhage with IV rt-PA (eg recent
surgery) surgery) The MERCI (Mechanical Embolus Removal in Cerebral The MERCI (Mechanical Embolus Removal in Cerebral
Ischemia) retrievalIschemia) retrieval system system
Has been FDA-approved for recanalizing acutely occluded Has been FDA-approved for recanalizing acutely occluded cerebral arteries cerebral arteries
In the Multi-MERCI study patients who did not improve In the Multi-MERCI study patients who did not improve immediately after IV rt-PA underwent mechanical immediately after IV rt-PA underwent mechanical embolectomy within 8 hours of symptom onset embolectomy within 8 hours of symptom onset
Partial or complete recanalization occurred in 74 of Partial or complete recanalization occurred in 74 of patientspatients
with a symptomatic intracerebral hemorrhage (sICH) rate of with a symptomatic intracerebral hemorrhage (sICH) rate of 67 67
Mechanical embolectomy with the MERCI retriever may be a Mechanical embolectomy with the MERCI retriever may be a feasible and safe option for patients after IV rt-PAfeasible and safe option for patients after IV rt-PA
Penumbra stroke systemPenumbra stroke system This device combines two methods of clot This device combines two methods of clot
extraction aspiration and mechanical extraction aspiration and mechanical extraction extraction
First the clot is aspirated then a thrombus First the clot is aspirated then a thrombus removal ring can be used if necessary to removal ring can be used if necessary to remove remaining clot remove remaining clot
successful recanalizing 82successful recanalizing 82 Bridging therapyBridging therapy
06 mgkg IV rt-PA followed by IAT with IA rt-06 mgkg IV rt-PA followed by IAT with IA rt-PA (up to 20 mg)PA (up to 20 mg)
achieved a higher recanalization rateachieved a higher recanalization rate
Criteria for thrombolysis with rTPACriteria for thrombolysis with rTPA
Inclusion criteriaInclusion criteria Clinical signs and symptoms consistent with ischemic Clinical signs and symptoms consistent with ischemic
strokestroke Patient last seen normal within 3 hoursPatient last seen normal within 3 hours Measurable neurologic deficitMeasurable neurologic deficit
Exclusion criteriaExclusion criteria Any hemorrhage on neuroimaging (CT or MRI)Any hemorrhage on neuroimaging (CT or MRI) Symptoms suggestive of subarachnoid hemorrhageSymptoms suggestive of subarachnoid hemorrhage Seizure at stroke onset that is thought to contribute to Seizure at stroke onset that is thought to contribute to
neurologic deficitneurologic deficit Hypodensity greater than one third cerebral hemisphere Hypodensity greater than one third cerebral hemisphere
on CTon CT SBP greater than 185 mm Hg or DBP greater than 110 SBP greater than 185 mm Hg or DBP greater than 110
mm Hgmm Hg International normalized ratio (INR) greater than 17International normalized ratio (INR) greater than 17
Ischemic Stroke Ischemic Stroke Treatment ndash 2006Treatment ndash 2006
IV tissue plasminogen activator (tPA)IV tissue plasminogen activator (tPA) ndash ndash Only FDA-approved acute stroke drugOnly FDA-approved acute stroke drug ndash ndash 3 hour treatment window3 hour treatment window
MERCI - Concentric clot retrieval MERCI - Concentric clot retrieval devicedevice ndash ndash Rescue therapy - approved 2004Rescue therapy - approved 2004 ndash ndash Device approval (not outcomes-based)Device approval (not outcomes-based)
Off label approachesOff label approaches ndash ndash IV tPA after 3 hoursIV tPA after 3 hours ndash ndash IV-IA tPA sequential strategiesIV-IA tPA sequential strategies ndash ndash IA tPA clot angioplasty fragmentationIA tPA clot angioplasty fragmentation ndash ndash Ultrasound-assisted tPA lysisUltrasound-assisted tPA lysis
rt-PA Trials NINDSrt-PA Trials NINDS
Acute stroke - 624 patientsAcute stroke - 624 patients Treat within 3 hrsTreat within 3 hrs Intravenous 09 mgkg rt-PA vs placeboIntravenous 09 mgkg rt-PA vs placebo Hemorrhage 64 tPA 06 placeboHemorrhage 64 tPA 06 placebo Neurologic recovery better with tPA 30 Neurologic recovery better with tPA 30
more like to have minimal or no disabilitymore like to have minimal or no disability
First proven approved treatment for First proven approved treatment for strokestroke
Limitations of tPALimitations of tPA Only 4 of acute strokes receive tPAOnly 4 of acute strokes receive tPA (Kleindorfer et al Stroke 2004 35 e27-e29)(Kleindorfer et al Stroke 2004 35 e27-e29)
Only 22 of patients present within 3 hoursOnly 22 of patients present within 3 hours1048707 1048707 51 of these ineligible due to51 of these ineligible due to
bull bull Mild severityMild severity bull bull Medical or surgical historyMedical or surgical history bull bull Blood testsBlood tests
Sustained recanalization only 13Sustained recanalization only 13 (Alexandrov et al NEJM 2004 351 2170-8)(Alexandrov et al NEJM 2004 351 2170-8)
Concern for hemorrhageConcern for hemorrhage tPA potentiates apoptotic injury tPA potentiates apoptotic injury (Liu et al Nature Med 2004 101379-83)(Liu et al Nature Med 2004 101379-83)
PROACT II IA Lysis TrialPROACT II IA Lysis Trial Baseline 24 hours 8 days
Baseline 60 minutes 120 minutes
9mg IAProurokinase
Desmoteplase Trials DEDAS Desmoteplase Trials DEDAS DIASDIAS
Trial OverviewTrial Overview Double blind randomized placebo Double blind randomized placebo
controlled trialscontrolled trials IV delivery 3-9 hour time windowIV delivery 3-9 hour time window Plasminogen activator ndash from Plasminogen activator ndash from vampire bat vampire bat
salivasaliva Selection based on PWI-DWI MismatchSelection based on PWI-DWI Mismatch
MRI InclusionMRI Inclusion PWI defect at least 2 cm AND ~20 larger PWI defect at least 2 cm AND ~20 larger
than DWIthan DWI PWI should be obvious even visible on PWI should be obvious even visible on
raw imagesraw imagesMRI ExclusionMRI Exclusion
DWI gt 13 MCADWI gt 13 MCA MRA ICA occlusionMRA ICA occlusion
Desmoteplase ndash DIAS Desmoteplase ndash DIAS ResultsResults
Mechanical Thrombolysis Mechanical Thrombolysis devicesdevices
mechanical thrombolysis potentially extends the treatment mechanical thrombolysis potentially extends the treatment window because they act promptly at the site of the thrombuswindow because they act promptly at the site of the thrombus
The devices can retrieve large clots that pharmaceutical agents The devices can retrieve large clots that pharmaceutical agents may not successfully lysemay not successfully lyse
Patients treated with IV tPA may be considered for treatment of Patients treated with IV tPA may be considered for treatment of residual clot with some of these devicesresidual clot with some of these devices
suction-creating saline jets suction-creating saline jets laser energy ultrasound laser energy ultrasound a corkscrew apparatus to treat strokesa corkscrew apparatus to treat strokes The AngioJet systemThe AngioJet system uses saline jets that are directed back into the catheter to uses saline jets that are directed back into the catheter to
create a low-pressure zone around the catheter tip inducing create a low-pressure zone around the catheter tip inducing suction suction
The clot is pulled into the exhaust lumen and removed from the The clot is pulled into the exhaust lumen and removed from the vessel Although US Food and Drug Administration (FDA) has vessel Although US Food and Drug Administration (FDA) has approved this device for use in arteriovenous dialysis grafts and approved this device for use in arteriovenous dialysis grafts and fistulae and for the treatment of coronary arteries saphenous fistulae and for the treatment of coronary arteries saphenous vein grafts and peripheral vessels clinical trials for the vein grafts and peripheral vessels clinical trials for the treatment of acute stroke are no longer in progress treatment of acute stroke are no longer in progress
Most devices are used in cerebral vessels that 2-5 mm
The Latis laser device The Latis laser device used laser energy to ablate clots used laser energy to ablate clots Arteries 2-5 mm in diameter could be Arteries 2-5 mm in diameter could be
treated including the ICA M1 or M2 treated including the ICA M1 or M2 branch of the MCA A1 branch of the branch of the MCA A1 branch of the anterior cerebral artery (ACA) basilar anterior cerebral artery (ACA) basilar artery posterior cerebral artery (PCA) artery posterior cerebral artery (PCA) and vertebral and vertebral
Patients could receive treatment as late Patients could receive treatment as late as 8 hours after symptom onset in the as 8 hours after symptom onset in the anterior circulation and within 24 hours in anterior circulation and within 24 hours in the posterior circulation the posterior circulation
Endovascular Photo Acoustic Endovascular Photo Acoustic Recanalization (EPAR) Recanalization (EPAR)
A laser power source generated energy for the A laser power source generated energy for the systemsystem
The energy was delivered by means of The energy was delivered by means of fiberoptics to the tip of the catheter at the fiberoptics to the tip of the catheter at the treatment sitetreatment site
Absorption of laser light by darkly pigmented Absorption of laser light by darkly pigmented materials (ie the clot) occurred inside the 1-mm materials (ie the clot) occurred inside the 1-mm catheter tipcatheter tip
the system was designed to minimize scattering the system was designed to minimize scattering of laser light of laser light
Absorption converted photo energy to acoustic Absorption converted photo energy to acoustic energy which then emulsified the clot inside the energy which then emulsified the clot inside the catheter tip catheter tip
EKOS ultrasound( the EKOS ultrasound( the Ultrasound Thrombolytic Ultrasound Thrombolytic
Infusion Catheter) Infusion Catheter) combines the use of a distal ultrasound transducer with combines the use of a distal ultrasound transducer with
infusion of a thrombolytic agent through the infusion of a thrombolytic agent through the microcathetermicrocatheter
Ultrasound changes the structure of the clot to Ultrasound changes the structure of the clot to temporarily increase its permeability while providing an temporarily increase its permeability while providing an acoustic pressure gradient to move the drug into the clot acoustic pressure gradient to move the drug into the clot to speed its dissolution to speed its dissolution
The EKOS catheter is placed in the proximal portion of the The EKOS catheter is placed in the proximal portion of the clot clot
After a 2-mg bolus of tPA was injected through the After a 2-mg bolus of tPA was injected through the catheter catheter
the patient received a continuous infusion of IA tPA 03 the patient received a continuous infusion of IA tPA 03 mgmin to a maximum of 20 mg and simultaneous mgmin to a maximum of 20 mg and simultaneous ultrasound transmission for as long as 60 minutes ultrasound transmission for as long as 60 minutes
One patient was treated with a total of 4 units of One patient was treated with a total of 4 units of recombinant reteplase (Retavase) hand-injected over 60 recombinant reteplase (Retavase) hand-injected over 60 minutes minutes
Penumbra system Penumbra system The Penumbra system (Penumbra Inc) provides a dual The Penumbra system (Penumbra Inc) provides a dual
approach to clot extraction using aspiration followed by approach to clot extraction using aspiration followed by clot retrieval with a ring device if needed clot retrieval with a ring device if needed
Mechanical Embolus Removal in Cerebral Ischemia Mechanical Embolus Removal in Cerebral Ischemia (MERCI)(MERCI)
a corkscrew-like apparatus to remove blood clots from a corkscrew-like apparatus to remove blood clots from the brain in patients experiencing an ischemic stroke the brain in patients experiencing an ischemic stroke
The corkscrew itself resides in the catheter tip which The corkscrew itself resides in the catheter tip which shields it from the wall of the vessel until it is ready to be shields it from the wall of the vessel until it is ready to be burrowed into the clot Once lodged in the clot the device burrowed into the clot Once lodged in the clot the device and clot are withdrawn from the vessel and clot are withdrawn from the vessel
Snarelike devicesSnarelike devices Snares such as the Neuronet snare (Guidant Snares such as the Neuronet snare (Guidant
Endovascular Santa Clara CA) have been developed Endovascular Santa Clara CA) have been developed specifically for use in the treatment of strokes specifically for use in the treatment of strokes
These devices are simple in design and do not require the These devices are simple in design and do not require the clot to be amenable to emulsification clot to be amenable to emulsification
X-Sizer deviceX-Sizer device a device with small moving blades at the a device with small moving blades at the
catheter tip catheter tip This device the X-Sizer device (EndiCor Medical This device the X-Sizer device (EndiCor Medical
San Clemente CA) can be used to excise the San Clemente CA) can be used to excise the thrombus and aspirate it thrombus and aspirate it
The device was being evaluated in randomized The device was being evaluated in randomized studies of coronary vessels and in a registry of studies of coronary vessels and in a registry of patients with acute myocardial infarctionpatients with acute myocardial infarction
Although the manufacturer had modified the Although the manufacturer had modified the device for use in cerebral vessels a safety and device for use in cerebral vessels a safety and feasibility study was indefinitely suspended after feasibility study was indefinitely suspended after only 1 patient was treated with the device in only 1 patient was treated with the device in Europe Europe
Suction thrombectomySuction thrombectomy This method of mechanical thrombolysis is one of the This method of mechanical thrombolysis is one of the
simplestsimplest In this readily available technique suction is applied with In this readily available technique suction is applied with
a syringe to remove thrombus in the ICA a syringe to remove thrombus in the ICA It requires no other devicesIt requires no other devices A catheter with a large inner diameter (Brite Tip Cordis A catheter with a large inner diameter (Brite Tip Cordis
Corporation Miami FL) was placed in the symptomatic Corporation Miami FL) was placed in the symptomatic vessel and navigated over a guidewire into the thrombusvessel and navigated over a guidewire into the thrombus
A 60-mL syringe was used to aspirate the thrombus A 60-mL syringe was used to aspirate the thrombus Each patient required angioplasty and stenting of carotid Each patient required angioplasty and stenting of carotid
bifurcation stenosis and received daily aspirin and bifurcation stenosis and received daily aspirin and ticlopidine after the procedure No complications ticlopidine after the procedure No complications occurred occurred
Summary Acute Stroke Summary Acute Stroke ImagingImaging
PhysiologyPhysiology importance collaterals importance collaterals
ndash ndashGrowing role for perfusion Growing role for perfusion assessmentassessment
tPAtPA guidelines amp limitations guidelines amp limitations Signs on CT amp MRSigns on CT amp MR follow physiology follow physiology Stroke trialsStroke trials PWI-DWI mismatch PWI-DWI mismatch
ndash ndashTreat based on physiology not timeTreat based on physiology not time ProtocolsProtocols should be fast and should be fast and
comprehensivecomprehensive
Intra-arterial Thrombolysis Tirofiban (04 microgkgmin bolus for 3 min followed by Tirofiban (04 microgkgmin bolus for 3 min followed by
0125 ugkgmin)0125 ugkgmin)
++
Heparin (2000ndash3000 IU bolus followed by Heparin (2000ndash3000 IU bolus followed by 1000 IUhour infusion 1000 IUhour infusion
with ACT maintained bw 200-300) throughout the with ACT maintained bw 200-300) throughout the interventional procedure and for 24ndash48 hours thereafter when interventional procedure and for 24ndash48 hours thereafter when there is neither intraprocedural bleeding nor suspicion of there is neither intraprocedural bleeding nor suspicion of increased risk of bleeding increased risk of bleeding
Maximum dose of Urokinase Maximum dose of Urokinase Anterior circulation stroke - 500000 IU (mean 400000 Anterior circulation stroke - 500000 IU (mean 400000
IU range 300000ndash500000 IU)IU range 300000ndash500000 IU) Posterior circulation stroke -1000000 IU (mean 837000 Posterior circulation stroke -1000000 IU (mean 837000
IU range 300000ndash1000000 IU)IU range 300000ndash1000000 IU)American Journal of NeuroradiologyAmerican Journal of Neuroradiology 262595-2601 2005262595-2601 2005
Intravenous ThrombolysisIntravenous Thrombolysis
The first method to restore cerebral The first method to restore cerebral perfusion is clot lysis with the goal perfusion is clot lysis with the goal of re-establishing blood flow to the of re-establishing blood flow to the affected tissue affected tissue
IV thrombolysis rt-PA is the only IV thrombolysis rt-PA is the only FDA- approved treatment for AIS FDA- approved treatment for AIS
Fibrinolysis is enhanced powerfully Fibrinolysis is enhanced powerfully by rt-PAby rt-PA
Intravenous rTPA Intravenous rTPA administration administration protocolprotocol
Total dose of rt-PA 09 mgkg (maximum dose Total dose of rt-PA 09 mgkg (maximum dose 90 mg)90 mg)
Give 10 as initial IV bolusGive 10 as initial IV bolus Infuse remainder over 1 hourInfuse remainder over 1 hour Admit patient to an ICU or stroke unit for Admit patient to an ICU or stroke unit for
monitoringmonitoring Neurologic assessments every 15 minutes Neurologic assessments every 15 minutes
during infusion then every 30 minutes for next during infusion then every 30 minutes for next 6 hours then every hour until 24hours after 6 hours then every hour until 24hours after treatmenttreatment
Favorable Outcome vs Treatment Time Favorable Outcome vs Treatment Time with IV rTPAwith IV rTPA
Protocol limit = 3 hrs
Benefit ~ 45 hrs
Thromboembolism During coilingThromboembolism During coiling Most feared and frequent complication Most feared and frequent complication Reported incidence - Approx 7 Reported incidence - Approx 7 SourcesSources of Thromboembolism are of Thromboembolism are
- Clots at the aneurysmal neck during or immediately- Clots at the aneurysmal neck during or immediately after after embolization embolization
- Thrombus forming on catheters during- Thrombus forming on catheters during proceduresprocedures
- Stenosis of an adjacent artery dt coil mass- Stenosis of an adjacent artery dt coil mass or herniationor herniation
- Migration of intraaneurysmal- Migration of intraaneurysmal thrombus during coil thrombus during coil placement placement
- Slow flow dt vasospasm - Slow flow dt vasospasm
- Rare and unlikely causes are hypercoagulable- Rare and unlikely causes are hypercoagulable state such state such as antiphospholipid antibody syndrome or due to HITas antiphospholipid antibody syndrome or due to HIT
Occur more often with wide-necked aneurysms (dt Occur more often with wide-necked aneurysms (dt increased exposed surface area of thrombogenic coil increased exposed surface area of thrombogenic coil material)material)
Current regimen of endovascular Current regimen of endovascular managementmanagement
The The glycoprotein IIbIIIa antagonist tirofiban glycoprotein IIbIIIa antagonist tirofiban (04 (04 microgkgmin bolus for 30 minutes followed by infusion of microgkgmin bolus for 30 minutes followed by infusion of 0125 ugkgmin until the thrombus dissolved) 0125 ugkgmin until the thrombus dissolved)
Intraarterial thrombolysis with Intraarterial thrombolysis with urokinase or r- TPA urokinase or r- TPA increase of intravenous (IV) heparin (measured by increase of intravenous (IV) heparin (measured by
ACT) ACT) Intravenous aspirin Intravenous aspirin
Coil-related platelet aggregation (white clot) is Coil-related platelet aggregation (white clot) is unlikely to respond to fibrinolytics but has a high risk unlikely to respond to fibrinolytics but has a high risk of hemorrhage (In ISAT) all 5 patients who had of hemorrhage (In ISAT) all 5 patients who had received thrombolytic therapy with tPA to treat a received thrombolytic therapy with tPA to treat a thromboembolic complication after endovascular thromboembolic complication after endovascular treatment rebleed and all of these patients died)treatment rebleed and all of these patients died)
IntracranialIntracranial Stenting Stenting Metallic foreign body such as stent will accumulate Metallic foreign body such as stent will accumulate
thrombus in the absence of platelet inhibitionthrombus in the absence of platelet inhibition Antiplatelet drugs are important to prevent peri or Antiplatelet drugs are important to prevent peri or
post-interventional thromboembolic eventspost-interventional thromboembolic events Optimal treatment regimens has not been determined Optimal treatment regimens has not been determined
but usually but usually Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-
procedureprocedureOrOr
Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on
morning of proceduremorning of procedure
If need to use stent is not pre-planned thanIf need to use stent is not pre-planned than
Abciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkgAbciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkg IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)
Glycoprotein IIbIIIa inhibitor are not used routinely during elective Glycoprotein IIbIIIa inhibitor are not used routinely during elective stenting procedure dt increased risk of ICH stenting procedure dt increased risk of ICH
Carotid StentingCarotid Stenting
Pre-procedurePre-procedure
Double Antiplatelet therapy is routinely given Double Antiplatelet therapy is routinely given beginning at least 3beginning at least 3
days before the proceduredays before the procedure
Aspirin 325mgd+Clopidogrel 75mgdAspirin 325mgd+Clopidogrel 75mgd During procedureDuring procedure
Heparin is given with target clotting time of 250-Heparin is given with target clotting time of 250-300sec300sec
Post-procedure Post-procedure
Aspirin 325mg is continued indefinitely and Aspirin 325mg is continued indefinitely and
Clopidogrel 75mgd for at least 6 weeks Clopidogrel 75mgd for at least 6 weeks
Inclusion criteria for Local ThrombolysisInclusion criteria for Local Thrombolysis a)a) Patients in severe clinical grade on admission Patients in severe clinical grade on admission
with evidence of dural venous sinus with evidence of dural venous sinus thrombosis and restrictive venous outflow on thrombosis and restrictive venous outflow on cerebral angiogramcerebral angiogram
b)b) Patients in clinical grade 3 worsening on Patients in clinical grade 3 worsening on heparin therapy Restriction to venous heparin therapy Restriction to venous outflow was defined as an increase in brain outflow was defined as an increase in brain circulation time gt 12 s delay in the drainage circulation time gt 12 s delay in the drainage of cortical veins with cortical veins hanging of cortical veins with cortical veins hanging in spacein space
Treatment Options for Venous Thrombosis
CT Grading for Venous ThrombosisCT Grading for Venous Thrombosis Grade I no parenchymal change Grade I no parenchymal change
(hyperdense (hyperdense sinuses cortical veins empty sinuses cortical veins empty delta sign)delta sign)
Grade II non hemorrhagic venous infarct Grade II non hemorrhagic venous infarct without mass effect without mass effect
Grade III non-hemorrhagic infarct with Grade III non-hemorrhagic infarct with mass effectmass effect
Grade IV hemorrhagic venous infarct (max Grade IV hemorrhagic venous infarct (max diameter lt 3 cm) with no mass effectdiameter lt 3 cm) with no mass effect
Grade V hemorrhagic venous infarct (max Grade V hemorrhagic venous infarct (max diameter gt 3 cm) with mass effect diameter gt 3 cm) with mass effect
Local ThrombolysisLocal Thrombolysis
Femoral Jugular access was secured and a guiding Femoral Jugular access was secured and a guiding catheter was placed in the jugular bulb catheter was placed in the jugular bulb Mechanical Mechanical clot maceration clot maceration was done with the guidewire was done with the guidewire following which a microcatheter (was navigated and following which a microcatheter (was navigated and placed in the thrombosed segment of sinus confirmed placed in the thrombosed segment of sinus confirmed on a selective venogram on a selective venogram
Urokinase infusion Bolus dose of 2-6 lacs followed Urokinase infusion Bolus dose of 2-6 lacs followed by 60000 to 100000 units per hour along with by 60000 to 100000 units per hour along with periodic check venogram Along with maintenance periodic check venogram Along with maintenance systemic infusion of Heparinsystemic infusion of Heparin Other agents such as Other agents such as streptokinase altepase or rTPAstreptokinase altepase or rTPA can be also used can be also used
After thrombolysis patient should subjected to oral After thrombolysis patient should subjected to oral anticoagulation for six monthsanticoagulation for six months
Low-molecular-weight Low-molecular-weight heparinheparin
PharmacologyPharmacologyLMWH as its name suggests is a glycosaminoglycan that is approximatelyLMWH as its name suggests is a glycosaminoglycan that is approximately
one third the molecular weight of UFH It is derived from UFH through one third the molecular weight of UFH It is derived from UFH through variousvarious
depolymerization processes LMWH binds to antithrombin which in turn depolymerization processes LMWH binds to antithrombin which in turn
Neutralizes actors Xa and IIa Because LMWH lacks many of the longer Neutralizes actors Xa and IIa Because LMWH lacks many of the longer chains chains
required for binding to thrombin it has less ability to neutralize thrombin required for binding to thrombin it has less ability to neutralize thrombin
relativeto its ability to neutralize factor Xa LMWH also has less relativeto its ability to neutralize factor Xa LMWH also has less nonspecific nonspecific
binding to other proteins There is greater bioavailability with more binding to other proteins There is greater bioavailability with more predictable predictable
pharmacokinetics that eliminates the need for monitoring The smaller pharmacokinetics that eliminates the need for monitoring The smaller size also size also
allows for enhanced subcutaneous absorption when compared with UFHallows for enhanced subcutaneous absorption when compared with UFH
Three LMWH preparations are Three LMWH preparations are currently approved for use in the currently approved for use in the United States (1) enoxaparin (2) United States (1) enoxaparin (2) dalteparin and (3) tinzaparin dalteparin and (3) tinzaparin
They are all administered They are all administered subcutaneously at intervals of either subcutaneously at intervals of either once or twice daily for both once or twice daily for both prophylaxis and treatment dosesprophylaxis and treatment doses
Few Experiences of Few Experiences of ThrombolysisThrombolysis
Vickey 25 Yrs male patient presented Vickey 25 Yrs male patient presented with 12with 12thth day HO severe headache with day HO severe headache with right sided hemiplegiaright sided hemiplegia
MRI shows thrombosis of the superior MRI shows thrombosis of the superior sagittal left transverse left sigmoid sagittal left transverse left sigmoid sinuses and cortical veins in the fronto-sinuses and cortical veins in the fronto-parietal regions with eo haemorrhagic parietal regions with eo haemorrhagic infarct in the left cerebral hemisphere infarct in the left cerebral hemisphere with mass effect( Grade ndashV)with mass effect( Grade ndashV)
Sashi Srivastava 64 yrs FSashi Srivastava 64 yrs F In a follow up case of MRD with infra-renal In a follow up case of MRD with infra-renal
aortic abdominal and bilateral renal artery aortic abdominal and bilateral renal artery thrombosis renal angiogram shows filling thrombosis renal angiogram shows filling defects in the right Renal artery defects in the right Renal artery
Initially Renal angioplasty was done Initially Renal angioplasty was done Following angioplasty few thrombi are seem Following angioplasty few thrombi are seem to extends into the segmental branches and to extends into the segmental branches and causing blockage So Thrombolysis was causing blockage So Thrombolysis was plane to dissolve the run-out thrombi with plane to dissolve the run-out thrombi with urokinase urokinase
Rakesh 34yrsMRakesh 34yrsM Left SFA pseudoaneurysm with Left SFA pseudoaneurysm with
Covered stent placementCovered stent placement Pre operative antiplatelets with post Pre operative antiplatelets with post
procedure heparin Tirofiban procedure heparin Tirofiban followed by aspirin and clopidogrel followed by aspirin and clopidogrel were usedwere used
IAT may be a treatment option for selected patients IAT may be a treatment option for selected patients Possible selection criteria include Possible selection criteria include
presentation between 3 and 6 hours from symptom onsetpresentation between 3 and 6 hours from symptom onset major cerebral artery occlusion major cerebral artery occlusion severe neurologic deficits severe neurologic deficits high risk of systemic hemorrhage with IV rt-PA (eg recent high risk of systemic hemorrhage with IV rt-PA (eg recent
surgery) surgery) The MERCI (Mechanical Embolus Removal in Cerebral The MERCI (Mechanical Embolus Removal in Cerebral
Ischemia) retrievalIschemia) retrieval system system
Has been FDA-approved for recanalizing acutely occluded Has been FDA-approved for recanalizing acutely occluded cerebral arteries cerebral arteries
In the Multi-MERCI study patients who did not improve In the Multi-MERCI study patients who did not improve immediately after IV rt-PA underwent mechanical immediately after IV rt-PA underwent mechanical embolectomy within 8 hours of symptom onset embolectomy within 8 hours of symptom onset
Partial or complete recanalization occurred in 74 of Partial or complete recanalization occurred in 74 of patientspatients
with a symptomatic intracerebral hemorrhage (sICH) rate of with a symptomatic intracerebral hemorrhage (sICH) rate of 67 67
Mechanical embolectomy with the MERCI retriever may be a Mechanical embolectomy with the MERCI retriever may be a feasible and safe option for patients after IV rt-PAfeasible and safe option for patients after IV rt-PA
Penumbra stroke systemPenumbra stroke system This device combines two methods of clot This device combines two methods of clot
extraction aspiration and mechanical extraction aspiration and mechanical extraction extraction
First the clot is aspirated then a thrombus First the clot is aspirated then a thrombus removal ring can be used if necessary to removal ring can be used if necessary to remove remaining clot remove remaining clot
successful recanalizing 82successful recanalizing 82 Bridging therapyBridging therapy
06 mgkg IV rt-PA followed by IAT with IA rt-06 mgkg IV rt-PA followed by IAT with IA rt-PA (up to 20 mg)PA (up to 20 mg)
achieved a higher recanalization rateachieved a higher recanalization rate
Criteria for thrombolysis with rTPACriteria for thrombolysis with rTPA
Inclusion criteriaInclusion criteria Clinical signs and symptoms consistent with ischemic Clinical signs and symptoms consistent with ischemic
strokestroke Patient last seen normal within 3 hoursPatient last seen normal within 3 hours Measurable neurologic deficitMeasurable neurologic deficit
Exclusion criteriaExclusion criteria Any hemorrhage on neuroimaging (CT or MRI)Any hemorrhage on neuroimaging (CT or MRI) Symptoms suggestive of subarachnoid hemorrhageSymptoms suggestive of subarachnoid hemorrhage Seizure at stroke onset that is thought to contribute to Seizure at stroke onset that is thought to contribute to
neurologic deficitneurologic deficit Hypodensity greater than one third cerebral hemisphere Hypodensity greater than one third cerebral hemisphere
on CTon CT SBP greater than 185 mm Hg or DBP greater than 110 SBP greater than 185 mm Hg or DBP greater than 110
mm Hgmm Hg International normalized ratio (INR) greater than 17International normalized ratio (INR) greater than 17
Ischemic Stroke Ischemic Stroke Treatment ndash 2006Treatment ndash 2006
IV tissue plasminogen activator (tPA)IV tissue plasminogen activator (tPA) ndash ndash Only FDA-approved acute stroke drugOnly FDA-approved acute stroke drug ndash ndash 3 hour treatment window3 hour treatment window
MERCI - Concentric clot retrieval MERCI - Concentric clot retrieval devicedevice ndash ndash Rescue therapy - approved 2004Rescue therapy - approved 2004 ndash ndash Device approval (not outcomes-based)Device approval (not outcomes-based)
Off label approachesOff label approaches ndash ndash IV tPA after 3 hoursIV tPA after 3 hours ndash ndash IV-IA tPA sequential strategiesIV-IA tPA sequential strategies ndash ndash IA tPA clot angioplasty fragmentationIA tPA clot angioplasty fragmentation ndash ndash Ultrasound-assisted tPA lysisUltrasound-assisted tPA lysis
rt-PA Trials NINDSrt-PA Trials NINDS
Acute stroke - 624 patientsAcute stroke - 624 patients Treat within 3 hrsTreat within 3 hrs Intravenous 09 mgkg rt-PA vs placeboIntravenous 09 mgkg rt-PA vs placebo Hemorrhage 64 tPA 06 placeboHemorrhage 64 tPA 06 placebo Neurologic recovery better with tPA 30 Neurologic recovery better with tPA 30
more like to have minimal or no disabilitymore like to have minimal or no disability
First proven approved treatment for First proven approved treatment for strokestroke
Limitations of tPALimitations of tPA Only 4 of acute strokes receive tPAOnly 4 of acute strokes receive tPA (Kleindorfer et al Stroke 2004 35 e27-e29)(Kleindorfer et al Stroke 2004 35 e27-e29)
Only 22 of patients present within 3 hoursOnly 22 of patients present within 3 hours1048707 1048707 51 of these ineligible due to51 of these ineligible due to
bull bull Mild severityMild severity bull bull Medical or surgical historyMedical or surgical history bull bull Blood testsBlood tests
Sustained recanalization only 13Sustained recanalization only 13 (Alexandrov et al NEJM 2004 351 2170-8)(Alexandrov et al NEJM 2004 351 2170-8)
Concern for hemorrhageConcern for hemorrhage tPA potentiates apoptotic injury tPA potentiates apoptotic injury (Liu et al Nature Med 2004 101379-83)(Liu et al Nature Med 2004 101379-83)
PROACT II IA Lysis TrialPROACT II IA Lysis Trial Baseline 24 hours 8 days
Baseline 60 minutes 120 minutes
9mg IAProurokinase
Desmoteplase Trials DEDAS Desmoteplase Trials DEDAS DIASDIAS
Trial OverviewTrial Overview Double blind randomized placebo Double blind randomized placebo
controlled trialscontrolled trials IV delivery 3-9 hour time windowIV delivery 3-9 hour time window Plasminogen activator ndash from Plasminogen activator ndash from vampire bat vampire bat
salivasaliva Selection based on PWI-DWI MismatchSelection based on PWI-DWI Mismatch
MRI InclusionMRI Inclusion PWI defect at least 2 cm AND ~20 larger PWI defect at least 2 cm AND ~20 larger
than DWIthan DWI PWI should be obvious even visible on PWI should be obvious even visible on
raw imagesraw imagesMRI ExclusionMRI Exclusion
DWI gt 13 MCADWI gt 13 MCA MRA ICA occlusionMRA ICA occlusion
Desmoteplase ndash DIAS Desmoteplase ndash DIAS ResultsResults
Mechanical Thrombolysis Mechanical Thrombolysis devicesdevices
mechanical thrombolysis potentially extends the treatment mechanical thrombolysis potentially extends the treatment window because they act promptly at the site of the thrombuswindow because they act promptly at the site of the thrombus
The devices can retrieve large clots that pharmaceutical agents The devices can retrieve large clots that pharmaceutical agents may not successfully lysemay not successfully lyse
Patients treated with IV tPA may be considered for treatment of Patients treated with IV tPA may be considered for treatment of residual clot with some of these devicesresidual clot with some of these devices
suction-creating saline jets suction-creating saline jets laser energy ultrasound laser energy ultrasound a corkscrew apparatus to treat strokesa corkscrew apparatus to treat strokes The AngioJet systemThe AngioJet system uses saline jets that are directed back into the catheter to uses saline jets that are directed back into the catheter to
create a low-pressure zone around the catheter tip inducing create a low-pressure zone around the catheter tip inducing suction suction
The clot is pulled into the exhaust lumen and removed from the The clot is pulled into the exhaust lumen and removed from the vessel Although US Food and Drug Administration (FDA) has vessel Although US Food and Drug Administration (FDA) has approved this device for use in arteriovenous dialysis grafts and approved this device for use in arteriovenous dialysis grafts and fistulae and for the treatment of coronary arteries saphenous fistulae and for the treatment of coronary arteries saphenous vein grafts and peripheral vessels clinical trials for the vein grafts and peripheral vessels clinical trials for the treatment of acute stroke are no longer in progress treatment of acute stroke are no longer in progress
Most devices are used in cerebral vessels that 2-5 mm
The Latis laser device The Latis laser device used laser energy to ablate clots used laser energy to ablate clots Arteries 2-5 mm in diameter could be Arteries 2-5 mm in diameter could be
treated including the ICA M1 or M2 treated including the ICA M1 or M2 branch of the MCA A1 branch of the branch of the MCA A1 branch of the anterior cerebral artery (ACA) basilar anterior cerebral artery (ACA) basilar artery posterior cerebral artery (PCA) artery posterior cerebral artery (PCA) and vertebral and vertebral
Patients could receive treatment as late Patients could receive treatment as late as 8 hours after symptom onset in the as 8 hours after symptom onset in the anterior circulation and within 24 hours in anterior circulation and within 24 hours in the posterior circulation the posterior circulation
Endovascular Photo Acoustic Endovascular Photo Acoustic Recanalization (EPAR) Recanalization (EPAR)
A laser power source generated energy for the A laser power source generated energy for the systemsystem
The energy was delivered by means of The energy was delivered by means of fiberoptics to the tip of the catheter at the fiberoptics to the tip of the catheter at the treatment sitetreatment site
Absorption of laser light by darkly pigmented Absorption of laser light by darkly pigmented materials (ie the clot) occurred inside the 1-mm materials (ie the clot) occurred inside the 1-mm catheter tipcatheter tip
the system was designed to minimize scattering the system was designed to minimize scattering of laser light of laser light
Absorption converted photo energy to acoustic Absorption converted photo energy to acoustic energy which then emulsified the clot inside the energy which then emulsified the clot inside the catheter tip catheter tip
EKOS ultrasound( the EKOS ultrasound( the Ultrasound Thrombolytic Ultrasound Thrombolytic
Infusion Catheter) Infusion Catheter) combines the use of a distal ultrasound transducer with combines the use of a distal ultrasound transducer with
infusion of a thrombolytic agent through the infusion of a thrombolytic agent through the microcathetermicrocatheter
Ultrasound changes the structure of the clot to Ultrasound changes the structure of the clot to temporarily increase its permeability while providing an temporarily increase its permeability while providing an acoustic pressure gradient to move the drug into the clot acoustic pressure gradient to move the drug into the clot to speed its dissolution to speed its dissolution
The EKOS catheter is placed in the proximal portion of the The EKOS catheter is placed in the proximal portion of the clot clot
After a 2-mg bolus of tPA was injected through the After a 2-mg bolus of tPA was injected through the catheter catheter
the patient received a continuous infusion of IA tPA 03 the patient received a continuous infusion of IA tPA 03 mgmin to a maximum of 20 mg and simultaneous mgmin to a maximum of 20 mg and simultaneous ultrasound transmission for as long as 60 minutes ultrasound transmission for as long as 60 minutes
One patient was treated with a total of 4 units of One patient was treated with a total of 4 units of recombinant reteplase (Retavase) hand-injected over 60 recombinant reteplase (Retavase) hand-injected over 60 minutes minutes
Penumbra system Penumbra system The Penumbra system (Penumbra Inc) provides a dual The Penumbra system (Penumbra Inc) provides a dual
approach to clot extraction using aspiration followed by approach to clot extraction using aspiration followed by clot retrieval with a ring device if needed clot retrieval with a ring device if needed
Mechanical Embolus Removal in Cerebral Ischemia Mechanical Embolus Removal in Cerebral Ischemia (MERCI)(MERCI)
a corkscrew-like apparatus to remove blood clots from a corkscrew-like apparatus to remove blood clots from the brain in patients experiencing an ischemic stroke the brain in patients experiencing an ischemic stroke
The corkscrew itself resides in the catheter tip which The corkscrew itself resides in the catheter tip which shields it from the wall of the vessel until it is ready to be shields it from the wall of the vessel until it is ready to be burrowed into the clot Once lodged in the clot the device burrowed into the clot Once lodged in the clot the device and clot are withdrawn from the vessel and clot are withdrawn from the vessel
Snarelike devicesSnarelike devices Snares such as the Neuronet snare (Guidant Snares such as the Neuronet snare (Guidant
Endovascular Santa Clara CA) have been developed Endovascular Santa Clara CA) have been developed specifically for use in the treatment of strokes specifically for use in the treatment of strokes
These devices are simple in design and do not require the These devices are simple in design and do not require the clot to be amenable to emulsification clot to be amenable to emulsification
X-Sizer deviceX-Sizer device a device with small moving blades at the a device with small moving blades at the
catheter tip catheter tip This device the X-Sizer device (EndiCor Medical This device the X-Sizer device (EndiCor Medical
San Clemente CA) can be used to excise the San Clemente CA) can be used to excise the thrombus and aspirate it thrombus and aspirate it
The device was being evaluated in randomized The device was being evaluated in randomized studies of coronary vessels and in a registry of studies of coronary vessels and in a registry of patients with acute myocardial infarctionpatients with acute myocardial infarction
Although the manufacturer had modified the Although the manufacturer had modified the device for use in cerebral vessels a safety and device for use in cerebral vessels a safety and feasibility study was indefinitely suspended after feasibility study was indefinitely suspended after only 1 patient was treated with the device in only 1 patient was treated with the device in Europe Europe
Suction thrombectomySuction thrombectomy This method of mechanical thrombolysis is one of the This method of mechanical thrombolysis is one of the
simplestsimplest In this readily available technique suction is applied with In this readily available technique suction is applied with
a syringe to remove thrombus in the ICA a syringe to remove thrombus in the ICA It requires no other devicesIt requires no other devices A catheter with a large inner diameter (Brite Tip Cordis A catheter with a large inner diameter (Brite Tip Cordis
Corporation Miami FL) was placed in the symptomatic Corporation Miami FL) was placed in the symptomatic vessel and navigated over a guidewire into the thrombusvessel and navigated over a guidewire into the thrombus
A 60-mL syringe was used to aspirate the thrombus A 60-mL syringe was used to aspirate the thrombus Each patient required angioplasty and stenting of carotid Each patient required angioplasty and stenting of carotid
bifurcation stenosis and received daily aspirin and bifurcation stenosis and received daily aspirin and ticlopidine after the procedure No complications ticlopidine after the procedure No complications occurred occurred
Summary Acute Stroke Summary Acute Stroke ImagingImaging
PhysiologyPhysiology importance collaterals importance collaterals
ndash ndashGrowing role for perfusion Growing role for perfusion assessmentassessment
tPAtPA guidelines amp limitations guidelines amp limitations Signs on CT amp MRSigns on CT amp MR follow physiology follow physiology Stroke trialsStroke trials PWI-DWI mismatch PWI-DWI mismatch
ndash ndashTreat based on physiology not timeTreat based on physiology not time ProtocolsProtocols should be fast and should be fast and
comprehensivecomprehensive
Intravenous ThrombolysisIntravenous Thrombolysis
The first method to restore cerebral The first method to restore cerebral perfusion is clot lysis with the goal perfusion is clot lysis with the goal of re-establishing blood flow to the of re-establishing blood flow to the affected tissue affected tissue
IV thrombolysis rt-PA is the only IV thrombolysis rt-PA is the only FDA- approved treatment for AIS FDA- approved treatment for AIS
Fibrinolysis is enhanced powerfully Fibrinolysis is enhanced powerfully by rt-PAby rt-PA
Intravenous rTPA Intravenous rTPA administration administration protocolprotocol
Total dose of rt-PA 09 mgkg (maximum dose Total dose of rt-PA 09 mgkg (maximum dose 90 mg)90 mg)
Give 10 as initial IV bolusGive 10 as initial IV bolus Infuse remainder over 1 hourInfuse remainder over 1 hour Admit patient to an ICU or stroke unit for Admit patient to an ICU or stroke unit for
monitoringmonitoring Neurologic assessments every 15 minutes Neurologic assessments every 15 minutes
during infusion then every 30 minutes for next during infusion then every 30 minutes for next 6 hours then every hour until 24hours after 6 hours then every hour until 24hours after treatmenttreatment
Favorable Outcome vs Treatment Time Favorable Outcome vs Treatment Time with IV rTPAwith IV rTPA
Protocol limit = 3 hrs
Benefit ~ 45 hrs
Thromboembolism During coilingThromboembolism During coiling Most feared and frequent complication Most feared and frequent complication Reported incidence - Approx 7 Reported incidence - Approx 7 SourcesSources of Thromboembolism are of Thromboembolism are
- Clots at the aneurysmal neck during or immediately- Clots at the aneurysmal neck during or immediately after after embolization embolization
- Thrombus forming on catheters during- Thrombus forming on catheters during proceduresprocedures
- Stenosis of an adjacent artery dt coil mass- Stenosis of an adjacent artery dt coil mass or herniationor herniation
- Migration of intraaneurysmal- Migration of intraaneurysmal thrombus during coil thrombus during coil placement placement
- Slow flow dt vasospasm - Slow flow dt vasospasm
- Rare and unlikely causes are hypercoagulable- Rare and unlikely causes are hypercoagulable state such state such as antiphospholipid antibody syndrome or due to HITas antiphospholipid antibody syndrome or due to HIT
Occur more often with wide-necked aneurysms (dt Occur more often with wide-necked aneurysms (dt increased exposed surface area of thrombogenic coil increased exposed surface area of thrombogenic coil material)material)
Current regimen of endovascular Current regimen of endovascular managementmanagement
The The glycoprotein IIbIIIa antagonist tirofiban glycoprotein IIbIIIa antagonist tirofiban (04 (04 microgkgmin bolus for 30 minutes followed by infusion of microgkgmin bolus for 30 minutes followed by infusion of 0125 ugkgmin until the thrombus dissolved) 0125 ugkgmin until the thrombus dissolved)
Intraarterial thrombolysis with Intraarterial thrombolysis with urokinase or r- TPA urokinase or r- TPA increase of intravenous (IV) heparin (measured by increase of intravenous (IV) heparin (measured by
ACT) ACT) Intravenous aspirin Intravenous aspirin
Coil-related platelet aggregation (white clot) is Coil-related platelet aggregation (white clot) is unlikely to respond to fibrinolytics but has a high risk unlikely to respond to fibrinolytics but has a high risk of hemorrhage (In ISAT) all 5 patients who had of hemorrhage (In ISAT) all 5 patients who had received thrombolytic therapy with tPA to treat a received thrombolytic therapy with tPA to treat a thromboembolic complication after endovascular thromboembolic complication after endovascular treatment rebleed and all of these patients died)treatment rebleed and all of these patients died)
IntracranialIntracranial Stenting Stenting Metallic foreign body such as stent will accumulate Metallic foreign body such as stent will accumulate
thrombus in the absence of platelet inhibitionthrombus in the absence of platelet inhibition Antiplatelet drugs are important to prevent peri or Antiplatelet drugs are important to prevent peri or
post-interventional thromboembolic eventspost-interventional thromboembolic events Optimal treatment regimens has not been determined Optimal treatment regimens has not been determined
but usually but usually Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-
procedureprocedureOrOr
Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on
morning of proceduremorning of procedure
If need to use stent is not pre-planned thanIf need to use stent is not pre-planned than
Abciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkgAbciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkg IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)
Glycoprotein IIbIIIa inhibitor are not used routinely during elective Glycoprotein IIbIIIa inhibitor are not used routinely during elective stenting procedure dt increased risk of ICH stenting procedure dt increased risk of ICH
Carotid StentingCarotid Stenting
Pre-procedurePre-procedure
Double Antiplatelet therapy is routinely given Double Antiplatelet therapy is routinely given beginning at least 3beginning at least 3
days before the proceduredays before the procedure
Aspirin 325mgd+Clopidogrel 75mgdAspirin 325mgd+Clopidogrel 75mgd During procedureDuring procedure
Heparin is given with target clotting time of 250-Heparin is given with target clotting time of 250-300sec300sec
Post-procedure Post-procedure
Aspirin 325mg is continued indefinitely and Aspirin 325mg is continued indefinitely and
Clopidogrel 75mgd for at least 6 weeks Clopidogrel 75mgd for at least 6 weeks
Inclusion criteria for Local ThrombolysisInclusion criteria for Local Thrombolysis a)a) Patients in severe clinical grade on admission Patients in severe clinical grade on admission
with evidence of dural venous sinus with evidence of dural venous sinus thrombosis and restrictive venous outflow on thrombosis and restrictive venous outflow on cerebral angiogramcerebral angiogram
b)b) Patients in clinical grade 3 worsening on Patients in clinical grade 3 worsening on heparin therapy Restriction to venous heparin therapy Restriction to venous outflow was defined as an increase in brain outflow was defined as an increase in brain circulation time gt 12 s delay in the drainage circulation time gt 12 s delay in the drainage of cortical veins with cortical veins hanging of cortical veins with cortical veins hanging in spacein space
Treatment Options for Venous Thrombosis
CT Grading for Venous ThrombosisCT Grading for Venous Thrombosis Grade I no parenchymal change Grade I no parenchymal change
(hyperdense (hyperdense sinuses cortical veins empty sinuses cortical veins empty delta sign)delta sign)
Grade II non hemorrhagic venous infarct Grade II non hemorrhagic venous infarct without mass effect without mass effect
Grade III non-hemorrhagic infarct with Grade III non-hemorrhagic infarct with mass effectmass effect
Grade IV hemorrhagic venous infarct (max Grade IV hemorrhagic venous infarct (max diameter lt 3 cm) with no mass effectdiameter lt 3 cm) with no mass effect
Grade V hemorrhagic venous infarct (max Grade V hemorrhagic venous infarct (max diameter gt 3 cm) with mass effect diameter gt 3 cm) with mass effect
Local ThrombolysisLocal Thrombolysis
Femoral Jugular access was secured and a guiding Femoral Jugular access was secured and a guiding catheter was placed in the jugular bulb catheter was placed in the jugular bulb Mechanical Mechanical clot maceration clot maceration was done with the guidewire was done with the guidewire following which a microcatheter (was navigated and following which a microcatheter (was navigated and placed in the thrombosed segment of sinus confirmed placed in the thrombosed segment of sinus confirmed on a selective venogram on a selective venogram
Urokinase infusion Bolus dose of 2-6 lacs followed Urokinase infusion Bolus dose of 2-6 lacs followed by 60000 to 100000 units per hour along with by 60000 to 100000 units per hour along with periodic check venogram Along with maintenance periodic check venogram Along with maintenance systemic infusion of Heparinsystemic infusion of Heparin Other agents such as Other agents such as streptokinase altepase or rTPAstreptokinase altepase or rTPA can be also used can be also used
After thrombolysis patient should subjected to oral After thrombolysis patient should subjected to oral anticoagulation for six monthsanticoagulation for six months
Low-molecular-weight Low-molecular-weight heparinheparin
PharmacologyPharmacologyLMWH as its name suggests is a glycosaminoglycan that is approximatelyLMWH as its name suggests is a glycosaminoglycan that is approximately
one third the molecular weight of UFH It is derived from UFH through one third the molecular weight of UFH It is derived from UFH through variousvarious
depolymerization processes LMWH binds to antithrombin which in turn depolymerization processes LMWH binds to antithrombin which in turn
Neutralizes actors Xa and IIa Because LMWH lacks many of the longer Neutralizes actors Xa and IIa Because LMWH lacks many of the longer chains chains
required for binding to thrombin it has less ability to neutralize thrombin required for binding to thrombin it has less ability to neutralize thrombin
relativeto its ability to neutralize factor Xa LMWH also has less relativeto its ability to neutralize factor Xa LMWH also has less nonspecific nonspecific
binding to other proteins There is greater bioavailability with more binding to other proteins There is greater bioavailability with more predictable predictable
pharmacokinetics that eliminates the need for monitoring The smaller pharmacokinetics that eliminates the need for monitoring The smaller size also size also
allows for enhanced subcutaneous absorption when compared with UFHallows for enhanced subcutaneous absorption when compared with UFH
Three LMWH preparations are Three LMWH preparations are currently approved for use in the currently approved for use in the United States (1) enoxaparin (2) United States (1) enoxaparin (2) dalteparin and (3) tinzaparin dalteparin and (3) tinzaparin
They are all administered They are all administered subcutaneously at intervals of either subcutaneously at intervals of either once or twice daily for both once or twice daily for both prophylaxis and treatment dosesprophylaxis and treatment doses
Few Experiences of Few Experiences of ThrombolysisThrombolysis
Vickey 25 Yrs male patient presented Vickey 25 Yrs male patient presented with 12with 12thth day HO severe headache with day HO severe headache with right sided hemiplegiaright sided hemiplegia
MRI shows thrombosis of the superior MRI shows thrombosis of the superior sagittal left transverse left sigmoid sagittal left transverse left sigmoid sinuses and cortical veins in the fronto-sinuses and cortical veins in the fronto-parietal regions with eo haemorrhagic parietal regions with eo haemorrhagic infarct in the left cerebral hemisphere infarct in the left cerebral hemisphere with mass effect( Grade ndashV)with mass effect( Grade ndashV)
Sashi Srivastava 64 yrs FSashi Srivastava 64 yrs F In a follow up case of MRD with infra-renal In a follow up case of MRD with infra-renal
aortic abdominal and bilateral renal artery aortic abdominal and bilateral renal artery thrombosis renal angiogram shows filling thrombosis renal angiogram shows filling defects in the right Renal artery defects in the right Renal artery
Initially Renal angioplasty was done Initially Renal angioplasty was done Following angioplasty few thrombi are seem Following angioplasty few thrombi are seem to extends into the segmental branches and to extends into the segmental branches and causing blockage So Thrombolysis was causing blockage So Thrombolysis was plane to dissolve the run-out thrombi with plane to dissolve the run-out thrombi with urokinase urokinase
Rakesh 34yrsMRakesh 34yrsM Left SFA pseudoaneurysm with Left SFA pseudoaneurysm with
Covered stent placementCovered stent placement Pre operative antiplatelets with post Pre operative antiplatelets with post
procedure heparin Tirofiban procedure heparin Tirofiban followed by aspirin and clopidogrel followed by aspirin and clopidogrel were usedwere used
IAT may be a treatment option for selected patients IAT may be a treatment option for selected patients Possible selection criteria include Possible selection criteria include
presentation between 3 and 6 hours from symptom onsetpresentation between 3 and 6 hours from symptom onset major cerebral artery occlusion major cerebral artery occlusion severe neurologic deficits severe neurologic deficits high risk of systemic hemorrhage with IV rt-PA (eg recent high risk of systemic hemorrhage with IV rt-PA (eg recent
surgery) surgery) The MERCI (Mechanical Embolus Removal in Cerebral The MERCI (Mechanical Embolus Removal in Cerebral
Ischemia) retrievalIschemia) retrieval system system
Has been FDA-approved for recanalizing acutely occluded Has been FDA-approved for recanalizing acutely occluded cerebral arteries cerebral arteries
In the Multi-MERCI study patients who did not improve In the Multi-MERCI study patients who did not improve immediately after IV rt-PA underwent mechanical immediately after IV rt-PA underwent mechanical embolectomy within 8 hours of symptom onset embolectomy within 8 hours of symptom onset
Partial or complete recanalization occurred in 74 of Partial or complete recanalization occurred in 74 of patientspatients
with a symptomatic intracerebral hemorrhage (sICH) rate of with a symptomatic intracerebral hemorrhage (sICH) rate of 67 67
Mechanical embolectomy with the MERCI retriever may be a Mechanical embolectomy with the MERCI retriever may be a feasible and safe option for patients after IV rt-PAfeasible and safe option for patients after IV rt-PA
Penumbra stroke systemPenumbra stroke system This device combines two methods of clot This device combines two methods of clot
extraction aspiration and mechanical extraction aspiration and mechanical extraction extraction
First the clot is aspirated then a thrombus First the clot is aspirated then a thrombus removal ring can be used if necessary to removal ring can be used if necessary to remove remaining clot remove remaining clot
successful recanalizing 82successful recanalizing 82 Bridging therapyBridging therapy
06 mgkg IV rt-PA followed by IAT with IA rt-06 mgkg IV rt-PA followed by IAT with IA rt-PA (up to 20 mg)PA (up to 20 mg)
achieved a higher recanalization rateachieved a higher recanalization rate
Criteria for thrombolysis with rTPACriteria for thrombolysis with rTPA
Inclusion criteriaInclusion criteria Clinical signs and symptoms consistent with ischemic Clinical signs and symptoms consistent with ischemic
strokestroke Patient last seen normal within 3 hoursPatient last seen normal within 3 hours Measurable neurologic deficitMeasurable neurologic deficit
Exclusion criteriaExclusion criteria Any hemorrhage on neuroimaging (CT or MRI)Any hemorrhage on neuroimaging (CT or MRI) Symptoms suggestive of subarachnoid hemorrhageSymptoms suggestive of subarachnoid hemorrhage Seizure at stroke onset that is thought to contribute to Seizure at stroke onset that is thought to contribute to
neurologic deficitneurologic deficit Hypodensity greater than one third cerebral hemisphere Hypodensity greater than one third cerebral hemisphere
on CTon CT SBP greater than 185 mm Hg or DBP greater than 110 SBP greater than 185 mm Hg or DBP greater than 110
mm Hgmm Hg International normalized ratio (INR) greater than 17International normalized ratio (INR) greater than 17
Ischemic Stroke Ischemic Stroke Treatment ndash 2006Treatment ndash 2006
IV tissue plasminogen activator (tPA)IV tissue plasminogen activator (tPA) ndash ndash Only FDA-approved acute stroke drugOnly FDA-approved acute stroke drug ndash ndash 3 hour treatment window3 hour treatment window
MERCI - Concentric clot retrieval MERCI - Concentric clot retrieval devicedevice ndash ndash Rescue therapy - approved 2004Rescue therapy - approved 2004 ndash ndash Device approval (not outcomes-based)Device approval (not outcomes-based)
Off label approachesOff label approaches ndash ndash IV tPA after 3 hoursIV tPA after 3 hours ndash ndash IV-IA tPA sequential strategiesIV-IA tPA sequential strategies ndash ndash IA tPA clot angioplasty fragmentationIA tPA clot angioplasty fragmentation ndash ndash Ultrasound-assisted tPA lysisUltrasound-assisted tPA lysis
rt-PA Trials NINDSrt-PA Trials NINDS
Acute stroke - 624 patientsAcute stroke - 624 patients Treat within 3 hrsTreat within 3 hrs Intravenous 09 mgkg rt-PA vs placeboIntravenous 09 mgkg rt-PA vs placebo Hemorrhage 64 tPA 06 placeboHemorrhage 64 tPA 06 placebo Neurologic recovery better with tPA 30 Neurologic recovery better with tPA 30
more like to have minimal or no disabilitymore like to have minimal or no disability
First proven approved treatment for First proven approved treatment for strokestroke
Limitations of tPALimitations of tPA Only 4 of acute strokes receive tPAOnly 4 of acute strokes receive tPA (Kleindorfer et al Stroke 2004 35 e27-e29)(Kleindorfer et al Stroke 2004 35 e27-e29)
Only 22 of patients present within 3 hoursOnly 22 of patients present within 3 hours1048707 1048707 51 of these ineligible due to51 of these ineligible due to
bull bull Mild severityMild severity bull bull Medical or surgical historyMedical or surgical history bull bull Blood testsBlood tests
Sustained recanalization only 13Sustained recanalization only 13 (Alexandrov et al NEJM 2004 351 2170-8)(Alexandrov et al NEJM 2004 351 2170-8)
Concern for hemorrhageConcern for hemorrhage tPA potentiates apoptotic injury tPA potentiates apoptotic injury (Liu et al Nature Med 2004 101379-83)(Liu et al Nature Med 2004 101379-83)
PROACT II IA Lysis TrialPROACT II IA Lysis Trial Baseline 24 hours 8 days
Baseline 60 minutes 120 minutes
9mg IAProurokinase
Desmoteplase Trials DEDAS Desmoteplase Trials DEDAS DIASDIAS
Trial OverviewTrial Overview Double blind randomized placebo Double blind randomized placebo
controlled trialscontrolled trials IV delivery 3-9 hour time windowIV delivery 3-9 hour time window Plasminogen activator ndash from Plasminogen activator ndash from vampire bat vampire bat
salivasaliva Selection based on PWI-DWI MismatchSelection based on PWI-DWI Mismatch
MRI InclusionMRI Inclusion PWI defect at least 2 cm AND ~20 larger PWI defect at least 2 cm AND ~20 larger
than DWIthan DWI PWI should be obvious even visible on PWI should be obvious even visible on
raw imagesraw imagesMRI ExclusionMRI Exclusion
DWI gt 13 MCADWI gt 13 MCA MRA ICA occlusionMRA ICA occlusion
Desmoteplase ndash DIAS Desmoteplase ndash DIAS ResultsResults
Mechanical Thrombolysis Mechanical Thrombolysis devicesdevices
mechanical thrombolysis potentially extends the treatment mechanical thrombolysis potentially extends the treatment window because they act promptly at the site of the thrombuswindow because they act promptly at the site of the thrombus
The devices can retrieve large clots that pharmaceutical agents The devices can retrieve large clots that pharmaceutical agents may not successfully lysemay not successfully lyse
Patients treated with IV tPA may be considered for treatment of Patients treated with IV tPA may be considered for treatment of residual clot with some of these devicesresidual clot with some of these devices
suction-creating saline jets suction-creating saline jets laser energy ultrasound laser energy ultrasound a corkscrew apparatus to treat strokesa corkscrew apparatus to treat strokes The AngioJet systemThe AngioJet system uses saline jets that are directed back into the catheter to uses saline jets that are directed back into the catheter to
create a low-pressure zone around the catheter tip inducing create a low-pressure zone around the catheter tip inducing suction suction
The clot is pulled into the exhaust lumen and removed from the The clot is pulled into the exhaust lumen and removed from the vessel Although US Food and Drug Administration (FDA) has vessel Although US Food and Drug Administration (FDA) has approved this device for use in arteriovenous dialysis grafts and approved this device for use in arteriovenous dialysis grafts and fistulae and for the treatment of coronary arteries saphenous fistulae and for the treatment of coronary arteries saphenous vein grafts and peripheral vessels clinical trials for the vein grafts and peripheral vessels clinical trials for the treatment of acute stroke are no longer in progress treatment of acute stroke are no longer in progress
Most devices are used in cerebral vessels that 2-5 mm
The Latis laser device The Latis laser device used laser energy to ablate clots used laser energy to ablate clots Arteries 2-5 mm in diameter could be Arteries 2-5 mm in diameter could be
treated including the ICA M1 or M2 treated including the ICA M1 or M2 branch of the MCA A1 branch of the branch of the MCA A1 branch of the anterior cerebral artery (ACA) basilar anterior cerebral artery (ACA) basilar artery posterior cerebral artery (PCA) artery posterior cerebral artery (PCA) and vertebral and vertebral
Patients could receive treatment as late Patients could receive treatment as late as 8 hours after symptom onset in the as 8 hours after symptom onset in the anterior circulation and within 24 hours in anterior circulation and within 24 hours in the posterior circulation the posterior circulation
Endovascular Photo Acoustic Endovascular Photo Acoustic Recanalization (EPAR) Recanalization (EPAR)
A laser power source generated energy for the A laser power source generated energy for the systemsystem
The energy was delivered by means of The energy was delivered by means of fiberoptics to the tip of the catheter at the fiberoptics to the tip of the catheter at the treatment sitetreatment site
Absorption of laser light by darkly pigmented Absorption of laser light by darkly pigmented materials (ie the clot) occurred inside the 1-mm materials (ie the clot) occurred inside the 1-mm catheter tipcatheter tip
the system was designed to minimize scattering the system was designed to minimize scattering of laser light of laser light
Absorption converted photo energy to acoustic Absorption converted photo energy to acoustic energy which then emulsified the clot inside the energy which then emulsified the clot inside the catheter tip catheter tip
EKOS ultrasound( the EKOS ultrasound( the Ultrasound Thrombolytic Ultrasound Thrombolytic
Infusion Catheter) Infusion Catheter) combines the use of a distal ultrasound transducer with combines the use of a distal ultrasound transducer with
infusion of a thrombolytic agent through the infusion of a thrombolytic agent through the microcathetermicrocatheter
Ultrasound changes the structure of the clot to Ultrasound changes the structure of the clot to temporarily increase its permeability while providing an temporarily increase its permeability while providing an acoustic pressure gradient to move the drug into the clot acoustic pressure gradient to move the drug into the clot to speed its dissolution to speed its dissolution
The EKOS catheter is placed in the proximal portion of the The EKOS catheter is placed in the proximal portion of the clot clot
After a 2-mg bolus of tPA was injected through the After a 2-mg bolus of tPA was injected through the catheter catheter
the patient received a continuous infusion of IA tPA 03 the patient received a continuous infusion of IA tPA 03 mgmin to a maximum of 20 mg and simultaneous mgmin to a maximum of 20 mg and simultaneous ultrasound transmission for as long as 60 minutes ultrasound transmission for as long as 60 minutes
One patient was treated with a total of 4 units of One patient was treated with a total of 4 units of recombinant reteplase (Retavase) hand-injected over 60 recombinant reteplase (Retavase) hand-injected over 60 minutes minutes
Penumbra system Penumbra system The Penumbra system (Penumbra Inc) provides a dual The Penumbra system (Penumbra Inc) provides a dual
approach to clot extraction using aspiration followed by approach to clot extraction using aspiration followed by clot retrieval with a ring device if needed clot retrieval with a ring device if needed
Mechanical Embolus Removal in Cerebral Ischemia Mechanical Embolus Removal in Cerebral Ischemia (MERCI)(MERCI)
a corkscrew-like apparatus to remove blood clots from a corkscrew-like apparatus to remove blood clots from the brain in patients experiencing an ischemic stroke the brain in patients experiencing an ischemic stroke
The corkscrew itself resides in the catheter tip which The corkscrew itself resides in the catheter tip which shields it from the wall of the vessel until it is ready to be shields it from the wall of the vessel until it is ready to be burrowed into the clot Once lodged in the clot the device burrowed into the clot Once lodged in the clot the device and clot are withdrawn from the vessel and clot are withdrawn from the vessel
Snarelike devicesSnarelike devices Snares such as the Neuronet snare (Guidant Snares such as the Neuronet snare (Guidant
Endovascular Santa Clara CA) have been developed Endovascular Santa Clara CA) have been developed specifically for use in the treatment of strokes specifically for use in the treatment of strokes
These devices are simple in design and do not require the These devices are simple in design and do not require the clot to be amenable to emulsification clot to be amenable to emulsification
X-Sizer deviceX-Sizer device a device with small moving blades at the a device with small moving blades at the
catheter tip catheter tip This device the X-Sizer device (EndiCor Medical This device the X-Sizer device (EndiCor Medical
San Clemente CA) can be used to excise the San Clemente CA) can be used to excise the thrombus and aspirate it thrombus and aspirate it
The device was being evaluated in randomized The device was being evaluated in randomized studies of coronary vessels and in a registry of studies of coronary vessels and in a registry of patients with acute myocardial infarctionpatients with acute myocardial infarction
Although the manufacturer had modified the Although the manufacturer had modified the device for use in cerebral vessels a safety and device for use in cerebral vessels a safety and feasibility study was indefinitely suspended after feasibility study was indefinitely suspended after only 1 patient was treated with the device in only 1 patient was treated with the device in Europe Europe
Suction thrombectomySuction thrombectomy This method of mechanical thrombolysis is one of the This method of mechanical thrombolysis is one of the
simplestsimplest In this readily available technique suction is applied with In this readily available technique suction is applied with
a syringe to remove thrombus in the ICA a syringe to remove thrombus in the ICA It requires no other devicesIt requires no other devices A catheter with a large inner diameter (Brite Tip Cordis A catheter with a large inner diameter (Brite Tip Cordis
Corporation Miami FL) was placed in the symptomatic Corporation Miami FL) was placed in the symptomatic vessel and navigated over a guidewire into the thrombusvessel and navigated over a guidewire into the thrombus
A 60-mL syringe was used to aspirate the thrombus A 60-mL syringe was used to aspirate the thrombus Each patient required angioplasty and stenting of carotid Each patient required angioplasty and stenting of carotid
bifurcation stenosis and received daily aspirin and bifurcation stenosis and received daily aspirin and ticlopidine after the procedure No complications ticlopidine after the procedure No complications occurred occurred
Summary Acute Stroke Summary Acute Stroke ImagingImaging
PhysiologyPhysiology importance collaterals importance collaterals
ndash ndashGrowing role for perfusion Growing role for perfusion assessmentassessment
tPAtPA guidelines amp limitations guidelines amp limitations Signs on CT amp MRSigns on CT amp MR follow physiology follow physiology Stroke trialsStroke trials PWI-DWI mismatch PWI-DWI mismatch
ndash ndashTreat based on physiology not timeTreat based on physiology not time ProtocolsProtocols should be fast and should be fast and
comprehensivecomprehensive
Intravenous rTPA Intravenous rTPA administration administration protocolprotocol
Total dose of rt-PA 09 mgkg (maximum dose Total dose of rt-PA 09 mgkg (maximum dose 90 mg)90 mg)
Give 10 as initial IV bolusGive 10 as initial IV bolus Infuse remainder over 1 hourInfuse remainder over 1 hour Admit patient to an ICU or stroke unit for Admit patient to an ICU or stroke unit for
monitoringmonitoring Neurologic assessments every 15 minutes Neurologic assessments every 15 minutes
during infusion then every 30 minutes for next during infusion then every 30 minutes for next 6 hours then every hour until 24hours after 6 hours then every hour until 24hours after treatmenttreatment
Favorable Outcome vs Treatment Time Favorable Outcome vs Treatment Time with IV rTPAwith IV rTPA
Protocol limit = 3 hrs
Benefit ~ 45 hrs
Thromboembolism During coilingThromboembolism During coiling Most feared and frequent complication Most feared and frequent complication Reported incidence - Approx 7 Reported incidence - Approx 7 SourcesSources of Thromboembolism are of Thromboembolism are
- Clots at the aneurysmal neck during or immediately- Clots at the aneurysmal neck during or immediately after after embolization embolization
- Thrombus forming on catheters during- Thrombus forming on catheters during proceduresprocedures
- Stenosis of an adjacent artery dt coil mass- Stenosis of an adjacent artery dt coil mass or herniationor herniation
- Migration of intraaneurysmal- Migration of intraaneurysmal thrombus during coil thrombus during coil placement placement
- Slow flow dt vasospasm - Slow flow dt vasospasm
- Rare and unlikely causes are hypercoagulable- Rare and unlikely causes are hypercoagulable state such state such as antiphospholipid antibody syndrome or due to HITas antiphospholipid antibody syndrome or due to HIT
Occur more often with wide-necked aneurysms (dt Occur more often with wide-necked aneurysms (dt increased exposed surface area of thrombogenic coil increased exposed surface area of thrombogenic coil material)material)
Current regimen of endovascular Current regimen of endovascular managementmanagement
The The glycoprotein IIbIIIa antagonist tirofiban glycoprotein IIbIIIa antagonist tirofiban (04 (04 microgkgmin bolus for 30 minutes followed by infusion of microgkgmin bolus for 30 minutes followed by infusion of 0125 ugkgmin until the thrombus dissolved) 0125 ugkgmin until the thrombus dissolved)
Intraarterial thrombolysis with Intraarterial thrombolysis with urokinase or r- TPA urokinase or r- TPA increase of intravenous (IV) heparin (measured by increase of intravenous (IV) heparin (measured by
ACT) ACT) Intravenous aspirin Intravenous aspirin
Coil-related platelet aggregation (white clot) is Coil-related platelet aggregation (white clot) is unlikely to respond to fibrinolytics but has a high risk unlikely to respond to fibrinolytics but has a high risk of hemorrhage (In ISAT) all 5 patients who had of hemorrhage (In ISAT) all 5 patients who had received thrombolytic therapy with tPA to treat a received thrombolytic therapy with tPA to treat a thromboembolic complication after endovascular thromboembolic complication after endovascular treatment rebleed and all of these patients died)treatment rebleed and all of these patients died)
IntracranialIntracranial Stenting Stenting Metallic foreign body such as stent will accumulate Metallic foreign body such as stent will accumulate
thrombus in the absence of platelet inhibitionthrombus in the absence of platelet inhibition Antiplatelet drugs are important to prevent peri or Antiplatelet drugs are important to prevent peri or
post-interventional thromboembolic eventspost-interventional thromboembolic events Optimal treatment regimens has not been determined Optimal treatment regimens has not been determined
but usually but usually Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-
procedureprocedureOrOr
Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on
morning of proceduremorning of procedure
If need to use stent is not pre-planned thanIf need to use stent is not pre-planned than
Abciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkgAbciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkg IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)
Glycoprotein IIbIIIa inhibitor are not used routinely during elective Glycoprotein IIbIIIa inhibitor are not used routinely during elective stenting procedure dt increased risk of ICH stenting procedure dt increased risk of ICH
Carotid StentingCarotid Stenting
Pre-procedurePre-procedure
Double Antiplatelet therapy is routinely given Double Antiplatelet therapy is routinely given beginning at least 3beginning at least 3
days before the proceduredays before the procedure
Aspirin 325mgd+Clopidogrel 75mgdAspirin 325mgd+Clopidogrel 75mgd During procedureDuring procedure
Heparin is given with target clotting time of 250-Heparin is given with target clotting time of 250-300sec300sec
Post-procedure Post-procedure
Aspirin 325mg is continued indefinitely and Aspirin 325mg is continued indefinitely and
Clopidogrel 75mgd for at least 6 weeks Clopidogrel 75mgd for at least 6 weeks
Inclusion criteria for Local ThrombolysisInclusion criteria for Local Thrombolysis a)a) Patients in severe clinical grade on admission Patients in severe clinical grade on admission
with evidence of dural venous sinus with evidence of dural venous sinus thrombosis and restrictive venous outflow on thrombosis and restrictive venous outflow on cerebral angiogramcerebral angiogram
b)b) Patients in clinical grade 3 worsening on Patients in clinical grade 3 worsening on heparin therapy Restriction to venous heparin therapy Restriction to venous outflow was defined as an increase in brain outflow was defined as an increase in brain circulation time gt 12 s delay in the drainage circulation time gt 12 s delay in the drainage of cortical veins with cortical veins hanging of cortical veins with cortical veins hanging in spacein space
Treatment Options for Venous Thrombosis
CT Grading for Venous ThrombosisCT Grading for Venous Thrombosis Grade I no parenchymal change Grade I no parenchymal change
(hyperdense (hyperdense sinuses cortical veins empty sinuses cortical veins empty delta sign)delta sign)
Grade II non hemorrhagic venous infarct Grade II non hemorrhagic venous infarct without mass effect without mass effect
Grade III non-hemorrhagic infarct with Grade III non-hemorrhagic infarct with mass effectmass effect
Grade IV hemorrhagic venous infarct (max Grade IV hemorrhagic venous infarct (max diameter lt 3 cm) with no mass effectdiameter lt 3 cm) with no mass effect
Grade V hemorrhagic venous infarct (max Grade V hemorrhagic venous infarct (max diameter gt 3 cm) with mass effect diameter gt 3 cm) with mass effect
Local ThrombolysisLocal Thrombolysis
Femoral Jugular access was secured and a guiding Femoral Jugular access was secured and a guiding catheter was placed in the jugular bulb catheter was placed in the jugular bulb Mechanical Mechanical clot maceration clot maceration was done with the guidewire was done with the guidewire following which a microcatheter (was navigated and following which a microcatheter (was navigated and placed in the thrombosed segment of sinus confirmed placed in the thrombosed segment of sinus confirmed on a selective venogram on a selective venogram
Urokinase infusion Bolus dose of 2-6 lacs followed Urokinase infusion Bolus dose of 2-6 lacs followed by 60000 to 100000 units per hour along with by 60000 to 100000 units per hour along with periodic check venogram Along with maintenance periodic check venogram Along with maintenance systemic infusion of Heparinsystemic infusion of Heparin Other agents such as Other agents such as streptokinase altepase or rTPAstreptokinase altepase or rTPA can be also used can be also used
After thrombolysis patient should subjected to oral After thrombolysis patient should subjected to oral anticoagulation for six monthsanticoagulation for six months
Low-molecular-weight Low-molecular-weight heparinheparin
PharmacologyPharmacologyLMWH as its name suggests is a glycosaminoglycan that is approximatelyLMWH as its name suggests is a glycosaminoglycan that is approximately
one third the molecular weight of UFH It is derived from UFH through one third the molecular weight of UFH It is derived from UFH through variousvarious
depolymerization processes LMWH binds to antithrombin which in turn depolymerization processes LMWH binds to antithrombin which in turn
Neutralizes actors Xa and IIa Because LMWH lacks many of the longer Neutralizes actors Xa and IIa Because LMWH lacks many of the longer chains chains
required for binding to thrombin it has less ability to neutralize thrombin required for binding to thrombin it has less ability to neutralize thrombin
relativeto its ability to neutralize factor Xa LMWH also has less relativeto its ability to neutralize factor Xa LMWH also has less nonspecific nonspecific
binding to other proteins There is greater bioavailability with more binding to other proteins There is greater bioavailability with more predictable predictable
pharmacokinetics that eliminates the need for monitoring The smaller pharmacokinetics that eliminates the need for monitoring The smaller size also size also
allows for enhanced subcutaneous absorption when compared with UFHallows for enhanced subcutaneous absorption when compared with UFH
Three LMWH preparations are Three LMWH preparations are currently approved for use in the currently approved for use in the United States (1) enoxaparin (2) United States (1) enoxaparin (2) dalteparin and (3) tinzaparin dalteparin and (3) tinzaparin
They are all administered They are all administered subcutaneously at intervals of either subcutaneously at intervals of either once or twice daily for both once or twice daily for both prophylaxis and treatment dosesprophylaxis and treatment doses
Few Experiences of Few Experiences of ThrombolysisThrombolysis
Vickey 25 Yrs male patient presented Vickey 25 Yrs male patient presented with 12with 12thth day HO severe headache with day HO severe headache with right sided hemiplegiaright sided hemiplegia
MRI shows thrombosis of the superior MRI shows thrombosis of the superior sagittal left transverse left sigmoid sagittal left transverse left sigmoid sinuses and cortical veins in the fronto-sinuses and cortical veins in the fronto-parietal regions with eo haemorrhagic parietal regions with eo haemorrhagic infarct in the left cerebral hemisphere infarct in the left cerebral hemisphere with mass effect( Grade ndashV)with mass effect( Grade ndashV)
Sashi Srivastava 64 yrs FSashi Srivastava 64 yrs F In a follow up case of MRD with infra-renal In a follow up case of MRD with infra-renal
aortic abdominal and bilateral renal artery aortic abdominal and bilateral renal artery thrombosis renal angiogram shows filling thrombosis renal angiogram shows filling defects in the right Renal artery defects in the right Renal artery
Initially Renal angioplasty was done Initially Renal angioplasty was done Following angioplasty few thrombi are seem Following angioplasty few thrombi are seem to extends into the segmental branches and to extends into the segmental branches and causing blockage So Thrombolysis was causing blockage So Thrombolysis was plane to dissolve the run-out thrombi with plane to dissolve the run-out thrombi with urokinase urokinase
Rakesh 34yrsMRakesh 34yrsM Left SFA pseudoaneurysm with Left SFA pseudoaneurysm with
Covered stent placementCovered stent placement Pre operative antiplatelets with post Pre operative antiplatelets with post
procedure heparin Tirofiban procedure heparin Tirofiban followed by aspirin and clopidogrel followed by aspirin and clopidogrel were usedwere used
IAT may be a treatment option for selected patients IAT may be a treatment option for selected patients Possible selection criteria include Possible selection criteria include
presentation between 3 and 6 hours from symptom onsetpresentation between 3 and 6 hours from symptom onset major cerebral artery occlusion major cerebral artery occlusion severe neurologic deficits severe neurologic deficits high risk of systemic hemorrhage with IV rt-PA (eg recent high risk of systemic hemorrhage with IV rt-PA (eg recent
surgery) surgery) The MERCI (Mechanical Embolus Removal in Cerebral The MERCI (Mechanical Embolus Removal in Cerebral
Ischemia) retrievalIschemia) retrieval system system
Has been FDA-approved for recanalizing acutely occluded Has been FDA-approved for recanalizing acutely occluded cerebral arteries cerebral arteries
In the Multi-MERCI study patients who did not improve In the Multi-MERCI study patients who did not improve immediately after IV rt-PA underwent mechanical immediately after IV rt-PA underwent mechanical embolectomy within 8 hours of symptom onset embolectomy within 8 hours of symptom onset
Partial or complete recanalization occurred in 74 of Partial or complete recanalization occurred in 74 of patientspatients
with a symptomatic intracerebral hemorrhage (sICH) rate of with a symptomatic intracerebral hemorrhage (sICH) rate of 67 67
Mechanical embolectomy with the MERCI retriever may be a Mechanical embolectomy with the MERCI retriever may be a feasible and safe option for patients after IV rt-PAfeasible and safe option for patients after IV rt-PA
Penumbra stroke systemPenumbra stroke system This device combines two methods of clot This device combines two methods of clot
extraction aspiration and mechanical extraction aspiration and mechanical extraction extraction
First the clot is aspirated then a thrombus First the clot is aspirated then a thrombus removal ring can be used if necessary to removal ring can be used if necessary to remove remaining clot remove remaining clot
successful recanalizing 82successful recanalizing 82 Bridging therapyBridging therapy
06 mgkg IV rt-PA followed by IAT with IA rt-06 mgkg IV rt-PA followed by IAT with IA rt-PA (up to 20 mg)PA (up to 20 mg)
achieved a higher recanalization rateachieved a higher recanalization rate
Criteria for thrombolysis with rTPACriteria for thrombolysis with rTPA
Inclusion criteriaInclusion criteria Clinical signs and symptoms consistent with ischemic Clinical signs and symptoms consistent with ischemic
strokestroke Patient last seen normal within 3 hoursPatient last seen normal within 3 hours Measurable neurologic deficitMeasurable neurologic deficit
Exclusion criteriaExclusion criteria Any hemorrhage on neuroimaging (CT or MRI)Any hemorrhage on neuroimaging (CT or MRI) Symptoms suggestive of subarachnoid hemorrhageSymptoms suggestive of subarachnoid hemorrhage Seizure at stroke onset that is thought to contribute to Seizure at stroke onset that is thought to contribute to
neurologic deficitneurologic deficit Hypodensity greater than one third cerebral hemisphere Hypodensity greater than one third cerebral hemisphere
on CTon CT SBP greater than 185 mm Hg or DBP greater than 110 SBP greater than 185 mm Hg or DBP greater than 110
mm Hgmm Hg International normalized ratio (INR) greater than 17International normalized ratio (INR) greater than 17
Ischemic Stroke Ischemic Stroke Treatment ndash 2006Treatment ndash 2006
IV tissue plasminogen activator (tPA)IV tissue plasminogen activator (tPA) ndash ndash Only FDA-approved acute stroke drugOnly FDA-approved acute stroke drug ndash ndash 3 hour treatment window3 hour treatment window
MERCI - Concentric clot retrieval MERCI - Concentric clot retrieval devicedevice ndash ndash Rescue therapy - approved 2004Rescue therapy - approved 2004 ndash ndash Device approval (not outcomes-based)Device approval (not outcomes-based)
Off label approachesOff label approaches ndash ndash IV tPA after 3 hoursIV tPA after 3 hours ndash ndash IV-IA tPA sequential strategiesIV-IA tPA sequential strategies ndash ndash IA tPA clot angioplasty fragmentationIA tPA clot angioplasty fragmentation ndash ndash Ultrasound-assisted tPA lysisUltrasound-assisted tPA lysis
rt-PA Trials NINDSrt-PA Trials NINDS
Acute stroke - 624 patientsAcute stroke - 624 patients Treat within 3 hrsTreat within 3 hrs Intravenous 09 mgkg rt-PA vs placeboIntravenous 09 mgkg rt-PA vs placebo Hemorrhage 64 tPA 06 placeboHemorrhage 64 tPA 06 placebo Neurologic recovery better with tPA 30 Neurologic recovery better with tPA 30
more like to have minimal or no disabilitymore like to have minimal or no disability
First proven approved treatment for First proven approved treatment for strokestroke
Limitations of tPALimitations of tPA Only 4 of acute strokes receive tPAOnly 4 of acute strokes receive tPA (Kleindorfer et al Stroke 2004 35 e27-e29)(Kleindorfer et al Stroke 2004 35 e27-e29)
Only 22 of patients present within 3 hoursOnly 22 of patients present within 3 hours1048707 1048707 51 of these ineligible due to51 of these ineligible due to
bull bull Mild severityMild severity bull bull Medical or surgical historyMedical or surgical history bull bull Blood testsBlood tests
Sustained recanalization only 13Sustained recanalization only 13 (Alexandrov et al NEJM 2004 351 2170-8)(Alexandrov et al NEJM 2004 351 2170-8)
Concern for hemorrhageConcern for hemorrhage tPA potentiates apoptotic injury tPA potentiates apoptotic injury (Liu et al Nature Med 2004 101379-83)(Liu et al Nature Med 2004 101379-83)
PROACT II IA Lysis TrialPROACT II IA Lysis Trial Baseline 24 hours 8 days
Baseline 60 minutes 120 minutes
9mg IAProurokinase
Desmoteplase Trials DEDAS Desmoteplase Trials DEDAS DIASDIAS
Trial OverviewTrial Overview Double blind randomized placebo Double blind randomized placebo
controlled trialscontrolled trials IV delivery 3-9 hour time windowIV delivery 3-9 hour time window Plasminogen activator ndash from Plasminogen activator ndash from vampire bat vampire bat
salivasaliva Selection based on PWI-DWI MismatchSelection based on PWI-DWI Mismatch
MRI InclusionMRI Inclusion PWI defect at least 2 cm AND ~20 larger PWI defect at least 2 cm AND ~20 larger
than DWIthan DWI PWI should be obvious even visible on PWI should be obvious even visible on
raw imagesraw imagesMRI ExclusionMRI Exclusion
DWI gt 13 MCADWI gt 13 MCA MRA ICA occlusionMRA ICA occlusion
Desmoteplase ndash DIAS Desmoteplase ndash DIAS ResultsResults
Mechanical Thrombolysis Mechanical Thrombolysis devicesdevices
mechanical thrombolysis potentially extends the treatment mechanical thrombolysis potentially extends the treatment window because they act promptly at the site of the thrombuswindow because they act promptly at the site of the thrombus
The devices can retrieve large clots that pharmaceutical agents The devices can retrieve large clots that pharmaceutical agents may not successfully lysemay not successfully lyse
Patients treated with IV tPA may be considered for treatment of Patients treated with IV tPA may be considered for treatment of residual clot with some of these devicesresidual clot with some of these devices
suction-creating saline jets suction-creating saline jets laser energy ultrasound laser energy ultrasound a corkscrew apparatus to treat strokesa corkscrew apparatus to treat strokes The AngioJet systemThe AngioJet system uses saline jets that are directed back into the catheter to uses saline jets that are directed back into the catheter to
create a low-pressure zone around the catheter tip inducing create a low-pressure zone around the catheter tip inducing suction suction
The clot is pulled into the exhaust lumen and removed from the The clot is pulled into the exhaust lumen and removed from the vessel Although US Food and Drug Administration (FDA) has vessel Although US Food and Drug Administration (FDA) has approved this device for use in arteriovenous dialysis grafts and approved this device for use in arteriovenous dialysis grafts and fistulae and for the treatment of coronary arteries saphenous fistulae and for the treatment of coronary arteries saphenous vein grafts and peripheral vessels clinical trials for the vein grafts and peripheral vessels clinical trials for the treatment of acute stroke are no longer in progress treatment of acute stroke are no longer in progress
Most devices are used in cerebral vessels that 2-5 mm
The Latis laser device The Latis laser device used laser energy to ablate clots used laser energy to ablate clots Arteries 2-5 mm in diameter could be Arteries 2-5 mm in diameter could be
treated including the ICA M1 or M2 treated including the ICA M1 or M2 branch of the MCA A1 branch of the branch of the MCA A1 branch of the anterior cerebral artery (ACA) basilar anterior cerebral artery (ACA) basilar artery posterior cerebral artery (PCA) artery posterior cerebral artery (PCA) and vertebral and vertebral
Patients could receive treatment as late Patients could receive treatment as late as 8 hours after symptom onset in the as 8 hours after symptom onset in the anterior circulation and within 24 hours in anterior circulation and within 24 hours in the posterior circulation the posterior circulation
Endovascular Photo Acoustic Endovascular Photo Acoustic Recanalization (EPAR) Recanalization (EPAR)
A laser power source generated energy for the A laser power source generated energy for the systemsystem
The energy was delivered by means of The energy was delivered by means of fiberoptics to the tip of the catheter at the fiberoptics to the tip of the catheter at the treatment sitetreatment site
Absorption of laser light by darkly pigmented Absorption of laser light by darkly pigmented materials (ie the clot) occurred inside the 1-mm materials (ie the clot) occurred inside the 1-mm catheter tipcatheter tip
the system was designed to minimize scattering the system was designed to minimize scattering of laser light of laser light
Absorption converted photo energy to acoustic Absorption converted photo energy to acoustic energy which then emulsified the clot inside the energy which then emulsified the clot inside the catheter tip catheter tip
EKOS ultrasound( the EKOS ultrasound( the Ultrasound Thrombolytic Ultrasound Thrombolytic
Infusion Catheter) Infusion Catheter) combines the use of a distal ultrasound transducer with combines the use of a distal ultrasound transducer with
infusion of a thrombolytic agent through the infusion of a thrombolytic agent through the microcathetermicrocatheter
Ultrasound changes the structure of the clot to Ultrasound changes the structure of the clot to temporarily increase its permeability while providing an temporarily increase its permeability while providing an acoustic pressure gradient to move the drug into the clot acoustic pressure gradient to move the drug into the clot to speed its dissolution to speed its dissolution
The EKOS catheter is placed in the proximal portion of the The EKOS catheter is placed in the proximal portion of the clot clot
After a 2-mg bolus of tPA was injected through the After a 2-mg bolus of tPA was injected through the catheter catheter
the patient received a continuous infusion of IA tPA 03 the patient received a continuous infusion of IA tPA 03 mgmin to a maximum of 20 mg and simultaneous mgmin to a maximum of 20 mg and simultaneous ultrasound transmission for as long as 60 minutes ultrasound transmission for as long as 60 minutes
One patient was treated with a total of 4 units of One patient was treated with a total of 4 units of recombinant reteplase (Retavase) hand-injected over 60 recombinant reteplase (Retavase) hand-injected over 60 minutes minutes
Penumbra system Penumbra system The Penumbra system (Penumbra Inc) provides a dual The Penumbra system (Penumbra Inc) provides a dual
approach to clot extraction using aspiration followed by approach to clot extraction using aspiration followed by clot retrieval with a ring device if needed clot retrieval with a ring device if needed
Mechanical Embolus Removal in Cerebral Ischemia Mechanical Embolus Removal in Cerebral Ischemia (MERCI)(MERCI)
a corkscrew-like apparatus to remove blood clots from a corkscrew-like apparatus to remove blood clots from the brain in patients experiencing an ischemic stroke the brain in patients experiencing an ischemic stroke
The corkscrew itself resides in the catheter tip which The corkscrew itself resides in the catheter tip which shields it from the wall of the vessel until it is ready to be shields it from the wall of the vessel until it is ready to be burrowed into the clot Once lodged in the clot the device burrowed into the clot Once lodged in the clot the device and clot are withdrawn from the vessel and clot are withdrawn from the vessel
Snarelike devicesSnarelike devices Snares such as the Neuronet snare (Guidant Snares such as the Neuronet snare (Guidant
Endovascular Santa Clara CA) have been developed Endovascular Santa Clara CA) have been developed specifically for use in the treatment of strokes specifically for use in the treatment of strokes
These devices are simple in design and do not require the These devices are simple in design and do not require the clot to be amenable to emulsification clot to be amenable to emulsification
X-Sizer deviceX-Sizer device a device with small moving blades at the a device with small moving blades at the
catheter tip catheter tip This device the X-Sizer device (EndiCor Medical This device the X-Sizer device (EndiCor Medical
San Clemente CA) can be used to excise the San Clemente CA) can be used to excise the thrombus and aspirate it thrombus and aspirate it
The device was being evaluated in randomized The device was being evaluated in randomized studies of coronary vessels and in a registry of studies of coronary vessels and in a registry of patients with acute myocardial infarctionpatients with acute myocardial infarction
Although the manufacturer had modified the Although the manufacturer had modified the device for use in cerebral vessels a safety and device for use in cerebral vessels a safety and feasibility study was indefinitely suspended after feasibility study was indefinitely suspended after only 1 patient was treated with the device in only 1 patient was treated with the device in Europe Europe
Suction thrombectomySuction thrombectomy This method of mechanical thrombolysis is one of the This method of mechanical thrombolysis is one of the
simplestsimplest In this readily available technique suction is applied with In this readily available technique suction is applied with
a syringe to remove thrombus in the ICA a syringe to remove thrombus in the ICA It requires no other devicesIt requires no other devices A catheter with a large inner diameter (Brite Tip Cordis A catheter with a large inner diameter (Brite Tip Cordis
Corporation Miami FL) was placed in the symptomatic Corporation Miami FL) was placed in the symptomatic vessel and navigated over a guidewire into the thrombusvessel and navigated over a guidewire into the thrombus
A 60-mL syringe was used to aspirate the thrombus A 60-mL syringe was used to aspirate the thrombus Each patient required angioplasty and stenting of carotid Each patient required angioplasty and stenting of carotid
bifurcation stenosis and received daily aspirin and bifurcation stenosis and received daily aspirin and ticlopidine after the procedure No complications ticlopidine after the procedure No complications occurred occurred
Summary Acute Stroke Summary Acute Stroke ImagingImaging
PhysiologyPhysiology importance collaterals importance collaterals
ndash ndashGrowing role for perfusion Growing role for perfusion assessmentassessment
tPAtPA guidelines amp limitations guidelines amp limitations Signs on CT amp MRSigns on CT amp MR follow physiology follow physiology Stroke trialsStroke trials PWI-DWI mismatch PWI-DWI mismatch
ndash ndashTreat based on physiology not timeTreat based on physiology not time ProtocolsProtocols should be fast and should be fast and
comprehensivecomprehensive
Favorable Outcome vs Treatment Time Favorable Outcome vs Treatment Time with IV rTPAwith IV rTPA
Protocol limit = 3 hrs
Benefit ~ 45 hrs
Thromboembolism During coilingThromboembolism During coiling Most feared and frequent complication Most feared and frequent complication Reported incidence - Approx 7 Reported incidence - Approx 7 SourcesSources of Thromboembolism are of Thromboembolism are
- Clots at the aneurysmal neck during or immediately- Clots at the aneurysmal neck during or immediately after after embolization embolization
- Thrombus forming on catheters during- Thrombus forming on catheters during proceduresprocedures
- Stenosis of an adjacent artery dt coil mass- Stenosis of an adjacent artery dt coil mass or herniationor herniation
- Migration of intraaneurysmal- Migration of intraaneurysmal thrombus during coil thrombus during coil placement placement
- Slow flow dt vasospasm - Slow flow dt vasospasm
- Rare and unlikely causes are hypercoagulable- Rare and unlikely causes are hypercoagulable state such state such as antiphospholipid antibody syndrome or due to HITas antiphospholipid antibody syndrome or due to HIT
Occur more often with wide-necked aneurysms (dt Occur more often with wide-necked aneurysms (dt increased exposed surface area of thrombogenic coil increased exposed surface area of thrombogenic coil material)material)
Current regimen of endovascular Current regimen of endovascular managementmanagement
The The glycoprotein IIbIIIa antagonist tirofiban glycoprotein IIbIIIa antagonist tirofiban (04 (04 microgkgmin bolus for 30 minutes followed by infusion of microgkgmin bolus for 30 minutes followed by infusion of 0125 ugkgmin until the thrombus dissolved) 0125 ugkgmin until the thrombus dissolved)
Intraarterial thrombolysis with Intraarterial thrombolysis with urokinase or r- TPA urokinase or r- TPA increase of intravenous (IV) heparin (measured by increase of intravenous (IV) heparin (measured by
ACT) ACT) Intravenous aspirin Intravenous aspirin
Coil-related platelet aggregation (white clot) is Coil-related platelet aggregation (white clot) is unlikely to respond to fibrinolytics but has a high risk unlikely to respond to fibrinolytics but has a high risk of hemorrhage (In ISAT) all 5 patients who had of hemorrhage (In ISAT) all 5 patients who had received thrombolytic therapy with tPA to treat a received thrombolytic therapy with tPA to treat a thromboembolic complication after endovascular thromboembolic complication after endovascular treatment rebleed and all of these patients died)treatment rebleed and all of these patients died)
IntracranialIntracranial Stenting Stenting Metallic foreign body such as stent will accumulate Metallic foreign body such as stent will accumulate
thrombus in the absence of platelet inhibitionthrombus in the absence of platelet inhibition Antiplatelet drugs are important to prevent peri or Antiplatelet drugs are important to prevent peri or
post-interventional thromboembolic eventspost-interventional thromboembolic events Optimal treatment regimens has not been determined Optimal treatment regimens has not been determined
but usually but usually Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-
procedureprocedureOrOr
Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on
morning of proceduremorning of procedure
If need to use stent is not pre-planned thanIf need to use stent is not pre-planned than
Abciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkgAbciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkg IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)
Glycoprotein IIbIIIa inhibitor are not used routinely during elective Glycoprotein IIbIIIa inhibitor are not used routinely during elective stenting procedure dt increased risk of ICH stenting procedure dt increased risk of ICH
Carotid StentingCarotid Stenting
Pre-procedurePre-procedure
Double Antiplatelet therapy is routinely given Double Antiplatelet therapy is routinely given beginning at least 3beginning at least 3
days before the proceduredays before the procedure
Aspirin 325mgd+Clopidogrel 75mgdAspirin 325mgd+Clopidogrel 75mgd During procedureDuring procedure
Heparin is given with target clotting time of 250-Heparin is given with target clotting time of 250-300sec300sec
Post-procedure Post-procedure
Aspirin 325mg is continued indefinitely and Aspirin 325mg is continued indefinitely and
Clopidogrel 75mgd for at least 6 weeks Clopidogrel 75mgd for at least 6 weeks
Inclusion criteria for Local ThrombolysisInclusion criteria for Local Thrombolysis a)a) Patients in severe clinical grade on admission Patients in severe clinical grade on admission
with evidence of dural venous sinus with evidence of dural venous sinus thrombosis and restrictive venous outflow on thrombosis and restrictive venous outflow on cerebral angiogramcerebral angiogram
b)b) Patients in clinical grade 3 worsening on Patients in clinical grade 3 worsening on heparin therapy Restriction to venous heparin therapy Restriction to venous outflow was defined as an increase in brain outflow was defined as an increase in brain circulation time gt 12 s delay in the drainage circulation time gt 12 s delay in the drainage of cortical veins with cortical veins hanging of cortical veins with cortical veins hanging in spacein space
Treatment Options for Venous Thrombosis
CT Grading for Venous ThrombosisCT Grading for Venous Thrombosis Grade I no parenchymal change Grade I no parenchymal change
(hyperdense (hyperdense sinuses cortical veins empty sinuses cortical veins empty delta sign)delta sign)
Grade II non hemorrhagic venous infarct Grade II non hemorrhagic venous infarct without mass effect without mass effect
Grade III non-hemorrhagic infarct with Grade III non-hemorrhagic infarct with mass effectmass effect
Grade IV hemorrhagic venous infarct (max Grade IV hemorrhagic venous infarct (max diameter lt 3 cm) with no mass effectdiameter lt 3 cm) with no mass effect
Grade V hemorrhagic venous infarct (max Grade V hemorrhagic venous infarct (max diameter gt 3 cm) with mass effect diameter gt 3 cm) with mass effect
Local ThrombolysisLocal Thrombolysis
Femoral Jugular access was secured and a guiding Femoral Jugular access was secured and a guiding catheter was placed in the jugular bulb catheter was placed in the jugular bulb Mechanical Mechanical clot maceration clot maceration was done with the guidewire was done with the guidewire following which a microcatheter (was navigated and following which a microcatheter (was navigated and placed in the thrombosed segment of sinus confirmed placed in the thrombosed segment of sinus confirmed on a selective venogram on a selective venogram
Urokinase infusion Bolus dose of 2-6 lacs followed Urokinase infusion Bolus dose of 2-6 lacs followed by 60000 to 100000 units per hour along with by 60000 to 100000 units per hour along with periodic check venogram Along with maintenance periodic check venogram Along with maintenance systemic infusion of Heparinsystemic infusion of Heparin Other agents such as Other agents such as streptokinase altepase or rTPAstreptokinase altepase or rTPA can be also used can be also used
After thrombolysis patient should subjected to oral After thrombolysis patient should subjected to oral anticoagulation for six monthsanticoagulation for six months
Low-molecular-weight Low-molecular-weight heparinheparin
PharmacologyPharmacologyLMWH as its name suggests is a glycosaminoglycan that is approximatelyLMWH as its name suggests is a glycosaminoglycan that is approximately
one third the molecular weight of UFH It is derived from UFH through one third the molecular weight of UFH It is derived from UFH through variousvarious
depolymerization processes LMWH binds to antithrombin which in turn depolymerization processes LMWH binds to antithrombin which in turn
Neutralizes actors Xa and IIa Because LMWH lacks many of the longer Neutralizes actors Xa and IIa Because LMWH lacks many of the longer chains chains
required for binding to thrombin it has less ability to neutralize thrombin required for binding to thrombin it has less ability to neutralize thrombin
relativeto its ability to neutralize factor Xa LMWH also has less relativeto its ability to neutralize factor Xa LMWH also has less nonspecific nonspecific
binding to other proteins There is greater bioavailability with more binding to other proteins There is greater bioavailability with more predictable predictable
pharmacokinetics that eliminates the need for monitoring The smaller pharmacokinetics that eliminates the need for monitoring The smaller size also size also
allows for enhanced subcutaneous absorption when compared with UFHallows for enhanced subcutaneous absorption when compared with UFH
Three LMWH preparations are Three LMWH preparations are currently approved for use in the currently approved for use in the United States (1) enoxaparin (2) United States (1) enoxaparin (2) dalteparin and (3) tinzaparin dalteparin and (3) tinzaparin
They are all administered They are all administered subcutaneously at intervals of either subcutaneously at intervals of either once or twice daily for both once or twice daily for both prophylaxis and treatment dosesprophylaxis and treatment doses
Few Experiences of Few Experiences of ThrombolysisThrombolysis
Vickey 25 Yrs male patient presented Vickey 25 Yrs male patient presented with 12with 12thth day HO severe headache with day HO severe headache with right sided hemiplegiaright sided hemiplegia
MRI shows thrombosis of the superior MRI shows thrombosis of the superior sagittal left transverse left sigmoid sagittal left transverse left sigmoid sinuses and cortical veins in the fronto-sinuses and cortical veins in the fronto-parietal regions with eo haemorrhagic parietal regions with eo haemorrhagic infarct in the left cerebral hemisphere infarct in the left cerebral hemisphere with mass effect( Grade ndashV)with mass effect( Grade ndashV)
Sashi Srivastava 64 yrs FSashi Srivastava 64 yrs F In a follow up case of MRD with infra-renal In a follow up case of MRD with infra-renal
aortic abdominal and bilateral renal artery aortic abdominal and bilateral renal artery thrombosis renal angiogram shows filling thrombosis renal angiogram shows filling defects in the right Renal artery defects in the right Renal artery
Initially Renal angioplasty was done Initially Renal angioplasty was done Following angioplasty few thrombi are seem Following angioplasty few thrombi are seem to extends into the segmental branches and to extends into the segmental branches and causing blockage So Thrombolysis was causing blockage So Thrombolysis was plane to dissolve the run-out thrombi with plane to dissolve the run-out thrombi with urokinase urokinase
Rakesh 34yrsMRakesh 34yrsM Left SFA pseudoaneurysm with Left SFA pseudoaneurysm with
Covered stent placementCovered stent placement Pre operative antiplatelets with post Pre operative antiplatelets with post
procedure heparin Tirofiban procedure heparin Tirofiban followed by aspirin and clopidogrel followed by aspirin and clopidogrel were usedwere used
IAT may be a treatment option for selected patients IAT may be a treatment option for selected patients Possible selection criteria include Possible selection criteria include
presentation between 3 and 6 hours from symptom onsetpresentation between 3 and 6 hours from symptom onset major cerebral artery occlusion major cerebral artery occlusion severe neurologic deficits severe neurologic deficits high risk of systemic hemorrhage with IV rt-PA (eg recent high risk of systemic hemorrhage with IV rt-PA (eg recent
surgery) surgery) The MERCI (Mechanical Embolus Removal in Cerebral The MERCI (Mechanical Embolus Removal in Cerebral
Ischemia) retrievalIschemia) retrieval system system
Has been FDA-approved for recanalizing acutely occluded Has been FDA-approved for recanalizing acutely occluded cerebral arteries cerebral arteries
In the Multi-MERCI study patients who did not improve In the Multi-MERCI study patients who did not improve immediately after IV rt-PA underwent mechanical immediately after IV rt-PA underwent mechanical embolectomy within 8 hours of symptom onset embolectomy within 8 hours of symptom onset
Partial or complete recanalization occurred in 74 of Partial or complete recanalization occurred in 74 of patientspatients
with a symptomatic intracerebral hemorrhage (sICH) rate of with a symptomatic intracerebral hemorrhage (sICH) rate of 67 67
Mechanical embolectomy with the MERCI retriever may be a Mechanical embolectomy with the MERCI retriever may be a feasible and safe option for patients after IV rt-PAfeasible and safe option for patients after IV rt-PA
Penumbra stroke systemPenumbra stroke system This device combines two methods of clot This device combines two methods of clot
extraction aspiration and mechanical extraction aspiration and mechanical extraction extraction
First the clot is aspirated then a thrombus First the clot is aspirated then a thrombus removal ring can be used if necessary to removal ring can be used if necessary to remove remaining clot remove remaining clot
successful recanalizing 82successful recanalizing 82 Bridging therapyBridging therapy
06 mgkg IV rt-PA followed by IAT with IA rt-06 mgkg IV rt-PA followed by IAT with IA rt-PA (up to 20 mg)PA (up to 20 mg)
achieved a higher recanalization rateachieved a higher recanalization rate
Criteria for thrombolysis with rTPACriteria for thrombolysis with rTPA
Inclusion criteriaInclusion criteria Clinical signs and symptoms consistent with ischemic Clinical signs and symptoms consistent with ischemic
strokestroke Patient last seen normal within 3 hoursPatient last seen normal within 3 hours Measurable neurologic deficitMeasurable neurologic deficit
Exclusion criteriaExclusion criteria Any hemorrhage on neuroimaging (CT or MRI)Any hemorrhage on neuroimaging (CT or MRI) Symptoms suggestive of subarachnoid hemorrhageSymptoms suggestive of subarachnoid hemorrhage Seizure at stroke onset that is thought to contribute to Seizure at stroke onset that is thought to contribute to
neurologic deficitneurologic deficit Hypodensity greater than one third cerebral hemisphere Hypodensity greater than one third cerebral hemisphere
on CTon CT SBP greater than 185 mm Hg or DBP greater than 110 SBP greater than 185 mm Hg or DBP greater than 110
mm Hgmm Hg International normalized ratio (INR) greater than 17International normalized ratio (INR) greater than 17
Ischemic Stroke Ischemic Stroke Treatment ndash 2006Treatment ndash 2006
IV tissue plasminogen activator (tPA)IV tissue plasminogen activator (tPA) ndash ndash Only FDA-approved acute stroke drugOnly FDA-approved acute stroke drug ndash ndash 3 hour treatment window3 hour treatment window
MERCI - Concentric clot retrieval MERCI - Concentric clot retrieval devicedevice ndash ndash Rescue therapy - approved 2004Rescue therapy - approved 2004 ndash ndash Device approval (not outcomes-based)Device approval (not outcomes-based)
Off label approachesOff label approaches ndash ndash IV tPA after 3 hoursIV tPA after 3 hours ndash ndash IV-IA tPA sequential strategiesIV-IA tPA sequential strategies ndash ndash IA tPA clot angioplasty fragmentationIA tPA clot angioplasty fragmentation ndash ndash Ultrasound-assisted tPA lysisUltrasound-assisted tPA lysis
rt-PA Trials NINDSrt-PA Trials NINDS
Acute stroke - 624 patientsAcute stroke - 624 patients Treat within 3 hrsTreat within 3 hrs Intravenous 09 mgkg rt-PA vs placeboIntravenous 09 mgkg rt-PA vs placebo Hemorrhage 64 tPA 06 placeboHemorrhage 64 tPA 06 placebo Neurologic recovery better with tPA 30 Neurologic recovery better with tPA 30
more like to have minimal or no disabilitymore like to have minimal or no disability
First proven approved treatment for First proven approved treatment for strokestroke
Limitations of tPALimitations of tPA Only 4 of acute strokes receive tPAOnly 4 of acute strokes receive tPA (Kleindorfer et al Stroke 2004 35 e27-e29)(Kleindorfer et al Stroke 2004 35 e27-e29)
Only 22 of patients present within 3 hoursOnly 22 of patients present within 3 hours1048707 1048707 51 of these ineligible due to51 of these ineligible due to
bull bull Mild severityMild severity bull bull Medical or surgical historyMedical or surgical history bull bull Blood testsBlood tests
Sustained recanalization only 13Sustained recanalization only 13 (Alexandrov et al NEJM 2004 351 2170-8)(Alexandrov et al NEJM 2004 351 2170-8)
Concern for hemorrhageConcern for hemorrhage tPA potentiates apoptotic injury tPA potentiates apoptotic injury (Liu et al Nature Med 2004 101379-83)(Liu et al Nature Med 2004 101379-83)
PROACT II IA Lysis TrialPROACT II IA Lysis Trial Baseline 24 hours 8 days
Baseline 60 minutes 120 minutes
9mg IAProurokinase
Desmoteplase Trials DEDAS Desmoteplase Trials DEDAS DIASDIAS
Trial OverviewTrial Overview Double blind randomized placebo Double blind randomized placebo
controlled trialscontrolled trials IV delivery 3-9 hour time windowIV delivery 3-9 hour time window Plasminogen activator ndash from Plasminogen activator ndash from vampire bat vampire bat
salivasaliva Selection based on PWI-DWI MismatchSelection based on PWI-DWI Mismatch
MRI InclusionMRI Inclusion PWI defect at least 2 cm AND ~20 larger PWI defect at least 2 cm AND ~20 larger
than DWIthan DWI PWI should be obvious even visible on PWI should be obvious even visible on
raw imagesraw imagesMRI ExclusionMRI Exclusion
DWI gt 13 MCADWI gt 13 MCA MRA ICA occlusionMRA ICA occlusion
Desmoteplase ndash DIAS Desmoteplase ndash DIAS ResultsResults
Mechanical Thrombolysis Mechanical Thrombolysis devicesdevices
mechanical thrombolysis potentially extends the treatment mechanical thrombolysis potentially extends the treatment window because they act promptly at the site of the thrombuswindow because they act promptly at the site of the thrombus
The devices can retrieve large clots that pharmaceutical agents The devices can retrieve large clots that pharmaceutical agents may not successfully lysemay not successfully lyse
Patients treated with IV tPA may be considered for treatment of Patients treated with IV tPA may be considered for treatment of residual clot with some of these devicesresidual clot with some of these devices
suction-creating saline jets suction-creating saline jets laser energy ultrasound laser energy ultrasound a corkscrew apparatus to treat strokesa corkscrew apparatus to treat strokes The AngioJet systemThe AngioJet system uses saline jets that are directed back into the catheter to uses saline jets that are directed back into the catheter to
create a low-pressure zone around the catheter tip inducing create a low-pressure zone around the catheter tip inducing suction suction
The clot is pulled into the exhaust lumen and removed from the The clot is pulled into the exhaust lumen and removed from the vessel Although US Food and Drug Administration (FDA) has vessel Although US Food and Drug Administration (FDA) has approved this device for use in arteriovenous dialysis grafts and approved this device for use in arteriovenous dialysis grafts and fistulae and for the treatment of coronary arteries saphenous fistulae and for the treatment of coronary arteries saphenous vein grafts and peripheral vessels clinical trials for the vein grafts and peripheral vessels clinical trials for the treatment of acute stroke are no longer in progress treatment of acute stroke are no longer in progress
Most devices are used in cerebral vessels that 2-5 mm
The Latis laser device The Latis laser device used laser energy to ablate clots used laser energy to ablate clots Arteries 2-5 mm in diameter could be Arteries 2-5 mm in diameter could be
treated including the ICA M1 or M2 treated including the ICA M1 or M2 branch of the MCA A1 branch of the branch of the MCA A1 branch of the anterior cerebral artery (ACA) basilar anterior cerebral artery (ACA) basilar artery posterior cerebral artery (PCA) artery posterior cerebral artery (PCA) and vertebral and vertebral
Patients could receive treatment as late Patients could receive treatment as late as 8 hours after symptom onset in the as 8 hours after symptom onset in the anterior circulation and within 24 hours in anterior circulation and within 24 hours in the posterior circulation the posterior circulation
Endovascular Photo Acoustic Endovascular Photo Acoustic Recanalization (EPAR) Recanalization (EPAR)
A laser power source generated energy for the A laser power source generated energy for the systemsystem
The energy was delivered by means of The energy was delivered by means of fiberoptics to the tip of the catheter at the fiberoptics to the tip of the catheter at the treatment sitetreatment site
Absorption of laser light by darkly pigmented Absorption of laser light by darkly pigmented materials (ie the clot) occurred inside the 1-mm materials (ie the clot) occurred inside the 1-mm catheter tipcatheter tip
the system was designed to minimize scattering the system was designed to minimize scattering of laser light of laser light
Absorption converted photo energy to acoustic Absorption converted photo energy to acoustic energy which then emulsified the clot inside the energy which then emulsified the clot inside the catheter tip catheter tip
EKOS ultrasound( the EKOS ultrasound( the Ultrasound Thrombolytic Ultrasound Thrombolytic
Infusion Catheter) Infusion Catheter) combines the use of a distal ultrasound transducer with combines the use of a distal ultrasound transducer with
infusion of a thrombolytic agent through the infusion of a thrombolytic agent through the microcathetermicrocatheter
Ultrasound changes the structure of the clot to Ultrasound changes the structure of the clot to temporarily increase its permeability while providing an temporarily increase its permeability while providing an acoustic pressure gradient to move the drug into the clot acoustic pressure gradient to move the drug into the clot to speed its dissolution to speed its dissolution
The EKOS catheter is placed in the proximal portion of the The EKOS catheter is placed in the proximal portion of the clot clot
After a 2-mg bolus of tPA was injected through the After a 2-mg bolus of tPA was injected through the catheter catheter
the patient received a continuous infusion of IA tPA 03 the patient received a continuous infusion of IA tPA 03 mgmin to a maximum of 20 mg and simultaneous mgmin to a maximum of 20 mg and simultaneous ultrasound transmission for as long as 60 minutes ultrasound transmission for as long as 60 minutes
One patient was treated with a total of 4 units of One patient was treated with a total of 4 units of recombinant reteplase (Retavase) hand-injected over 60 recombinant reteplase (Retavase) hand-injected over 60 minutes minutes
Penumbra system Penumbra system The Penumbra system (Penumbra Inc) provides a dual The Penumbra system (Penumbra Inc) provides a dual
approach to clot extraction using aspiration followed by approach to clot extraction using aspiration followed by clot retrieval with a ring device if needed clot retrieval with a ring device if needed
Mechanical Embolus Removal in Cerebral Ischemia Mechanical Embolus Removal in Cerebral Ischemia (MERCI)(MERCI)
a corkscrew-like apparatus to remove blood clots from a corkscrew-like apparatus to remove blood clots from the brain in patients experiencing an ischemic stroke the brain in patients experiencing an ischemic stroke
The corkscrew itself resides in the catheter tip which The corkscrew itself resides in the catheter tip which shields it from the wall of the vessel until it is ready to be shields it from the wall of the vessel until it is ready to be burrowed into the clot Once lodged in the clot the device burrowed into the clot Once lodged in the clot the device and clot are withdrawn from the vessel and clot are withdrawn from the vessel
Snarelike devicesSnarelike devices Snares such as the Neuronet snare (Guidant Snares such as the Neuronet snare (Guidant
Endovascular Santa Clara CA) have been developed Endovascular Santa Clara CA) have been developed specifically for use in the treatment of strokes specifically for use in the treatment of strokes
These devices are simple in design and do not require the These devices are simple in design and do not require the clot to be amenable to emulsification clot to be amenable to emulsification
X-Sizer deviceX-Sizer device a device with small moving blades at the a device with small moving blades at the
catheter tip catheter tip This device the X-Sizer device (EndiCor Medical This device the X-Sizer device (EndiCor Medical
San Clemente CA) can be used to excise the San Clemente CA) can be used to excise the thrombus and aspirate it thrombus and aspirate it
The device was being evaluated in randomized The device was being evaluated in randomized studies of coronary vessels and in a registry of studies of coronary vessels and in a registry of patients with acute myocardial infarctionpatients with acute myocardial infarction
Although the manufacturer had modified the Although the manufacturer had modified the device for use in cerebral vessels a safety and device for use in cerebral vessels a safety and feasibility study was indefinitely suspended after feasibility study was indefinitely suspended after only 1 patient was treated with the device in only 1 patient was treated with the device in Europe Europe
Suction thrombectomySuction thrombectomy This method of mechanical thrombolysis is one of the This method of mechanical thrombolysis is one of the
simplestsimplest In this readily available technique suction is applied with In this readily available technique suction is applied with
a syringe to remove thrombus in the ICA a syringe to remove thrombus in the ICA It requires no other devicesIt requires no other devices A catheter with a large inner diameter (Brite Tip Cordis A catheter with a large inner diameter (Brite Tip Cordis
Corporation Miami FL) was placed in the symptomatic Corporation Miami FL) was placed in the symptomatic vessel and navigated over a guidewire into the thrombusvessel and navigated over a guidewire into the thrombus
A 60-mL syringe was used to aspirate the thrombus A 60-mL syringe was used to aspirate the thrombus Each patient required angioplasty and stenting of carotid Each patient required angioplasty and stenting of carotid
bifurcation stenosis and received daily aspirin and bifurcation stenosis and received daily aspirin and ticlopidine after the procedure No complications ticlopidine after the procedure No complications occurred occurred
Summary Acute Stroke Summary Acute Stroke ImagingImaging
PhysiologyPhysiology importance collaterals importance collaterals
ndash ndashGrowing role for perfusion Growing role for perfusion assessmentassessment
tPAtPA guidelines amp limitations guidelines amp limitations Signs on CT amp MRSigns on CT amp MR follow physiology follow physiology Stroke trialsStroke trials PWI-DWI mismatch PWI-DWI mismatch
ndash ndashTreat based on physiology not timeTreat based on physiology not time ProtocolsProtocols should be fast and should be fast and
comprehensivecomprehensive
Thromboembolism During coilingThromboembolism During coiling Most feared and frequent complication Most feared and frequent complication Reported incidence - Approx 7 Reported incidence - Approx 7 SourcesSources of Thromboembolism are of Thromboembolism are
- Clots at the aneurysmal neck during or immediately- Clots at the aneurysmal neck during or immediately after after embolization embolization
- Thrombus forming on catheters during- Thrombus forming on catheters during proceduresprocedures
- Stenosis of an adjacent artery dt coil mass- Stenosis of an adjacent artery dt coil mass or herniationor herniation
- Migration of intraaneurysmal- Migration of intraaneurysmal thrombus during coil thrombus during coil placement placement
- Slow flow dt vasospasm - Slow flow dt vasospasm
- Rare and unlikely causes are hypercoagulable- Rare and unlikely causes are hypercoagulable state such state such as antiphospholipid antibody syndrome or due to HITas antiphospholipid antibody syndrome or due to HIT
Occur more often with wide-necked aneurysms (dt Occur more often with wide-necked aneurysms (dt increased exposed surface area of thrombogenic coil increased exposed surface area of thrombogenic coil material)material)
Current regimen of endovascular Current regimen of endovascular managementmanagement
The The glycoprotein IIbIIIa antagonist tirofiban glycoprotein IIbIIIa antagonist tirofiban (04 (04 microgkgmin bolus for 30 minutes followed by infusion of microgkgmin bolus for 30 minutes followed by infusion of 0125 ugkgmin until the thrombus dissolved) 0125 ugkgmin until the thrombus dissolved)
Intraarterial thrombolysis with Intraarterial thrombolysis with urokinase or r- TPA urokinase or r- TPA increase of intravenous (IV) heparin (measured by increase of intravenous (IV) heparin (measured by
ACT) ACT) Intravenous aspirin Intravenous aspirin
Coil-related platelet aggregation (white clot) is Coil-related platelet aggregation (white clot) is unlikely to respond to fibrinolytics but has a high risk unlikely to respond to fibrinolytics but has a high risk of hemorrhage (In ISAT) all 5 patients who had of hemorrhage (In ISAT) all 5 patients who had received thrombolytic therapy with tPA to treat a received thrombolytic therapy with tPA to treat a thromboembolic complication after endovascular thromboembolic complication after endovascular treatment rebleed and all of these patients died)treatment rebleed and all of these patients died)
IntracranialIntracranial Stenting Stenting Metallic foreign body such as stent will accumulate Metallic foreign body such as stent will accumulate
thrombus in the absence of platelet inhibitionthrombus in the absence of platelet inhibition Antiplatelet drugs are important to prevent peri or Antiplatelet drugs are important to prevent peri or
post-interventional thromboembolic eventspost-interventional thromboembolic events Optimal treatment regimens has not been determined Optimal treatment regimens has not been determined
but usually but usually Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-
procedureprocedureOrOr
Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on
morning of proceduremorning of procedure
If need to use stent is not pre-planned thanIf need to use stent is not pre-planned than
Abciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkgAbciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkg IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)
Glycoprotein IIbIIIa inhibitor are not used routinely during elective Glycoprotein IIbIIIa inhibitor are not used routinely during elective stenting procedure dt increased risk of ICH stenting procedure dt increased risk of ICH
Carotid StentingCarotid Stenting
Pre-procedurePre-procedure
Double Antiplatelet therapy is routinely given Double Antiplatelet therapy is routinely given beginning at least 3beginning at least 3
days before the proceduredays before the procedure
Aspirin 325mgd+Clopidogrel 75mgdAspirin 325mgd+Clopidogrel 75mgd During procedureDuring procedure
Heparin is given with target clotting time of 250-Heparin is given with target clotting time of 250-300sec300sec
Post-procedure Post-procedure
Aspirin 325mg is continued indefinitely and Aspirin 325mg is continued indefinitely and
Clopidogrel 75mgd for at least 6 weeks Clopidogrel 75mgd for at least 6 weeks
Inclusion criteria for Local ThrombolysisInclusion criteria for Local Thrombolysis a)a) Patients in severe clinical grade on admission Patients in severe clinical grade on admission
with evidence of dural venous sinus with evidence of dural venous sinus thrombosis and restrictive venous outflow on thrombosis and restrictive venous outflow on cerebral angiogramcerebral angiogram
b)b) Patients in clinical grade 3 worsening on Patients in clinical grade 3 worsening on heparin therapy Restriction to venous heparin therapy Restriction to venous outflow was defined as an increase in brain outflow was defined as an increase in brain circulation time gt 12 s delay in the drainage circulation time gt 12 s delay in the drainage of cortical veins with cortical veins hanging of cortical veins with cortical veins hanging in spacein space
Treatment Options for Venous Thrombosis
CT Grading for Venous ThrombosisCT Grading for Venous Thrombosis Grade I no parenchymal change Grade I no parenchymal change
(hyperdense (hyperdense sinuses cortical veins empty sinuses cortical veins empty delta sign)delta sign)
Grade II non hemorrhagic venous infarct Grade II non hemorrhagic venous infarct without mass effect without mass effect
Grade III non-hemorrhagic infarct with Grade III non-hemorrhagic infarct with mass effectmass effect
Grade IV hemorrhagic venous infarct (max Grade IV hemorrhagic venous infarct (max diameter lt 3 cm) with no mass effectdiameter lt 3 cm) with no mass effect
Grade V hemorrhagic venous infarct (max Grade V hemorrhagic venous infarct (max diameter gt 3 cm) with mass effect diameter gt 3 cm) with mass effect
Local ThrombolysisLocal Thrombolysis
Femoral Jugular access was secured and a guiding Femoral Jugular access was secured and a guiding catheter was placed in the jugular bulb catheter was placed in the jugular bulb Mechanical Mechanical clot maceration clot maceration was done with the guidewire was done with the guidewire following which a microcatheter (was navigated and following which a microcatheter (was navigated and placed in the thrombosed segment of sinus confirmed placed in the thrombosed segment of sinus confirmed on a selective venogram on a selective venogram
Urokinase infusion Bolus dose of 2-6 lacs followed Urokinase infusion Bolus dose of 2-6 lacs followed by 60000 to 100000 units per hour along with by 60000 to 100000 units per hour along with periodic check venogram Along with maintenance periodic check venogram Along with maintenance systemic infusion of Heparinsystemic infusion of Heparin Other agents such as Other agents such as streptokinase altepase or rTPAstreptokinase altepase or rTPA can be also used can be also used
After thrombolysis patient should subjected to oral After thrombolysis patient should subjected to oral anticoagulation for six monthsanticoagulation for six months
Low-molecular-weight Low-molecular-weight heparinheparin
PharmacologyPharmacologyLMWH as its name suggests is a glycosaminoglycan that is approximatelyLMWH as its name suggests is a glycosaminoglycan that is approximately
one third the molecular weight of UFH It is derived from UFH through one third the molecular weight of UFH It is derived from UFH through variousvarious
depolymerization processes LMWH binds to antithrombin which in turn depolymerization processes LMWH binds to antithrombin which in turn
Neutralizes actors Xa and IIa Because LMWH lacks many of the longer Neutralizes actors Xa and IIa Because LMWH lacks many of the longer chains chains
required for binding to thrombin it has less ability to neutralize thrombin required for binding to thrombin it has less ability to neutralize thrombin
relativeto its ability to neutralize factor Xa LMWH also has less relativeto its ability to neutralize factor Xa LMWH also has less nonspecific nonspecific
binding to other proteins There is greater bioavailability with more binding to other proteins There is greater bioavailability with more predictable predictable
pharmacokinetics that eliminates the need for monitoring The smaller pharmacokinetics that eliminates the need for monitoring The smaller size also size also
allows for enhanced subcutaneous absorption when compared with UFHallows for enhanced subcutaneous absorption when compared with UFH
Three LMWH preparations are Three LMWH preparations are currently approved for use in the currently approved for use in the United States (1) enoxaparin (2) United States (1) enoxaparin (2) dalteparin and (3) tinzaparin dalteparin and (3) tinzaparin
They are all administered They are all administered subcutaneously at intervals of either subcutaneously at intervals of either once or twice daily for both once or twice daily for both prophylaxis and treatment dosesprophylaxis and treatment doses
Few Experiences of Few Experiences of ThrombolysisThrombolysis
Vickey 25 Yrs male patient presented Vickey 25 Yrs male patient presented with 12with 12thth day HO severe headache with day HO severe headache with right sided hemiplegiaright sided hemiplegia
MRI shows thrombosis of the superior MRI shows thrombosis of the superior sagittal left transverse left sigmoid sagittal left transverse left sigmoid sinuses and cortical veins in the fronto-sinuses and cortical veins in the fronto-parietal regions with eo haemorrhagic parietal regions with eo haemorrhagic infarct in the left cerebral hemisphere infarct in the left cerebral hemisphere with mass effect( Grade ndashV)with mass effect( Grade ndashV)
Sashi Srivastava 64 yrs FSashi Srivastava 64 yrs F In a follow up case of MRD with infra-renal In a follow up case of MRD with infra-renal
aortic abdominal and bilateral renal artery aortic abdominal and bilateral renal artery thrombosis renal angiogram shows filling thrombosis renal angiogram shows filling defects in the right Renal artery defects in the right Renal artery
Initially Renal angioplasty was done Initially Renal angioplasty was done Following angioplasty few thrombi are seem Following angioplasty few thrombi are seem to extends into the segmental branches and to extends into the segmental branches and causing blockage So Thrombolysis was causing blockage So Thrombolysis was plane to dissolve the run-out thrombi with plane to dissolve the run-out thrombi with urokinase urokinase
Rakesh 34yrsMRakesh 34yrsM Left SFA pseudoaneurysm with Left SFA pseudoaneurysm with
Covered stent placementCovered stent placement Pre operative antiplatelets with post Pre operative antiplatelets with post
procedure heparin Tirofiban procedure heparin Tirofiban followed by aspirin and clopidogrel followed by aspirin and clopidogrel were usedwere used
IAT may be a treatment option for selected patients IAT may be a treatment option for selected patients Possible selection criteria include Possible selection criteria include
presentation between 3 and 6 hours from symptom onsetpresentation between 3 and 6 hours from symptom onset major cerebral artery occlusion major cerebral artery occlusion severe neurologic deficits severe neurologic deficits high risk of systemic hemorrhage with IV rt-PA (eg recent high risk of systemic hemorrhage with IV rt-PA (eg recent
surgery) surgery) The MERCI (Mechanical Embolus Removal in Cerebral The MERCI (Mechanical Embolus Removal in Cerebral
Ischemia) retrievalIschemia) retrieval system system
Has been FDA-approved for recanalizing acutely occluded Has been FDA-approved for recanalizing acutely occluded cerebral arteries cerebral arteries
In the Multi-MERCI study patients who did not improve In the Multi-MERCI study patients who did not improve immediately after IV rt-PA underwent mechanical immediately after IV rt-PA underwent mechanical embolectomy within 8 hours of symptom onset embolectomy within 8 hours of symptom onset
Partial or complete recanalization occurred in 74 of Partial or complete recanalization occurred in 74 of patientspatients
with a symptomatic intracerebral hemorrhage (sICH) rate of with a symptomatic intracerebral hemorrhage (sICH) rate of 67 67
Mechanical embolectomy with the MERCI retriever may be a Mechanical embolectomy with the MERCI retriever may be a feasible and safe option for patients after IV rt-PAfeasible and safe option for patients after IV rt-PA
Penumbra stroke systemPenumbra stroke system This device combines two methods of clot This device combines two methods of clot
extraction aspiration and mechanical extraction aspiration and mechanical extraction extraction
First the clot is aspirated then a thrombus First the clot is aspirated then a thrombus removal ring can be used if necessary to removal ring can be used if necessary to remove remaining clot remove remaining clot
successful recanalizing 82successful recanalizing 82 Bridging therapyBridging therapy
06 mgkg IV rt-PA followed by IAT with IA rt-06 mgkg IV rt-PA followed by IAT with IA rt-PA (up to 20 mg)PA (up to 20 mg)
achieved a higher recanalization rateachieved a higher recanalization rate
Criteria for thrombolysis with rTPACriteria for thrombolysis with rTPA
Inclusion criteriaInclusion criteria Clinical signs and symptoms consistent with ischemic Clinical signs and symptoms consistent with ischemic
strokestroke Patient last seen normal within 3 hoursPatient last seen normal within 3 hours Measurable neurologic deficitMeasurable neurologic deficit
Exclusion criteriaExclusion criteria Any hemorrhage on neuroimaging (CT or MRI)Any hemorrhage on neuroimaging (CT or MRI) Symptoms suggestive of subarachnoid hemorrhageSymptoms suggestive of subarachnoid hemorrhage Seizure at stroke onset that is thought to contribute to Seizure at stroke onset that is thought to contribute to
neurologic deficitneurologic deficit Hypodensity greater than one third cerebral hemisphere Hypodensity greater than one third cerebral hemisphere
on CTon CT SBP greater than 185 mm Hg or DBP greater than 110 SBP greater than 185 mm Hg or DBP greater than 110
mm Hgmm Hg International normalized ratio (INR) greater than 17International normalized ratio (INR) greater than 17
Ischemic Stroke Ischemic Stroke Treatment ndash 2006Treatment ndash 2006
IV tissue plasminogen activator (tPA)IV tissue plasminogen activator (tPA) ndash ndash Only FDA-approved acute stroke drugOnly FDA-approved acute stroke drug ndash ndash 3 hour treatment window3 hour treatment window
MERCI - Concentric clot retrieval MERCI - Concentric clot retrieval devicedevice ndash ndash Rescue therapy - approved 2004Rescue therapy - approved 2004 ndash ndash Device approval (not outcomes-based)Device approval (not outcomes-based)
Off label approachesOff label approaches ndash ndash IV tPA after 3 hoursIV tPA after 3 hours ndash ndash IV-IA tPA sequential strategiesIV-IA tPA sequential strategies ndash ndash IA tPA clot angioplasty fragmentationIA tPA clot angioplasty fragmentation ndash ndash Ultrasound-assisted tPA lysisUltrasound-assisted tPA lysis
rt-PA Trials NINDSrt-PA Trials NINDS
Acute stroke - 624 patientsAcute stroke - 624 patients Treat within 3 hrsTreat within 3 hrs Intravenous 09 mgkg rt-PA vs placeboIntravenous 09 mgkg rt-PA vs placebo Hemorrhage 64 tPA 06 placeboHemorrhage 64 tPA 06 placebo Neurologic recovery better with tPA 30 Neurologic recovery better with tPA 30
more like to have minimal or no disabilitymore like to have minimal or no disability
First proven approved treatment for First proven approved treatment for strokestroke
Limitations of tPALimitations of tPA Only 4 of acute strokes receive tPAOnly 4 of acute strokes receive tPA (Kleindorfer et al Stroke 2004 35 e27-e29)(Kleindorfer et al Stroke 2004 35 e27-e29)
Only 22 of patients present within 3 hoursOnly 22 of patients present within 3 hours1048707 1048707 51 of these ineligible due to51 of these ineligible due to
bull bull Mild severityMild severity bull bull Medical or surgical historyMedical or surgical history bull bull Blood testsBlood tests
Sustained recanalization only 13Sustained recanalization only 13 (Alexandrov et al NEJM 2004 351 2170-8)(Alexandrov et al NEJM 2004 351 2170-8)
Concern for hemorrhageConcern for hemorrhage tPA potentiates apoptotic injury tPA potentiates apoptotic injury (Liu et al Nature Med 2004 101379-83)(Liu et al Nature Med 2004 101379-83)
PROACT II IA Lysis TrialPROACT II IA Lysis Trial Baseline 24 hours 8 days
Baseline 60 minutes 120 minutes
9mg IAProurokinase
Desmoteplase Trials DEDAS Desmoteplase Trials DEDAS DIASDIAS
Trial OverviewTrial Overview Double blind randomized placebo Double blind randomized placebo
controlled trialscontrolled trials IV delivery 3-9 hour time windowIV delivery 3-9 hour time window Plasminogen activator ndash from Plasminogen activator ndash from vampire bat vampire bat
salivasaliva Selection based on PWI-DWI MismatchSelection based on PWI-DWI Mismatch
MRI InclusionMRI Inclusion PWI defect at least 2 cm AND ~20 larger PWI defect at least 2 cm AND ~20 larger
than DWIthan DWI PWI should be obvious even visible on PWI should be obvious even visible on
raw imagesraw imagesMRI ExclusionMRI Exclusion
DWI gt 13 MCADWI gt 13 MCA MRA ICA occlusionMRA ICA occlusion
Desmoteplase ndash DIAS Desmoteplase ndash DIAS ResultsResults
Mechanical Thrombolysis Mechanical Thrombolysis devicesdevices
mechanical thrombolysis potentially extends the treatment mechanical thrombolysis potentially extends the treatment window because they act promptly at the site of the thrombuswindow because they act promptly at the site of the thrombus
The devices can retrieve large clots that pharmaceutical agents The devices can retrieve large clots that pharmaceutical agents may not successfully lysemay not successfully lyse
Patients treated with IV tPA may be considered for treatment of Patients treated with IV tPA may be considered for treatment of residual clot with some of these devicesresidual clot with some of these devices
suction-creating saline jets suction-creating saline jets laser energy ultrasound laser energy ultrasound a corkscrew apparatus to treat strokesa corkscrew apparatus to treat strokes The AngioJet systemThe AngioJet system uses saline jets that are directed back into the catheter to uses saline jets that are directed back into the catheter to
create a low-pressure zone around the catheter tip inducing create a low-pressure zone around the catheter tip inducing suction suction
The clot is pulled into the exhaust lumen and removed from the The clot is pulled into the exhaust lumen and removed from the vessel Although US Food and Drug Administration (FDA) has vessel Although US Food and Drug Administration (FDA) has approved this device for use in arteriovenous dialysis grafts and approved this device for use in arteriovenous dialysis grafts and fistulae and for the treatment of coronary arteries saphenous fistulae and for the treatment of coronary arteries saphenous vein grafts and peripheral vessels clinical trials for the vein grafts and peripheral vessels clinical trials for the treatment of acute stroke are no longer in progress treatment of acute stroke are no longer in progress
Most devices are used in cerebral vessels that 2-5 mm
The Latis laser device The Latis laser device used laser energy to ablate clots used laser energy to ablate clots Arteries 2-5 mm in diameter could be Arteries 2-5 mm in diameter could be
treated including the ICA M1 or M2 treated including the ICA M1 or M2 branch of the MCA A1 branch of the branch of the MCA A1 branch of the anterior cerebral artery (ACA) basilar anterior cerebral artery (ACA) basilar artery posterior cerebral artery (PCA) artery posterior cerebral artery (PCA) and vertebral and vertebral
Patients could receive treatment as late Patients could receive treatment as late as 8 hours after symptom onset in the as 8 hours after symptom onset in the anterior circulation and within 24 hours in anterior circulation and within 24 hours in the posterior circulation the posterior circulation
Endovascular Photo Acoustic Endovascular Photo Acoustic Recanalization (EPAR) Recanalization (EPAR)
A laser power source generated energy for the A laser power source generated energy for the systemsystem
The energy was delivered by means of The energy was delivered by means of fiberoptics to the tip of the catheter at the fiberoptics to the tip of the catheter at the treatment sitetreatment site
Absorption of laser light by darkly pigmented Absorption of laser light by darkly pigmented materials (ie the clot) occurred inside the 1-mm materials (ie the clot) occurred inside the 1-mm catheter tipcatheter tip
the system was designed to minimize scattering the system was designed to minimize scattering of laser light of laser light
Absorption converted photo energy to acoustic Absorption converted photo energy to acoustic energy which then emulsified the clot inside the energy which then emulsified the clot inside the catheter tip catheter tip
EKOS ultrasound( the EKOS ultrasound( the Ultrasound Thrombolytic Ultrasound Thrombolytic
Infusion Catheter) Infusion Catheter) combines the use of a distal ultrasound transducer with combines the use of a distal ultrasound transducer with
infusion of a thrombolytic agent through the infusion of a thrombolytic agent through the microcathetermicrocatheter
Ultrasound changes the structure of the clot to Ultrasound changes the structure of the clot to temporarily increase its permeability while providing an temporarily increase its permeability while providing an acoustic pressure gradient to move the drug into the clot acoustic pressure gradient to move the drug into the clot to speed its dissolution to speed its dissolution
The EKOS catheter is placed in the proximal portion of the The EKOS catheter is placed in the proximal portion of the clot clot
After a 2-mg bolus of tPA was injected through the After a 2-mg bolus of tPA was injected through the catheter catheter
the patient received a continuous infusion of IA tPA 03 the patient received a continuous infusion of IA tPA 03 mgmin to a maximum of 20 mg and simultaneous mgmin to a maximum of 20 mg and simultaneous ultrasound transmission for as long as 60 minutes ultrasound transmission for as long as 60 minutes
One patient was treated with a total of 4 units of One patient was treated with a total of 4 units of recombinant reteplase (Retavase) hand-injected over 60 recombinant reteplase (Retavase) hand-injected over 60 minutes minutes
Penumbra system Penumbra system The Penumbra system (Penumbra Inc) provides a dual The Penumbra system (Penumbra Inc) provides a dual
approach to clot extraction using aspiration followed by approach to clot extraction using aspiration followed by clot retrieval with a ring device if needed clot retrieval with a ring device if needed
Mechanical Embolus Removal in Cerebral Ischemia Mechanical Embolus Removal in Cerebral Ischemia (MERCI)(MERCI)
a corkscrew-like apparatus to remove blood clots from a corkscrew-like apparatus to remove blood clots from the brain in patients experiencing an ischemic stroke the brain in patients experiencing an ischemic stroke
The corkscrew itself resides in the catheter tip which The corkscrew itself resides in the catheter tip which shields it from the wall of the vessel until it is ready to be shields it from the wall of the vessel until it is ready to be burrowed into the clot Once lodged in the clot the device burrowed into the clot Once lodged in the clot the device and clot are withdrawn from the vessel and clot are withdrawn from the vessel
Snarelike devicesSnarelike devices Snares such as the Neuronet snare (Guidant Snares such as the Neuronet snare (Guidant
Endovascular Santa Clara CA) have been developed Endovascular Santa Clara CA) have been developed specifically for use in the treatment of strokes specifically for use in the treatment of strokes
These devices are simple in design and do not require the These devices are simple in design and do not require the clot to be amenable to emulsification clot to be amenable to emulsification
X-Sizer deviceX-Sizer device a device with small moving blades at the a device with small moving blades at the
catheter tip catheter tip This device the X-Sizer device (EndiCor Medical This device the X-Sizer device (EndiCor Medical
San Clemente CA) can be used to excise the San Clemente CA) can be used to excise the thrombus and aspirate it thrombus and aspirate it
The device was being evaluated in randomized The device was being evaluated in randomized studies of coronary vessels and in a registry of studies of coronary vessels and in a registry of patients with acute myocardial infarctionpatients with acute myocardial infarction
Although the manufacturer had modified the Although the manufacturer had modified the device for use in cerebral vessels a safety and device for use in cerebral vessels a safety and feasibility study was indefinitely suspended after feasibility study was indefinitely suspended after only 1 patient was treated with the device in only 1 patient was treated with the device in Europe Europe
Suction thrombectomySuction thrombectomy This method of mechanical thrombolysis is one of the This method of mechanical thrombolysis is one of the
simplestsimplest In this readily available technique suction is applied with In this readily available technique suction is applied with
a syringe to remove thrombus in the ICA a syringe to remove thrombus in the ICA It requires no other devicesIt requires no other devices A catheter with a large inner diameter (Brite Tip Cordis A catheter with a large inner diameter (Brite Tip Cordis
Corporation Miami FL) was placed in the symptomatic Corporation Miami FL) was placed in the symptomatic vessel and navigated over a guidewire into the thrombusvessel and navigated over a guidewire into the thrombus
A 60-mL syringe was used to aspirate the thrombus A 60-mL syringe was used to aspirate the thrombus Each patient required angioplasty and stenting of carotid Each patient required angioplasty and stenting of carotid
bifurcation stenosis and received daily aspirin and bifurcation stenosis and received daily aspirin and ticlopidine after the procedure No complications ticlopidine after the procedure No complications occurred occurred
Summary Acute Stroke Summary Acute Stroke ImagingImaging
PhysiologyPhysiology importance collaterals importance collaterals
ndash ndashGrowing role for perfusion Growing role for perfusion assessmentassessment
tPAtPA guidelines amp limitations guidelines amp limitations Signs on CT amp MRSigns on CT amp MR follow physiology follow physiology Stroke trialsStroke trials PWI-DWI mismatch PWI-DWI mismatch
ndash ndashTreat based on physiology not timeTreat based on physiology not time ProtocolsProtocols should be fast and should be fast and
comprehensivecomprehensive
Current regimen of endovascular Current regimen of endovascular managementmanagement
The The glycoprotein IIbIIIa antagonist tirofiban glycoprotein IIbIIIa antagonist tirofiban (04 (04 microgkgmin bolus for 30 minutes followed by infusion of microgkgmin bolus for 30 minutes followed by infusion of 0125 ugkgmin until the thrombus dissolved) 0125 ugkgmin until the thrombus dissolved)
Intraarterial thrombolysis with Intraarterial thrombolysis with urokinase or r- TPA urokinase or r- TPA increase of intravenous (IV) heparin (measured by increase of intravenous (IV) heparin (measured by
ACT) ACT) Intravenous aspirin Intravenous aspirin
Coil-related platelet aggregation (white clot) is Coil-related platelet aggregation (white clot) is unlikely to respond to fibrinolytics but has a high risk unlikely to respond to fibrinolytics but has a high risk of hemorrhage (In ISAT) all 5 patients who had of hemorrhage (In ISAT) all 5 patients who had received thrombolytic therapy with tPA to treat a received thrombolytic therapy with tPA to treat a thromboembolic complication after endovascular thromboembolic complication after endovascular treatment rebleed and all of these patients died)treatment rebleed and all of these patients died)
IntracranialIntracranial Stenting Stenting Metallic foreign body such as stent will accumulate Metallic foreign body such as stent will accumulate
thrombus in the absence of platelet inhibitionthrombus in the absence of platelet inhibition Antiplatelet drugs are important to prevent peri or Antiplatelet drugs are important to prevent peri or
post-interventional thromboembolic eventspost-interventional thromboembolic events Optimal treatment regimens has not been determined Optimal treatment regimens has not been determined
but usually but usually Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-
procedureprocedureOrOr
Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on
morning of proceduremorning of procedure
If need to use stent is not pre-planned thanIf need to use stent is not pre-planned than
Abciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkgAbciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkg IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)
Glycoprotein IIbIIIa inhibitor are not used routinely during elective Glycoprotein IIbIIIa inhibitor are not used routinely during elective stenting procedure dt increased risk of ICH stenting procedure dt increased risk of ICH
Carotid StentingCarotid Stenting
Pre-procedurePre-procedure
Double Antiplatelet therapy is routinely given Double Antiplatelet therapy is routinely given beginning at least 3beginning at least 3
days before the proceduredays before the procedure
Aspirin 325mgd+Clopidogrel 75mgdAspirin 325mgd+Clopidogrel 75mgd During procedureDuring procedure
Heparin is given with target clotting time of 250-Heparin is given with target clotting time of 250-300sec300sec
Post-procedure Post-procedure
Aspirin 325mg is continued indefinitely and Aspirin 325mg is continued indefinitely and
Clopidogrel 75mgd for at least 6 weeks Clopidogrel 75mgd for at least 6 weeks
Inclusion criteria for Local ThrombolysisInclusion criteria for Local Thrombolysis a)a) Patients in severe clinical grade on admission Patients in severe clinical grade on admission
with evidence of dural venous sinus with evidence of dural venous sinus thrombosis and restrictive venous outflow on thrombosis and restrictive venous outflow on cerebral angiogramcerebral angiogram
b)b) Patients in clinical grade 3 worsening on Patients in clinical grade 3 worsening on heparin therapy Restriction to venous heparin therapy Restriction to venous outflow was defined as an increase in brain outflow was defined as an increase in brain circulation time gt 12 s delay in the drainage circulation time gt 12 s delay in the drainage of cortical veins with cortical veins hanging of cortical veins with cortical veins hanging in spacein space
Treatment Options for Venous Thrombosis
CT Grading for Venous ThrombosisCT Grading for Venous Thrombosis Grade I no parenchymal change Grade I no parenchymal change
(hyperdense (hyperdense sinuses cortical veins empty sinuses cortical veins empty delta sign)delta sign)
Grade II non hemorrhagic venous infarct Grade II non hemorrhagic venous infarct without mass effect without mass effect
Grade III non-hemorrhagic infarct with Grade III non-hemorrhagic infarct with mass effectmass effect
Grade IV hemorrhagic venous infarct (max Grade IV hemorrhagic venous infarct (max diameter lt 3 cm) with no mass effectdiameter lt 3 cm) with no mass effect
Grade V hemorrhagic venous infarct (max Grade V hemorrhagic venous infarct (max diameter gt 3 cm) with mass effect diameter gt 3 cm) with mass effect
Local ThrombolysisLocal Thrombolysis
Femoral Jugular access was secured and a guiding Femoral Jugular access was secured and a guiding catheter was placed in the jugular bulb catheter was placed in the jugular bulb Mechanical Mechanical clot maceration clot maceration was done with the guidewire was done with the guidewire following which a microcatheter (was navigated and following which a microcatheter (was navigated and placed in the thrombosed segment of sinus confirmed placed in the thrombosed segment of sinus confirmed on a selective venogram on a selective venogram
Urokinase infusion Bolus dose of 2-6 lacs followed Urokinase infusion Bolus dose of 2-6 lacs followed by 60000 to 100000 units per hour along with by 60000 to 100000 units per hour along with periodic check venogram Along with maintenance periodic check venogram Along with maintenance systemic infusion of Heparinsystemic infusion of Heparin Other agents such as Other agents such as streptokinase altepase or rTPAstreptokinase altepase or rTPA can be also used can be also used
After thrombolysis patient should subjected to oral After thrombolysis patient should subjected to oral anticoagulation for six monthsanticoagulation for six months
Low-molecular-weight Low-molecular-weight heparinheparin
PharmacologyPharmacologyLMWH as its name suggests is a glycosaminoglycan that is approximatelyLMWH as its name suggests is a glycosaminoglycan that is approximately
one third the molecular weight of UFH It is derived from UFH through one third the molecular weight of UFH It is derived from UFH through variousvarious
depolymerization processes LMWH binds to antithrombin which in turn depolymerization processes LMWH binds to antithrombin which in turn
Neutralizes actors Xa and IIa Because LMWH lacks many of the longer Neutralizes actors Xa and IIa Because LMWH lacks many of the longer chains chains
required for binding to thrombin it has less ability to neutralize thrombin required for binding to thrombin it has less ability to neutralize thrombin
relativeto its ability to neutralize factor Xa LMWH also has less relativeto its ability to neutralize factor Xa LMWH also has less nonspecific nonspecific
binding to other proteins There is greater bioavailability with more binding to other proteins There is greater bioavailability with more predictable predictable
pharmacokinetics that eliminates the need for monitoring The smaller pharmacokinetics that eliminates the need for monitoring The smaller size also size also
allows for enhanced subcutaneous absorption when compared with UFHallows for enhanced subcutaneous absorption when compared with UFH
Three LMWH preparations are Three LMWH preparations are currently approved for use in the currently approved for use in the United States (1) enoxaparin (2) United States (1) enoxaparin (2) dalteparin and (3) tinzaparin dalteparin and (3) tinzaparin
They are all administered They are all administered subcutaneously at intervals of either subcutaneously at intervals of either once or twice daily for both once or twice daily for both prophylaxis and treatment dosesprophylaxis and treatment doses
Few Experiences of Few Experiences of ThrombolysisThrombolysis
Vickey 25 Yrs male patient presented Vickey 25 Yrs male patient presented with 12with 12thth day HO severe headache with day HO severe headache with right sided hemiplegiaright sided hemiplegia
MRI shows thrombosis of the superior MRI shows thrombosis of the superior sagittal left transverse left sigmoid sagittal left transverse left sigmoid sinuses and cortical veins in the fronto-sinuses and cortical veins in the fronto-parietal regions with eo haemorrhagic parietal regions with eo haemorrhagic infarct in the left cerebral hemisphere infarct in the left cerebral hemisphere with mass effect( Grade ndashV)with mass effect( Grade ndashV)
Sashi Srivastava 64 yrs FSashi Srivastava 64 yrs F In a follow up case of MRD with infra-renal In a follow up case of MRD with infra-renal
aortic abdominal and bilateral renal artery aortic abdominal and bilateral renal artery thrombosis renal angiogram shows filling thrombosis renal angiogram shows filling defects in the right Renal artery defects in the right Renal artery
Initially Renal angioplasty was done Initially Renal angioplasty was done Following angioplasty few thrombi are seem Following angioplasty few thrombi are seem to extends into the segmental branches and to extends into the segmental branches and causing blockage So Thrombolysis was causing blockage So Thrombolysis was plane to dissolve the run-out thrombi with plane to dissolve the run-out thrombi with urokinase urokinase
Rakesh 34yrsMRakesh 34yrsM Left SFA pseudoaneurysm with Left SFA pseudoaneurysm with
Covered stent placementCovered stent placement Pre operative antiplatelets with post Pre operative antiplatelets with post
procedure heparin Tirofiban procedure heparin Tirofiban followed by aspirin and clopidogrel followed by aspirin and clopidogrel were usedwere used
IAT may be a treatment option for selected patients IAT may be a treatment option for selected patients Possible selection criteria include Possible selection criteria include
presentation between 3 and 6 hours from symptom onsetpresentation between 3 and 6 hours from symptom onset major cerebral artery occlusion major cerebral artery occlusion severe neurologic deficits severe neurologic deficits high risk of systemic hemorrhage with IV rt-PA (eg recent high risk of systemic hemorrhage with IV rt-PA (eg recent
surgery) surgery) The MERCI (Mechanical Embolus Removal in Cerebral The MERCI (Mechanical Embolus Removal in Cerebral
Ischemia) retrievalIschemia) retrieval system system
Has been FDA-approved for recanalizing acutely occluded Has been FDA-approved for recanalizing acutely occluded cerebral arteries cerebral arteries
In the Multi-MERCI study patients who did not improve In the Multi-MERCI study patients who did not improve immediately after IV rt-PA underwent mechanical immediately after IV rt-PA underwent mechanical embolectomy within 8 hours of symptom onset embolectomy within 8 hours of symptom onset
Partial or complete recanalization occurred in 74 of Partial or complete recanalization occurred in 74 of patientspatients
with a symptomatic intracerebral hemorrhage (sICH) rate of with a symptomatic intracerebral hemorrhage (sICH) rate of 67 67
Mechanical embolectomy with the MERCI retriever may be a Mechanical embolectomy with the MERCI retriever may be a feasible and safe option for patients after IV rt-PAfeasible and safe option for patients after IV rt-PA
Penumbra stroke systemPenumbra stroke system This device combines two methods of clot This device combines two methods of clot
extraction aspiration and mechanical extraction aspiration and mechanical extraction extraction
First the clot is aspirated then a thrombus First the clot is aspirated then a thrombus removal ring can be used if necessary to removal ring can be used if necessary to remove remaining clot remove remaining clot
successful recanalizing 82successful recanalizing 82 Bridging therapyBridging therapy
06 mgkg IV rt-PA followed by IAT with IA rt-06 mgkg IV rt-PA followed by IAT with IA rt-PA (up to 20 mg)PA (up to 20 mg)
achieved a higher recanalization rateachieved a higher recanalization rate
Criteria for thrombolysis with rTPACriteria for thrombolysis with rTPA
Inclusion criteriaInclusion criteria Clinical signs and symptoms consistent with ischemic Clinical signs and symptoms consistent with ischemic
strokestroke Patient last seen normal within 3 hoursPatient last seen normal within 3 hours Measurable neurologic deficitMeasurable neurologic deficit
Exclusion criteriaExclusion criteria Any hemorrhage on neuroimaging (CT or MRI)Any hemorrhage on neuroimaging (CT or MRI) Symptoms suggestive of subarachnoid hemorrhageSymptoms suggestive of subarachnoid hemorrhage Seizure at stroke onset that is thought to contribute to Seizure at stroke onset that is thought to contribute to
neurologic deficitneurologic deficit Hypodensity greater than one third cerebral hemisphere Hypodensity greater than one third cerebral hemisphere
on CTon CT SBP greater than 185 mm Hg or DBP greater than 110 SBP greater than 185 mm Hg or DBP greater than 110
mm Hgmm Hg International normalized ratio (INR) greater than 17International normalized ratio (INR) greater than 17
Ischemic Stroke Ischemic Stroke Treatment ndash 2006Treatment ndash 2006
IV tissue plasminogen activator (tPA)IV tissue plasminogen activator (tPA) ndash ndash Only FDA-approved acute stroke drugOnly FDA-approved acute stroke drug ndash ndash 3 hour treatment window3 hour treatment window
MERCI - Concentric clot retrieval MERCI - Concentric clot retrieval devicedevice ndash ndash Rescue therapy - approved 2004Rescue therapy - approved 2004 ndash ndash Device approval (not outcomes-based)Device approval (not outcomes-based)
Off label approachesOff label approaches ndash ndash IV tPA after 3 hoursIV tPA after 3 hours ndash ndash IV-IA tPA sequential strategiesIV-IA tPA sequential strategies ndash ndash IA tPA clot angioplasty fragmentationIA tPA clot angioplasty fragmentation ndash ndash Ultrasound-assisted tPA lysisUltrasound-assisted tPA lysis
rt-PA Trials NINDSrt-PA Trials NINDS
Acute stroke - 624 patientsAcute stroke - 624 patients Treat within 3 hrsTreat within 3 hrs Intravenous 09 mgkg rt-PA vs placeboIntravenous 09 mgkg rt-PA vs placebo Hemorrhage 64 tPA 06 placeboHemorrhage 64 tPA 06 placebo Neurologic recovery better with tPA 30 Neurologic recovery better with tPA 30
more like to have minimal or no disabilitymore like to have minimal or no disability
First proven approved treatment for First proven approved treatment for strokestroke
Limitations of tPALimitations of tPA Only 4 of acute strokes receive tPAOnly 4 of acute strokes receive tPA (Kleindorfer et al Stroke 2004 35 e27-e29)(Kleindorfer et al Stroke 2004 35 e27-e29)
Only 22 of patients present within 3 hoursOnly 22 of patients present within 3 hours1048707 1048707 51 of these ineligible due to51 of these ineligible due to
bull bull Mild severityMild severity bull bull Medical or surgical historyMedical or surgical history bull bull Blood testsBlood tests
Sustained recanalization only 13Sustained recanalization only 13 (Alexandrov et al NEJM 2004 351 2170-8)(Alexandrov et al NEJM 2004 351 2170-8)
Concern for hemorrhageConcern for hemorrhage tPA potentiates apoptotic injury tPA potentiates apoptotic injury (Liu et al Nature Med 2004 101379-83)(Liu et al Nature Med 2004 101379-83)
PROACT II IA Lysis TrialPROACT II IA Lysis Trial Baseline 24 hours 8 days
Baseline 60 minutes 120 minutes
9mg IAProurokinase
Desmoteplase Trials DEDAS Desmoteplase Trials DEDAS DIASDIAS
Trial OverviewTrial Overview Double blind randomized placebo Double blind randomized placebo
controlled trialscontrolled trials IV delivery 3-9 hour time windowIV delivery 3-9 hour time window Plasminogen activator ndash from Plasminogen activator ndash from vampire bat vampire bat
salivasaliva Selection based on PWI-DWI MismatchSelection based on PWI-DWI Mismatch
MRI InclusionMRI Inclusion PWI defect at least 2 cm AND ~20 larger PWI defect at least 2 cm AND ~20 larger
than DWIthan DWI PWI should be obvious even visible on PWI should be obvious even visible on
raw imagesraw imagesMRI ExclusionMRI Exclusion
DWI gt 13 MCADWI gt 13 MCA MRA ICA occlusionMRA ICA occlusion
Desmoteplase ndash DIAS Desmoteplase ndash DIAS ResultsResults
Mechanical Thrombolysis Mechanical Thrombolysis devicesdevices
mechanical thrombolysis potentially extends the treatment mechanical thrombolysis potentially extends the treatment window because they act promptly at the site of the thrombuswindow because they act promptly at the site of the thrombus
The devices can retrieve large clots that pharmaceutical agents The devices can retrieve large clots that pharmaceutical agents may not successfully lysemay not successfully lyse
Patients treated with IV tPA may be considered for treatment of Patients treated with IV tPA may be considered for treatment of residual clot with some of these devicesresidual clot with some of these devices
suction-creating saline jets suction-creating saline jets laser energy ultrasound laser energy ultrasound a corkscrew apparatus to treat strokesa corkscrew apparatus to treat strokes The AngioJet systemThe AngioJet system uses saline jets that are directed back into the catheter to uses saline jets that are directed back into the catheter to
create a low-pressure zone around the catheter tip inducing create a low-pressure zone around the catheter tip inducing suction suction
The clot is pulled into the exhaust lumen and removed from the The clot is pulled into the exhaust lumen and removed from the vessel Although US Food and Drug Administration (FDA) has vessel Although US Food and Drug Administration (FDA) has approved this device for use in arteriovenous dialysis grafts and approved this device for use in arteriovenous dialysis grafts and fistulae and for the treatment of coronary arteries saphenous fistulae and for the treatment of coronary arteries saphenous vein grafts and peripheral vessels clinical trials for the vein grafts and peripheral vessels clinical trials for the treatment of acute stroke are no longer in progress treatment of acute stroke are no longer in progress
Most devices are used in cerebral vessels that 2-5 mm
The Latis laser device The Latis laser device used laser energy to ablate clots used laser energy to ablate clots Arteries 2-5 mm in diameter could be Arteries 2-5 mm in diameter could be
treated including the ICA M1 or M2 treated including the ICA M1 or M2 branch of the MCA A1 branch of the branch of the MCA A1 branch of the anterior cerebral artery (ACA) basilar anterior cerebral artery (ACA) basilar artery posterior cerebral artery (PCA) artery posterior cerebral artery (PCA) and vertebral and vertebral
Patients could receive treatment as late Patients could receive treatment as late as 8 hours after symptom onset in the as 8 hours after symptom onset in the anterior circulation and within 24 hours in anterior circulation and within 24 hours in the posterior circulation the posterior circulation
Endovascular Photo Acoustic Endovascular Photo Acoustic Recanalization (EPAR) Recanalization (EPAR)
A laser power source generated energy for the A laser power source generated energy for the systemsystem
The energy was delivered by means of The energy was delivered by means of fiberoptics to the tip of the catheter at the fiberoptics to the tip of the catheter at the treatment sitetreatment site
Absorption of laser light by darkly pigmented Absorption of laser light by darkly pigmented materials (ie the clot) occurred inside the 1-mm materials (ie the clot) occurred inside the 1-mm catheter tipcatheter tip
the system was designed to minimize scattering the system was designed to minimize scattering of laser light of laser light
Absorption converted photo energy to acoustic Absorption converted photo energy to acoustic energy which then emulsified the clot inside the energy which then emulsified the clot inside the catheter tip catheter tip
EKOS ultrasound( the EKOS ultrasound( the Ultrasound Thrombolytic Ultrasound Thrombolytic
Infusion Catheter) Infusion Catheter) combines the use of a distal ultrasound transducer with combines the use of a distal ultrasound transducer with
infusion of a thrombolytic agent through the infusion of a thrombolytic agent through the microcathetermicrocatheter
Ultrasound changes the structure of the clot to Ultrasound changes the structure of the clot to temporarily increase its permeability while providing an temporarily increase its permeability while providing an acoustic pressure gradient to move the drug into the clot acoustic pressure gradient to move the drug into the clot to speed its dissolution to speed its dissolution
The EKOS catheter is placed in the proximal portion of the The EKOS catheter is placed in the proximal portion of the clot clot
After a 2-mg bolus of tPA was injected through the After a 2-mg bolus of tPA was injected through the catheter catheter
the patient received a continuous infusion of IA tPA 03 the patient received a continuous infusion of IA tPA 03 mgmin to a maximum of 20 mg and simultaneous mgmin to a maximum of 20 mg and simultaneous ultrasound transmission for as long as 60 minutes ultrasound transmission for as long as 60 minutes
One patient was treated with a total of 4 units of One patient was treated with a total of 4 units of recombinant reteplase (Retavase) hand-injected over 60 recombinant reteplase (Retavase) hand-injected over 60 minutes minutes
Penumbra system Penumbra system The Penumbra system (Penumbra Inc) provides a dual The Penumbra system (Penumbra Inc) provides a dual
approach to clot extraction using aspiration followed by approach to clot extraction using aspiration followed by clot retrieval with a ring device if needed clot retrieval with a ring device if needed
Mechanical Embolus Removal in Cerebral Ischemia Mechanical Embolus Removal in Cerebral Ischemia (MERCI)(MERCI)
a corkscrew-like apparatus to remove blood clots from a corkscrew-like apparatus to remove blood clots from the brain in patients experiencing an ischemic stroke the brain in patients experiencing an ischemic stroke
The corkscrew itself resides in the catheter tip which The corkscrew itself resides in the catheter tip which shields it from the wall of the vessel until it is ready to be shields it from the wall of the vessel until it is ready to be burrowed into the clot Once lodged in the clot the device burrowed into the clot Once lodged in the clot the device and clot are withdrawn from the vessel and clot are withdrawn from the vessel
Snarelike devicesSnarelike devices Snares such as the Neuronet snare (Guidant Snares such as the Neuronet snare (Guidant
Endovascular Santa Clara CA) have been developed Endovascular Santa Clara CA) have been developed specifically for use in the treatment of strokes specifically for use in the treatment of strokes
These devices are simple in design and do not require the These devices are simple in design and do not require the clot to be amenable to emulsification clot to be amenable to emulsification
X-Sizer deviceX-Sizer device a device with small moving blades at the a device with small moving blades at the
catheter tip catheter tip This device the X-Sizer device (EndiCor Medical This device the X-Sizer device (EndiCor Medical
San Clemente CA) can be used to excise the San Clemente CA) can be used to excise the thrombus and aspirate it thrombus and aspirate it
The device was being evaluated in randomized The device was being evaluated in randomized studies of coronary vessels and in a registry of studies of coronary vessels and in a registry of patients with acute myocardial infarctionpatients with acute myocardial infarction
Although the manufacturer had modified the Although the manufacturer had modified the device for use in cerebral vessels a safety and device for use in cerebral vessels a safety and feasibility study was indefinitely suspended after feasibility study was indefinitely suspended after only 1 patient was treated with the device in only 1 patient was treated with the device in Europe Europe
Suction thrombectomySuction thrombectomy This method of mechanical thrombolysis is one of the This method of mechanical thrombolysis is one of the
simplestsimplest In this readily available technique suction is applied with In this readily available technique suction is applied with
a syringe to remove thrombus in the ICA a syringe to remove thrombus in the ICA It requires no other devicesIt requires no other devices A catheter with a large inner diameter (Brite Tip Cordis A catheter with a large inner diameter (Brite Tip Cordis
Corporation Miami FL) was placed in the symptomatic Corporation Miami FL) was placed in the symptomatic vessel and navigated over a guidewire into the thrombusvessel and navigated over a guidewire into the thrombus
A 60-mL syringe was used to aspirate the thrombus A 60-mL syringe was used to aspirate the thrombus Each patient required angioplasty and stenting of carotid Each patient required angioplasty and stenting of carotid
bifurcation stenosis and received daily aspirin and bifurcation stenosis and received daily aspirin and ticlopidine after the procedure No complications ticlopidine after the procedure No complications occurred occurred
Summary Acute Stroke Summary Acute Stroke ImagingImaging
PhysiologyPhysiology importance collaterals importance collaterals
ndash ndashGrowing role for perfusion Growing role for perfusion assessmentassessment
tPAtPA guidelines amp limitations guidelines amp limitations Signs on CT amp MRSigns on CT amp MR follow physiology follow physiology Stroke trialsStroke trials PWI-DWI mismatch PWI-DWI mismatch
ndash ndashTreat based on physiology not timeTreat based on physiology not time ProtocolsProtocols should be fast and should be fast and
comprehensivecomprehensive
IntracranialIntracranial Stenting Stenting Metallic foreign body such as stent will accumulate Metallic foreign body such as stent will accumulate
thrombus in the absence of platelet inhibitionthrombus in the absence of platelet inhibition Antiplatelet drugs are important to prevent peri or Antiplatelet drugs are important to prevent peri or
post-interventional thromboembolic eventspost-interventional thromboembolic events Optimal treatment regimens has not been determined Optimal treatment regimens has not been determined
but usually but usually Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-Aspirin(250mgd)+Clopidogrel(75mgd) ndash for 3 days pre-
procedureprocedureOrOr
Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure Bolus Clopidogrel(225mg)+Aspirin(250mg) orally- 1day before procedure With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on With these additional dose of Aspirin(250mg)+Clopidogrel(75mg) ndash on
morning of proceduremorning of procedure
If need to use stent is not pre-planned thanIf need to use stent is not pre-planned than
Abciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkgAbciximab ( glycoprotein IIbIIIa inhibitor) is used (025 ugkg IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)IVbolus followed by IV infusion of 0125ugkgmin for 12 hours)
Glycoprotein IIbIIIa inhibitor are not used routinely during elective Glycoprotein IIbIIIa inhibitor are not used routinely during elective stenting procedure dt increased risk of ICH stenting procedure dt increased risk of ICH
Carotid StentingCarotid Stenting
Pre-procedurePre-procedure
Double Antiplatelet therapy is routinely given Double Antiplatelet therapy is routinely given beginning at least 3beginning at least 3
days before the proceduredays before the procedure
Aspirin 325mgd+Clopidogrel 75mgdAspirin 325mgd+Clopidogrel 75mgd During procedureDuring procedure
Heparin is given with target clotting time of 250-Heparin is given with target clotting time of 250-300sec300sec
Post-procedure Post-procedure
Aspirin 325mg is continued indefinitely and Aspirin 325mg is continued indefinitely and
Clopidogrel 75mgd for at least 6 weeks Clopidogrel 75mgd for at least 6 weeks
Inclusion criteria for Local ThrombolysisInclusion criteria for Local Thrombolysis a)a) Patients in severe clinical grade on admission Patients in severe clinical grade on admission
with evidence of dural venous sinus with evidence of dural venous sinus thrombosis and restrictive venous outflow on thrombosis and restrictive venous outflow on cerebral angiogramcerebral angiogram
b)b) Patients in clinical grade 3 worsening on Patients in clinical grade 3 worsening on heparin therapy Restriction to venous heparin therapy Restriction to venous outflow was defined as an increase in brain outflow was defined as an increase in brain circulation time gt 12 s delay in the drainage circulation time gt 12 s delay in the drainage of cortical veins with cortical veins hanging of cortical veins with cortical veins hanging in spacein space
Treatment Options for Venous Thrombosis
CT Grading for Venous ThrombosisCT Grading for Venous Thrombosis Grade I no parenchymal change Grade I no parenchymal change
(hyperdense (hyperdense sinuses cortical veins empty sinuses cortical veins empty delta sign)delta sign)
Grade II non hemorrhagic venous infarct Grade II non hemorrhagic venous infarct without mass effect without mass effect
Grade III non-hemorrhagic infarct with Grade III non-hemorrhagic infarct with mass effectmass effect
Grade IV hemorrhagic venous infarct (max Grade IV hemorrhagic venous infarct (max diameter lt 3 cm) with no mass effectdiameter lt 3 cm) with no mass effect
Grade V hemorrhagic venous infarct (max Grade V hemorrhagic venous infarct (max diameter gt 3 cm) with mass effect diameter gt 3 cm) with mass effect
Local ThrombolysisLocal Thrombolysis
Femoral Jugular access was secured and a guiding Femoral Jugular access was secured and a guiding catheter was placed in the jugular bulb catheter was placed in the jugular bulb Mechanical Mechanical clot maceration clot maceration was done with the guidewire was done with the guidewire following which a microcatheter (was navigated and following which a microcatheter (was navigated and placed in the thrombosed segment of sinus confirmed placed in the thrombosed segment of sinus confirmed on a selective venogram on a selective venogram
Urokinase infusion Bolus dose of 2-6 lacs followed Urokinase infusion Bolus dose of 2-6 lacs followed by 60000 to 100000 units per hour along with by 60000 to 100000 units per hour along with periodic check venogram Along with maintenance periodic check venogram Along with maintenance systemic infusion of Heparinsystemic infusion of Heparin Other agents such as Other agents such as streptokinase altepase or rTPAstreptokinase altepase or rTPA can be also used can be also used
After thrombolysis patient should subjected to oral After thrombolysis patient should subjected to oral anticoagulation for six monthsanticoagulation for six months
Low-molecular-weight Low-molecular-weight heparinheparin
PharmacologyPharmacologyLMWH as its name suggests is a glycosaminoglycan that is approximatelyLMWH as its name suggests is a glycosaminoglycan that is approximately
one third the molecular weight of UFH It is derived from UFH through one third the molecular weight of UFH It is derived from UFH through variousvarious
depolymerization processes LMWH binds to antithrombin which in turn depolymerization processes LMWH binds to antithrombin which in turn
Neutralizes actors Xa and IIa Because LMWH lacks many of the longer Neutralizes actors Xa and IIa Because LMWH lacks many of the longer chains chains
required for binding to thrombin it has less ability to neutralize thrombin required for binding to thrombin it has less ability to neutralize thrombin
relativeto its ability to neutralize factor Xa LMWH also has less relativeto its ability to neutralize factor Xa LMWH also has less nonspecific nonspecific
binding to other proteins There is greater bioavailability with more binding to other proteins There is greater bioavailability with more predictable predictable
pharmacokinetics that eliminates the need for monitoring The smaller pharmacokinetics that eliminates the need for monitoring The smaller size also size also
allows for enhanced subcutaneous absorption when compared with UFHallows for enhanced subcutaneous absorption when compared with UFH
Three LMWH preparations are Three LMWH preparations are currently approved for use in the currently approved for use in the United States (1) enoxaparin (2) United States (1) enoxaparin (2) dalteparin and (3) tinzaparin dalteparin and (3) tinzaparin
They are all administered They are all administered subcutaneously at intervals of either subcutaneously at intervals of either once or twice daily for both once or twice daily for both prophylaxis and treatment dosesprophylaxis and treatment doses
Few Experiences of Few Experiences of ThrombolysisThrombolysis
Vickey 25 Yrs male patient presented Vickey 25 Yrs male patient presented with 12with 12thth day HO severe headache with day HO severe headache with right sided hemiplegiaright sided hemiplegia
MRI shows thrombosis of the superior MRI shows thrombosis of the superior sagittal left transverse left sigmoid sagittal left transverse left sigmoid sinuses and cortical veins in the fronto-sinuses and cortical veins in the fronto-parietal regions with eo haemorrhagic parietal regions with eo haemorrhagic infarct in the left cerebral hemisphere infarct in the left cerebral hemisphere with mass effect( Grade ndashV)with mass effect( Grade ndashV)
Sashi Srivastava 64 yrs FSashi Srivastava 64 yrs F In a follow up case of MRD with infra-renal In a follow up case of MRD with infra-renal
aortic abdominal and bilateral renal artery aortic abdominal and bilateral renal artery thrombosis renal angiogram shows filling thrombosis renal angiogram shows filling defects in the right Renal artery defects in the right Renal artery
Initially Renal angioplasty was done Initially Renal angioplasty was done Following angioplasty few thrombi are seem Following angioplasty few thrombi are seem to extends into the segmental branches and to extends into the segmental branches and causing blockage So Thrombolysis was causing blockage So Thrombolysis was plane to dissolve the run-out thrombi with plane to dissolve the run-out thrombi with urokinase urokinase
Rakesh 34yrsMRakesh 34yrsM Left SFA pseudoaneurysm with Left SFA pseudoaneurysm with
Covered stent placementCovered stent placement Pre operative antiplatelets with post Pre operative antiplatelets with post
procedure heparin Tirofiban procedure heparin Tirofiban followed by aspirin and clopidogrel followed by aspirin and clopidogrel were usedwere used
IAT may be a treatment option for selected patients IAT may be a treatment option for selected patients Possible selection criteria include Possible selection criteria include
presentation between 3 and 6 hours from symptom onsetpresentation between 3 and 6 hours from symptom onset major cerebral artery occlusion major cerebral artery occlusion severe neurologic deficits severe neurologic deficits high risk of systemic hemorrhage with IV rt-PA (eg recent high risk of systemic hemorrhage with IV rt-PA (eg recent
surgery) surgery) The MERCI (Mechanical Embolus Removal in Cerebral The MERCI (Mechanical Embolus Removal in Cerebral
Ischemia) retrievalIschemia) retrieval system system
Has been FDA-approved for recanalizing acutely occluded Has been FDA-approved for recanalizing acutely occluded cerebral arteries cerebral arteries
In the Multi-MERCI study patients who did not improve In the Multi-MERCI study patients who did not improve immediately after IV rt-PA underwent mechanical immediately after IV rt-PA underwent mechanical embolectomy within 8 hours of symptom onset embolectomy within 8 hours of symptom onset
Partial or complete recanalization occurred in 74 of Partial or complete recanalization occurred in 74 of patientspatients
with a symptomatic intracerebral hemorrhage (sICH) rate of with a symptomatic intracerebral hemorrhage (sICH) rate of 67 67
Mechanical embolectomy with the MERCI retriever may be a Mechanical embolectomy with the MERCI retriever may be a feasible and safe option for patients after IV rt-PAfeasible and safe option for patients after IV rt-PA
Penumbra stroke systemPenumbra stroke system This device combines two methods of clot This device combines two methods of clot
extraction aspiration and mechanical extraction aspiration and mechanical extraction extraction
First the clot is aspirated then a thrombus First the clot is aspirated then a thrombus removal ring can be used if necessary to removal ring can be used if necessary to remove remaining clot remove remaining clot
successful recanalizing 82successful recanalizing 82 Bridging therapyBridging therapy
06 mgkg IV rt-PA followed by IAT with IA rt-06 mgkg IV rt-PA followed by IAT with IA rt-PA (up to 20 mg)PA (up to 20 mg)
achieved a higher recanalization rateachieved a higher recanalization rate
Criteria for thrombolysis with rTPACriteria for thrombolysis with rTPA
Inclusion criteriaInclusion criteria Clinical signs and symptoms consistent with ischemic Clinical signs and symptoms consistent with ischemic
strokestroke Patient last seen normal within 3 hoursPatient last seen normal within 3 hours Measurable neurologic deficitMeasurable neurologic deficit
Exclusion criteriaExclusion criteria Any hemorrhage on neuroimaging (CT or MRI)Any hemorrhage on neuroimaging (CT or MRI) Symptoms suggestive of subarachnoid hemorrhageSymptoms suggestive of subarachnoid hemorrhage Seizure at stroke onset that is thought to contribute to Seizure at stroke onset that is thought to contribute to
neurologic deficitneurologic deficit Hypodensity greater than one third cerebral hemisphere Hypodensity greater than one third cerebral hemisphere
on CTon CT SBP greater than 185 mm Hg or DBP greater than 110 SBP greater than 185 mm Hg or DBP greater than 110
mm Hgmm Hg International normalized ratio (INR) greater than 17International normalized ratio (INR) greater than 17
Ischemic Stroke Ischemic Stroke Treatment ndash 2006Treatment ndash 2006
IV tissue plasminogen activator (tPA)IV tissue plasminogen activator (tPA) ndash ndash Only FDA-approved acute stroke drugOnly FDA-approved acute stroke drug ndash ndash 3 hour treatment window3 hour treatment window
MERCI - Concentric clot retrieval MERCI - Concentric clot retrieval devicedevice ndash ndash Rescue therapy - approved 2004Rescue therapy - approved 2004 ndash ndash Device approval (not outcomes-based)Device approval (not outcomes-based)
Off label approachesOff label approaches ndash ndash IV tPA after 3 hoursIV tPA after 3 hours ndash ndash IV-IA tPA sequential strategiesIV-IA tPA sequential strategies ndash ndash IA tPA clot angioplasty fragmentationIA tPA clot angioplasty fragmentation ndash ndash Ultrasound-assisted tPA lysisUltrasound-assisted tPA lysis
rt-PA Trials NINDSrt-PA Trials NINDS
Acute stroke - 624 patientsAcute stroke - 624 patients Treat within 3 hrsTreat within 3 hrs Intravenous 09 mgkg rt-PA vs placeboIntravenous 09 mgkg rt-PA vs placebo Hemorrhage 64 tPA 06 placeboHemorrhage 64 tPA 06 placebo Neurologic recovery better with tPA 30 Neurologic recovery better with tPA 30
more like to have minimal or no disabilitymore like to have minimal or no disability
First proven approved treatment for First proven approved treatment for strokestroke
Limitations of tPALimitations of tPA Only 4 of acute strokes receive tPAOnly 4 of acute strokes receive tPA (Kleindorfer et al Stroke 2004 35 e27-e29)(Kleindorfer et al Stroke 2004 35 e27-e29)
Only 22 of patients present within 3 hoursOnly 22 of patients present within 3 hours1048707 1048707 51 of these ineligible due to51 of these ineligible due to
bull bull Mild severityMild severity bull bull Medical or surgical historyMedical or surgical history bull bull Blood testsBlood tests
Sustained recanalization only 13Sustained recanalization only 13 (Alexandrov et al NEJM 2004 351 2170-8)(Alexandrov et al NEJM 2004 351 2170-8)
Concern for hemorrhageConcern for hemorrhage tPA potentiates apoptotic injury tPA potentiates apoptotic injury (Liu et al Nature Med 2004 101379-83)(Liu et al Nature Med 2004 101379-83)
PROACT II IA Lysis TrialPROACT II IA Lysis Trial Baseline 24 hours 8 days
Baseline 60 minutes 120 minutes
9mg IAProurokinase
Desmoteplase Trials DEDAS Desmoteplase Trials DEDAS DIASDIAS
Trial OverviewTrial Overview Double blind randomized placebo Double blind randomized placebo
controlled trialscontrolled trials IV delivery 3-9 hour time windowIV delivery 3-9 hour time window Plasminogen activator ndash from Plasminogen activator ndash from vampire bat vampire bat
salivasaliva Selection based on PWI-DWI MismatchSelection based on PWI-DWI Mismatch
MRI InclusionMRI Inclusion PWI defect at least 2 cm AND ~20 larger PWI defect at least 2 cm AND ~20 larger
than DWIthan DWI PWI should be obvious even visible on PWI should be obvious even visible on
raw imagesraw imagesMRI ExclusionMRI Exclusion
DWI gt 13 MCADWI gt 13 MCA MRA ICA occlusionMRA ICA occlusion
Desmoteplase ndash DIAS Desmoteplase ndash DIAS ResultsResults
Mechanical Thrombolysis Mechanical Thrombolysis devicesdevices
mechanical thrombolysis potentially extends the treatment mechanical thrombolysis potentially extends the treatment window because they act promptly at the site of the thrombuswindow because they act promptly at the site of the thrombus
The devices can retrieve large clots that pharmaceutical agents The devices can retrieve large clots that pharmaceutical agents may not successfully lysemay not successfully lyse
Patients treated with IV tPA may be considered for treatment of Patients treated with IV tPA may be considered for treatment of residual clot with some of these devicesresidual clot with some of these devices
suction-creating saline jets suction-creating saline jets laser energy ultrasound laser energy ultrasound a corkscrew apparatus to treat strokesa corkscrew apparatus to treat strokes The AngioJet systemThe AngioJet system uses saline jets that are directed back into the catheter to uses saline jets that are directed back into the catheter to
create a low-pressure zone around the catheter tip inducing create a low-pressure zone around the catheter tip inducing suction suction
The clot is pulled into the exhaust lumen and removed from the The clot is pulled into the exhaust lumen and removed from the vessel Although US Food and Drug Administration (FDA) has vessel Although US Food and Drug Administration (FDA) has approved this device for use in arteriovenous dialysis grafts and approved this device for use in arteriovenous dialysis grafts and fistulae and for the treatment of coronary arteries saphenous fistulae and for the treatment of coronary arteries saphenous vein grafts and peripheral vessels clinical trials for the vein grafts and peripheral vessels clinical trials for the treatment of acute stroke are no longer in progress treatment of acute stroke are no longer in progress
Most devices are used in cerebral vessels that 2-5 mm
The Latis laser device The Latis laser device used laser energy to ablate clots used laser energy to ablate clots Arteries 2-5 mm in diameter could be Arteries 2-5 mm in diameter could be
treated including the ICA M1 or M2 treated including the ICA M1 or M2 branch of the MCA A1 branch of the branch of the MCA A1 branch of the anterior cerebral artery (ACA) basilar anterior cerebral artery (ACA) basilar artery posterior cerebral artery (PCA) artery posterior cerebral artery (PCA) and vertebral and vertebral
Patients could receive treatment as late Patients could receive treatment as late as 8 hours after symptom onset in the as 8 hours after symptom onset in the anterior circulation and within 24 hours in anterior circulation and within 24 hours in the posterior circulation the posterior circulation
Endovascular Photo Acoustic Endovascular Photo Acoustic Recanalization (EPAR) Recanalization (EPAR)
A laser power source generated energy for the A laser power source generated energy for the systemsystem
The energy was delivered by means of The energy was delivered by means of fiberoptics to the tip of the catheter at the fiberoptics to the tip of the catheter at the treatment sitetreatment site
Absorption of laser light by darkly pigmented Absorption of laser light by darkly pigmented materials (ie the clot) occurred inside the 1-mm materials (ie the clot) occurred inside the 1-mm catheter tipcatheter tip
the system was designed to minimize scattering the system was designed to minimize scattering of laser light of laser light
Absorption converted photo energy to acoustic Absorption converted photo energy to acoustic energy which then emulsified the clot inside the energy which then emulsified the clot inside the catheter tip catheter tip
EKOS ultrasound( the EKOS ultrasound( the Ultrasound Thrombolytic Ultrasound Thrombolytic
Infusion Catheter) Infusion Catheter) combines the use of a distal ultrasound transducer with combines the use of a distal ultrasound transducer with
infusion of a thrombolytic agent through the infusion of a thrombolytic agent through the microcathetermicrocatheter
Ultrasound changes the structure of the clot to Ultrasound changes the structure of the clot to temporarily increase its permeability while providing an temporarily increase its permeability while providing an acoustic pressure gradient to move the drug into the clot acoustic pressure gradient to move the drug into the clot to speed its dissolution to speed its dissolution
The EKOS catheter is placed in the proximal portion of the The EKOS catheter is placed in the proximal portion of the clot clot
After a 2-mg bolus of tPA was injected through the After a 2-mg bolus of tPA was injected through the catheter catheter
the patient received a continuous infusion of IA tPA 03 the patient received a continuous infusion of IA tPA 03 mgmin to a maximum of 20 mg and simultaneous mgmin to a maximum of 20 mg and simultaneous ultrasound transmission for as long as 60 minutes ultrasound transmission for as long as 60 minutes
One patient was treated with a total of 4 units of One patient was treated with a total of 4 units of recombinant reteplase (Retavase) hand-injected over 60 recombinant reteplase (Retavase) hand-injected over 60 minutes minutes
Penumbra system Penumbra system The Penumbra system (Penumbra Inc) provides a dual The Penumbra system (Penumbra Inc) provides a dual
approach to clot extraction using aspiration followed by approach to clot extraction using aspiration followed by clot retrieval with a ring device if needed clot retrieval with a ring device if needed
Mechanical Embolus Removal in Cerebral Ischemia Mechanical Embolus Removal in Cerebral Ischemia (MERCI)(MERCI)
a corkscrew-like apparatus to remove blood clots from a corkscrew-like apparatus to remove blood clots from the brain in patients experiencing an ischemic stroke the brain in patients experiencing an ischemic stroke
The corkscrew itself resides in the catheter tip which The corkscrew itself resides in the catheter tip which shields it from the wall of the vessel until it is ready to be shields it from the wall of the vessel until it is ready to be burrowed into the clot Once lodged in the clot the device burrowed into the clot Once lodged in the clot the device and clot are withdrawn from the vessel and clot are withdrawn from the vessel
Snarelike devicesSnarelike devices Snares such as the Neuronet snare (Guidant Snares such as the Neuronet snare (Guidant
Endovascular Santa Clara CA) have been developed Endovascular Santa Clara CA) have been developed specifically for use in the treatment of strokes specifically for use in the treatment of strokes
These devices are simple in design and do not require the These devices are simple in design and do not require the clot to be amenable to emulsification clot to be amenable to emulsification
X-Sizer deviceX-Sizer device a device with small moving blades at the a device with small moving blades at the
catheter tip catheter tip This device the X-Sizer device (EndiCor Medical This device the X-Sizer device (EndiCor Medical
San Clemente CA) can be used to excise the San Clemente CA) can be used to excise the thrombus and aspirate it thrombus and aspirate it
The device was being evaluated in randomized The device was being evaluated in randomized studies of coronary vessels and in a registry of studies of coronary vessels and in a registry of patients with acute myocardial infarctionpatients with acute myocardial infarction
Although the manufacturer had modified the Although the manufacturer had modified the device for use in cerebral vessels a safety and device for use in cerebral vessels a safety and feasibility study was indefinitely suspended after feasibility study was indefinitely suspended after only 1 patient was treated with the device in only 1 patient was treated with the device in Europe Europe
Suction thrombectomySuction thrombectomy This method of mechanical thrombolysis is one of the This method of mechanical thrombolysis is one of the
simplestsimplest In this readily available technique suction is applied with In this readily available technique suction is applied with
a syringe to remove thrombus in the ICA a syringe to remove thrombus in the ICA It requires no other devicesIt requires no other devices A catheter with a large inner diameter (Brite Tip Cordis A catheter with a large inner diameter (Brite Tip Cordis
Corporation Miami FL) was placed in the symptomatic Corporation Miami FL) was placed in the symptomatic vessel and navigated over a guidewire into the thrombusvessel and navigated over a guidewire into the thrombus
A 60-mL syringe was used to aspirate the thrombus A 60-mL syringe was used to aspirate the thrombus Each patient required angioplasty and stenting of carotid Each patient required angioplasty and stenting of carotid
bifurcation stenosis and received daily aspirin and bifurcation stenosis and received daily aspirin and ticlopidine after the procedure No complications ticlopidine after the procedure No complications occurred occurred
Summary Acute Stroke Summary Acute Stroke ImagingImaging
PhysiologyPhysiology importance collaterals importance collaterals
ndash ndashGrowing role for perfusion Growing role for perfusion assessmentassessment
tPAtPA guidelines amp limitations guidelines amp limitations Signs on CT amp MRSigns on CT amp MR follow physiology follow physiology Stroke trialsStroke trials PWI-DWI mismatch PWI-DWI mismatch
ndash ndashTreat based on physiology not timeTreat based on physiology not time ProtocolsProtocols should be fast and should be fast and
comprehensivecomprehensive
Carotid StentingCarotid Stenting
Pre-procedurePre-procedure
Double Antiplatelet therapy is routinely given Double Antiplatelet therapy is routinely given beginning at least 3beginning at least 3
days before the proceduredays before the procedure
Aspirin 325mgd+Clopidogrel 75mgdAspirin 325mgd+Clopidogrel 75mgd During procedureDuring procedure
Heparin is given with target clotting time of 250-Heparin is given with target clotting time of 250-300sec300sec
Post-procedure Post-procedure
Aspirin 325mg is continued indefinitely and Aspirin 325mg is continued indefinitely and
Clopidogrel 75mgd for at least 6 weeks Clopidogrel 75mgd for at least 6 weeks
Inclusion criteria for Local ThrombolysisInclusion criteria for Local Thrombolysis a)a) Patients in severe clinical grade on admission Patients in severe clinical grade on admission
with evidence of dural venous sinus with evidence of dural venous sinus thrombosis and restrictive venous outflow on thrombosis and restrictive venous outflow on cerebral angiogramcerebral angiogram
b)b) Patients in clinical grade 3 worsening on Patients in clinical grade 3 worsening on heparin therapy Restriction to venous heparin therapy Restriction to venous outflow was defined as an increase in brain outflow was defined as an increase in brain circulation time gt 12 s delay in the drainage circulation time gt 12 s delay in the drainage of cortical veins with cortical veins hanging of cortical veins with cortical veins hanging in spacein space
Treatment Options for Venous Thrombosis
CT Grading for Venous ThrombosisCT Grading for Venous Thrombosis Grade I no parenchymal change Grade I no parenchymal change
(hyperdense (hyperdense sinuses cortical veins empty sinuses cortical veins empty delta sign)delta sign)
Grade II non hemorrhagic venous infarct Grade II non hemorrhagic venous infarct without mass effect without mass effect
Grade III non-hemorrhagic infarct with Grade III non-hemorrhagic infarct with mass effectmass effect
Grade IV hemorrhagic venous infarct (max Grade IV hemorrhagic venous infarct (max diameter lt 3 cm) with no mass effectdiameter lt 3 cm) with no mass effect
Grade V hemorrhagic venous infarct (max Grade V hemorrhagic venous infarct (max diameter gt 3 cm) with mass effect diameter gt 3 cm) with mass effect
Local ThrombolysisLocal Thrombolysis
Femoral Jugular access was secured and a guiding Femoral Jugular access was secured and a guiding catheter was placed in the jugular bulb catheter was placed in the jugular bulb Mechanical Mechanical clot maceration clot maceration was done with the guidewire was done with the guidewire following which a microcatheter (was navigated and following which a microcatheter (was navigated and placed in the thrombosed segment of sinus confirmed placed in the thrombosed segment of sinus confirmed on a selective venogram on a selective venogram
Urokinase infusion Bolus dose of 2-6 lacs followed Urokinase infusion Bolus dose of 2-6 lacs followed by 60000 to 100000 units per hour along with by 60000 to 100000 units per hour along with periodic check venogram Along with maintenance periodic check venogram Along with maintenance systemic infusion of Heparinsystemic infusion of Heparin Other agents such as Other agents such as streptokinase altepase or rTPAstreptokinase altepase or rTPA can be also used can be also used
After thrombolysis patient should subjected to oral After thrombolysis patient should subjected to oral anticoagulation for six monthsanticoagulation for six months
Low-molecular-weight Low-molecular-weight heparinheparin
PharmacologyPharmacologyLMWH as its name suggests is a glycosaminoglycan that is approximatelyLMWH as its name suggests is a glycosaminoglycan that is approximately
one third the molecular weight of UFH It is derived from UFH through one third the molecular weight of UFH It is derived from UFH through variousvarious
depolymerization processes LMWH binds to antithrombin which in turn depolymerization processes LMWH binds to antithrombin which in turn
Neutralizes actors Xa and IIa Because LMWH lacks many of the longer Neutralizes actors Xa and IIa Because LMWH lacks many of the longer chains chains
required for binding to thrombin it has less ability to neutralize thrombin required for binding to thrombin it has less ability to neutralize thrombin
relativeto its ability to neutralize factor Xa LMWH also has less relativeto its ability to neutralize factor Xa LMWH also has less nonspecific nonspecific
binding to other proteins There is greater bioavailability with more binding to other proteins There is greater bioavailability with more predictable predictable
pharmacokinetics that eliminates the need for monitoring The smaller pharmacokinetics that eliminates the need for monitoring The smaller size also size also
allows for enhanced subcutaneous absorption when compared with UFHallows for enhanced subcutaneous absorption when compared with UFH
Three LMWH preparations are Three LMWH preparations are currently approved for use in the currently approved for use in the United States (1) enoxaparin (2) United States (1) enoxaparin (2) dalteparin and (3) tinzaparin dalteparin and (3) tinzaparin
They are all administered They are all administered subcutaneously at intervals of either subcutaneously at intervals of either once or twice daily for both once or twice daily for both prophylaxis and treatment dosesprophylaxis and treatment doses
Few Experiences of Few Experiences of ThrombolysisThrombolysis
Vickey 25 Yrs male patient presented Vickey 25 Yrs male patient presented with 12with 12thth day HO severe headache with day HO severe headache with right sided hemiplegiaright sided hemiplegia
MRI shows thrombosis of the superior MRI shows thrombosis of the superior sagittal left transverse left sigmoid sagittal left transverse left sigmoid sinuses and cortical veins in the fronto-sinuses and cortical veins in the fronto-parietal regions with eo haemorrhagic parietal regions with eo haemorrhagic infarct in the left cerebral hemisphere infarct in the left cerebral hemisphere with mass effect( Grade ndashV)with mass effect( Grade ndashV)
Sashi Srivastava 64 yrs FSashi Srivastava 64 yrs F In a follow up case of MRD with infra-renal In a follow up case of MRD with infra-renal
aortic abdominal and bilateral renal artery aortic abdominal and bilateral renal artery thrombosis renal angiogram shows filling thrombosis renal angiogram shows filling defects in the right Renal artery defects in the right Renal artery
Initially Renal angioplasty was done Initially Renal angioplasty was done Following angioplasty few thrombi are seem Following angioplasty few thrombi are seem to extends into the segmental branches and to extends into the segmental branches and causing blockage So Thrombolysis was causing blockage So Thrombolysis was plane to dissolve the run-out thrombi with plane to dissolve the run-out thrombi with urokinase urokinase
Rakesh 34yrsMRakesh 34yrsM Left SFA pseudoaneurysm with Left SFA pseudoaneurysm with
Covered stent placementCovered stent placement Pre operative antiplatelets with post Pre operative antiplatelets with post
procedure heparin Tirofiban procedure heparin Tirofiban followed by aspirin and clopidogrel followed by aspirin and clopidogrel were usedwere used
IAT may be a treatment option for selected patients IAT may be a treatment option for selected patients Possible selection criteria include Possible selection criteria include
presentation between 3 and 6 hours from symptom onsetpresentation between 3 and 6 hours from symptom onset major cerebral artery occlusion major cerebral artery occlusion severe neurologic deficits severe neurologic deficits high risk of systemic hemorrhage with IV rt-PA (eg recent high risk of systemic hemorrhage with IV rt-PA (eg recent
surgery) surgery) The MERCI (Mechanical Embolus Removal in Cerebral The MERCI (Mechanical Embolus Removal in Cerebral
Ischemia) retrievalIschemia) retrieval system system
Has been FDA-approved for recanalizing acutely occluded Has been FDA-approved for recanalizing acutely occluded cerebral arteries cerebral arteries
In the Multi-MERCI study patients who did not improve In the Multi-MERCI study patients who did not improve immediately after IV rt-PA underwent mechanical immediately after IV rt-PA underwent mechanical embolectomy within 8 hours of symptom onset embolectomy within 8 hours of symptom onset
Partial or complete recanalization occurred in 74 of Partial or complete recanalization occurred in 74 of patientspatients
with a symptomatic intracerebral hemorrhage (sICH) rate of with a symptomatic intracerebral hemorrhage (sICH) rate of 67 67
Mechanical embolectomy with the MERCI retriever may be a Mechanical embolectomy with the MERCI retriever may be a feasible and safe option for patients after IV rt-PAfeasible and safe option for patients after IV rt-PA
Penumbra stroke systemPenumbra stroke system This device combines two methods of clot This device combines two methods of clot
extraction aspiration and mechanical extraction aspiration and mechanical extraction extraction
First the clot is aspirated then a thrombus First the clot is aspirated then a thrombus removal ring can be used if necessary to removal ring can be used if necessary to remove remaining clot remove remaining clot
successful recanalizing 82successful recanalizing 82 Bridging therapyBridging therapy
06 mgkg IV rt-PA followed by IAT with IA rt-06 mgkg IV rt-PA followed by IAT with IA rt-PA (up to 20 mg)PA (up to 20 mg)
achieved a higher recanalization rateachieved a higher recanalization rate
Criteria for thrombolysis with rTPACriteria for thrombolysis with rTPA
Inclusion criteriaInclusion criteria Clinical signs and symptoms consistent with ischemic Clinical signs and symptoms consistent with ischemic
strokestroke Patient last seen normal within 3 hoursPatient last seen normal within 3 hours Measurable neurologic deficitMeasurable neurologic deficit
Exclusion criteriaExclusion criteria Any hemorrhage on neuroimaging (CT or MRI)Any hemorrhage on neuroimaging (CT or MRI) Symptoms suggestive of subarachnoid hemorrhageSymptoms suggestive of subarachnoid hemorrhage Seizure at stroke onset that is thought to contribute to Seizure at stroke onset that is thought to contribute to
neurologic deficitneurologic deficit Hypodensity greater than one third cerebral hemisphere Hypodensity greater than one third cerebral hemisphere
on CTon CT SBP greater than 185 mm Hg or DBP greater than 110 SBP greater than 185 mm Hg or DBP greater than 110
mm Hgmm Hg International normalized ratio (INR) greater than 17International normalized ratio (INR) greater than 17
Ischemic Stroke Ischemic Stroke Treatment ndash 2006Treatment ndash 2006
IV tissue plasminogen activator (tPA)IV tissue plasminogen activator (tPA) ndash ndash Only FDA-approved acute stroke drugOnly FDA-approved acute stroke drug ndash ndash 3 hour treatment window3 hour treatment window
MERCI - Concentric clot retrieval MERCI - Concentric clot retrieval devicedevice ndash ndash Rescue therapy - approved 2004Rescue therapy - approved 2004 ndash ndash Device approval (not outcomes-based)Device approval (not outcomes-based)
Off label approachesOff label approaches ndash ndash IV tPA after 3 hoursIV tPA after 3 hours ndash ndash IV-IA tPA sequential strategiesIV-IA tPA sequential strategies ndash ndash IA tPA clot angioplasty fragmentationIA tPA clot angioplasty fragmentation ndash ndash Ultrasound-assisted tPA lysisUltrasound-assisted tPA lysis
rt-PA Trials NINDSrt-PA Trials NINDS
Acute stroke - 624 patientsAcute stroke - 624 patients Treat within 3 hrsTreat within 3 hrs Intravenous 09 mgkg rt-PA vs placeboIntravenous 09 mgkg rt-PA vs placebo Hemorrhage 64 tPA 06 placeboHemorrhage 64 tPA 06 placebo Neurologic recovery better with tPA 30 Neurologic recovery better with tPA 30
more like to have minimal or no disabilitymore like to have minimal or no disability
First proven approved treatment for First proven approved treatment for strokestroke
Limitations of tPALimitations of tPA Only 4 of acute strokes receive tPAOnly 4 of acute strokes receive tPA (Kleindorfer et al Stroke 2004 35 e27-e29)(Kleindorfer et al Stroke 2004 35 e27-e29)
Only 22 of patients present within 3 hoursOnly 22 of patients present within 3 hours1048707 1048707 51 of these ineligible due to51 of these ineligible due to
bull bull Mild severityMild severity bull bull Medical or surgical historyMedical or surgical history bull bull Blood testsBlood tests
Sustained recanalization only 13Sustained recanalization only 13 (Alexandrov et al NEJM 2004 351 2170-8)(Alexandrov et al NEJM 2004 351 2170-8)
Concern for hemorrhageConcern for hemorrhage tPA potentiates apoptotic injury tPA potentiates apoptotic injury (Liu et al Nature Med 2004 101379-83)(Liu et al Nature Med 2004 101379-83)
PROACT II IA Lysis TrialPROACT II IA Lysis Trial Baseline 24 hours 8 days
Baseline 60 minutes 120 minutes
9mg IAProurokinase
Desmoteplase Trials DEDAS Desmoteplase Trials DEDAS DIASDIAS
Trial OverviewTrial Overview Double blind randomized placebo Double blind randomized placebo
controlled trialscontrolled trials IV delivery 3-9 hour time windowIV delivery 3-9 hour time window Plasminogen activator ndash from Plasminogen activator ndash from vampire bat vampire bat
salivasaliva Selection based on PWI-DWI MismatchSelection based on PWI-DWI Mismatch
MRI InclusionMRI Inclusion PWI defect at least 2 cm AND ~20 larger PWI defect at least 2 cm AND ~20 larger
than DWIthan DWI PWI should be obvious even visible on PWI should be obvious even visible on
raw imagesraw imagesMRI ExclusionMRI Exclusion
DWI gt 13 MCADWI gt 13 MCA MRA ICA occlusionMRA ICA occlusion
Desmoteplase ndash DIAS Desmoteplase ndash DIAS ResultsResults
Mechanical Thrombolysis Mechanical Thrombolysis devicesdevices
mechanical thrombolysis potentially extends the treatment mechanical thrombolysis potentially extends the treatment window because they act promptly at the site of the thrombuswindow because they act promptly at the site of the thrombus
The devices can retrieve large clots that pharmaceutical agents The devices can retrieve large clots that pharmaceutical agents may not successfully lysemay not successfully lyse
Patients treated with IV tPA may be considered for treatment of Patients treated with IV tPA may be considered for treatment of residual clot with some of these devicesresidual clot with some of these devices
suction-creating saline jets suction-creating saline jets laser energy ultrasound laser energy ultrasound a corkscrew apparatus to treat strokesa corkscrew apparatus to treat strokes The AngioJet systemThe AngioJet system uses saline jets that are directed back into the catheter to uses saline jets that are directed back into the catheter to
create a low-pressure zone around the catheter tip inducing create a low-pressure zone around the catheter tip inducing suction suction
The clot is pulled into the exhaust lumen and removed from the The clot is pulled into the exhaust lumen and removed from the vessel Although US Food and Drug Administration (FDA) has vessel Although US Food and Drug Administration (FDA) has approved this device for use in arteriovenous dialysis grafts and approved this device for use in arteriovenous dialysis grafts and fistulae and for the treatment of coronary arteries saphenous fistulae and for the treatment of coronary arteries saphenous vein grafts and peripheral vessels clinical trials for the vein grafts and peripheral vessels clinical trials for the treatment of acute stroke are no longer in progress treatment of acute stroke are no longer in progress
Most devices are used in cerebral vessels that 2-5 mm
The Latis laser device The Latis laser device used laser energy to ablate clots used laser energy to ablate clots Arteries 2-5 mm in diameter could be Arteries 2-5 mm in diameter could be
treated including the ICA M1 or M2 treated including the ICA M1 or M2 branch of the MCA A1 branch of the branch of the MCA A1 branch of the anterior cerebral artery (ACA) basilar anterior cerebral artery (ACA) basilar artery posterior cerebral artery (PCA) artery posterior cerebral artery (PCA) and vertebral and vertebral
Patients could receive treatment as late Patients could receive treatment as late as 8 hours after symptom onset in the as 8 hours after symptom onset in the anterior circulation and within 24 hours in anterior circulation and within 24 hours in the posterior circulation the posterior circulation
Endovascular Photo Acoustic Endovascular Photo Acoustic Recanalization (EPAR) Recanalization (EPAR)
A laser power source generated energy for the A laser power source generated energy for the systemsystem
The energy was delivered by means of The energy was delivered by means of fiberoptics to the tip of the catheter at the fiberoptics to the tip of the catheter at the treatment sitetreatment site
Absorption of laser light by darkly pigmented Absorption of laser light by darkly pigmented materials (ie the clot) occurred inside the 1-mm materials (ie the clot) occurred inside the 1-mm catheter tipcatheter tip
the system was designed to minimize scattering the system was designed to minimize scattering of laser light of laser light
Absorption converted photo energy to acoustic Absorption converted photo energy to acoustic energy which then emulsified the clot inside the energy which then emulsified the clot inside the catheter tip catheter tip
EKOS ultrasound( the EKOS ultrasound( the Ultrasound Thrombolytic Ultrasound Thrombolytic
Infusion Catheter) Infusion Catheter) combines the use of a distal ultrasound transducer with combines the use of a distal ultrasound transducer with
infusion of a thrombolytic agent through the infusion of a thrombolytic agent through the microcathetermicrocatheter
Ultrasound changes the structure of the clot to Ultrasound changes the structure of the clot to temporarily increase its permeability while providing an temporarily increase its permeability while providing an acoustic pressure gradient to move the drug into the clot acoustic pressure gradient to move the drug into the clot to speed its dissolution to speed its dissolution
The EKOS catheter is placed in the proximal portion of the The EKOS catheter is placed in the proximal portion of the clot clot
After a 2-mg bolus of tPA was injected through the After a 2-mg bolus of tPA was injected through the catheter catheter
the patient received a continuous infusion of IA tPA 03 the patient received a continuous infusion of IA tPA 03 mgmin to a maximum of 20 mg and simultaneous mgmin to a maximum of 20 mg and simultaneous ultrasound transmission for as long as 60 minutes ultrasound transmission for as long as 60 minutes
One patient was treated with a total of 4 units of One patient was treated with a total of 4 units of recombinant reteplase (Retavase) hand-injected over 60 recombinant reteplase (Retavase) hand-injected over 60 minutes minutes
Penumbra system Penumbra system The Penumbra system (Penumbra Inc) provides a dual The Penumbra system (Penumbra Inc) provides a dual
approach to clot extraction using aspiration followed by approach to clot extraction using aspiration followed by clot retrieval with a ring device if needed clot retrieval with a ring device if needed
Mechanical Embolus Removal in Cerebral Ischemia Mechanical Embolus Removal in Cerebral Ischemia (MERCI)(MERCI)
a corkscrew-like apparatus to remove blood clots from a corkscrew-like apparatus to remove blood clots from the brain in patients experiencing an ischemic stroke the brain in patients experiencing an ischemic stroke
The corkscrew itself resides in the catheter tip which The corkscrew itself resides in the catheter tip which shields it from the wall of the vessel until it is ready to be shields it from the wall of the vessel until it is ready to be burrowed into the clot Once lodged in the clot the device burrowed into the clot Once lodged in the clot the device and clot are withdrawn from the vessel and clot are withdrawn from the vessel
Snarelike devicesSnarelike devices Snares such as the Neuronet snare (Guidant Snares such as the Neuronet snare (Guidant
Endovascular Santa Clara CA) have been developed Endovascular Santa Clara CA) have been developed specifically for use in the treatment of strokes specifically for use in the treatment of strokes
These devices are simple in design and do not require the These devices are simple in design and do not require the clot to be amenable to emulsification clot to be amenable to emulsification
X-Sizer deviceX-Sizer device a device with small moving blades at the a device with small moving blades at the
catheter tip catheter tip This device the X-Sizer device (EndiCor Medical This device the X-Sizer device (EndiCor Medical
San Clemente CA) can be used to excise the San Clemente CA) can be used to excise the thrombus and aspirate it thrombus and aspirate it
The device was being evaluated in randomized The device was being evaluated in randomized studies of coronary vessels and in a registry of studies of coronary vessels and in a registry of patients with acute myocardial infarctionpatients with acute myocardial infarction
Although the manufacturer had modified the Although the manufacturer had modified the device for use in cerebral vessels a safety and device for use in cerebral vessels a safety and feasibility study was indefinitely suspended after feasibility study was indefinitely suspended after only 1 patient was treated with the device in only 1 patient was treated with the device in Europe Europe
Suction thrombectomySuction thrombectomy This method of mechanical thrombolysis is one of the This method of mechanical thrombolysis is one of the
simplestsimplest In this readily available technique suction is applied with In this readily available technique suction is applied with
a syringe to remove thrombus in the ICA a syringe to remove thrombus in the ICA It requires no other devicesIt requires no other devices A catheter with a large inner diameter (Brite Tip Cordis A catheter with a large inner diameter (Brite Tip Cordis
Corporation Miami FL) was placed in the symptomatic Corporation Miami FL) was placed in the symptomatic vessel and navigated over a guidewire into the thrombusvessel and navigated over a guidewire into the thrombus
A 60-mL syringe was used to aspirate the thrombus A 60-mL syringe was used to aspirate the thrombus Each patient required angioplasty and stenting of carotid Each patient required angioplasty and stenting of carotid
bifurcation stenosis and received daily aspirin and bifurcation stenosis and received daily aspirin and ticlopidine after the procedure No complications ticlopidine after the procedure No complications occurred occurred
Summary Acute Stroke Summary Acute Stroke ImagingImaging
PhysiologyPhysiology importance collaterals importance collaterals
ndash ndashGrowing role for perfusion Growing role for perfusion assessmentassessment
tPAtPA guidelines amp limitations guidelines amp limitations Signs on CT amp MRSigns on CT amp MR follow physiology follow physiology Stroke trialsStroke trials PWI-DWI mismatch PWI-DWI mismatch
ndash ndashTreat based on physiology not timeTreat based on physiology not time ProtocolsProtocols should be fast and should be fast and
comprehensivecomprehensive
Inclusion criteria for Local ThrombolysisInclusion criteria for Local Thrombolysis a)a) Patients in severe clinical grade on admission Patients in severe clinical grade on admission
with evidence of dural venous sinus with evidence of dural venous sinus thrombosis and restrictive venous outflow on thrombosis and restrictive venous outflow on cerebral angiogramcerebral angiogram
b)b) Patients in clinical grade 3 worsening on Patients in clinical grade 3 worsening on heparin therapy Restriction to venous heparin therapy Restriction to venous outflow was defined as an increase in brain outflow was defined as an increase in brain circulation time gt 12 s delay in the drainage circulation time gt 12 s delay in the drainage of cortical veins with cortical veins hanging of cortical veins with cortical veins hanging in spacein space
Treatment Options for Venous Thrombosis
CT Grading for Venous ThrombosisCT Grading for Venous Thrombosis Grade I no parenchymal change Grade I no parenchymal change
(hyperdense (hyperdense sinuses cortical veins empty sinuses cortical veins empty delta sign)delta sign)
Grade II non hemorrhagic venous infarct Grade II non hemorrhagic venous infarct without mass effect without mass effect
Grade III non-hemorrhagic infarct with Grade III non-hemorrhagic infarct with mass effectmass effect
Grade IV hemorrhagic venous infarct (max Grade IV hemorrhagic venous infarct (max diameter lt 3 cm) with no mass effectdiameter lt 3 cm) with no mass effect
Grade V hemorrhagic venous infarct (max Grade V hemorrhagic venous infarct (max diameter gt 3 cm) with mass effect diameter gt 3 cm) with mass effect
Local ThrombolysisLocal Thrombolysis
Femoral Jugular access was secured and a guiding Femoral Jugular access was secured and a guiding catheter was placed in the jugular bulb catheter was placed in the jugular bulb Mechanical Mechanical clot maceration clot maceration was done with the guidewire was done with the guidewire following which a microcatheter (was navigated and following which a microcatheter (was navigated and placed in the thrombosed segment of sinus confirmed placed in the thrombosed segment of sinus confirmed on a selective venogram on a selective venogram
Urokinase infusion Bolus dose of 2-6 lacs followed Urokinase infusion Bolus dose of 2-6 lacs followed by 60000 to 100000 units per hour along with by 60000 to 100000 units per hour along with periodic check venogram Along with maintenance periodic check venogram Along with maintenance systemic infusion of Heparinsystemic infusion of Heparin Other agents such as Other agents such as streptokinase altepase or rTPAstreptokinase altepase or rTPA can be also used can be also used
After thrombolysis patient should subjected to oral After thrombolysis patient should subjected to oral anticoagulation for six monthsanticoagulation for six months
Low-molecular-weight Low-molecular-weight heparinheparin
PharmacologyPharmacologyLMWH as its name suggests is a glycosaminoglycan that is approximatelyLMWH as its name suggests is a glycosaminoglycan that is approximately
one third the molecular weight of UFH It is derived from UFH through one third the molecular weight of UFH It is derived from UFH through variousvarious
depolymerization processes LMWH binds to antithrombin which in turn depolymerization processes LMWH binds to antithrombin which in turn
Neutralizes actors Xa and IIa Because LMWH lacks many of the longer Neutralizes actors Xa and IIa Because LMWH lacks many of the longer chains chains
required for binding to thrombin it has less ability to neutralize thrombin required for binding to thrombin it has less ability to neutralize thrombin
relativeto its ability to neutralize factor Xa LMWH also has less relativeto its ability to neutralize factor Xa LMWH also has less nonspecific nonspecific
binding to other proteins There is greater bioavailability with more binding to other proteins There is greater bioavailability with more predictable predictable
pharmacokinetics that eliminates the need for monitoring The smaller pharmacokinetics that eliminates the need for monitoring The smaller size also size also
allows for enhanced subcutaneous absorption when compared with UFHallows for enhanced subcutaneous absorption when compared with UFH
Three LMWH preparations are Three LMWH preparations are currently approved for use in the currently approved for use in the United States (1) enoxaparin (2) United States (1) enoxaparin (2) dalteparin and (3) tinzaparin dalteparin and (3) tinzaparin
They are all administered They are all administered subcutaneously at intervals of either subcutaneously at intervals of either once or twice daily for both once or twice daily for both prophylaxis and treatment dosesprophylaxis and treatment doses
Few Experiences of Few Experiences of ThrombolysisThrombolysis
Vickey 25 Yrs male patient presented Vickey 25 Yrs male patient presented with 12with 12thth day HO severe headache with day HO severe headache with right sided hemiplegiaright sided hemiplegia
MRI shows thrombosis of the superior MRI shows thrombosis of the superior sagittal left transverse left sigmoid sagittal left transverse left sigmoid sinuses and cortical veins in the fronto-sinuses and cortical veins in the fronto-parietal regions with eo haemorrhagic parietal regions with eo haemorrhagic infarct in the left cerebral hemisphere infarct in the left cerebral hemisphere with mass effect( Grade ndashV)with mass effect( Grade ndashV)
Sashi Srivastava 64 yrs FSashi Srivastava 64 yrs F In a follow up case of MRD with infra-renal In a follow up case of MRD with infra-renal
aortic abdominal and bilateral renal artery aortic abdominal and bilateral renal artery thrombosis renal angiogram shows filling thrombosis renal angiogram shows filling defects in the right Renal artery defects in the right Renal artery
Initially Renal angioplasty was done Initially Renal angioplasty was done Following angioplasty few thrombi are seem Following angioplasty few thrombi are seem to extends into the segmental branches and to extends into the segmental branches and causing blockage So Thrombolysis was causing blockage So Thrombolysis was plane to dissolve the run-out thrombi with plane to dissolve the run-out thrombi with urokinase urokinase
Rakesh 34yrsMRakesh 34yrsM Left SFA pseudoaneurysm with Left SFA pseudoaneurysm with
Covered stent placementCovered stent placement Pre operative antiplatelets with post Pre operative antiplatelets with post
procedure heparin Tirofiban procedure heparin Tirofiban followed by aspirin and clopidogrel followed by aspirin and clopidogrel were usedwere used
IAT may be a treatment option for selected patients IAT may be a treatment option for selected patients Possible selection criteria include Possible selection criteria include
presentation between 3 and 6 hours from symptom onsetpresentation between 3 and 6 hours from symptom onset major cerebral artery occlusion major cerebral artery occlusion severe neurologic deficits severe neurologic deficits high risk of systemic hemorrhage with IV rt-PA (eg recent high risk of systemic hemorrhage with IV rt-PA (eg recent
surgery) surgery) The MERCI (Mechanical Embolus Removal in Cerebral The MERCI (Mechanical Embolus Removal in Cerebral
Ischemia) retrievalIschemia) retrieval system system
Has been FDA-approved for recanalizing acutely occluded Has been FDA-approved for recanalizing acutely occluded cerebral arteries cerebral arteries
In the Multi-MERCI study patients who did not improve In the Multi-MERCI study patients who did not improve immediately after IV rt-PA underwent mechanical immediately after IV rt-PA underwent mechanical embolectomy within 8 hours of symptom onset embolectomy within 8 hours of symptom onset
Partial or complete recanalization occurred in 74 of Partial or complete recanalization occurred in 74 of patientspatients
with a symptomatic intracerebral hemorrhage (sICH) rate of with a symptomatic intracerebral hemorrhage (sICH) rate of 67 67
Mechanical embolectomy with the MERCI retriever may be a Mechanical embolectomy with the MERCI retriever may be a feasible and safe option for patients after IV rt-PAfeasible and safe option for patients after IV rt-PA
Penumbra stroke systemPenumbra stroke system This device combines two methods of clot This device combines two methods of clot
extraction aspiration and mechanical extraction aspiration and mechanical extraction extraction
First the clot is aspirated then a thrombus First the clot is aspirated then a thrombus removal ring can be used if necessary to removal ring can be used if necessary to remove remaining clot remove remaining clot
successful recanalizing 82successful recanalizing 82 Bridging therapyBridging therapy
06 mgkg IV rt-PA followed by IAT with IA rt-06 mgkg IV rt-PA followed by IAT with IA rt-PA (up to 20 mg)PA (up to 20 mg)
achieved a higher recanalization rateachieved a higher recanalization rate
Criteria for thrombolysis with rTPACriteria for thrombolysis with rTPA
Inclusion criteriaInclusion criteria Clinical signs and symptoms consistent with ischemic Clinical signs and symptoms consistent with ischemic
strokestroke Patient last seen normal within 3 hoursPatient last seen normal within 3 hours Measurable neurologic deficitMeasurable neurologic deficit
Exclusion criteriaExclusion criteria Any hemorrhage on neuroimaging (CT or MRI)Any hemorrhage on neuroimaging (CT or MRI) Symptoms suggestive of subarachnoid hemorrhageSymptoms suggestive of subarachnoid hemorrhage Seizure at stroke onset that is thought to contribute to Seizure at stroke onset that is thought to contribute to
neurologic deficitneurologic deficit Hypodensity greater than one third cerebral hemisphere Hypodensity greater than one third cerebral hemisphere
on CTon CT SBP greater than 185 mm Hg or DBP greater than 110 SBP greater than 185 mm Hg or DBP greater than 110
mm Hgmm Hg International normalized ratio (INR) greater than 17International normalized ratio (INR) greater than 17
Ischemic Stroke Ischemic Stroke Treatment ndash 2006Treatment ndash 2006
IV tissue plasminogen activator (tPA)IV tissue plasminogen activator (tPA) ndash ndash Only FDA-approved acute stroke drugOnly FDA-approved acute stroke drug ndash ndash 3 hour treatment window3 hour treatment window
MERCI - Concentric clot retrieval MERCI - Concentric clot retrieval devicedevice ndash ndash Rescue therapy - approved 2004Rescue therapy - approved 2004 ndash ndash Device approval (not outcomes-based)Device approval (not outcomes-based)
Off label approachesOff label approaches ndash ndash IV tPA after 3 hoursIV tPA after 3 hours ndash ndash IV-IA tPA sequential strategiesIV-IA tPA sequential strategies ndash ndash IA tPA clot angioplasty fragmentationIA tPA clot angioplasty fragmentation ndash ndash Ultrasound-assisted tPA lysisUltrasound-assisted tPA lysis
rt-PA Trials NINDSrt-PA Trials NINDS
Acute stroke - 624 patientsAcute stroke - 624 patients Treat within 3 hrsTreat within 3 hrs Intravenous 09 mgkg rt-PA vs placeboIntravenous 09 mgkg rt-PA vs placebo Hemorrhage 64 tPA 06 placeboHemorrhage 64 tPA 06 placebo Neurologic recovery better with tPA 30 Neurologic recovery better with tPA 30
more like to have minimal or no disabilitymore like to have minimal or no disability
First proven approved treatment for First proven approved treatment for strokestroke
Limitations of tPALimitations of tPA Only 4 of acute strokes receive tPAOnly 4 of acute strokes receive tPA (Kleindorfer et al Stroke 2004 35 e27-e29)(Kleindorfer et al Stroke 2004 35 e27-e29)
Only 22 of patients present within 3 hoursOnly 22 of patients present within 3 hours1048707 1048707 51 of these ineligible due to51 of these ineligible due to
bull bull Mild severityMild severity bull bull Medical or surgical historyMedical or surgical history bull bull Blood testsBlood tests
Sustained recanalization only 13Sustained recanalization only 13 (Alexandrov et al NEJM 2004 351 2170-8)(Alexandrov et al NEJM 2004 351 2170-8)
Concern for hemorrhageConcern for hemorrhage tPA potentiates apoptotic injury tPA potentiates apoptotic injury (Liu et al Nature Med 2004 101379-83)(Liu et al Nature Med 2004 101379-83)
PROACT II IA Lysis TrialPROACT II IA Lysis Trial Baseline 24 hours 8 days
Baseline 60 minutes 120 minutes
9mg IAProurokinase
Desmoteplase Trials DEDAS Desmoteplase Trials DEDAS DIASDIAS
Trial OverviewTrial Overview Double blind randomized placebo Double blind randomized placebo
controlled trialscontrolled trials IV delivery 3-9 hour time windowIV delivery 3-9 hour time window Plasminogen activator ndash from Plasminogen activator ndash from vampire bat vampire bat
salivasaliva Selection based on PWI-DWI MismatchSelection based on PWI-DWI Mismatch
MRI InclusionMRI Inclusion PWI defect at least 2 cm AND ~20 larger PWI defect at least 2 cm AND ~20 larger
than DWIthan DWI PWI should be obvious even visible on PWI should be obvious even visible on
raw imagesraw imagesMRI ExclusionMRI Exclusion
DWI gt 13 MCADWI gt 13 MCA MRA ICA occlusionMRA ICA occlusion
Desmoteplase ndash DIAS Desmoteplase ndash DIAS ResultsResults
Mechanical Thrombolysis Mechanical Thrombolysis devicesdevices
mechanical thrombolysis potentially extends the treatment mechanical thrombolysis potentially extends the treatment window because they act promptly at the site of the thrombuswindow because they act promptly at the site of the thrombus
The devices can retrieve large clots that pharmaceutical agents The devices can retrieve large clots that pharmaceutical agents may not successfully lysemay not successfully lyse
Patients treated with IV tPA may be considered for treatment of Patients treated with IV tPA may be considered for treatment of residual clot with some of these devicesresidual clot with some of these devices
suction-creating saline jets suction-creating saline jets laser energy ultrasound laser energy ultrasound a corkscrew apparatus to treat strokesa corkscrew apparatus to treat strokes The AngioJet systemThe AngioJet system uses saline jets that are directed back into the catheter to uses saline jets that are directed back into the catheter to
create a low-pressure zone around the catheter tip inducing create a low-pressure zone around the catheter tip inducing suction suction
The clot is pulled into the exhaust lumen and removed from the The clot is pulled into the exhaust lumen and removed from the vessel Although US Food and Drug Administration (FDA) has vessel Although US Food and Drug Administration (FDA) has approved this device for use in arteriovenous dialysis grafts and approved this device for use in arteriovenous dialysis grafts and fistulae and for the treatment of coronary arteries saphenous fistulae and for the treatment of coronary arteries saphenous vein grafts and peripheral vessels clinical trials for the vein grafts and peripheral vessels clinical trials for the treatment of acute stroke are no longer in progress treatment of acute stroke are no longer in progress
Most devices are used in cerebral vessels that 2-5 mm
The Latis laser device The Latis laser device used laser energy to ablate clots used laser energy to ablate clots Arteries 2-5 mm in diameter could be Arteries 2-5 mm in diameter could be
treated including the ICA M1 or M2 treated including the ICA M1 or M2 branch of the MCA A1 branch of the branch of the MCA A1 branch of the anterior cerebral artery (ACA) basilar anterior cerebral artery (ACA) basilar artery posterior cerebral artery (PCA) artery posterior cerebral artery (PCA) and vertebral and vertebral
Patients could receive treatment as late Patients could receive treatment as late as 8 hours after symptom onset in the as 8 hours after symptom onset in the anterior circulation and within 24 hours in anterior circulation and within 24 hours in the posterior circulation the posterior circulation
Endovascular Photo Acoustic Endovascular Photo Acoustic Recanalization (EPAR) Recanalization (EPAR)
A laser power source generated energy for the A laser power source generated energy for the systemsystem
The energy was delivered by means of The energy was delivered by means of fiberoptics to the tip of the catheter at the fiberoptics to the tip of the catheter at the treatment sitetreatment site
Absorption of laser light by darkly pigmented Absorption of laser light by darkly pigmented materials (ie the clot) occurred inside the 1-mm materials (ie the clot) occurred inside the 1-mm catheter tipcatheter tip
the system was designed to minimize scattering the system was designed to minimize scattering of laser light of laser light
Absorption converted photo energy to acoustic Absorption converted photo energy to acoustic energy which then emulsified the clot inside the energy which then emulsified the clot inside the catheter tip catheter tip
EKOS ultrasound( the EKOS ultrasound( the Ultrasound Thrombolytic Ultrasound Thrombolytic
Infusion Catheter) Infusion Catheter) combines the use of a distal ultrasound transducer with combines the use of a distal ultrasound transducer with
infusion of a thrombolytic agent through the infusion of a thrombolytic agent through the microcathetermicrocatheter
Ultrasound changes the structure of the clot to Ultrasound changes the structure of the clot to temporarily increase its permeability while providing an temporarily increase its permeability while providing an acoustic pressure gradient to move the drug into the clot acoustic pressure gradient to move the drug into the clot to speed its dissolution to speed its dissolution
The EKOS catheter is placed in the proximal portion of the The EKOS catheter is placed in the proximal portion of the clot clot
After a 2-mg bolus of tPA was injected through the After a 2-mg bolus of tPA was injected through the catheter catheter
the patient received a continuous infusion of IA tPA 03 the patient received a continuous infusion of IA tPA 03 mgmin to a maximum of 20 mg and simultaneous mgmin to a maximum of 20 mg and simultaneous ultrasound transmission for as long as 60 minutes ultrasound transmission for as long as 60 minutes
One patient was treated with a total of 4 units of One patient was treated with a total of 4 units of recombinant reteplase (Retavase) hand-injected over 60 recombinant reteplase (Retavase) hand-injected over 60 minutes minutes
Penumbra system Penumbra system The Penumbra system (Penumbra Inc) provides a dual The Penumbra system (Penumbra Inc) provides a dual
approach to clot extraction using aspiration followed by approach to clot extraction using aspiration followed by clot retrieval with a ring device if needed clot retrieval with a ring device if needed
Mechanical Embolus Removal in Cerebral Ischemia Mechanical Embolus Removal in Cerebral Ischemia (MERCI)(MERCI)
a corkscrew-like apparatus to remove blood clots from a corkscrew-like apparatus to remove blood clots from the brain in patients experiencing an ischemic stroke the brain in patients experiencing an ischemic stroke
The corkscrew itself resides in the catheter tip which The corkscrew itself resides in the catheter tip which shields it from the wall of the vessel until it is ready to be shields it from the wall of the vessel until it is ready to be burrowed into the clot Once lodged in the clot the device burrowed into the clot Once lodged in the clot the device and clot are withdrawn from the vessel and clot are withdrawn from the vessel
Snarelike devicesSnarelike devices Snares such as the Neuronet snare (Guidant Snares such as the Neuronet snare (Guidant
Endovascular Santa Clara CA) have been developed Endovascular Santa Clara CA) have been developed specifically for use in the treatment of strokes specifically for use in the treatment of strokes
These devices are simple in design and do not require the These devices are simple in design and do not require the clot to be amenable to emulsification clot to be amenable to emulsification
X-Sizer deviceX-Sizer device a device with small moving blades at the a device with small moving blades at the
catheter tip catheter tip This device the X-Sizer device (EndiCor Medical This device the X-Sizer device (EndiCor Medical
San Clemente CA) can be used to excise the San Clemente CA) can be used to excise the thrombus and aspirate it thrombus and aspirate it
The device was being evaluated in randomized The device was being evaluated in randomized studies of coronary vessels and in a registry of studies of coronary vessels and in a registry of patients with acute myocardial infarctionpatients with acute myocardial infarction
Although the manufacturer had modified the Although the manufacturer had modified the device for use in cerebral vessels a safety and device for use in cerebral vessels a safety and feasibility study was indefinitely suspended after feasibility study was indefinitely suspended after only 1 patient was treated with the device in only 1 patient was treated with the device in Europe Europe
Suction thrombectomySuction thrombectomy This method of mechanical thrombolysis is one of the This method of mechanical thrombolysis is one of the
simplestsimplest In this readily available technique suction is applied with In this readily available technique suction is applied with
a syringe to remove thrombus in the ICA a syringe to remove thrombus in the ICA It requires no other devicesIt requires no other devices A catheter with a large inner diameter (Brite Tip Cordis A catheter with a large inner diameter (Brite Tip Cordis
Corporation Miami FL) was placed in the symptomatic Corporation Miami FL) was placed in the symptomatic vessel and navigated over a guidewire into the thrombusvessel and navigated over a guidewire into the thrombus
A 60-mL syringe was used to aspirate the thrombus A 60-mL syringe was used to aspirate the thrombus Each patient required angioplasty and stenting of carotid Each patient required angioplasty and stenting of carotid
bifurcation stenosis and received daily aspirin and bifurcation stenosis and received daily aspirin and ticlopidine after the procedure No complications ticlopidine after the procedure No complications occurred occurred
Summary Acute Stroke Summary Acute Stroke ImagingImaging
PhysiologyPhysiology importance collaterals importance collaterals
ndash ndashGrowing role for perfusion Growing role for perfusion assessmentassessment
tPAtPA guidelines amp limitations guidelines amp limitations Signs on CT amp MRSigns on CT amp MR follow physiology follow physiology Stroke trialsStroke trials PWI-DWI mismatch PWI-DWI mismatch
ndash ndashTreat based on physiology not timeTreat based on physiology not time ProtocolsProtocols should be fast and should be fast and
comprehensivecomprehensive
CT Grading for Venous ThrombosisCT Grading for Venous Thrombosis Grade I no parenchymal change Grade I no parenchymal change
(hyperdense (hyperdense sinuses cortical veins empty sinuses cortical veins empty delta sign)delta sign)
Grade II non hemorrhagic venous infarct Grade II non hemorrhagic venous infarct without mass effect without mass effect
Grade III non-hemorrhagic infarct with Grade III non-hemorrhagic infarct with mass effectmass effect
Grade IV hemorrhagic venous infarct (max Grade IV hemorrhagic venous infarct (max diameter lt 3 cm) with no mass effectdiameter lt 3 cm) with no mass effect
Grade V hemorrhagic venous infarct (max Grade V hemorrhagic venous infarct (max diameter gt 3 cm) with mass effect diameter gt 3 cm) with mass effect
Local ThrombolysisLocal Thrombolysis
Femoral Jugular access was secured and a guiding Femoral Jugular access was secured and a guiding catheter was placed in the jugular bulb catheter was placed in the jugular bulb Mechanical Mechanical clot maceration clot maceration was done with the guidewire was done with the guidewire following which a microcatheter (was navigated and following which a microcatheter (was navigated and placed in the thrombosed segment of sinus confirmed placed in the thrombosed segment of sinus confirmed on a selective venogram on a selective venogram
Urokinase infusion Bolus dose of 2-6 lacs followed Urokinase infusion Bolus dose of 2-6 lacs followed by 60000 to 100000 units per hour along with by 60000 to 100000 units per hour along with periodic check venogram Along with maintenance periodic check venogram Along with maintenance systemic infusion of Heparinsystemic infusion of Heparin Other agents such as Other agents such as streptokinase altepase or rTPAstreptokinase altepase or rTPA can be also used can be also used
After thrombolysis patient should subjected to oral After thrombolysis patient should subjected to oral anticoagulation for six monthsanticoagulation for six months
Low-molecular-weight Low-molecular-weight heparinheparin
PharmacologyPharmacologyLMWH as its name suggests is a glycosaminoglycan that is approximatelyLMWH as its name suggests is a glycosaminoglycan that is approximately
one third the molecular weight of UFH It is derived from UFH through one third the molecular weight of UFH It is derived from UFH through variousvarious
depolymerization processes LMWH binds to antithrombin which in turn depolymerization processes LMWH binds to antithrombin which in turn
Neutralizes actors Xa and IIa Because LMWH lacks many of the longer Neutralizes actors Xa and IIa Because LMWH lacks many of the longer chains chains
required for binding to thrombin it has less ability to neutralize thrombin required for binding to thrombin it has less ability to neutralize thrombin
relativeto its ability to neutralize factor Xa LMWH also has less relativeto its ability to neutralize factor Xa LMWH also has less nonspecific nonspecific
binding to other proteins There is greater bioavailability with more binding to other proteins There is greater bioavailability with more predictable predictable
pharmacokinetics that eliminates the need for monitoring The smaller pharmacokinetics that eliminates the need for monitoring The smaller size also size also
allows for enhanced subcutaneous absorption when compared with UFHallows for enhanced subcutaneous absorption when compared with UFH
Three LMWH preparations are Three LMWH preparations are currently approved for use in the currently approved for use in the United States (1) enoxaparin (2) United States (1) enoxaparin (2) dalteparin and (3) tinzaparin dalteparin and (3) tinzaparin
They are all administered They are all administered subcutaneously at intervals of either subcutaneously at intervals of either once or twice daily for both once or twice daily for both prophylaxis and treatment dosesprophylaxis and treatment doses
Few Experiences of Few Experiences of ThrombolysisThrombolysis
Vickey 25 Yrs male patient presented Vickey 25 Yrs male patient presented with 12with 12thth day HO severe headache with day HO severe headache with right sided hemiplegiaright sided hemiplegia
MRI shows thrombosis of the superior MRI shows thrombosis of the superior sagittal left transverse left sigmoid sagittal left transverse left sigmoid sinuses and cortical veins in the fronto-sinuses and cortical veins in the fronto-parietal regions with eo haemorrhagic parietal regions with eo haemorrhagic infarct in the left cerebral hemisphere infarct in the left cerebral hemisphere with mass effect( Grade ndashV)with mass effect( Grade ndashV)
Sashi Srivastava 64 yrs FSashi Srivastava 64 yrs F In a follow up case of MRD with infra-renal In a follow up case of MRD with infra-renal
aortic abdominal and bilateral renal artery aortic abdominal and bilateral renal artery thrombosis renal angiogram shows filling thrombosis renal angiogram shows filling defects in the right Renal artery defects in the right Renal artery
Initially Renal angioplasty was done Initially Renal angioplasty was done Following angioplasty few thrombi are seem Following angioplasty few thrombi are seem to extends into the segmental branches and to extends into the segmental branches and causing blockage So Thrombolysis was causing blockage So Thrombolysis was plane to dissolve the run-out thrombi with plane to dissolve the run-out thrombi with urokinase urokinase
Rakesh 34yrsMRakesh 34yrsM Left SFA pseudoaneurysm with Left SFA pseudoaneurysm with
Covered stent placementCovered stent placement Pre operative antiplatelets with post Pre operative antiplatelets with post
procedure heparin Tirofiban procedure heparin Tirofiban followed by aspirin and clopidogrel followed by aspirin and clopidogrel were usedwere used
IAT may be a treatment option for selected patients IAT may be a treatment option for selected patients Possible selection criteria include Possible selection criteria include
presentation between 3 and 6 hours from symptom onsetpresentation between 3 and 6 hours from symptom onset major cerebral artery occlusion major cerebral artery occlusion severe neurologic deficits severe neurologic deficits high risk of systemic hemorrhage with IV rt-PA (eg recent high risk of systemic hemorrhage with IV rt-PA (eg recent
surgery) surgery) The MERCI (Mechanical Embolus Removal in Cerebral The MERCI (Mechanical Embolus Removal in Cerebral
Ischemia) retrievalIschemia) retrieval system system
Has been FDA-approved for recanalizing acutely occluded Has been FDA-approved for recanalizing acutely occluded cerebral arteries cerebral arteries
In the Multi-MERCI study patients who did not improve In the Multi-MERCI study patients who did not improve immediately after IV rt-PA underwent mechanical immediately after IV rt-PA underwent mechanical embolectomy within 8 hours of symptom onset embolectomy within 8 hours of symptom onset
Partial or complete recanalization occurred in 74 of Partial or complete recanalization occurred in 74 of patientspatients
with a symptomatic intracerebral hemorrhage (sICH) rate of with a symptomatic intracerebral hemorrhage (sICH) rate of 67 67
Mechanical embolectomy with the MERCI retriever may be a Mechanical embolectomy with the MERCI retriever may be a feasible and safe option for patients after IV rt-PAfeasible and safe option for patients after IV rt-PA
Penumbra stroke systemPenumbra stroke system This device combines two methods of clot This device combines two methods of clot
extraction aspiration and mechanical extraction aspiration and mechanical extraction extraction
First the clot is aspirated then a thrombus First the clot is aspirated then a thrombus removal ring can be used if necessary to removal ring can be used if necessary to remove remaining clot remove remaining clot
successful recanalizing 82successful recanalizing 82 Bridging therapyBridging therapy
06 mgkg IV rt-PA followed by IAT with IA rt-06 mgkg IV rt-PA followed by IAT with IA rt-PA (up to 20 mg)PA (up to 20 mg)
achieved a higher recanalization rateachieved a higher recanalization rate
Criteria for thrombolysis with rTPACriteria for thrombolysis with rTPA
Inclusion criteriaInclusion criteria Clinical signs and symptoms consistent with ischemic Clinical signs and symptoms consistent with ischemic
strokestroke Patient last seen normal within 3 hoursPatient last seen normal within 3 hours Measurable neurologic deficitMeasurable neurologic deficit
Exclusion criteriaExclusion criteria Any hemorrhage on neuroimaging (CT or MRI)Any hemorrhage on neuroimaging (CT or MRI) Symptoms suggestive of subarachnoid hemorrhageSymptoms suggestive of subarachnoid hemorrhage Seizure at stroke onset that is thought to contribute to Seizure at stroke onset that is thought to contribute to
neurologic deficitneurologic deficit Hypodensity greater than one third cerebral hemisphere Hypodensity greater than one third cerebral hemisphere
on CTon CT SBP greater than 185 mm Hg or DBP greater than 110 SBP greater than 185 mm Hg or DBP greater than 110
mm Hgmm Hg International normalized ratio (INR) greater than 17International normalized ratio (INR) greater than 17
Ischemic Stroke Ischemic Stroke Treatment ndash 2006Treatment ndash 2006
IV tissue plasminogen activator (tPA)IV tissue plasminogen activator (tPA) ndash ndash Only FDA-approved acute stroke drugOnly FDA-approved acute stroke drug ndash ndash 3 hour treatment window3 hour treatment window
MERCI - Concentric clot retrieval MERCI - Concentric clot retrieval devicedevice ndash ndash Rescue therapy - approved 2004Rescue therapy - approved 2004 ndash ndash Device approval (not outcomes-based)Device approval (not outcomes-based)
Off label approachesOff label approaches ndash ndash IV tPA after 3 hoursIV tPA after 3 hours ndash ndash IV-IA tPA sequential strategiesIV-IA tPA sequential strategies ndash ndash IA tPA clot angioplasty fragmentationIA tPA clot angioplasty fragmentation ndash ndash Ultrasound-assisted tPA lysisUltrasound-assisted tPA lysis
rt-PA Trials NINDSrt-PA Trials NINDS
Acute stroke - 624 patientsAcute stroke - 624 patients Treat within 3 hrsTreat within 3 hrs Intravenous 09 mgkg rt-PA vs placeboIntravenous 09 mgkg rt-PA vs placebo Hemorrhage 64 tPA 06 placeboHemorrhage 64 tPA 06 placebo Neurologic recovery better with tPA 30 Neurologic recovery better with tPA 30
more like to have minimal or no disabilitymore like to have minimal or no disability
First proven approved treatment for First proven approved treatment for strokestroke
Limitations of tPALimitations of tPA Only 4 of acute strokes receive tPAOnly 4 of acute strokes receive tPA (Kleindorfer et al Stroke 2004 35 e27-e29)(Kleindorfer et al Stroke 2004 35 e27-e29)
Only 22 of patients present within 3 hoursOnly 22 of patients present within 3 hours1048707 1048707 51 of these ineligible due to51 of these ineligible due to
bull bull Mild severityMild severity bull bull Medical or surgical historyMedical or surgical history bull bull Blood testsBlood tests
Sustained recanalization only 13Sustained recanalization only 13 (Alexandrov et al NEJM 2004 351 2170-8)(Alexandrov et al NEJM 2004 351 2170-8)
Concern for hemorrhageConcern for hemorrhage tPA potentiates apoptotic injury tPA potentiates apoptotic injury (Liu et al Nature Med 2004 101379-83)(Liu et al Nature Med 2004 101379-83)
PROACT II IA Lysis TrialPROACT II IA Lysis Trial Baseline 24 hours 8 days
Baseline 60 minutes 120 minutes
9mg IAProurokinase
Desmoteplase Trials DEDAS Desmoteplase Trials DEDAS DIASDIAS
Trial OverviewTrial Overview Double blind randomized placebo Double blind randomized placebo
controlled trialscontrolled trials IV delivery 3-9 hour time windowIV delivery 3-9 hour time window Plasminogen activator ndash from Plasminogen activator ndash from vampire bat vampire bat
salivasaliva Selection based on PWI-DWI MismatchSelection based on PWI-DWI Mismatch
MRI InclusionMRI Inclusion PWI defect at least 2 cm AND ~20 larger PWI defect at least 2 cm AND ~20 larger
than DWIthan DWI PWI should be obvious even visible on PWI should be obvious even visible on
raw imagesraw imagesMRI ExclusionMRI Exclusion
DWI gt 13 MCADWI gt 13 MCA MRA ICA occlusionMRA ICA occlusion
Desmoteplase ndash DIAS Desmoteplase ndash DIAS ResultsResults
Mechanical Thrombolysis Mechanical Thrombolysis devicesdevices
mechanical thrombolysis potentially extends the treatment mechanical thrombolysis potentially extends the treatment window because they act promptly at the site of the thrombuswindow because they act promptly at the site of the thrombus
The devices can retrieve large clots that pharmaceutical agents The devices can retrieve large clots that pharmaceutical agents may not successfully lysemay not successfully lyse
Patients treated with IV tPA may be considered for treatment of Patients treated with IV tPA may be considered for treatment of residual clot with some of these devicesresidual clot with some of these devices
suction-creating saline jets suction-creating saline jets laser energy ultrasound laser energy ultrasound a corkscrew apparatus to treat strokesa corkscrew apparatus to treat strokes The AngioJet systemThe AngioJet system uses saline jets that are directed back into the catheter to uses saline jets that are directed back into the catheter to
create a low-pressure zone around the catheter tip inducing create a low-pressure zone around the catheter tip inducing suction suction
The clot is pulled into the exhaust lumen and removed from the The clot is pulled into the exhaust lumen and removed from the vessel Although US Food and Drug Administration (FDA) has vessel Although US Food and Drug Administration (FDA) has approved this device for use in arteriovenous dialysis grafts and approved this device for use in arteriovenous dialysis grafts and fistulae and for the treatment of coronary arteries saphenous fistulae and for the treatment of coronary arteries saphenous vein grafts and peripheral vessels clinical trials for the vein grafts and peripheral vessels clinical trials for the treatment of acute stroke are no longer in progress treatment of acute stroke are no longer in progress
Most devices are used in cerebral vessels that 2-5 mm
The Latis laser device The Latis laser device used laser energy to ablate clots used laser energy to ablate clots Arteries 2-5 mm in diameter could be Arteries 2-5 mm in diameter could be
treated including the ICA M1 or M2 treated including the ICA M1 or M2 branch of the MCA A1 branch of the branch of the MCA A1 branch of the anterior cerebral artery (ACA) basilar anterior cerebral artery (ACA) basilar artery posterior cerebral artery (PCA) artery posterior cerebral artery (PCA) and vertebral and vertebral
Patients could receive treatment as late Patients could receive treatment as late as 8 hours after symptom onset in the as 8 hours after symptom onset in the anterior circulation and within 24 hours in anterior circulation and within 24 hours in the posterior circulation the posterior circulation
Endovascular Photo Acoustic Endovascular Photo Acoustic Recanalization (EPAR) Recanalization (EPAR)
A laser power source generated energy for the A laser power source generated energy for the systemsystem
The energy was delivered by means of The energy was delivered by means of fiberoptics to the tip of the catheter at the fiberoptics to the tip of the catheter at the treatment sitetreatment site
Absorption of laser light by darkly pigmented Absorption of laser light by darkly pigmented materials (ie the clot) occurred inside the 1-mm materials (ie the clot) occurred inside the 1-mm catheter tipcatheter tip
the system was designed to minimize scattering the system was designed to minimize scattering of laser light of laser light
Absorption converted photo energy to acoustic Absorption converted photo energy to acoustic energy which then emulsified the clot inside the energy which then emulsified the clot inside the catheter tip catheter tip
EKOS ultrasound( the EKOS ultrasound( the Ultrasound Thrombolytic Ultrasound Thrombolytic
Infusion Catheter) Infusion Catheter) combines the use of a distal ultrasound transducer with combines the use of a distal ultrasound transducer with
infusion of a thrombolytic agent through the infusion of a thrombolytic agent through the microcathetermicrocatheter
Ultrasound changes the structure of the clot to Ultrasound changes the structure of the clot to temporarily increase its permeability while providing an temporarily increase its permeability while providing an acoustic pressure gradient to move the drug into the clot acoustic pressure gradient to move the drug into the clot to speed its dissolution to speed its dissolution
The EKOS catheter is placed in the proximal portion of the The EKOS catheter is placed in the proximal portion of the clot clot
After a 2-mg bolus of tPA was injected through the After a 2-mg bolus of tPA was injected through the catheter catheter
the patient received a continuous infusion of IA tPA 03 the patient received a continuous infusion of IA tPA 03 mgmin to a maximum of 20 mg and simultaneous mgmin to a maximum of 20 mg and simultaneous ultrasound transmission for as long as 60 minutes ultrasound transmission for as long as 60 minutes
One patient was treated with a total of 4 units of One patient was treated with a total of 4 units of recombinant reteplase (Retavase) hand-injected over 60 recombinant reteplase (Retavase) hand-injected over 60 minutes minutes
Penumbra system Penumbra system The Penumbra system (Penumbra Inc) provides a dual The Penumbra system (Penumbra Inc) provides a dual
approach to clot extraction using aspiration followed by approach to clot extraction using aspiration followed by clot retrieval with a ring device if needed clot retrieval with a ring device if needed
Mechanical Embolus Removal in Cerebral Ischemia Mechanical Embolus Removal in Cerebral Ischemia (MERCI)(MERCI)
a corkscrew-like apparatus to remove blood clots from a corkscrew-like apparatus to remove blood clots from the brain in patients experiencing an ischemic stroke the brain in patients experiencing an ischemic stroke
The corkscrew itself resides in the catheter tip which The corkscrew itself resides in the catheter tip which shields it from the wall of the vessel until it is ready to be shields it from the wall of the vessel until it is ready to be burrowed into the clot Once lodged in the clot the device burrowed into the clot Once lodged in the clot the device and clot are withdrawn from the vessel and clot are withdrawn from the vessel
Snarelike devicesSnarelike devices Snares such as the Neuronet snare (Guidant Snares such as the Neuronet snare (Guidant
Endovascular Santa Clara CA) have been developed Endovascular Santa Clara CA) have been developed specifically for use in the treatment of strokes specifically for use in the treatment of strokes
These devices are simple in design and do not require the These devices are simple in design and do not require the clot to be amenable to emulsification clot to be amenable to emulsification
X-Sizer deviceX-Sizer device a device with small moving blades at the a device with small moving blades at the
catheter tip catheter tip This device the X-Sizer device (EndiCor Medical This device the X-Sizer device (EndiCor Medical
San Clemente CA) can be used to excise the San Clemente CA) can be used to excise the thrombus and aspirate it thrombus and aspirate it
The device was being evaluated in randomized The device was being evaluated in randomized studies of coronary vessels and in a registry of studies of coronary vessels and in a registry of patients with acute myocardial infarctionpatients with acute myocardial infarction
Although the manufacturer had modified the Although the manufacturer had modified the device for use in cerebral vessels a safety and device for use in cerebral vessels a safety and feasibility study was indefinitely suspended after feasibility study was indefinitely suspended after only 1 patient was treated with the device in only 1 patient was treated with the device in Europe Europe
Suction thrombectomySuction thrombectomy This method of mechanical thrombolysis is one of the This method of mechanical thrombolysis is one of the
simplestsimplest In this readily available technique suction is applied with In this readily available technique suction is applied with
a syringe to remove thrombus in the ICA a syringe to remove thrombus in the ICA It requires no other devicesIt requires no other devices A catheter with a large inner diameter (Brite Tip Cordis A catheter with a large inner diameter (Brite Tip Cordis
Corporation Miami FL) was placed in the symptomatic Corporation Miami FL) was placed in the symptomatic vessel and navigated over a guidewire into the thrombusvessel and navigated over a guidewire into the thrombus
A 60-mL syringe was used to aspirate the thrombus A 60-mL syringe was used to aspirate the thrombus Each patient required angioplasty and stenting of carotid Each patient required angioplasty and stenting of carotid
bifurcation stenosis and received daily aspirin and bifurcation stenosis and received daily aspirin and ticlopidine after the procedure No complications ticlopidine after the procedure No complications occurred occurred
Summary Acute Stroke Summary Acute Stroke ImagingImaging
PhysiologyPhysiology importance collaterals importance collaterals
ndash ndashGrowing role for perfusion Growing role for perfusion assessmentassessment
tPAtPA guidelines amp limitations guidelines amp limitations Signs on CT amp MRSigns on CT amp MR follow physiology follow physiology Stroke trialsStroke trials PWI-DWI mismatch PWI-DWI mismatch
ndash ndashTreat based on physiology not timeTreat based on physiology not time ProtocolsProtocols should be fast and should be fast and
comprehensivecomprehensive
Local ThrombolysisLocal Thrombolysis
Femoral Jugular access was secured and a guiding Femoral Jugular access was secured and a guiding catheter was placed in the jugular bulb catheter was placed in the jugular bulb Mechanical Mechanical clot maceration clot maceration was done with the guidewire was done with the guidewire following which a microcatheter (was navigated and following which a microcatheter (was navigated and placed in the thrombosed segment of sinus confirmed placed in the thrombosed segment of sinus confirmed on a selective venogram on a selective venogram
Urokinase infusion Bolus dose of 2-6 lacs followed Urokinase infusion Bolus dose of 2-6 lacs followed by 60000 to 100000 units per hour along with by 60000 to 100000 units per hour along with periodic check venogram Along with maintenance periodic check venogram Along with maintenance systemic infusion of Heparinsystemic infusion of Heparin Other agents such as Other agents such as streptokinase altepase or rTPAstreptokinase altepase or rTPA can be also used can be also used
After thrombolysis patient should subjected to oral After thrombolysis patient should subjected to oral anticoagulation for six monthsanticoagulation for six months
Low-molecular-weight Low-molecular-weight heparinheparin
PharmacologyPharmacologyLMWH as its name suggests is a glycosaminoglycan that is approximatelyLMWH as its name suggests is a glycosaminoglycan that is approximately
one third the molecular weight of UFH It is derived from UFH through one third the molecular weight of UFH It is derived from UFH through variousvarious
depolymerization processes LMWH binds to antithrombin which in turn depolymerization processes LMWH binds to antithrombin which in turn
Neutralizes actors Xa and IIa Because LMWH lacks many of the longer Neutralizes actors Xa and IIa Because LMWH lacks many of the longer chains chains
required for binding to thrombin it has less ability to neutralize thrombin required for binding to thrombin it has less ability to neutralize thrombin
relativeto its ability to neutralize factor Xa LMWH also has less relativeto its ability to neutralize factor Xa LMWH also has less nonspecific nonspecific
binding to other proteins There is greater bioavailability with more binding to other proteins There is greater bioavailability with more predictable predictable
pharmacokinetics that eliminates the need for monitoring The smaller pharmacokinetics that eliminates the need for monitoring The smaller size also size also
allows for enhanced subcutaneous absorption when compared with UFHallows for enhanced subcutaneous absorption when compared with UFH
Three LMWH preparations are Three LMWH preparations are currently approved for use in the currently approved for use in the United States (1) enoxaparin (2) United States (1) enoxaparin (2) dalteparin and (3) tinzaparin dalteparin and (3) tinzaparin
They are all administered They are all administered subcutaneously at intervals of either subcutaneously at intervals of either once or twice daily for both once or twice daily for both prophylaxis and treatment dosesprophylaxis and treatment doses
Few Experiences of Few Experiences of ThrombolysisThrombolysis
Vickey 25 Yrs male patient presented Vickey 25 Yrs male patient presented with 12with 12thth day HO severe headache with day HO severe headache with right sided hemiplegiaright sided hemiplegia
MRI shows thrombosis of the superior MRI shows thrombosis of the superior sagittal left transverse left sigmoid sagittal left transverse left sigmoid sinuses and cortical veins in the fronto-sinuses and cortical veins in the fronto-parietal regions with eo haemorrhagic parietal regions with eo haemorrhagic infarct in the left cerebral hemisphere infarct in the left cerebral hemisphere with mass effect( Grade ndashV)with mass effect( Grade ndashV)
Sashi Srivastava 64 yrs FSashi Srivastava 64 yrs F In a follow up case of MRD with infra-renal In a follow up case of MRD with infra-renal
aortic abdominal and bilateral renal artery aortic abdominal and bilateral renal artery thrombosis renal angiogram shows filling thrombosis renal angiogram shows filling defects in the right Renal artery defects in the right Renal artery
Initially Renal angioplasty was done Initially Renal angioplasty was done Following angioplasty few thrombi are seem Following angioplasty few thrombi are seem to extends into the segmental branches and to extends into the segmental branches and causing blockage So Thrombolysis was causing blockage So Thrombolysis was plane to dissolve the run-out thrombi with plane to dissolve the run-out thrombi with urokinase urokinase
Rakesh 34yrsMRakesh 34yrsM Left SFA pseudoaneurysm with Left SFA pseudoaneurysm with
Covered stent placementCovered stent placement Pre operative antiplatelets with post Pre operative antiplatelets with post
procedure heparin Tirofiban procedure heparin Tirofiban followed by aspirin and clopidogrel followed by aspirin and clopidogrel were usedwere used
IAT may be a treatment option for selected patients IAT may be a treatment option for selected patients Possible selection criteria include Possible selection criteria include
presentation between 3 and 6 hours from symptom onsetpresentation between 3 and 6 hours from symptom onset major cerebral artery occlusion major cerebral artery occlusion severe neurologic deficits severe neurologic deficits high risk of systemic hemorrhage with IV rt-PA (eg recent high risk of systemic hemorrhage with IV rt-PA (eg recent
surgery) surgery) The MERCI (Mechanical Embolus Removal in Cerebral The MERCI (Mechanical Embolus Removal in Cerebral
Ischemia) retrievalIschemia) retrieval system system
Has been FDA-approved for recanalizing acutely occluded Has been FDA-approved for recanalizing acutely occluded cerebral arteries cerebral arteries
In the Multi-MERCI study patients who did not improve In the Multi-MERCI study patients who did not improve immediately after IV rt-PA underwent mechanical immediately after IV rt-PA underwent mechanical embolectomy within 8 hours of symptom onset embolectomy within 8 hours of symptom onset
Partial or complete recanalization occurred in 74 of Partial or complete recanalization occurred in 74 of patientspatients
with a symptomatic intracerebral hemorrhage (sICH) rate of with a symptomatic intracerebral hemorrhage (sICH) rate of 67 67
Mechanical embolectomy with the MERCI retriever may be a Mechanical embolectomy with the MERCI retriever may be a feasible and safe option for patients after IV rt-PAfeasible and safe option for patients after IV rt-PA
Penumbra stroke systemPenumbra stroke system This device combines two methods of clot This device combines two methods of clot
extraction aspiration and mechanical extraction aspiration and mechanical extraction extraction
First the clot is aspirated then a thrombus First the clot is aspirated then a thrombus removal ring can be used if necessary to removal ring can be used if necessary to remove remaining clot remove remaining clot
successful recanalizing 82successful recanalizing 82 Bridging therapyBridging therapy
06 mgkg IV rt-PA followed by IAT with IA rt-06 mgkg IV rt-PA followed by IAT with IA rt-PA (up to 20 mg)PA (up to 20 mg)
achieved a higher recanalization rateachieved a higher recanalization rate
Criteria for thrombolysis with rTPACriteria for thrombolysis with rTPA
Inclusion criteriaInclusion criteria Clinical signs and symptoms consistent with ischemic Clinical signs and symptoms consistent with ischemic
strokestroke Patient last seen normal within 3 hoursPatient last seen normal within 3 hours Measurable neurologic deficitMeasurable neurologic deficit
Exclusion criteriaExclusion criteria Any hemorrhage on neuroimaging (CT or MRI)Any hemorrhage on neuroimaging (CT or MRI) Symptoms suggestive of subarachnoid hemorrhageSymptoms suggestive of subarachnoid hemorrhage Seizure at stroke onset that is thought to contribute to Seizure at stroke onset that is thought to contribute to
neurologic deficitneurologic deficit Hypodensity greater than one third cerebral hemisphere Hypodensity greater than one third cerebral hemisphere
on CTon CT SBP greater than 185 mm Hg or DBP greater than 110 SBP greater than 185 mm Hg or DBP greater than 110
mm Hgmm Hg International normalized ratio (INR) greater than 17International normalized ratio (INR) greater than 17
Ischemic Stroke Ischemic Stroke Treatment ndash 2006Treatment ndash 2006
IV tissue plasminogen activator (tPA)IV tissue plasminogen activator (tPA) ndash ndash Only FDA-approved acute stroke drugOnly FDA-approved acute stroke drug ndash ndash 3 hour treatment window3 hour treatment window
MERCI - Concentric clot retrieval MERCI - Concentric clot retrieval devicedevice ndash ndash Rescue therapy - approved 2004Rescue therapy - approved 2004 ndash ndash Device approval (not outcomes-based)Device approval (not outcomes-based)
Off label approachesOff label approaches ndash ndash IV tPA after 3 hoursIV tPA after 3 hours ndash ndash IV-IA tPA sequential strategiesIV-IA tPA sequential strategies ndash ndash IA tPA clot angioplasty fragmentationIA tPA clot angioplasty fragmentation ndash ndash Ultrasound-assisted tPA lysisUltrasound-assisted tPA lysis
rt-PA Trials NINDSrt-PA Trials NINDS
Acute stroke - 624 patientsAcute stroke - 624 patients Treat within 3 hrsTreat within 3 hrs Intravenous 09 mgkg rt-PA vs placeboIntravenous 09 mgkg rt-PA vs placebo Hemorrhage 64 tPA 06 placeboHemorrhage 64 tPA 06 placebo Neurologic recovery better with tPA 30 Neurologic recovery better with tPA 30
more like to have minimal or no disabilitymore like to have minimal or no disability
First proven approved treatment for First proven approved treatment for strokestroke
Limitations of tPALimitations of tPA Only 4 of acute strokes receive tPAOnly 4 of acute strokes receive tPA (Kleindorfer et al Stroke 2004 35 e27-e29)(Kleindorfer et al Stroke 2004 35 e27-e29)
Only 22 of patients present within 3 hoursOnly 22 of patients present within 3 hours1048707 1048707 51 of these ineligible due to51 of these ineligible due to
bull bull Mild severityMild severity bull bull Medical or surgical historyMedical or surgical history bull bull Blood testsBlood tests
Sustained recanalization only 13Sustained recanalization only 13 (Alexandrov et al NEJM 2004 351 2170-8)(Alexandrov et al NEJM 2004 351 2170-8)
Concern for hemorrhageConcern for hemorrhage tPA potentiates apoptotic injury tPA potentiates apoptotic injury (Liu et al Nature Med 2004 101379-83)(Liu et al Nature Med 2004 101379-83)
PROACT II IA Lysis TrialPROACT II IA Lysis Trial Baseline 24 hours 8 days
Baseline 60 minutes 120 minutes
9mg IAProurokinase
Desmoteplase Trials DEDAS Desmoteplase Trials DEDAS DIASDIAS
Trial OverviewTrial Overview Double blind randomized placebo Double blind randomized placebo
controlled trialscontrolled trials IV delivery 3-9 hour time windowIV delivery 3-9 hour time window Plasminogen activator ndash from Plasminogen activator ndash from vampire bat vampire bat
salivasaliva Selection based on PWI-DWI MismatchSelection based on PWI-DWI Mismatch
MRI InclusionMRI Inclusion PWI defect at least 2 cm AND ~20 larger PWI defect at least 2 cm AND ~20 larger
than DWIthan DWI PWI should be obvious even visible on PWI should be obvious even visible on
raw imagesraw imagesMRI ExclusionMRI Exclusion
DWI gt 13 MCADWI gt 13 MCA MRA ICA occlusionMRA ICA occlusion
Desmoteplase ndash DIAS Desmoteplase ndash DIAS ResultsResults
Mechanical Thrombolysis Mechanical Thrombolysis devicesdevices
mechanical thrombolysis potentially extends the treatment mechanical thrombolysis potentially extends the treatment window because they act promptly at the site of the thrombuswindow because they act promptly at the site of the thrombus
The devices can retrieve large clots that pharmaceutical agents The devices can retrieve large clots that pharmaceutical agents may not successfully lysemay not successfully lyse
Patients treated with IV tPA may be considered for treatment of Patients treated with IV tPA may be considered for treatment of residual clot with some of these devicesresidual clot with some of these devices
suction-creating saline jets suction-creating saline jets laser energy ultrasound laser energy ultrasound a corkscrew apparatus to treat strokesa corkscrew apparatus to treat strokes The AngioJet systemThe AngioJet system uses saline jets that are directed back into the catheter to uses saline jets that are directed back into the catheter to
create a low-pressure zone around the catheter tip inducing create a low-pressure zone around the catheter tip inducing suction suction
The clot is pulled into the exhaust lumen and removed from the The clot is pulled into the exhaust lumen and removed from the vessel Although US Food and Drug Administration (FDA) has vessel Although US Food and Drug Administration (FDA) has approved this device for use in arteriovenous dialysis grafts and approved this device for use in arteriovenous dialysis grafts and fistulae and for the treatment of coronary arteries saphenous fistulae and for the treatment of coronary arteries saphenous vein grafts and peripheral vessels clinical trials for the vein grafts and peripheral vessels clinical trials for the treatment of acute stroke are no longer in progress treatment of acute stroke are no longer in progress
Most devices are used in cerebral vessels that 2-5 mm
The Latis laser device The Latis laser device used laser energy to ablate clots used laser energy to ablate clots Arteries 2-5 mm in diameter could be Arteries 2-5 mm in diameter could be
treated including the ICA M1 or M2 treated including the ICA M1 or M2 branch of the MCA A1 branch of the branch of the MCA A1 branch of the anterior cerebral artery (ACA) basilar anterior cerebral artery (ACA) basilar artery posterior cerebral artery (PCA) artery posterior cerebral artery (PCA) and vertebral and vertebral
Patients could receive treatment as late Patients could receive treatment as late as 8 hours after symptom onset in the as 8 hours after symptom onset in the anterior circulation and within 24 hours in anterior circulation and within 24 hours in the posterior circulation the posterior circulation
Endovascular Photo Acoustic Endovascular Photo Acoustic Recanalization (EPAR) Recanalization (EPAR)
A laser power source generated energy for the A laser power source generated energy for the systemsystem
The energy was delivered by means of The energy was delivered by means of fiberoptics to the tip of the catheter at the fiberoptics to the tip of the catheter at the treatment sitetreatment site
Absorption of laser light by darkly pigmented Absorption of laser light by darkly pigmented materials (ie the clot) occurred inside the 1-mm materials (ie the clot) occurred inside the 1-mm catheter tipcatheter tip
the system was designed to minimize scattering the system was designed to minimize scattering of laser light of laser light
Absorption converted photo energy to acoustic Absorption converted photo energy to acoustic energy which then emulsified the clot inside the energy which then emulsified the clot inside the catheter tip catheter tip
EKOS ultrasound( the EKOS ultrasound( the Ultrasound Thrombolytic Ultrasound Thrombolytic
Infusion Catheter) Infusion Catheter) combines the use of a distal ultrasound transducer with combines the use of a distal ultrasound transducer with
infusion of a thrombolytic agent through the infusion of a thrombolytic agent through the microcathetermicrocatheter
Ultrasound changes the structure of the clot to Ultrasound changes the structure of the clot to temporarily increase its permeability while providing an temporarily increase its permeability while providing an acoustic pressure gradient to move the drug into the clot acoustic pressure gradient to move the drug into the clot to speed its dissolution to speed its dissolution
The EKOS catheter is placed in the proximal portion of the The EKOS catheter is placed in the proximal portion of the clot clot
After a 2-mg bolus of tPA was injected through the After a 2-mg bolus of tPA was injected through the catheter catheter
the patient received a continuous infusion of IA tPA 03 the patient received a continuous infusion of IA tPA 03 mgmin to a maximum of 20 mg and simultaneous mgmin to a maximum of 20 mg and simultaneous ultrasound transmission for as long as 60 minutes ultrasound transmission for as long as 60 minutes
One patient was treated with a total of 4 units of One patient was treated with a total of 4 units of recombinant reteplase (Retavase) hand-injected over 60 recombinant reteplase (Retavase) hand-injected over 60 minutes minutes
Penumbra system Penumbra system The Penumbra system (Penumbra Inc) provides a dual The Penumbra system (Penumbra Inc) provides a dual
approach to clot extraction using aspiration followed by approach to clot extraction using aspiration followed by clot retrieval with a ring device if needed clot retrieval with a ring device if needed
Mechanical Embolus Removal in Cerebral Ischemia Mechanical Embolus Removal in Cerebral Ischemia (MERCI)(MERCI)
a corkscrew-like apparatus to remove blood clots from a corkscrew-like apparatus to remove blood clots from the brain in patients experiencing an ischemic stroke the brain in patients experiencing an ischemic stroke
The corkscrew itself resides in the catheter tip which The corkscrew itself resides in the catheter tip which shields it from the wall of the vessel until it is ready to be shields it from the wall of the vessel until it is ready to be burrowed into the clot Once lodged in the clot the device burrowed into the clot Once lodged in the clot the device and clot are withdrawn from the vessel and clot are withdrawn from the vessel
Snarelike devicesSnarelike devices Snares such as the Neuronet snare (Guidant Snares such as the Neuronet snare (Guidant
Endovascular Santa Clara CA) have been developed Endovascular Santa Clara CA) have been developed specifically for use in the treatment of strokes specifically for use in the treatment of strokes
These devices are simple in design and do not require the These devices are simple in design and do not require the clot to be amenable to emulsification clot to be amenable to emulsification
X-Sizer deviceX-Sizer device a device with small moving blades at the a device with small moving blades at the
catheter tip catheter tip This device the X-Sizer device (EndiCor Medical This device the X-Sizer device (EndiCor Medical
San Clemente CA) can be used to excise the San Clemente CA) can be used to excise the thrombus and aspirate it thrombus and aspirate it
The device was being evaluated in randomized The device was being evaluated in randomized studies of coronary vessels and in a registry of studies of coronary vessels and in a registry of patients with acute myocardial infarctionpatients with acute myocardial infarction
Although the manufacturer had modified the Although the manufacturer had modified the device for use in cerebral vessels a safety and device for use in cerebral vessels a safety and feasibility study was indefinitely suspended after feasibility study was indefinitely suspended after only 1 patient was treated with the device in only 1 patient was treated with the device in Europe Europe
Suction thrombectomySuction thrombectomy This method of mechanical thrombolysis is one of the This method of mechanical thrombolysis is one of the
simplestsimplest In this readily available technique suction is applied with In this readily available technique suction is applied with
a syringe to remove thrombus in the ICA a syringe to remove thrombus in the ICA It requires no other devicesIt requires no other devices A catheter with a large inner diameter (Brite Tip Cordis A catheter with a large inner diameter (Brite Tip Cordis
Corporation Miami FL) was placed in the symptomatic Corporation Miami FL) was placed in the symptomatic vessel and navigated over a guidewire into the thrombusvessel and navigated over a guidewire into the thrombus
A 60-mL syringe was used to aspirate the thrombus A 60-mL syringe was used to aspirate the thrombus Each patient required angioplasty and stenting of carotid Each patient required angioplasty and stenting of carotid
bifurcation stenosis and received daily aspirin and bifurcation stenosis and received daily aspirin and ticlopidine after the procedure No complications ticlopidine after the procedure No complications occurred occurred
Summary Acute Stroke Summary Acute Stroke ImagingImaging
PhysiologyPhysiology importance collaterals importance collaterals
ndash ndashGrowing role for perfusion Growing role for perfusion assessmentassessment
tPAtPA guidelines amp limitations guidelines amp limitations Signs on CT amp MRSigns on CT amp MR follow physiology follow physiology Stroke trialsStroke trials PWI-DWI mismatch PWI-DWI mismatch
ndash ndashTreat based on physiology not timeTreat based on physiology not time ProtocolsProtocols should be fast and should be fast and
comprehensivecomprehensive
Low-molecular-weight Low-molecular-weight heparinheparin
PharmacologyPharmacologyLMWH as its name suggests is a glycosaminoglycan that is approximatelyLMWH as its name suggests is a glycosaminoglycan that is approximately
one third the molecular weight of UFH It is derived from UFH through one third the molecular weight of UFH It is derived from UFH through variousvarious
depolymerization processes LMWH binds to antithrombin which in turn depolymerization processes LMWH binds to antithrombin which in turn
Neutralizes actors Xa and IIa Because LMWH lacks many of the longer Neutralizes actors Xa and IIa Because LMWH lacks many of the longer chains chains
required for binding to thrombin it has less ability to neutralize thrombin required for binding to thrombin it has less ability to neutralize thrombin
relativeto its ability to neutralize factor Xa LMWH also has less relativeto its ability to neutralize factor Xa LMWH also has less nonspecific nonspecific
binding to other proteins There is greater bioavailability with more binding to other proteins There is greater bioavailability with more predictable predictable
pharmacokinetics that eliminates the need for monitoring The smaller pharmacokinetics that eliminates the need for monitoring The smaller size also size also
allows for enhanced subcutaneous absorption when compared with UFHallows for enhanced subcutaneous absorption when compared with UFH
Three LMWH preparations are Three LMWH preparations are currently approved for use in the currently approved for use in the United States (1) enoxaparin (2) United States (1) enoxaparin (2) dalteparin and (3) tinzaparin dalteparin and (3) tinzaparin
They are all administered They are all administered subcutaneously at intervals of either subcutaneously at intervals of either once or twice daily for both once or twice daily for both prophylaxis and treatment dosesprophylaxis and treatment doses
Few Experiences of Few Experiences of ThrombolysisThrombolysis
Vickey 25 Yrs male patient presented Vickey 25 Yrs male patient presented with 12with 12thth day HO severe headache with day HO severe headache with right sided hemiplegiaright sided hemiplegia
MRI shows thrombosis of the superior MRI shows thrombosis of the superior sagittal left transverse left sigmoid sagittal left transverse left sigmoid sinuses and cortical veins in the fronto-sinuses and cortical veins in the fronto-parietal regions with eo haemorrhagic parietal regions with eo haemorrhagic infarct in the left cerebral hemisphere infarct in the left cerebral hemisphere with mass effect( Grade ndashV)with mass effect( Grade ndashV)
Sashi Srivastava 64 yrs FSashi Srivastava 64 yrs F In a follow up case of MRD with infra-renal In a follow up case of MRD with infra-renal
aortic abdominal and bilateral renal artery aortic abdominal and bilateral renal artery thrombosis renal angiogram shows filling thrombosis renal angiogram shows filling defects in the right Renal artery defects in the right Renal artery
Initially Renal angioplasty was done Initially Renal angioplasty was done Following angioplasty few thrombi are seem Following angioplasty few thrombi are seem to extends into the segmental branches and to extends into the segmental branches and causing blockage So Thrombolysis was causing blockage So Thrombolysis was plane to dissolve the run-out thrombi with plane to dissolve the run-out thrombi with urokinase urokinase
Rakesh 34yrsMRakesh 34yrsM Left SFA pseudoaneurysm with Left SFA pseudoaneurysm with
Covered stent placementCovered stent placement Pre operative antiplatelets with post Pre operative antiplatelets with post
procedure heparin Tirofiban procedure heparin Tirofiban followed by aspirin and clopidogrel followed by aspirin and clopidogrel were usedwere used
IAT may be a treatment option for selected patients IAT may be a treatment option for selected patients Possible selection criteria include Possible selection criteria include
presentation between 3 and 6 hours from symptom onsetpresentation between 3 and 6 hours from symptom onset major cerebral artery occlusion major cerebral artery occlusion severe neurologic deficits severe neurologic deficits high risk of systemic hemorrhage with IV rt-PA (eg recent high risk of systemic hemorrhage with IV rt-PA (eg recent
surgery) surgery) The MERCI (Mechanical Embolus Removal in Cerebral The MERCI (Mechanical Embolus Removal in Cerebral
Ischemia) retrievalIschemia) retrieval system system
Has been FDA-approved for recanalizing acutely occluded Has been FDA-approved for recanalizing acutely occluded cerebral arteries cerebral arteries
In the Multi-MERCI study patients who did not improve In the Multi-MERCI study patients who did not improve immediately after IV rt-PA underwent mechanical immediately after IV rt-PA underwent mechanical embolectomy within 8 hours of symptom onset embolectomy within 8 hours of symptom onset
Partial or complete recanalization occurred in 74 of Partial or complete recanalization occurred in 74 of patientspatients
with a symptomatic intracerebral hemorrhage (sICH) rate of with a symptomatic intracerebral hemorrhage (sICH) rate of 67 67
Mechanical embolectomy with the MERCI retriever may be a Mechanical embolectomy with the MERCI retriever may be a feasible and safe option for patients after IV rt-PAfeasible and safe option for patients after IV rt-PA
Penumbra stroke systemPenumbra stroke system This device combines two methods of clot This device combines two methods of clot
extraction aspiration and mechanical extraction aspiration and mechanical extraction extraction
First the clot is aspirated then a thrombus First the clot is aspirated then a thrombus removal ring can be used if necessary to removal ring can be used if necessary to remove remaining clot remove remaining clot
successful recanalizing 82successful recanalizing 82 Bridging therapyBridging therapy
06 mgkg IV rt-PA followed by IAT with IA rt-06 mgkg IV rt-PA followed by IAT with IA rt-PA (up to 20 mg)PA (up to 20 mg)
achieved a higher recanalization rateachieved a higher recanalization rate
Criteria for thrombolysis with rTPACriteria for thrombolysis with rTPA
Inclusion criteriaInclusion criteria Clinical signs and symptoms consistent with ischemic Clinical signs and symptoms consistent with ischemic
strokestroke Patient last seen normal within 3 hoursPatient last seen normal within 3 hours Measurable neurologic deficitMeasurable neurologic deficit
Exclusion criteriaExclusion criteria Any hemorrhage on neuroimaging (CT or MRI)Any hemorrhage on neuroimaging (CT or MRI) Symptoms suggestive of subarachnoid hemorrhageSymptoms suggestive of subarachnoid hemorrhage Seizure at stroke onset that is thought to contribute to Seizure at stroke onset that is thought to contribute to
neurologic deficitneurologic deficit Hypodensity greater than one third cerebral hemisphere Hypodensity greater than one third cerebral hemisphere
on CTon CT SBP greater than 185 mm Hg or DBP greater than 110 SBP greater than 185 mm Hg or DBP greater than 110
mm Hgmm Hg International normalized ratio (INR) greater than 17International normalized ratio (INR) greater than 17
Ischemic Stroke Ischemic Stroke Treatment ndash 2006Treatment ndash 2006
IV tissue plasminogen activator (tPA)IV tissue plasminogen activator (tPA) ndash ndash Only FDA-approved acute stroke drugOnly FDA-approved acute stroke drug ndash ndash 3 hour treatment window3 hour treatment window
MERCI - Concentric clot retrieval MERCI - Concentric clot retrieval devicedevice ndash ndash Rescue therapy - approved 2004Rescue therapy - approved 2004 ndash ndash Device approval (not outcomes-based)Device approval (not outcomes-based)
Off label approachesOff label approaches ndash ndash IV tPA after 3 hoursIV tPA after 3 hours ndash ndash IV-IA tPA sequential strategiesIV-IA tPA sequential strategies ndash ndash IA tPA clot angioplasty fragmentationIA tPA clot angioplasty fragmentation ndash ndash Ultrasound-assisted tPA lysisUltrasound-assisted tPA lysis
rt-PA Trials NINDSrt-PA Trials NINDS
Acute stroke - 624 patientsAcute stroke - 624 patients Treat within 3 hrsTreat within 3 hrs Intravenous 09 mgkg rt-PA vs placeboIntravenous 09 mgkg rt-PA vs placebo Hemorrhage 64 tPA 06 placeboHemorrhage 64 tPA 06 placebo Neurologic recovery better with tPA 30 Neurologic recovery better with tPA 30
more like to have minimal or no disabilitymore like to have minimal or no disability
First proven approved treatment for First proven approved treatment for strokestroke
Limitations of tPALimitations of tPA Only 4 of acute strokes receive tPAOnly 4 of acute strokes receive tPA (Kleindorfer et al Stroke 2004 35 e27-e29)(Kleindorfer et al Stroke 2004 35 e27-e29)
Only 22 of patients present within 3 hoursOnly 22 of patients present within 3 hours1048707 1048707 51 of these ineligible due to51 of these ineligible due to
bull bull Mild severityMild severity bull bull Medical or surgical historyMedical or surgical history bull bull Blood testsBlood tests
Sustained recanalization only 13Sustained recanalization only 13 (Alexandrov et al NEJM 2004 351 2170-8)(Alexandrov et al NEJM 2004 351 2170-8)
Concern for hemorrhageConcern for hemorrhage tPA potentiates apoptotic injury tPA potentiates apoptotic injury (Liu et al Nature Med 2004 101379-83)(Liu et al Nature Med 2004 101379-83)
PROACT II IA Lysis TrialPROACT II IA Lysis Trial Baseline 24 hours 8 days
Baseline 60 minutes 120 minutes
9mg IAProurokinase
Desmoteplase Trials DEDAS Desmoteplase Trials DEDAS DIASDIAS
Trial OverviewTrial Overview Double blind randomized placebo Double blind randomized placebo
controlled trialscontrolled trials IV delivery 3-9 hour time windowIV delivery 3-9 hour time window Plasminogen activator ndash from Plasminogen activator ndash from vampire bat vampire bat
salivasaliva Selection based on PWI-DWI MismatchSelection based on PWI-DWI Mismatch
MRI InclusionMRI Inclusion PWI defect at least 2 cm AND ~20 larger PWI defect at least 2 cm AND ~20 larger
than DWIthan DWI PWI should be obvious even visible on PWI should be obvious even visible on
raw imagesraw imagesMRI ExclusionMRI Exclusion
DWI gt 13 MCADWI gt 13 MCA MRA ICA occlusionMRA ICA occlusion
Desmoteplase ndash DIAS Desmoteplase ndash DIAS ResultsResults
Mechanical Thrombolysis Mechanical Thrombolysis devicesdevices
mechanical thrombolysis potentially extends the treatment mechanical thrombolysis potentially extends the treatment window because they act promptly at the site of the thrombuswindow because they act promptly at the site of the thrombus
The devices can retrieve large clots that pharmaceutical agents The devices can retrieve large clots that pharmaceutical agents may not successfully lysemay not successfully lyse
Patients treated with IV tPA may be considered for treatment of Patients treated with IV tPA may be considered for treatment of residual clot with some of these devicesresidual clot with some of these devices
suction-creating saline jets suction-creating saline jets laser energy ultrasound laser energy ultrasound a corkscrew apparatus to treat strokesa corkscrew apparatus to treat strokes The AngioJet systemThe AngioJet system uses saline jets that are directed back into the catheter to uses saline jets that are directed back into the catheter to
create a low-pressure zone around the catheter tip inducing create a low-pressure zone around the catheter tip inducing suction suction
The clot is pulled into the exhaust lumen and removed from the The clot is pulled into the exhaust lumen and removed from the vessel Although US Food and Drug Administration (FDA) has vessel Although US Food and Drug Administration (FDA) has approved this device for use in arteriovenous dialysis grafts and approved this device for use in arteriovenous dialysis grafts and fistulae and for the treatment of coronary arteries saphenous fistulae and for the treatment of coronary arteries saphenous vein grafts and peripheral vessels clinical trials for the vein grafts and peripheral vessels clinical trials for the treatment of acute stroke are no longer in progress treatment of acute stroke are no longer in progress
Most devices are used in cerebral vessels that 2-5 mm
The Latis laser device The Latis laser device used laser energy to ablate clots used laser energy to ablate clots Arteries 2-5 mm in diameter could be Arteries 2-5 mm in diameter could be
treated including the ICA M1 or M2 treated including the ICA M1 or M2 branch of the MCA A1 branch of the branch of the MCA A1 branch of the anterior cerebral artery (ACA) basilar anterior cerebral artery (ACA) basilar artery posterior cerebral artery (PCA) artery posterior cerebral artery (PCA) and vertebral and vertebral
Patients could receive treatment as late Patients could receive treatment as late as 8 hours after symptom onset in the as 8 hours after symptom onset in the anterior circulation and within 24 hours in anterior circulation and within 24 hours in the posterior circulation the posterior circulation
Endovascular Photo Acoustic Endovascular Photo Acoustic Recanalization (EPAR) Recanalization (EPAR)
A laser power source generated energy for the A laser power source generated energy for the systemsystem
The energy was delivered by means of The energy was delivered by means of fiberoptics to the tip of the catheter at the fiberoptics to the tip of the catheter at the treatment sitetreatment site
Absorption of laser light by darkly pigmented Absorption of laser light by darkly pigmented materials (ie the clot) occurred inside the 1-mm materials (ie the clot) occurred inside the 1-mm catheter tipcatheter tip
the system was designed to minimize scattering the system was designed to minimize scattering of laser light of laser light
Absorption converted photo energy to acoustic Absorption converted photo energy to acoustic energy which then emulsified the clot inside the energy which then emulsified the clot inside the catheter tip catheter tip
EKOS ultrasound( the EKOS ultrasound( the Ultrasound Thrombolytic Ultrasound Thrombolytic
Infusion Catheter) Infusion Catheter) combines the use of a distal ultrasound transducer with combines the use of a distal ultrasound transducer with
infusion of a thrombolytic agent through the infusion of a thrombolytic agent through the microcathetermicrocatheter
Ultrasound changes the structure of the clot to Ultrasound changes the structure of the clot to temporarily increase its permeability while providing an temporarily increase its permeability while providing an acoustic pressure gradient to move the drug into the clot acoustic pressure gradient to move the drug into the clot to speed its dissolution to speed its dissolution
The EKOS catheter is placed in the proximal portion of the The EKOS catheter is placed in the proximal portion of the clot clot
After a 2-mg bolus of tPA was injected through the After a 2-mg bolus of tPA was injected through the catheter catheter
the patient received a continuous infusion of IA tPA 03 the patient received a continuous infusion of IA tPA 03 mgmin to a maximum of 20 mg and simultaneous mgmin to a maximum of 20 mg and simultaneous ultrasound transmission for as long as 60 minutes ultrasound transmission for as long as 60 minutes
One patient was treated with a total of 4 units of One patient was treated with a total of 4 units of recombinant reteplase (Retavase) hand-injected over 60 recombinant reteplase (Retavase) hand-injected over 60 minutes minutes
Penumbra system Penumbra system The Penumbra system (Penumbra Inc) provides a dual The Penumbra system (Penumbra Inc) provides a dual
approach to clot extraction using aspiration followed by approach to clot extraction using aspiration followed by clot retrieval with a ring device if needed clot retrieval with a ring device if needed
Mechanical Embolus Removal in Cerebral Ischemia Mechanical Embolus Removal in Cerebral Ischemia (MERCI)(MERCI)
a corkscrew-like apparatus to remove blood clots from a corkscrew-like apparatus to remove blood clots from the brain in patients experiencing an ischemic stroke the brain in patients experiencing an ischemic stroke
The corkscrew itself resides in the catheter tip which The corkscrew itself resides in the catheter tip which shields it from the wall of the vessel until it is ready to be shields it from the wall of the vessel until it is ready to be burrowed into the clot Once lodged in the clot the device burrowed into the clot Once lodged in the clot the device and clot are withdrawn from the vessel and clot are withdrawn from the vessel
Snarelike devicesSnarelike devices Snares such as the Neuronet snare (Guidant Snares such as the Neuronet snare (Guidant
Endovascular Santa Clara CA) have been developed Endovascular Santa Clara CA) have been developed specifically for use in the treatment of strokes specifically for use in the treatment of strokes
These devices are simple in design and do not require the These devices are simple in design and do not require the clot to be amenable to emulsification clot to be amenable to emulsification
X-Sizer deviceX-Sizer device a device with small moving blades at the a device with small moving blades at the
catheter tip catheter tip This device the X-Sizer device (EndiCor Medical This device the X-Sizer device (EndiCor Medical
San Clemente CA) can be used to excise the San Clemente CA) can be used to excise the thrombus and aspirate it thrombus and aspirate it
The device was being evaluated in randomized The device was being evaluated in randomized studies of coronary vessels and in a registry of studies of coronary vessels and in a registry of patients with acute myocardial infarctionpatients with acute myocardial infarction
Although the manufacturer had modified the Although the manufacturer had modified the device for use in cerebral vessels a safety and device for use in cerebral vessels a safety and feasibility study was indefinitely suspended after feasibility study was indefinitely suspended after only 1 patient was treated with the device in only 1 patient was treated with the device in Europe Europe
Suction thrombectomySuction thrombectomy This method of mechanical thrombolysis is one of the This method of mechanical thrombolysis is one of the
simplestsimplest In this readily available technique suction is applied with In this readily available technique suction is applied with
a syringe to remove thrombus in the ICA a syringe to remove thrombus in the ICA It requires no other devicesIt requires no other devices A catheter with a large inner diameter (Brite Tip Cordis A catheter with a large inner diameter (Brite Tip Cordis
Corporation Miami FL) was placed in the symptomatic Corporation Miami FL) was placed in the symptomatic vessel and navigated over a guidewire into the thrombusvessel and navigated over a guidewire into the thrombus
A 60-mL syringe was used to aspirate the thrombus A 60-mL syringe was used to aspirate the thrombus Each patient required angioplasty and stenting of carotid Each patient required angioplasty and stenting of carotid
bifurcation stenosis and received daily aspirin and bifurcation stenosis and received daily aspirin and ticlopidine after the procedure No complications ticlopidine after the procedure No complications occurred occurred
Summary Acute Stroke Summary Acute Stroke ImagingImaging
PhysiologyPhysiology importance collaterals importance collaterals
ndash ndashGrowing role for perfusion Growing role for perfusion assessmentassessment
tPAtPA guidelines amp limitations guidelines amp limitations Signs on CT amp MRSigns on CT amp MR follow physiology follow physiology Stroke trialsStroke trials PWI-DWI mismatch PWI-DWI mismatch
ndash ndashTreat based on physiology not timeTreat based on physiology not time ProtocolsProtocols should be fast and should be fast and
comprehensivecomprehensive
Three LMWH preparations are Three LMWH preparations are currently approved for use in the currently approved for use in the United States (1) enoxaparin (2) United States (1) enoxaparin (2) dalteparin and (3) tinzaparin dalteparin and (3) tinzaparin
They are all administered They are all administered subcutaneously at intervals of either subcutaneously at intervals of either once or twice daily for both once or twice daily for both prophylaxis and treatment dosesprophylaxis and treatment doses
Few Experiences of Few Experiences of ThrombolysisThrombolysis
Vickey 25 Yrs male patient presented Vickey 25 Yrs male patient presented with 12with 12thth day HO severe headache with day HO severe headache with right sided hemiplegiaright sided hemiplegia
MRI shows thrombosis of the superior MRI shows thrombosis of the superior sagittal left transverse left sigmoid sagittal left transverse left sigmoid sinuses and cortical veins in the fronto-sinuses and cortical veins in the fronto-parietal regions with eo haemorrhagic parietal regions with eo haemorrhagic infarct in the left cerebral hemisphere infarct in the left cerebral hemisphere with mass effect( Grade ndashV)with mass effect( Grade ndashV)
Sashi Srivastava 64 yrs FSashi Srivastava 64 yrs F In a follow up case of MRD with infra-renal In a follow up case of MRD with infra-renal
aortic abdominal and bilateral renal artery aortic abdominal and bilateral renal artery thrombosis renal angiogram shows filling thrombosis renal angiogram shows filling defects in the right Renal artery defects in the right Renal artery
Initially Renal angioplasty was done Initially Renal angioplasty was done Following angioplasty few thrombi are seem Following angioplasty few thrombi are seem to extends into the segmental branches and to extends into the segmental branches and causing blockage So Thrombolysis was causing blockage So Thrombolysis was plane to dissolve the run-out thrombi with plane to dissolve the run-out thrombi with urokinase urokinase
Rakesh 34yrsMRakesh 34yrsM Left SFA pseudoaneurysm with Left SFA pseudoaneurysm with
Covered stent placementCovered stent placement Pre operative antiplatelets with post Pre operative antiplatelets with post
procedure heparin Tirofiban procedure heparin Tirofiban followed by aspirin and clopidogrel followed by aspirin and clopidogrel were usedwere used
IAT may be a treatment option for selected patients IAT may be a treatment option for selected patients Possible selection criteria include Possible selection criteria include
presentation between 3 and 6 hours from symptom onsetpresentation between 3 and 6 hours from symptom onset major cerebral artery occlusion major cerebral artery occlusion severe neurologic deficits severe neurologic deficits high risk of systemic hemorrhage with IV rt-PA (eg recent high risk of systemic hemorrhage with IV rt-PA (eg recent
surgery) surgery) The MERCI (Mechanical Embolus Removal in Cerebral The MERCI (Mechanical Embolus Removal in Cerebral
Ischemia) retrievalIschemia) retrieval system system
Has been FDA-approved for recanalizing acutely occluded Has been FDA-approved for recanalizing acutely occluded cerebral arteries cerebral arteries
In the Multi-MERCI study patients who did not improve In the Multi-MERCI study patients who did not improve immediately after IV rt-PA underwent mechanical immediately after IV rt-PA underwent mechanical embolectomy within 8 hours of symptom onset embolectomy within 8 hours of symptom onset
Partial or complete recanalization occurred in 74 of Partial or complete recanalization occurred in 74 of patientspatients
with a symptomatic intracerebral hemorrhage (sICH) rate of with a symptomatic intracerebral hemorrhage (sICH) rate of 67 67
Mechanical embolectomy with the MERCI retriever may be a Mechanical embolectomy with the MERCI retriever may be a feasible and safe option for patients after IV rt-PAfeasible and safe option for patients after IV rt-PA
Penumbra stroke systemPenumbra stroke system This device combines two methods of clot This device combines two methods of clot
extraction aspiration and mechanical extraction aspiration and mechanical extraction extraction
First the clot is aspirated then a thrombus First the clot is aspirated then a thrombus removal ring can be used if necessary to removal ring can be used if necessary to remove remaining clot remove remaining clot
successful recanalizing 82successful recanalizing 82 Bridging therapyBridging therapy
06 mgkg IV rt-PA followed by IAT with IA rt-06 mgkg IV rt-PA followed by IAT with IA rt-PA (up to 20 mg)PA (up to 20 mg)
achieved a higher recanalization rateachieved a higher recanalization rate
Criteria for thrombolysis with rTPACriteria for thrombolysis with rTPA
Inclusion criteriaInclusion criteria Clinical signs and symptoms consistent with ischemic Clinical signs and symptoms consistent with ischemic
strokestroke Patient last seen normal within 3 hoursPatient last seen normal within 3 hours Measurable neurologic deficitMeasurable neurologic deficit
Exclusion criteriaExclusion criteria Any hemorrhage on neuroimaging (CT or MRI)Any hemorrhage on neuroimaging (CT or MRI) Symptoms suggestive of subarachnoid hemorrhageSymptoms suggestive of subarachnoid hemorrhage Seizure at stroke onset that is thought to contribute to Seizure at stroke onset that is thought to contribute to
neurologic deficitneurologic deficit Hypodensity greater than one third cerebral hemisphere Hypodensity greater than one third cerebral hemisphere
on CTon CT SBP greater than 185 mm Hg or DBP greater than 110 SBP greater than 185 mm Hg or DBP greater than 110
mm Hgmm Hg International normalized ratio (INR) greater than 17International normalized ratio (INR) greater than 17
Ischemic Stroke Ischemic Stroke Treatment ndash 2006Treatment ndash 2006
IV tissue plasminogen activator (tPA)IV tissue plasminogen activator (tPA) ndash ndash Only FDA-approved acute stroke drugOnly FDA-approved acute stroke drug ndash ndash 3 hour treatment window3 hour treatment window
MERCI - Concentric clot retrieval MERCI - Concentric clot retrieval devicedevice ndash ndash Rescue therapy - approved 2004Rescue therapy - approved 2004 ndash ndash Device approval (not outcomes-based)Device approval (not outcomes-based)
Off label approachesOff label approaches ndash ndash IV tPA after 3 hoursIV tPA after 3 hours ndash ndash IV-IA tPA sequential strategiesIV-IA tPA sequential strategies ndash ndash IA tPA clot angioplasty fragmentationIA tPA clot angioplasty fragmentation ndash ndash Ultrasound-assisted tPA lysisUltrasound-assisted tPA lysis
rt-PA Trials NINDSrt-PA Trials NINDS
Acute stroke - 624 patientsAcute stroke - 624 patients Treat within 3 hrsTreat within 3 hrs Intravenous 09 mgkg rt-PA vs placeboIntravenous 09 mgkg rt-PA vs placebo Hemorrhage 64 tPA 06 placeboHemorrhage 64 tPA 06 placebo Neurologic recovery better with tPA 30 Neurologic recovery better with tPA 30
more like to have minimal or no disabilitymore like to have minimal or no disability
First proven approved treatment for First proven approved treatment for strokestroke
Limitations of tPALimitations of tPA Only 4 of acute strokes receive tPAOnly 4 of acute strokes receive tPA (Kleindorfer et al Stroke 2004 35 e27-e29)(Kleindorfer et al Stroke 2004 35 e27-e29)
Only 22 of patients present within 3 hoursOnly 22 of patients present within 3 hours1048707 1048707 51 of these ineligible due to51 of these ineligible due to
bull bull Mild severityMild severity bull bull Medical or surgical historyMedical or surgical history bull bull Blood testsBlood tests
Sustained recanalization only 13Sustained recanalization only 13 (Alexandrov et al NEJM 2004 351 2170-8)(Alexandrov et al NEJM 2004 351 2170-8)
Concern for hemorrhageConcern for hemorrhage tPA potentiates apoptotic injury tPA potentiates apoptotic injury (Liu et al Nature Med 2004 101379-83)(Liu et al Nature Med 2004 101379-83)
PROACT II IA Lysis TrialPROACT II IA Lysis Trial Baseline 24 hours 8 days
Baseline 60 minutes 120 minutes
9mg IAProurokinase
Desmoteplase Trials DEDAS Desmoteplase Trials DEDAS DIASDIAS
Trial OverviewTrial Overview Double blind randomized placebo Double blind randomized placebo
controlled trialscontrolled trials IV delivery 3-9 hour time windowIV delivery 3-9 hour time window Plasminogen activator ndash from Plasminogen activator ndash from vampire bat vampire bat
salivasaliva Selection based on PWI-DWI MismatchSelection based on PWI-DWI Mismatch
MRI InclusionMRI Inclusion PWI defect at least 2 cm AND ~20 larger PWI defect at least 2 cm AND ~20 larger
than DWIthan DWI PWI should be obvious even visible on PWI should be obvious even visible on
raw imagesraw imagesMRI ExclusionMRI Exclusion
DWI gt 13 MCADWI gt 13 MCA MRA ICA occlusionMRA ICA occlusion
Desmoteplase ndash DIAS Desmoteplase ndash DIAS ResultsResults
Mechanical Thrombolysis Mechanical Thrombolysis devicesdevices
mechanical thrombolysis potentially extends the treatment mechanical thrombolysis potentially extends the treatment window because they act promptly at the site of the thrombuswindow because they act promptly at the site of the thrombus
The devices can retrieve large clots that pharmaceutical agents The devices can retrieve large clots that pharmaceutical agents may not successfully lysemay not successfully lyse
Patients treated with IV tPA may be considered for treatment of Patients treated with IV tPA may be considered for treatment of residual clot with some of these devicesresidual clot with some of these devices
suction-creating saline jets suction-creating saline jets laser energy ultrasound laser energy ultrasound a corkscrew apparatus to treat strokesa corkscrew apparatus to treat strokes The AngioJet systemThe AngioJet system uses saline jets that are directed back into the catheter to uses saline jets that are directed back into the catheter to
create a low-pressure zone around the catheter tip inducing create a low-pressure zone around the catheter tip inducing suction suction
The clot is pulled into the exhaust lumen and removed from the The clot is pulled into the exhaust lumen and removed from the vessel Although US Food and Drug Administration (FDA) has vessel Although US Food and Drug Administration (FDA) has approved this device for use in arteriovenous dialysis grafts and approved this device for use in arteriovenous dialysis grafts and fistulae and for the treatment of coronary arteries saphenous fistulae and for the treatment of coronary arteries saphenous vein grafts and peripheral vessels clinical trials for the vein grafts and peripheral vessels clinical trials for the treatment of acute stroke are no longer in progress treatment of acute stroke are no longer in progress
Most devices are used in cerebral vessels that 2-5 mm
The Latis laser device The Latis laser device used laser energy to ablate clots used laser energy to ablate clots Arteries 2-5 mm in diameter could be Arteries 2-5 mm in diameter could be
treated including the ICA M1 or M2 treated including the ICA M1 or M2 branch of the MCA A1 branch of the branch of the MCA A1 branch of the anterior cerebral artery (ACA) basilar anterior cerebral artery (ACA) basilar artery posterior cerebral artery (PCA) artery posterior cerebral artery (PCA) and vertebral and vertebral
Patients could receive treatment as late Patients could receive treatment as late as 8 hours after symptom onset in the as 8 hours after symptom onset in the anterior circulation and within 24 hours in anterior circulation and within 24 hours in the posterior circulation the posterior circulation
Endovascular Photo Acoustic Endovascular Photo Acoustic Recanalization (EPAR) Recanalization (EPAR)
A laser power source generated energy for the A laser power source generated energy for the systemsystem
The energy was delivered by means of The energy was delivered by means of fiberoptics to the tip of the catheter at the fiberoptics to the tip of the catheter at the treatment sitetreatment site
Absorption of laser light by darkly pigmented Absorption of laser light by darkly pigmented materials (ie the clot) occurred inside the 1-mm materials (ie the clot) occurred inside the 1-mm catheter tipcatheter tip
the system was designed to minimize scattering the system was designed to minimize scattering of laser light of laser light
Absorption converted photo energy to acoustic Absorption converted photo energy to acoustic energy which then emulsified the clot inside the energy which then emulsified the clot inside the catheter tip catheter tip
EKOS ultrasound( the EKOS ultrasound( the Ultrasound Thrombolytic Ultrasound Thrombolytic
Infusion Catheter) Infusion Catheter) combines the use of a distal ultrasound transducer with combines the use of a distal ultrasound transducer with
infusion of a thrombolytic agent through the infusion of a thrombolytic agent through the microcathetermicrocatheter
Ultrasound changes the structure of the clot to Ultrasound changes the structure of the clot to temporarily increase its permeability while providing an temporarily increase its permeability while providing an acoustic pressure gradient to move the drug into the clot acoustic pressure gradient to move the drug into the clot to speed its dissolution to speed its dissolution
The EKOS catheter is placed in the proximal portion of the The EKOS catheter is placed in the proximal portion of the clot clot
After a 2-mg bolus of tPA was injected through the After a 2-mg bolus of tPA was injected through the catheter catheter
the patient received a continuous infusion of IA tPA 03 the patient received a continuous infusion of IA tPA 03 mgmin to a maximum of 20 mg and simultaneous mgmin to a maximum of 20 mg and simultaneous ultrasound transmission for as long as 60 minutes ultrasound transmission for as long as 60 minutes
One patient was treated with a total of 4 units of One patient was treated with a total of 4 units of recombinant reteplase (Retavase) hand-injected over 60 recombinant reteplase (Retavase) hand-injected over 60 minutes minutes
Penumbra system Penumbra system The Penumbra system (Penumbra Inc) provides a dual The Penumbra system (Penumbra Inc) provides a dual
approach to clot extraction using aspiration followed by approach to clot extraction using aspiration followed by clot retrieval with a ring device if needed clot retrieval with a ring device if needed
Mechanical Embolus Removal in Cerebral Ischemia Mechanical Embolus Removal in Cerebral Ischemia (MERCI)(MERCI)
a corkscrew-like apparatus to remove blood clots from a corkscrew-like apparatus to remove blood clots from the brain in patients experiencing an ischemic stroke the brain in patients experiencing an ischemic stroke
The corkscrew itself resides in the catheter tip which The corkscrew itself resides in the catheter tip which shields it from the wall of the vessel until it is ready to be shields it from the wall of the vessel until it is ready to be burrowed into the clot Once lodged in the clot the device burrowed into the clot Once lodged in the clot the device and clot are withdrawn from the vessel and clot are withdrawn from the vessel
Snarelike devicesSnarelike devices Snares such as the Neuronet snare (Guidant Snares such as the Neuronet snare (Guidant
Endovascular Santa Clara CA) have been developed Endovascular Santa Clara CA) have been developed specifically for use in the treatment of strokes specifically for use in the treatment of strokes
These devices are simple in design and do not require the These devices are simple in design and do not require the clot to be amenable to emulsification clot to be amenable to emulsification
X-Sizer deviceX-Sizer device a device with small moving blades at the a device with small moving blades at the
catheter tip catheter tip This device the X-Sizer device (EndiCor Medical This device the X-Sizer device (EndiCor Medical
San Clemente CA) can be used to excise the San Clemente CA) can be used to excise the thrombus and aspirate it thrombus and aspirate it
The device was being evaluated in randomized The device was being evaluated in randomized studies of coronary vessels and in a registry of studies of coronary vessels and in a registry of patients with acute myocardial infarctionpatients with acute myocardial infarction
Although the manufacturer had modified the Although the manufacturer had modified the device for use in cerebral vessels a safety and device for use in cerebral vessels a safety and feasibility study was indefinitely suspended after feasibility study was indefinitely suspended after only 1 patient was treated with the device in only 1 patient was treated with the device in Europe Europe
Suction thrombectomySuction thrombectomy This method of mechanical thrombolysis is one of the This method of mechanical thrombolysis is one of the
simplestsimplest In this readily available technique suction is applied with In this readily available technique suction is applied with
a syringe to remove thrombus in the ICA a syringe to remove thrombus in the ICA It requires no other devicesIt requires no other devices A catheter with a large inner diameter (Brite Tip Cordis A catheter with a large inner diameter (Brite Tip Cordis
Corporation Miami FL) was placed in the symptomatic Corporation Miami FL) was placed in the symptomatic vessel and navigated over a guidewire into the thrombusvessel and navigated over a guidewire into the thrombus
A 60-mL syringe was used to aspirate the thrombus A 60-mL syringe was used to aspirate the thrombus Each patient required angioplasty and stenting of carotid Each patient required angioplasty and stenting of carotid
bifurcation stenosis and received daily aspirin and bifurcation stenosis and received daily aspirin and ticlopidine after the procedure No complications ticlopidine after the procedure No complications occurred occurred
Summary Acute Stroke Summary Acute Stroke ImagingImaging
PhysiologyPhysiology importance collaterals importance collaterals
ndash ndashGrowing role for perfusion Growing role for perfusion assessmentassessment
tPAtPA guidelines amp limitations guidelines amp limitations Signs on CT amp MRSigns on CT amp MR follow physiology follow physiology Stroke trialsStroke trials PWI-DWI mismatch PWI-DWI mismatch
ndash ndashTreat based on physiology not timeTreat based on physiology not time ProtocolsProtocols should be fast and should be fast and
comprehensivecomprehensive
Few Experiences of Few Experiences of ThrombolysisThrombolysis
Vickey 25 Yrs male patient presented Vickey 25 Yrs male patient presented with 12with 12thth day HO severe headache with day HO severe headache with right sided hemiplegiaright sided hemiplegia
MRI shows thrombosis of the superior MRI shows thrombosis of the superior sagittal left transverse left sigmoid sagittal left transverse left sigmoid sinuses and cortical veins in the fronto-sinuses and cortical veins in the fronto-parietal regions with eo haemorrhagic parietal regions with eo haemorrhagic infarct in the left cerebral hemisphere infarct in the left cerebral hemisphere with mass effect( Grade ndashV)with mass effect( Grade ndashV)
Sashi Srivastava 64 yrs FSashi Srivastava 64 yrs F In a follow up case of MRD with infra-renal In a follow up case of MRD with infra-renal
aortic abdominal and bilateral renal artery aortic abdominal and bilateral renal artery thrombosis renal angiogram shows filling thrombosis renal angiogram shows filling defects in the right Renal artery defects in the right Renal artery
Initially Renal angioplasty was done Initially Renal angioplasty was done Following angioplasty few thrombi are seem Following angioplasty few thrombi are seem to extends into the segmental branches and to extends into the segmental branches and causing blockage So Thrombolysis was causing blockage So Thrombolysis was plane to dissolve the run-out thrombi with plane to dissolve the run-out thrombi with urokinase urokinase
Rakesh 34yrsMRakesh 34yrsM Left SFA pseudoaneurysm with Left SFA pseudoaneurysm with
Covered stent placementCovered stent placement Pre operative antiplatelets with post Pre operative antiplatelets with post
procedure heparin Tirofiban procedure heparin Tirofiban followed by aspirin and clopidogrel followed by aspirin and clopidogrel were usedwere used
IAT may be a treatment option for selected patients IAT may be a treatment option for selected patients Possible selection criteria include Possible selection criteria include
presentation between 3 and 6 hours from symptom onsetpresentation between 3 and 6 hours from symptom onset major cerebral artery occlusion major cerebral artery occlusion severe neurologic deficits severe neurologic deficits high risk of systemic hemorrhage with IV rt-PA (eg recent high risk of systemic hemorrhage with IV rt-PA (eg recent
surgery) surgery) The MERCI (Mechanical Embolus Removal in Cerebral The MERCI (Mechanical Embolus Removal in Cerebral
Ischemia) retrievalIschemia) retrieval system system
Has been FDA-approved for recanalizing acutely occluded Has been FDA-approved for recanalizing acutely occluded cerebral arteries cerebral arteries
In the Multi-MERCI study patients who did not improve In the Multi-MERCI study patients who did not improve immediately after IV rt-PA underwent mechanical immediately after IV rt-PA underwent mechanical embolectomy within 8 hours of symptom onset embolectomy within 8 hours of symptom onset
Partial or complete recanalization occurred in 74 of Partial or complete recanalization occurred in 74 of patientspatients
with a symptomatic intracerebral hemorrhage (sICH) rate of with a symptomatic intracerebral hemorrhage (sICH) rate of 67 67
Mechanical embolectomy with the MERCI retriever may be a Mechanical embolectomy with the MERCI retriever may be a feasible and safe option for patients after IV rt-PAfeasible and safe option for patients after IV rt-PA
Penumbra stroke systemPenumbra stroke system This device combines two methods of clot This device combines two methods of clot
extraction aspiration and mechanical extraction aspiration and mechanical extraction extraction
First the clot is aspirated then a thrombus First the clot is aspirated then a thrombus removal ring can be used if necessary to removal ring can be used if necessary to remove remaining clot remove remaining clot
successful recanalizing 82successful recanalizing 82 Bridging therapyBridging therapy
06 mgkg IV rt-PA followed by IAT with IA rt-06 mgkg IV rt-PA followed by IAT with IA rt-PA (up to 20 mg)PA (up to 20 mg)
achieved a higher recanalization rateachieved a higher recanalization rate
Criteria for thrombolysis with rTPACriteria for thrombolysis with rTPA
Inclusion criteriaInclusion criteria Clinical signs and symptoms consistent with ischemic Clinical signs and symptoms consistent with ischemic
strokestroke Patient last seen normal within 3 hoursPatient last seen normal within 3 hours Measurable neurologic deficitMeasurable neurologic deficit
Exclusion criteriaExclusion criteria Any hemorrhage on neuroimaging (CT or MRI)Any hemorrhage on neuroimaging (CT or MRI) Symptoms suggestive of subarachnoid hemorrhageSymptoms suggestive of subarachnoid hemorrhage Seizure at stroke onset that is thought to contribute to Seizure at stroke onset that is thought to contribute to
neurologic deficitneurologic deficit Hypodensity greater than one third cerebral hemisphere Hypodensity greater than one third cerebral hemisphere
on CTon CT SBP greater than 185 mm Hg or DBP greater than 110 SBP greater than 185 mm Hg or DBP greater than 110
mm Hgmm Hg International normalized ratio (INR) greater than 17International normalized ratio (INR) greater than 17
Ischemic Stroke Ischemic Stroke Treatment ndash 2006Treatment ndash 2006
IV tissue plasminogen activator (tPA)IV tissue plasminogen activator (tPA) ndash ndash Only FDA-approved acute stroke drugOnly FDA-approved acute stroke drug ndash ndash 3 hour treatment window3 hour treatment window
MERCI - Concentric clot retrieval MERCI - Concentric clot retrieval devicedevice ndash ndash Rescue therapy - approved 2004Rescue therapy - approved 2004 ndash ndash Device approval (not outcomes-based)Device approval (not outcomes-based)
Off label approachesOff label approaches ndash ndash IV tPA after 3 hoursIV tPA after 3 hours ndash ndash IV-IA tPA sequential strategiesIV-IA tPA sequential strategies ndash ndash IA tPA clot angioplasty fragmentationIA tPA clot angioplasty fragmentation ndash ndash Ultrasound-assisted tPA lysisUltrasound-assisted tPA lysis
rt-PA Trials NINDSrt-PA Trials NINDS
Acute stroke - 624 patientsAcute stroke - 624 patients Treat within 3 hrsTreat within 3 hrs Intravenous 09 mgkg rt-PA vs placeboIntravenous 09 mgkg rt-PA vs placebo Hemorrhage 64 tPA 06 placeboHemorrhage 64 tPA 06 placebo Neurologic recovery better with tPA 30 Neurologic recovery better with tPA 30
more like to have minimal or no disabilitymore like to have minimal or no disability
First proven approved treatment for First proven approved treatment for strokestroke
Limitations of tPALimitations of tPA Only 4 of acute strokes receive tPAOnly 4 of acute strokes receive tPA (Kleindorfer et al Stroke 2004 35 e27-e29)(Kleindorfer et al Stroke 2004 35 e27-e29)
Only 22 of patients present within 3 hoursOnly 22 of patients present within 3 hours1048707 1048707 51 of these ineligible due to51 of these ineligible due to
bull bull Mild severityMild severity bull bull Medical or surgical historyMedical or surgical history bull bull Blood testsBlood tests
Sustained recanalization only 13Sustained recanalization only 13 (Alexandrov et al NEJM 2004 351 2170-8)(Alexandrov et al NEJM 2004 351 2170-8)
Concern for hemorrhageConcern for hemorrhage tPA potentiates apoptotic injury tPA potentiates apoptotic injury (Liu et al Nature Med 2004 101379-83)(Liu et al Nature Med 2004 101379-83)
PROACT II IA Lysis TrialPROACT II IA Lysis Trial Baseline 24 hours 8 days
Baseline 60 minutes 120 minutes
9mg IAProurokinase
Desmoteplase Trials DEDAS Desmoteplase Trials DEDAS DIASDIAS
Trial OverviewTrial Overview Double blind randomized placebo Double blind randomized placebo
controlled trialscontrolled trials IV delivery 3-9 hour time windowIV delivery 3-9 hour time window Plasminogen activator ndash from Plasminogen activator ndash from vampire bat vampire bat
salivasaliva Selection based on PWI-DWI MismatchSelection based on PWI-DWI Mismatch
MRI InclusionMRI Inclusion PWI defect at least 2 cm AND ~20 larger PWI defect at least 2 cm AND ~20 larger
than DWIthan DWI PWI should be obvious even visible on PWI should be obvious even visible on
raw imagesraw imagesMRI ExclusionMRI Exclusion
DWI gt 13 MCADWI gt 13 MCA MRA ICA occlusionMRA ICA occlusion
Desmoteplase ndash DIAS Desmoteplase ndash DIAS ResultsResults
Mechanical Thrombolysis Mechanical Thrombolysis devicesdevices
mechanical thrombolysis potentially extends the treatment mechanical thrombolysis potentially extends the treatment window because they act promptly at the site of the thrombuswindow because they act promptly at the site of the thrombus
The devices can retrieve large clots that pharmaceutical agents The devices can retrieve large clots that pharmaceutical agents may not successfully lysemay not successfully lyse
Patients treated with IV tPA may be considered for treatment of Patients treated with IV tPA may be considered for treatment of residual clot with some of these devicesresidual clot with some of these devices
suction-creating saline jets suction-creating saline jets laser energy ultrasound laser energy ultrasound a corkscrew apparatus to treat strokesa corkscrew apparatus to treat strokes The AngioJet systemThe AngioJet system uses saline jets that are directed back into the catheter to uses saline jets that are directed back into the catheter to
create a low-pressure zone around the catheter tip inducing create a low-pressure zone around the catheter tip inducing suction suction
The clot is pulled into the exhaust lumen and removed from the The clot is pulled into the exhaust lumen and removed from the vessel Although US Food and Drug Administration (FDA) has vessel Although US Food and Drug Administration (FDA) has approved this device for use in arteriovenous dialysis grafts and approved this device for use in arteriovenous dialysis grafts and fistulae and for the treatment of coronary arteries saphenous fistulae and for the treatment of coronary arteries saphenous vein grafts and peripheral vessels clinical trials for the vein grafts and peripheral vessels clinical trials for the treatment of acute stroke are no longer in progress treatment of acute stroke are no longer in progress
Most devices are used in cerebral vessels that 2-5 mm
The Latis laser device The Latis laser device used laser energy to ablate clots used laser energy to ablate clots Arteries 2-5 mm in diameter could be Arteries 2-5 mm in diameter could be
treated including the ICA M1 or M2 treated including the ICA M1 or M2 branch of the MCA A1 branch of the branch of the MCA A1 branch of the anterior cerebral artery (ACA) basilar anterior cerebral artery (ACA) basilar artery posterior cerebral artery (PCA) artery posterior cerebral artery (PCA) and vertebral and vertebral
Patients could receive treatment as late Patients could receive treatment as late as 8 hours after symptom onset in the as 8 hours after symptom onset in the anterior circulation and within 24 hours in anterior circulation and within 24 hours in the posterior circulation the posterior circulation
Endovascular Photo Acoustic Endovascular Photo Acoustic Recanalization (EPAR) Recanalization (EPAR)
A laser power source generated energy for the A laser power source generated energy for the systemsystem
The energy was delivered by means of The energy was delivered by means of fiberoptics to the tip of the catheter at the fiberoptics to the tip of the catheter at the treatment sitetreatment site
Absorption of laser light by darkly pigmented Absorption of laser light by darkly pigmented materials (ie the clot) occurred inside the 1-mm materials (ie the clot) occurred inside the 1-mm catheter tipcatheter tip
the system was designed to minimize scattering the system was designed to minimize scattering of laser light of laser light
Absorption converted photo energy to acoustic Absorption converted photo energy to acoustic energy which then emulsified the clot inside the energy which then emulsified the clot inside the catheter tip catheter tip
EKOS ultrasound( the EKOS ultrasound( the Ultrasound Thrombolytic Ultrasound Thrombolytic
Infusion Catheter) Infusion Catheter) combines the use of a distal ultrasound transducer with combines the use of a distal ultrasound transducer with
infusion of a thrombolytic agent through the infusion of a thrombolytic agent through the microcathetermicrocatheter
Ultrasound changes the structure of the clot to Ultrasound changes the structure of the clot to temporarily increase its permeability while providing an temporarily increase its permeability while providing an acoustic pressure gradient to move the drug into the clot acoustic pressure gradient to move the drug into the clot to speed its dissolution to speed its dissolution
The EKOS catheter is placed in the proximal portion of the The EKOS catheter is placed in the proximal portion of the clot clot
After a 2-mg bolus of tPA was injected through the After a 2-mg bolus of tPA was injected through the catheter catheter
the patient received a continuous infusion of IA tPA 03 the patient received a continuous infusion of IA tPA 03 mgmin to a maximum of 20 mg and simultaneous mgmin to a maximum of 20 mg and simultaneous ultrasound transmission for as long as 60 minutes ultrasound transmission for as long as 60 minutes
One patient was treated with a total of 4 units of One patient was treated with a total of 4 units of recombinant reteplase (Retavase) hand-injected over 60 recombinant reteplase (Retavase) hand-injected over 60 minutes minutes
Penumbra system Penumbra system The Penumbra system (Penumbra Inc) provides a dual The Penumbra system (Penumbra Inc) provides a dual
approach to clot extraction using aspiration followed by approach to clot extraction using aspiration followed by clot retrieval with a ring device if needed clot retrieval with a ring device if needed
Mechanical Embolus Removal in Cerebral Ischemia Mechanical Embolus Removal in Cerebral Ischemia (MERCI)(MERCI)
a corkscrew-like apparatus to remove blood clots from a corkscrew-like apparatus to remove blood clots from the brain in patients experiencing an ischemic stroke the brain in patients experiencing an ischemic stroke
The corkscrew itself resides in the catheter tip which The corkscrew itself resides in the catheter tip which shields it from the wall of the vessel until it is ready to be shields it from the wall of the vessel until it is ready to be burrowed into the clot Once lodged in the clot the device burrowed into the clot Once lodged in the clot the device and clot are withdrawn from the vessel and clot are withdrawn from the vessel
Snarelike devicesSnarelike devices Snares such as the Neuronet snare (Guidant Snares such as the Neuronet snare (Guidant
Endovascular Santa Clara CA) have been developed Endovascular Santa Clara CA) have been developed specifically for use in the treatment of strokes specifically for use in the treatment of strokes
These devices are simple in design and do not require the These devices are simple in design and do not require the clot to be amenable to emulsification clot to be amenable to emulsification
X-Sizer deviceX-Sizer device a device with small moving blades at the a device with small moving blades at the
catheter tip catheter tip This device the X-Sizer device (EndiCor Medical This device the X-Sizer device (EndiCor Medical
San Clemente CA) can be used to excise the San Clemente CA) can be used to excise the thrombus and aspirate it thrombus and aspirate it
The device was being evaluated in randomized The device was being evaluated in randomized studies of coronary vessels and in a registry of studies of coronary vessels and in a registry of patients with acute myocardial infarctionpatients with acute myocardial infarction
Although the manufacturer had modified the Although the manufacturer had modified the device for use in cerebral vessels a safety and device for use in cerebral vessels a safety and feasibility study was indefinitely suspended after feasibility study was indefinitely suspended after only 1 patient was treated with the device in only 1 patient was treated with the device in Europe Europe
Suction thrombectomySuction thrombectomy This method of mechanical thrombolysis is one of the This method of mechanical thrombolysis is one of the
simplestsimplest In this readily available technique suction is applied with In this readily available technique suction is applied with
a syringe to remove thrombus in the ICA a syringe to remove thrombus in the ICA It requires no other devicesIt requires no other devices A catheter with a large inner diameter (Brite Tip Cordis A catheter with a large inner diameter (Brite Tip Cordis
Corporation Miami FL) was placed in the symptomatic Corporation Miami FL) was placed in the symptomatic vessel and navigated over a guidewire into the thrombusvessel and navigated over a guidewire into the thrombus
A 60-mL syringe was used to aspirate the thrombus A 60-mL syringe was used to aspirate the thrombus Each patient required angioplasty and stenting of carotid Each patient required angioplasty and stenting of carotid
bifurcation stenosis and received daily aspirin and bifurcation stenosis and received daily aspirin and ticlopidine after the procedure No complications ticlopidine after the procedure No complications occurred occurred
Summary Acute Stroke Summary Acute Stroke ImagingImaging
PhysiologyPhysiology importance collaterals importance collaterals
ndash ndashGrowing role for perfusion Growing role for perfusion assessmentassessment
tPAtPA guidelines amp limitations guidelines amp limitations Signs on CT amp MRSigns on CT amp MR follow physiology follow physiology Stroke trialsStroke trials PWI-DWI mismatch PWI-DWI mismatch
ndash ndashTreat based on physiology not timeTreat based on physiology not time ProtocolsProtocols should be fast and should be fast and
comprehensivecomprehensive
Vickey 25 Yrs male patient presented Vickey 25 Yrs male patient presented with 12with 12thth day HO severe headache with day HO severe headache with right sided hemiplegiaright sided hemiplegia
MRI shows thrombosis of the superior MRI shows thrombosis of the superior sagittal left transverse left sigmoid sagittal left transverse left sigmoid sinuses and cortical veins in the fronto-sinuses and cortical veins in the fronto-parietal regions with eo haemorrhagic parietal regions with eo haemorrhagic infarct in the left cerebral hemisphere infarct in the left cerebral hemisphere with mass effect( Grade ndashV)with mass effect( Grade ndashV)
Sashi Srivastava 64 yrs FSashi Srivastava 64 yrs F In a follow up case of MRD with infra-renal In a follow up case of MRD with infra-renal
aortic abdominal and bilateral renal artery aortic abdominal and bilateral renal artery thrombosis renal angiogram shows filling thrombosis renal angiogram shows filling defects in the right Renal artery defects in the right Renal artery
Initially Renal angioplasty was done Initially Renal angioplasty was done Following angioplasty few thrombi are seem Following angioplasty few thrombi are seem to extends into the segmental branches and to extends into the segmental branches and causing blockage So Thrombolysis was causing blockage So Thrombolysis was plane to dissolve the run-out thrombi with plane to dissolve the run-out thrombi with urokinase urokinase
Rakesh 34yrsMRakesh 34yrsM Left SFA pseudoaneurysm with Left SFA pseudoaneurysm with
Covered stent placementCovered stent placement Pre operative antiplatelets with post Pre operative antiplatelets with post
procedure heparin Tirofiban procedure heparin Tirofiban followed by aspirin and clopidogrel followed by aspirin and clopidogrel were usedwere used
IAT may be a treatment option for selected patients IAT may be a treatment option for selected patients Possible selection criteria include Possible selection criteria include
presentation between 3 and 6 hours from symptom onsetpresentation between 3 and 6 hours from symptom onset major cerebral artery occlusion major cerebral artery occlusion severe neurologic deficits severe neurologic deficits high risk of systemic hemorrhage with IV rt-PA (eg recent high risk of systemic hemorrhage with IV rt-PA (eg recent
surgery) surgery) The MERCI (Mechanical Embolus Removal in Cerebral The MERCI (Mechanical Embolus Removal in Cerebral
Ischemia) retrievalIschemia) retrieval system system
Has been FDA-approved for recanalizing acutely occluded Has been FDA-approved for recanalizing acutely occluded cerebral arteries cerebral arteries
In the Multi-MERCI study patients who did not improve In the Multi-MERCI study patients who did not improve immediately after IV rt-PA underwent mechanical immediately after IV rt-PA underwent mechanical embolectomy within 8 hours of symptom onset embolectomy within 8 hours of symptom onset
Partial or complete recanalization occurred in 74 of Partial or complete recanalization occurred in 74 of patientspatients
with a symptomatic intracerebral hemorrhage (sICH) rate of with a symptomatic intracerebral hemorrhage (sICH) rate of 67 67
Mechanical embolectomy with the MERCI retriever may be a Mechanical embolectomy with the MERCI retriever may be a feasible and safe option for patients after IV rt-PAfeasible and safe option for patients after IV rt-PA
Penumbra stroke systemPenumbra stroke system This device combines two methods of clot This device combines two methods of clot
extraction aspiration and mechanical extraction aspiration and mechanical extraction extraction
First the clot is aspirated then a thrombus First the clot is aspirated then a thrombus removal ring can be used if necessary to removal ring can be used if necessary to remove remaining clot remove remaining clot
successful recanalizing 82successful recanalizing 82 Bridging therapyBridging therapy
06 mgkg IV rt-PA followed by IAT with IA rt-06 mgkg IV rt-PA followed by IAT with IA rt-PA (up to 20 mg)PA (up to 20 mg)
achieved a higher recanalization rateachieved a higher recanalization rate
Criteria for thrombolysis with rTPACriteria for thrombolysis with rTPA
Inclusion criteriaInclusion criteria Clinical signs and symptoms consistent with ischemic Clinical signs and symptoms consistent with ischemic
strokestroke Patient last seen normal within 3 hoursPatient last seen normal within 3 hours Measurable neurologic deficitMeasurable neurologic deficit
Exclusion criteriaExclusion criteria Any hemorrhage on neuroimaging (CT or MRI)Any hemorrhage on neuroimaging (CT or MRI) Symptoms suggestive of subarachnoid hemorrhageSymptoms suggestive of subarachnoid hemorrhage Seizure at stroke onset that is thought to contribute to Seizure at stroke onset that is thought to contribute to
neurologic deficitneurologic deficit Hypodensity greater than one third cerebral hemisphere Hypodensity greater than one third cerebral hemisphere
on CTon CT SBP greater than 185 mm Hg or DBP greater than 110 SBP greater than 185 mm Hg or DBP greater than 110
mm Hgmm Hg International normalized ratio (INR) greater than 17International normalized ratio (INR) greater than 17
Ischemic Stroke Ischemic Stroke Treatment ndash 2006Treatment ndash 2006
IV tissue plasminogen activator (tPA)IV tissue plasminogen activator (tPA) ndash ndash Only FDA-approved acute stroke drugOnly FDA-approved acute stroke drug ndash ndash 3 hour treatment window3 hour treatment window
MERCI - Concentric clot retrieval MERCI - Concentric clot retrieval devicedevice ndash ndash Rescue therapy - approved 2004Rescue therapy - approved 2004 ndash ndash Device approval (not outcomes-based)Device approval (not outcomes-based)
Off label approachesOff label approaches ndash ndash IV tPA after 3 hoursIV tPA after 3 hours ndash ndash IV-IA tPA sequential strategiesIV-IA tPA sequential strategies ndash ndash IA tPA clot angioplasty fragmentationIA tPA clot angioplasty fragmentation ndash ndash Ultrasound-assisted tPA lysisUltrasound-assisted tPA lysis
rt-PA Trials NINDSrt-PA Trials NINDS
Acute stroke - 624 patientsAcute stroke - 624 patients Treat within 3 hrsTreat within 3 hrs Intravenous 09 mgkg rt-PA vs placeboIntravenous 09 mgkg rt-PA vs placebo Hemorrhage 64 tPA 06 placeboHemorrhage 64 tPA 06 placebo Neurologic recovery better with tPA 30 Neurologic recovery better with tPA 30
more like to have minimal or no disabilitymore like to have minimal or no disability
First proven approved treatment for First proven approved treatment for strokestroke
Limitations of tPALimitations of tPA Only 4 of acute strokes receive tPAOnly 4 of acute strokes receive tPA (Kleindorfer et al Stroke 2004 35 e27-e29)(Kleindorfer et al Stroke 2004 35 e27-e29)
Only 22 of patients present within 3 hoursOnly 22 of patients present within 3 hours1048707 1048707 51 of these ineligible due to51 of these ineligible due to
bull bull Mild severityMild severity bull bull Medical or surgical historyMedical or surgical history bull bull Blood testsBlood tests
Sustained recanalization only 13Sustained recanalization only 13 (Alexandrov et al NEJM 2004 351 2170-8)(Alexandrov et al NEJM 2004 351 2170-8)
Concern for hemorrhageConcern for hemorrhage tPA potentiates apoptotic injury tPA potentiates apoptotic injury (Liu et al Nature Med 2004 101379-83)(Liu et al Nature Med 2004 101379-83)
PROACT II IA Lysis TrialPROACT II IA Lysis Trial Baseline 24 hours 8 days
Baseline 60 minutes 120 minutes
9mg IAProurokinase
Desmoteplase Trials DEDAS Desmoteplase Trials DEDAS DIASDIAS
Trial OverviewTrial Overview Double blind randomized placebo Double blind randomized placebo
controlled trialscontrolled trials IV delivery 3-9 hour time windowIV delivery 3-9 hour time window Plasminogen activator ndash from Plasminogen activator ndash from vampire bat vampire bat
salivasaliva Selection based on PWI-DWI MismatchSelection based on PWI-DWI Mismatch
MRI InclusionMRI Inclusion PWI defect at least 2 cm AND ~20 larger PWI defect at least 2 cm AND ~20 larger
than DWIthan DWI PWI should be obvious even visible on PWI should be obvious even visible on
raw imagesraw imagesMRI ExclusionMRI Exclusion
DWI gt 13 MCADWI gt 13 MCA MRA ICA occlusionMRA ICA occlusion
Desmoteplase ndash DIAS Desmoteplase ndash DIAS ResultsResults
Mechanical Thrombolysis Mechanical Thrombolysis devicesdevices
mechanical thrombolysis potentially extends the treatment mechanical thrombolysis potentially extends the treatment window because they act promptly at the site of the thrombuswindow because they act promptly at the site of the thrombus
The devices can retrieve large clots that pharmaceutical agents The devices can retrieve large clots that pharmaceutical agents may not successfully lysemay not successfully lyse
Patients treated with IV tPA may be considered for treatment of Patients treated with IV tPA may be considered for treatment of residual clot with some of these devicesresidual clot with some of these devices
suction-creating saline jets suction-creating saline jets laser energy ultrasound laser energy ultrasound a corkscrew apparatus to treat strokesa corkscrew apparatus to treat strokes The AngioJet systemThe AngioJet system uses saline jets that are directed back into the catheter to uses saline jets that are directed back into the catheter to
create a low-pressure zone around the catheter tip inducing create a low-pressure zone around the catheter tip inducing suction suction
The clot is pulled into the exhaust lumen and removed from the The clot is pulled into the exhaust lumen and removed from the vessel Although US Food and Drug Administration (FDA) has vessel Although US Food and Drug Administration (FDA) has approved this device for use in arteriovenous dialysis grafts and approved this device for use in arteriovenous dialysis grafts and fistulae and for the treatment of coronary arteries saphenous fistulae and for the treatment of coronary arteries saphenous vein grafts and peripheral vessels clinical trials for the vein grafts and peripheral vessels clinical trials for the treatment of acute stroke are no longer in progress treatment of acute stroke are no longer in progress
Most devices are used in cerebral vessels that 2-5 mm
The Latis laser device The Latis laser device used laser energy to ablate clots used laser energy to ablate clots Arteries 2-5 mm in diameter could be Arteries 2-5 mm in diameter could be
treated including the ICA M1 or M2 treated including the ICA M1 or M2 branch of the MCA A1 branch of the branch of the MCA A1 branch of the anterior cerebral artery (ACA) basilar anterior cerebral artery (ACA) basilar artery posterior cerebral artery (PCA) artery posterior cerebral artery (PCA) and vertebral and vertebral
Patients could receive treatment as late Patients could receive treatment as late as 8 hours after symptom onset in the as 8 hours after symptom onset in the anterior circulation and within 24 hours in anterior circulation and within 24 hours in the posterior circulation the posterior circulation
Endovascular Photo Acoustic Endovascular Photo Acoustic Recanalization (EPAR) Recanalization (EPAR)
A laser power source generated energy for the A laser power source generated energy for the systemsystem
The energy was delivered by means of The energy was delivered by means of fiberoptics to the tip of the catheter at the fiberoptics to the tip of the catheter at the treatment sitetreatment site
Absorption of laser light by darkly pigmented Absorption of laser light by darkly pigmented materials (ie the clot) occurred inside the 1-mm materials (ie the clot) occurred inside the 1-mm catheter tipcatheter tip
the system was designed to minimize scattering the system was designed to minimize scattering of laser light of laser light
Absorption converted photo energy to acoustic Absorption converted photo energy to acoustic energy which then emulsified the clot inside the energy which then emulsified the clot inside the catheter tip catheter tip
EKOS ultrasound( the EKOS ultrasound( the Ultrasound Thrombolytic Ultrasound Thrombolytic
Infusion Catheter) Infusion Catheter) combines the use of a distal ultrasound transducer with combines the use of a distal ultrasound transducer with
infusion of a thrombolytic agent through the infusion of a thrombolytic agent through the microcathetermicrocatheter
Ultrasound changes the structure of the clot to Ultrasound changes the structure of the clot to temporarily increase its permeability while providing an temporarily increase its permeability while providing an acoustic pressure gradient to move the drug into the clot acoustic pressure gradient to move the drug into the clot to speed its dissolution to speed its dissolution
The EKOS catheter is placed in the proximal portion of the The EKOS catheter is placed in the proximal portion of the clot clot
After a 2-mg bolus of tPA was injected through the After a 2-mg bolus of tPA was injected through the catheter catheter
the patient received a continuous infusion of IA tPA 03 the patient received a continuous infusion of IA tPA 03 mgmin to a maximum of 20 mg and simultaneous mgmin to a maximum of 20 mg and simultaneous ultrasound transmission for as long as 60 minutes ultrasound transmission for as long as 60 minutes
One patient was treated with a total of 4 units of One patient was treated with a total of 4 units of recombinant reteplase (Retavase) hand-injected over 60 recombinant reteplase (Retavase) hand-injected over 60 minutes minutes
Penumbra system Penumbra system The Penumbra system (Penumbra Inc) provides a dual The Penumbra system (Penumbra Inc) provides a dual
approach to clot extraction using aspiration followed by approach to clot extraction using aspiration followed by clot retrieval with a ring device if needed clot retrieval with a ring device if needed
Mechanical Embolus Removal in Cerebral Ischemia Mechanical Embolus Removal in Cerebral Ischemia (MERCI)(MERCI)
a corkscrew-like apparatus to remove blood clots from a corkscrew-like apparatus to remove blood clots from the brain in patients experiencing an ischemic stroke the brain in patients experiencing an ischemic stroke
The corkscrew itself resides in the catheter tip which The corkscrew itself resides in the catheter tip which shields it from the wall of the vessel until it is ready to be shields it from the wall of the vessel until it is ready to be burrowed into the clot Once lodged in the clot the device burrowed into the clot Once lodged in the clot the device and clot are withdrawn from the vessel and clot are withdrawn from the vessel
Snarelike devicesSnarelike devices Snares such as the Neuronet snare (Guidant Snares such as the Neuronet snare (Guidant
Endovascular Santa Clara CA) have been developed Endovascular Santa Clara CA) have been developed specifically for use in the treatment of strokes specifically for use in the treatment of strokes
These devices are simple in design and do not require the These devices are simple in design and do not require the clot to be amenable to emulsification clot to be amenable to emulsification
X-Sizer deviceX-Sizer device a device with small moving blades at the a device with small moving blades at the
catheter tip catheter tip This device the X-Sizer device (EndiCor Medical This device the X-Sizer device (EndiCor Medical
San Clemente CA) can be used to excise the San Clemente CA) can be used to excise the thrombus and aspirate it thrombus and aspirate it
The device was being evaluated in randomized The device was being evaluated in randomized studies of coronary vessels and in a registry of studies of coronary vessels and in a registry of patients with acute myocardial infarctionpatients with acute myocardial infarction
Although the manufacturer had modified the Although the manufacturer had modified the device for use in cerebral vessels a safety and device for use in cerebral vessels a safety and feasibility study was indefinitely suspended after feasibility study was indefinitely suspended after only 1 patient was treated with the device in only 1 patient was treated with the device in Europe Europe
Suction thrombectomySuction thrombectomy This method of mechanical thrombolysis is one of the This method of mechanical thrombolysis is one of the
simplestsimplest In this readily available technique suction is applied with In this readily available technique suction is applied with
a syringe to remove thrombus in the ICA a syringe to remove thrombus in the ICA It requires no other devicesIt requires no other devices A catheter with a large inner diameter (Brite Tip Cordis A catheter with a large inner diameter (Brite Tip Cordis
Corporation Miami FL) was placed in the symptomatic Corporation Miami FL) was placed in the symptomatic vessel and navigated over a guidewire into the thrombusvessel and navigated over a guidewire into the thrombus
A 60-mL syringe was used to aspirate the thrombus A 60-mL syringe was used to aspirate the thrombus Each patient required angioplasty and stenting of carotid Each patient required angioplasty and stenting of carotid
bifurcation stenosis and received daily aspirin and bifurcation stenosis and received daily aspirin and ticlopidine after the procedure No complications ticlopidine after the procedure No complications occurred occurred
Summary Acute Stroke Summary Acute Stroke ImagingImaging
PhysiologyPhysiology importance collaterals importance collaterals
ndash ndashGrowing role for perfusion Growing role for perfusion assessmentassessment
tPAtPA guidelines amp limitations guidelines amp limitations Signs on CT amp MRSigns on CT amp MR follow physiology follow physiology Stroke trialsStroke trials PWI-DWI mismatch PWI-DWI mismatch
ndash ndashTreat based on physiology not timeTreat based on physiology not time ProtocolsProtocols should be fast and should be fast and
comprehensivecomprehensive
Sashi Srivastava 64 yrs FSashi Srivastava 64 yrs F In a follow up case of MRD with infra-renal In a follow up case of MRD with infra-renal
aortic abdominal and bilateral renal artery aortic abdominal and bilateral renal artery thrombosis renal angiogram shows filling thrombosis renal angiogram shows filling defects in the right Renal artery defects in the right Renal artery
Initially Renal angioplasty was done Initially Renal angioplasty was done Following angioplasty few thrombi are seem Following angioplasty few thrombi are seem to extends into the segmental branches and to extends into the segmental branches and causing blockage So Thrombolysis was causing blockage So Thrombolysis was plane to dissolve the run-out thrombi with plane to dissolve the run-out thrombi with urokinase urokinase
Rakesh 34yrsMRakesh 34yrsM Left SFA pseudoaneurysm with Left SFA pseudoaneurysm with
Covered stent placementCovered stent placement Pre operative antiplatelets with post Pre operative antiplatelets with post
procedure heparin Tirofiban procedure heparin Tirofiban followed by aspirin and clopidogrel followed by aspirin and clopidogrel were usedwere used
IAT may be a treatment option for selected patients IAT may be a treatment option for selected patients Possible selection criteria include Possible selection criteria include
presentation between 3 and 6 hours from symptom onsetpresentation between 3 and 6 hours from symptom onset major cerebral artery occlusion major cerebral artery occlusion severe neurologic deficits severe neurologic deficits high risk of systemic hemorrhage with IV rt-PA (eg recent high risk of systemic hemorrhage with IV rt-PA (eg recent
surgery) surgery) The MERCI (Mechanical Embolus Removal in Cerebral The MERCI (Mechanical Embolus Removal in Cerebral
Ischemia) retrievalIschemia) retrieval system system
Has been FDA-approved for recanalizing acutely occluded Has been FDA-approved for recanalizing acutely occluded cerebral arteries cerebral arteries
In the Multi-MERCI study patients who did not improve In the Multi-MERCI study patients who did not improve immediately after IV rt-PA underwent mechanical immediately after IV rt-PA underwent mechanical embolectomy within 8 hours of symptom onset embolectomy within 8 hours of symptom onset
Partial or complete recanalization occurred in 74 of Partial or complete recanalization occurred in 74 of patientspatients
with a symptomatic intracerebral hemorrhage (sICH) rate of with a symptomatic intracerebral hemorrhage (sICH) rate of 67 67
Mechanical embolectomy with the MERCI retriever may be a Mechanical embolectomy with the MERCI retriever may be a feasible and safe option for patients after IV rt-PAfeasible and safe option for patients after IV rt-PA
Penumbra stroke systemPenumbra stroke system This device combines two methods of clot This device combines two methods of clot
extraction aspiration and mechanical extraction aspiration and mechanical extraction extraction
First the clot is aspirated then a thrombus First the clot is aspirated then a thrombus removal ring can be used if necessary to removal ring can be used if necessary to remove remaining clot remove remaining clot
successful recanalizing 82successful recanalizing 82 Bridging therapyBridging therapy
06 mgkg IV rt-PA followed by IAT with IA rt-06 mgkg IV rt-PA followed by IAT with IA rt-PA (up to 20 mg)PA (up to 20 mg)
achieved a higher recanalization rateachieved a higher recanalization rate
Criteria for thrombolysis with rTPACriteria for thrombolysis with rTPA
Inclusion criteriaInclusion criteria Clinical signs and symptoms consistent with ischemic Clinical signs and symptoms consistent with ischemic
strokestroke Patient last seen normal within 3 hoursPatient last seen normal within 3 hours Measurable neurologic deficitMeasurable neurologic deficit
Exclusion criteriaExclusion criteria Any hemorrhage on neuroimaging (CT or MRI)Any hemorrhage on neuroimaging (CT or MRI) Symptoms suggestive of subarachnoid hemorrhageSymptoms suggestive of subarachnoid hemorrhage Seizure at stroke onset that is thought to contribute to Seizure at stroke onset that is thought to contribute to
neurologic deficitneurologic deficit Hypodensity greater than one third cerebral hemisphere Hypodensity greater than one third cerebral hemisphere
on CTon CT SBP greater than 185 mm Hg or DBP greater than 110 SBP greater than 185 mm Hg or DBP greater than 110
mm Hgmm Hg International normalized ratio (INR) greater than 17International normalized ratio (INR) greater than 17
Ischemic Stroke Ischemic Stroke Treatment ndash 2006Treatment ndash 2006
IV tissue plasminogen activator (tPA)IV tissue plasminogen activator (tPA) ndash ndash Only FDA-approved acute stroke drugOnly FDA-approved acute stroke drug ndash ndash 3 hour treatment window3 hour treatment window
MERCI - Concentric clot retrieval MERCI - Concentric clot retrieval devicedevice ndash ndash Rescue therapy - approved 2004Rescue therapy - approved 2004 ndash ndash Device approval (not outcomes-based)Device approval (not outcomes-based)
Off label approachesOff label approaches ndash ndash IV tPA after 3 hoursIV tPA after 3 hours ndash ndash IV-IA tPA sequential strategiesIV-IA tPA sequential strategies ndash ndash IA tPA clot angioplasty fragmentationIA tPA clot angioplasty fragmentation ndash ndash Ultrasound-assisted tPA lysisUltrasound-assisted tPA lysis
rt-PA Trials NINDSrt-PA Trials NINDS
Acute stroke - 624 patientsAcute stroke - 624 patients Treat within 3 hrsTreat within 3 hrs Intravenous 09 mgkg rt-PA vs placeboIntravenous 09 mgkg rt-PA vs placebo Hemorrhage 64 tPA 06 placeboHemorrhage 64 tPA 06 placebo Neurologic recovery better with tPA 30 Neurologic recovery better with tPA 30
more like to have minimal or no disabilitymore like to have minimal or no disability
First proven approved treatment for First proven approved treatment for strokestroke
Limitations of tPALimitations of tPA Only 4 of acute strokes receive tPAOnly 4 of acute strokes receive tPA (Kleindorfer et al Stroke 2004 35 e27-e29)(Kleindorfer et al Stroke 2004 35 e27-e29)
Only 22 of patients present within 3 hoursOnly 22 of patients present within 3 hours1048707 1048707 51 of these ineligible due to51 of these ineligible due to
bull bull Mild severityMild severity bull bull Medical or surgical historyMedical or surgical history bull bull Blood testsBlood tests
Sustained recanalization only 13Sustained recanalization only 13 (Alexandrov et al NEJM 2004 351 2170-8)(Alexandrov et al NEJM 2004 351 2170-8)
Concern for hemorrhageConcern for hemorrhage tPA potentiates apoptotic injury tPA potentiates apoptotic injury (Liu et al Nature Med 2004 101379-83)(Liu et al Nature Med 2004 101379-83)
PROACT II IA Lysis TrialPROACT II IA Lysis Trial Baseline 24 hours 8 days
Baseline 60 minutes 120 minutes
9mg IAProurokinase
Desmoteplase Trials DEDAS Desmoteplase Trials DEDAS DIASDIAS
Trial OverviewTrial Overview Double blind randomized placebo Double blind randomized placebo
controlled trialscontrolled trials IV delivery 3-9 hour time windowIV delivery 3-9 hour time window Plasminogen activator ndash from Plasminogen activator ndash from vampire bat vampire bat
salivasaliva Selection based on PWI-DWI MismatchSelection based on PWI-DWI Mismatch
MRI InclusionMRI Inclusion PWI defect at least 2 cm AND ~20 larger PWI defect at least 2 cm AND ~20 larger
than DWIthan DWI PWI should be obvious even visible on PWI should be obvious even visible on
raw imagesraw imagesMRI ExclusionMRI Exclusion
DWI gt 13 MCADWI gt 13 MCA MRA ICA occlusionMRA ICA occlusion
Desmoteplase ndash DIAS Desmoteplase ndash DIAS ResultsResults
Mechanical Thrombolysis Mechanical Thrombolysis devicesdevices
mechanical thrombolysis potentially extends the treatment mechanical thrombolysis potentially extends the treatment window because they act promptly at the site of the thrombuswindow because they act promptly at the site of the thrombus
The devices can retrieve large clots that pharmaceutical agents The devices can retrieve large clots that pharmaceutical agents may not successfully lysemay not successfully lyse
Patients treated with IV tPA may be considered for treatment of Patients treated with IV tPA may be considered for treatment of residual clot with some of these devicesresidual clot with some of these devices
suction-creating saline jets suction-creating saline jets laser energy ultrasound laser energy ultrasound a corkscrew apparatus to treat strokesa corkscrew apparatus to treat strokes The AngioJet systemThe AngioJet system uses saline jets that are directed back into the catheter to uses saline jets that are directed back into the catheter to
create a low-pressure zone around the catheter tip inducing create a low-pressure zone around the catheter tip inducing suction suction
The clot is pulled into the exhaust lumen and removed from the The clot is pulled into the exhaust lumen and removed from the vessel Although US Food and Drug Administration (FDA) has vessel Although US Food and Drug Administration (FDA) has approved this device for use in arteriovenous dialysis grafts and approved this device for use in arteriovenous dialysis grafts and fistulae and for the treatment of coronary arteries saphenous fistulae and for the treatment of coronary arteries saphenous vein grafts and peripheral vessels clinical trials for the vein grafts and peripheral vessels clinical trials for the treatment of acute stroke are no longer in progress treatment of acute stroke are no longer in progress
Most devices are used in cerebral vessels that 2-5 mm
The Latis laser device The Latis laser device used laser energy to ablate clots used laser energy to ablate clots Arteries 2-5 mm in diameter could be Arteries 2-5 mm in diameter could be
treated including the ICA M1 or M2 treated including the ICA M1 or M2 branch of the MCA A1 branch of the branch of the MCA A1 branch of the anterior cerebral artery (ACA) basilar anterior cerebral artery (ACA) basilar artery posterior cerebral artery (PCA) artery posterior cerebral artery (PCA) and vertebral and vertebral
Patients could receive treatment as late Patients could receive treatment as late as 8 hours after symptom onset in the as 8 hours after symptom onset in the anterior circulation and within 24 hours in anterior circulation and within 24 hours in the posterior circulation the posterior circulation
Endovascular Photo Acoustic Endovascular Photo Acoustic Recanalization (EPAR) Recanalization (EPAR)
A laser power source generated energy for the A laser power source generated energy for the systemsystem
The energy was delivered by means of The energy was delivered by means of fiberoptics to the tip of the catheter at the fiberoptics to the tip of the catheter at the treatment sitetreatment site
Absorption of laser light by darkly pigmented Absorption of laser light by darkly pigmented materials (ie the clot) occurred inside the 1-mm materials (ie the clot) occurred inside the 1-mm catheter tipcatheter tip
the system was designed to minimize scattering the system was designed to minimize scattering of laser light of laser light
Absorption converted photo energy to acoustic Absorption converted photo energy to acoustic energy which then emulsified the clot inside the energy which then emulsified the clot inside the catheter tip catheter tip
EKOS ultrasound( the EKOS ultrasound( the Ultrasound Thrombolytic Ultrasound Thrombolytic
Infusion Catheter) Infusion Catheter) combines the use of a distal ultrasound transducer with combines the use of a distal ultrasound transducer with
infusion of a thrombolytic agent through the infusion of a thrombolytic agent through the microcathetermicrocatheter
Ultrasound changes the structure of the clot to Ultrasound changes the structure of the clot to temporarily increase its permeability while providing an temporarily increase its permeability while providing an acoustic pressure gradient to move the drug into the clot acoustic pressure gradient to move the drug into the clot to speed its dissolution to speed its dissolution
The EKOS catheter is placed in the proximal portion of the The EKOS catheter is placed in the proximal portion of the clot clot
After a 2-mg bolus of tPA was injected through the After a 2-mg bolus of tPA was injected through the catheter catheter
the patient received a continuous infusion of IA tPA 03 the patient received a continuous infusion of IA tPA 03 mgmin to a maximum of 20 mg and simultaneous mgmin to a maximum of 20 mg and simultaneous ultrasound transmission for as long as 60 minutes ultrasound transmission for as long as 60 minutes
One patient was treated with a total of 4 units of One patient was treated with a total of 4 units of recombinant reteplase (Retavase) hand-injected over 60 recombinant reteplase (Retavase) hand-injected over 60 minutes minutes
Penumbra system Penumbra system The Penumbra system (Penumbra Inc) provides a dual The Penumbra system (Penumbra Inc) provides a dual
approach to clot extraction using aspiration followed by approach to clot extraction using aspiration followed by clot retrieval with a ring device if needed clot retrieval with a ring device if needed
Mechanical Embolus Removal in Cerebral Ischemia Mechanical Embolus Removal in Cerebral Ischemia (MERCI)(MERCI)
a corkscrew-like apparatus to remove blood clots from a corkscrew-like apparatus to remove blood clots from the brain in patients experiencing an ischemic stroke the brain in patients experiencing an ischemic stroke
The corkscrew itself resides in the catheter tip which The corkscrew itself resides in the catheter tip which shields it from the wall of the vessel until it is ready to be shields it from the wall of the vessel until it is ready to be burrowed into the clot Once lodged in the clot the device burrowed into the clot Once lodged in the clot the device and clot are withdrawn from the vessel and clot are withdrawn from the vessel
Snarelike devicesSnarelike devices Snares such as the Neuronet snare (Guidant Snares such as the Neuronet snare (Guidant
Endovascular Santa Clara CA) have been developed Endovascular Santa Clara CA) have been developed specifically for use in the treatment of strokes specifically for use in the treatment of strokes
These devices are simple in design and do not require the These devices are simple in design and do not require the clot to be amenable to emulsification clot to be amenable to emulsification
X-Sizer deviceX-Sizer device a device with small moving blades at the a device with small moving blades at the
catheter tip catheter tip This device the X-Sizer device (EndiCor Medical This device the X-Sizer device (EndiCor Medical
San Clemente CA) can be used to excise the San Clemente CA) can be used to excise the thrombus and aspirate it thrombus and aspirate it
The device was being evaluated in randomized The device was being evaluated in randomized studies of coronary vessels and in a registry of studies of coronary vessels and in a registry of patients with acute myocardial infarctionpatients with acute myocardial infarction
Although the manufacturer had modified the Although the manufacturer had modified the device for use in cerebral vessels a safety and device for use in cerebral vessels a safety and feasibility study was indefinitely suspended after feasibility study was indefinitely suspended after only 1 patient was treated with the device in only 1 patient was treated with the device in Europe Europe
Suction thrombectomySuction thrombectomy This method of mechanical thrombolysis is one of the This method of mechanical thrombolysis is one of the
simplestsimplest In this readily available technique suction is applied with In this readily available technique suction is applied with
a syringe to remove thrombus in the ICA a syringe to remove thrombus in the ICA It requires no other devicesIt requires no other devices A catheter with a large inner diameter (Brite Tip Cordis A catheter with a large inner diameter (Brite Tip Cordis
Corporation Miami FL) was placed in the symptomatic Corporation Miami FL) was placed in the symptomatic vessel and navigated over a guidewire into the thrombusvessel and navigated over a guidewire into the thrombus
A 60-mL syringe was used to aspirate the thrombus A 60-mL syringe was used to aspirate the thrombus Each patient required angioplasty and stenting of carotid Each patient required angioplasty and stenting of carotid
bifurcation stenosis and received daily aspirin and bifurcation stenosis and received daily aspirin and ticlopidine after the procedure No complications ticlopidine after the procedure No complications occurred occurred
Summary Acute Stroke Summary Acute Stroke ImagingImaging
PhysiologyPhysiology importance collaterals importance collaterals
ndash ndashGrowing role for perfusion Growing role for perfusion assessmentassessment
tPAtPA guidelines amp limitations guidelines amp limitations Signs on CT amp MRSigns on CT amp MR follow physiology follow physiology Stroke trialsStroke trials PWI-DWI mismatch PWI-DWI mismatch
ndash ndashTreat based on physiology not timeTreat based on physiology not time ProtocolsProtocols should be fast and should be fast and
comprehensivecomprehensive
Rakesh 34yrsMRakesh 34yrsM Left SFA pseudoaneurysm with Left SFA pseudoaneurysm with
Covered stent placementCovered stent placement Pre operative antiplatelets with post Pre operative antiplatelets with post
procedure heparin Tirofiban procedure heparin Tirofiban followed by aspirin and clopidogrel followed by aspirin and clopidogrel were usedwere used
IAT may be a treatment option for selected patients IAT may be a treatment option for selected patients Possible selection criteria include Possible selection criteria include
presentation between 3 and 6 hours from symptom onsetpresentation between 3 and 6 hours from symptom onset major cerebral artery occlusion major cerebral artery occlusion severe neurologic deficits severe neurologic deficits high risk of systemic hemorrhage with IV rt-PA (eg recent high risk of systemic hemorrhage with IV rt-PA (eg recent
surgery) surgery) The MERCI (Mechanical Embolus Removal in Cerebral The MERCI (Mechanical Embolus Removal in Cerebral
Ischemia) retrievalIschemia) retrieval system system
Has been FDA-approved for recanalizing acutely occluded Has been FDA-approved for recanalizing acutely occluded cerebral arteries cerebral arteries
In the Multi-MERCI study patients who did not improve In the Multi-MERCI study patients who did not improve immediately after IV rt-PA underwent mechanical immediately after IV rt-PA underwent mechanical embolectomy within 8 hours of symptom onset embolectomy within 8 hours of symptom onset
Partial or complete recanalization occurred in 74 of Partial or complete recanalization occurred in 74 of patientspatients
with a symptomatic intracerebral hemorrhage (sICH) rate of with a symptomatic intracerebral hemorrhage (sICH) rate of 67 67
Mechanical embolectomy with the MERCI retriever may be a Mechanical embolectomy with the MERCI retriever may be a feasible and safe option for patients after IV rt-PAfeasible and safe option for patients after IV rt-PA
Penumbra stroke systemPenumbra stroke system This device combines two methods of clot This device combines two methods of clot
extraction aspiration and mechanical extraction aspiration and mechanical extraction extraction
First the clot is aspirated then a thrombus First the clot is aspirated then a thrombus removal ring can be used if necessary to removal ring can be used if necessary to remove remaining clot remove remaining clot
successful recanalizing 82successful recanalizing 82 Bridging therapyBridging therapy
06 mgkg IV rt-PA followed by IAT with IA rt-06 mgkg IV rt-PA followed by IAT with IA rt-PA (up to 20 mg)PA (up to 20 mg)
achieved a higher recanalization rateachieved a higher recanalization rate
Criteria for thrombolysis with rTPACriteria for thrombolysis with rTPA
Inclusion criteriaInclusion criteria Clinical signs and symptoms consistent with ischemic Clinical signs and symptoms consistent with ischemic
strokestroke Patient last seen normal within 3 hoursPatient last seen normal within 3 hours Measurable neurologic deficitMeasurable neurologic deficit
Exclusion criteriaExclusion criteria Any hemorrhage on neuroimaging (CT or MRI)Any hemorrhage on neuroimaging (CT or MRI) Symptoms suggestive of subarachnoid hemorrhageSymptoms suggestive of subarachnoid hemorrhage Seizure at stroke onset that is thought to contribute to Seizure at stroke onset that is thought to contribute to
neurologic deficitneurologic deficit Hypodensity greater than one third cerebral hemisphere Hypodensity greater than one third cerebral hemisphere
on CTon CT SBP greater than 185 mm Hg or DBP greater than 110 SBP greater than 185 mm Hg or DBP greater than 110
mm Hgmm Hg International normalized ratio (INR) greater than 17International normalized ratio (INR) greater than 17
Ischemic Stroke Ischemic Stroke Treatment ndash 2006Treatment ndash 2006
IV tissue plasminogen activator (tPA)IV tissue plasminogen activator (tPA) ndash ndash Only FDA-approved acute stroke drugOnly FDA-approved acute stroke drug ndash ndash 3 hour treatment window3 hour treatment window
MERCI - Concentric clot retrieval MERCI - Concentric clot retrieval devicedevice ndash ndash Rescue therapy - approved 2004Rescue therapy - approved 2004 ndash ndash Device approval (not outcomes-based)Device approval (not outcomes-based)
Off label approachesOff label approaches ndash ndash IV tPA after 3 hoursIV tPA after 3 hours ndash ndash IV-IA tPA sequential strategiesIV-IA tPA sequential strategies ndash ndash IA tPA clot angioplasty fragmentationIA tPA clot angioplasty fragmentation ndash ndash Ultrasound-assisted tPA lysisUltrasound-assisted tPA lysis
rt-PA Trials NINDSrt-PA Trials NINDS
Acute stroke - 624 patientsAcute stroke - 624 patients Treat within 3 hrsTreat within 3 hrs Intravenous 09 mgkg rt-PA vs placeboIntravenous 09 mgkg rt-PA vs placebo Hemorrhage 64 tPA 06 placeboHemorrhage 64 tPA 06 placebo Neurologic recovery better with tPA 30 Neurologic recovery better with tPA 30
more like to have minimal or no disabilitymore like to have minimal or no disability
First proven approved treatment for First proven approved treatment for strokestroke
Limitations of tPALimitations of tPA Only 4 of acute strokes receive tPAOnly 4 of acute strokes receive tPA (Kleindorfer et al Stroke 2004 35 e27-e29)(Kleindorfer et al Stroke 2004 35 e27-e29)
Only 22 of patients present within 3 hoursOnly 22 of patients present within 3 hours1048707 1048707 51 of these ineligible due to51 of these ineligible due to
bull bull Mild severityMild severity bull bull Medical or surgical historyMedical or surgical history bull bull Blood testsBlood tests
Sustained recanalization only 13Sustained recanalization only 13 (Alexandrov et al NEJM 2004 351 2170-8)(Alexandrov et al NEJM 2004 351 2170-8)
Concern for hemorrhageConcern for hemorrhage tPA potentiates apoptotic injury tPA potentiates apoptotic injury (Liu et al Nature Med 2004 101379-83)(Liu et al Nature Med 2004 101379-83)
PROACT II IA Lysis TrialPROACT II IA Lysis Trial Baseline 24 hours 8 days
Baseline 60 minutes 120 minutes
9mg IAProurokinase
Desmoteplase Trials DEDAS Desmoteplase Trials DEDAS DIASDIAS
Trial OverviewTrial Overview Double blind randomized placebo Double blind randomized placebo
controlled trialscontrolled trials IV delivery 3-9 hour time windowIV delivery 3-9 hour time window Plasminogen activator ndash from Plasminogen activator ndash from vampire bat vampire bat
salivasaliva Selection based on PWI-DWI MismatchSelection based on PWI-DWI Mismatch
MRI InclusionMRI Inclusion PWI defect at least 2 cm AND ~20 larger PWI defect at least 2 cm AND ~20 larger
than DWIthan DWI PWI should be obvious even visible on PWI should be obvious even visible on
raw imagesraw imagesMRI ExclusionMRI Exclusion
DWI gt 13 MCADWI gt 13 MCA MRA ICA occlusionMRA ICA occlusion
Desmoteplase ndash DIAS Desmoteplase ndash DIAS ResultsResults
Mechanical Thrombolysis Mechanical Thrombolysis devicesdevices
mechanical thrombolysis potentially extends the treatment mechanical thrombolysis potentially extends the treatment window because they act promptly at the site of the thrombuswindow because they act promptly at the site of the thrombus
The devices can retrieve large clots that pharmaceutical agents The devices can retrieve large clots that pharmaceutical agents may not successfully lysemay not successfully lyse
Patients treated with IV tPA may be considered for treatment of Patients treated with IV tPA may be considered for treatment of residual clot with some of these devicesresidual clot with some of these devices
suction-creating saline jets suction-creating saline jets laser energy ultrasound laser energy ultrasound a corkscrew apparatus to treat strokesa corkscrew apparatus to treat strokes The AngioJet systemThe AngioJet system uses saline jets that are directed back into the catheter to uses saline jets that are directed back into the catheter to
create a low-pressure zone around the catheter tip inducing create a low-pressure zone around the catheter tip inducing suction suction
The clot is pulled into the exhaust lumen and removed from the The clot is pulled into the exhaust lumen and removed from the vessel Although US Food and Drug Administration (FDA) has vessel Although US Food and Drug Administration (FDA) has approved this device for use in arteriovenous dialysis grafts and approved this device for use in arteriovenous dialysis grafts and fistulae and for the treatment of coronary arteries saphenous fistulae and for the treatment of coronary arteries saphenous vein grafts and peripheral vessels clinical trials for the vein grafts and peripheral vessels clinical trials for the treatment of acute stroke are no longer in progress treatment of acute stroke are no longer in progress
Most devices are used in cerebral vessels that 2-5 mm
The Latis laser device The Latis laser device used laser energy to ablate clots used laser energy to ablate clots Arteries 2-5 mm in diameter could be Arteries 2-5 mm in diameter could be
treated including the ICA M1 or M2 treated including the ICA M1 or M2 branch of the MCA A1 branch of the branch of the MCA A1 branch of the anterior cerebral artery (ACA) basilar anterior cerebral artery (ACA) basilar artery posterior cerebral artery (PCA) artery posterior cerebral artery (PCA) and vertebral and vertebral
Patients could receive treatment as late Patients could receive treatment as late as 8 hours after symptom onset in the as 8 hours after symptom onset in the anterior circulation and within 24 hours in anterior circulation and within 24 hours in the posterior circulation the posterior circulation
Endovascular Photo Acoustic Endovascular Photo Acoustic Recanalization (EPAR) Recanalization (EPAR)
A laser power source generated energy for the A laser power source generated energy for the systemsystem
The energy was delivered by means of The energy was delivered by means of fiberoptics to the tip of the catheter at the fiberoptics to the tip of the catheter at the treatment sitetreatment site
Absorption of laser light by darkly pigmented Absorption of laser light by darkly pigmented materials (ie the clot) occurred inside the 1-mm materials (ie the clot) occurred inside the 1-mm catheter tipcatheter tip
the system was designed to minimize scattering the system was designed to minimize scattering of laser light of laser light
Absorption converted photo energy to acoustic Absorption converted photo energy to acoustic energy which then emulsified the clot inside the energy which then emulsified the clot inside the catheter tip catheter tip
EKOS ultrasound( the EKOS ultrasound( the Ultrasound Thrombolytic Ultrasound Thrombolytic
Infusion Catheter) Infusion Catheter) combines the use of a distal ultrasound transducer with combines the use of a distal ultrasound transducer with
infusion of a thrombolytic agent through the infusion of a thrombolytic agent through the microcathetermicrocatheter
Ultrasound changes the structure of the clot to Ultrasound changes the structure of the clot to temporarily increase its permeability while providing an temporarily increase its permeability while providing an acoustic pressure gradient to move the drug into the clot acoustic pressure gradient to move the drug into the clot to speed its dissolution to speed its dissolution
The EKOS catheter is placed in the proximal portion of the The EKOS catheter is placed in the proximal portion of the clot clot
After a 2-mg bolus of tPA was injected through the After a 2-mg bolus of tPA was injected through the catheter catheter
the patient received a continuous infusion of IA tPA 03 the patient received a continuous infusion of IA tPA 03 mgmin to a maximum of 20 mg and simultaneous mgmin to a maximum of 20 mg and simultaneous ultrasound transmission for as long as 60 minutes ultrasound transmission for as long as 60 minutes
One patient was treated with a total of 4 units of One patient was treated with a total of 4 units of recombinant reteplase (Retavase) hand-injected over 60 recombinant reteplase (Retavase) hand-injected over 60 minutes minutes
Penumbra system Penumbra system The Penumbra system (Penumbra Inc) provides a dual The Penumbra system (Penumbra Inc) provides a dual
approach to clot extraction using aspiration followed by approach to clot extraction using aspiration followed by clot retrieval with a ring device if needed clot retrieval with a ring device if needed
Mechanical Embolus Removal in Cerebral Ischemia Mechanical Embolus Removal in Cerebral Ischemia (MERCI)(MERCI)
a corkscrew-like apparatus to remove blood clots from a corkscrew-like apparatus to remove blood clots from the brain in patients experiencing an ischemic stroke the brain in patients experiencing an ischemic stroke
The corkscrew itself resides in the catheter tip which The corkscrew itself resides in the catheter tip which shields it from the wall of the vessel until it is ready to be shields it from the wall of the vessel until it is ready to be burrowed into the clot Once lodged in the clot the device burrowed into the clot Once lodged in the clot the device and clot are withdrawn from the vessel and clot are withdrawn from the vessel
Snarelike devicesSnarelike devices Snares such as the Neuronet snare (Guidant Snares such as the Neuronet snare (Guidant
Endovascular Santa Clara CA) have been developed Endovascular Santa Clara CA) have been developed specifically for use in the treatment of strokes specifically for use in the treatment of strokes
These devices are simple in design and do not require the These devices are simple in design and do not require the clot to be amenable to emulsification clot to be amenable to emulsification
X-Sizer deviceX-Sizer device a device with small moving blades at the a device with small moving blades at the
catheter tip catheter tip This device the X-Sizer device (EndiCor Medical This device the X-Sizer device (EndiCor Medical
San Clemente CA) can be used to excise the San Clemente CA) can be used to excise the thrombus and aspirate it thrombus and aspirate it
The device was being evaluated in randomized The device was being evaluated in randomized studies of coronary vessels and in a registry of studies of coronary vessels and in a registry of patients with acute myocardial infarctionpatients with acute myocardial infarction
Although the manufacturer had modified the Although the manufacturer had modified the device for use in cerebral vessels a safety and device for use in cerebral vessels a safety and feasibility study was indefinitely suspended after feasibility study was indefinitely suspended after only 1 patient was treated with the device in only 1 patient was treated with the device in Europe Europe
Suction thrombectomySuction thrombectomy This method of mechanical thrombolysis is one of the This method of mechanical thrombolysis is one of the
simplestsimplest In this readily available technique suction is applied with In this readily available technique suction is applied with
a syringe to remove thrombus in the ICA a syringe to remove thrombus in the ICA It requires no other devicesIt requires no other devices A catheter with a large inner diameter (Brite Tip Cordis A catheter with a large inner diameter (Brite Tip Cordis
Corporation Miami FL) was placed in the symptomatic Corporation Miami FL) was placed in the symptomatic vessel and navigated over a guidewire into the thrombusvessel and navigated over a guidewire into the thrombus
A 60-mL syringe was used to aspirate the thrombus A 60-mL syringe was used to aspirate the thrombus Each patient required angioplasty and stenting of carotid Each patient required angioplasty and stenting of carotid
bifurcation stenosis and received daily aspirin and bifurcation stenosis and received daily aspirin and ticlopidine after the procedure No complications ticlopidine after the procedure No complications occurred occurred
Summary Acute Stroke Summary Acute Stroke ImagingImaging
PhysiologyPhysiology importance collaterals importance collaterals
ndash ndashGrowing role for perfusion Growing role for perfusion assessmentassessment
tPAtPA guidelines amp limitations guidelines amp limitations Signs on CT amp MRSigns on CT amp MR follow physiology follow physiology Stroke trialsStroke trials PWI-DWI mismatch PWI-DWI mismatch
ndash ndashTreat based on physiology not timeTreat based on physiology not time ProtocolsProtocols should be fast and should be fast and
comprehensivecomprehensive
IAT may be a treatment option for selected patients IAT may be a treatment option for selected patients Possible selection criteria include Possible selection criteria include
presentation between 3 and 6 hours from symptom onsetpresentation between 3 and 6 hours from symptom onset major cerebral artery occlusion major cerebral artery occlusion severe neurologic deficits severe neurologic deficits high risk of systemic hemorrhage with IV rt-PA (eg recent high risk of systemic hemorrhage with IV rt-PA (eg recent
surgery) surgery) The MERCI (Mechanical Embolus Removal in Cerebral The MERCI (Mechanical Embolus Removal in Cerebral
Ischemia) retrievalIschemia) retrieval system system
Has been FDA-approved for recanalizing acutely occluded Has been FDA-approved for recanalizing acutely occluded cerebral arteries cerebral arteries
In the Multi-MERCI study patients who did not improve In the Multi-MERCI study patients who did not improve immediately after IV rt-PA underwent mechanical immediately after IV rt-PA underwent mechanical embolectomy within 8 hours of symptom onset embolectomy within 8 hours of symptom onset
Partial or complete recanalization occurred in 74 of Partial or complete recanalization occurred in 74 of patientspatients
with a symptomatic intracerebral hemorrhage (sICH) rate of with a symptomatic intracerebral hemorrhage (sICH) rate of 67 67
Mechanical embolectomy with the MERCI retriever may be a Mechanical embolectomy with the MERCI retriever may be a feasible and safe option for patients after IV rt-PAfeasible and safe option for patients after IV rt-PA
Penumbra stroke systemPenumbra stroke system This device combines two methods of clot This device combines two methods of clot
extraction aspiration and mechanical extraction aspiration and mechanical extraction extraction
First the clot is aspirated then a thrombus First the clot is aspirated then a thrombus removal ring can be used if necessary to removal ring can be used if necessary to remove remaining clot remove remaining clot
successful recanalizing 82successful recanalizing 82 Bridging therapyBridging therapy
06 mgkg IV rt-PA followed by IAT with IA rt-06 mgkg IV rt-PA followed by IAT with IA rt-PA (up to 20 mg)PA (up to 20 mg)
achieved a higher recanalization rateachieved a higher recanalization rate
Criteria for thrombolysis with rTPACriteria for thrombolysis with rTPA
Inclusion criteriaInclusion criteria Clinical signs and symptoms consistent with ischemic Clinical signs and symptoms consistent with ischemic
strokestroke Patient last seen normal within 3 hoursPatient last seen normal within 3 hours Measurable neurologic deficitMeasurable neurologic deficit
Exclusion criteriaExclusion criteria Any hemorrhage on neuroimaging (CT or MRI)Any hemorrhage on neuroimaging (CT or MRI) Symptoms suggestive of subarachnoid hemorrhageSymptoms suggestive of subarachnoid hemorrhage Seizure at stroke onset that is thought to contribute to Seizure at stroke onset that is thought to contribute to
neurologic deficitneurologic deficit Hypodensity greater than one third cerebral hemisphere Hypodensity greater than one third cerebral hemisphere
on CTon CT SBP greater than 185 mm Hg or DBP greater than 110 SBP greater than 185 mm Hg or DBP greater than 110
mm Hgmm Hg International normalized ratio (INR) greater than 17International normalized ratio (INR) greater than 17
Ischemic Stroke Ischemic Stroke Treatment ndash 2006Treatment ndash 2006
IV tissue plasminogen activator (tPA)IV tissue plasminogen activator (tPA) ndash ndash Only FDA-approved acute stroke drugOnly FDA-approved acute stroke drug ndash ndash 3 hour treatment window3 hour treatment window
MERCI - Concentric clot retrieval MERCI - Concentric clot retrieval devicedevice ndash ndash Rescue therapy - approved 2004Rescue therapy - approved 2004 ndash ndash Device approval (not outcomes-based)Device approval (not outcomes-based)
Off label approachesOff label approaches ndash ndash IV tPA after 3 hoursIV tPA after 3 hours ndash ndash IV-IA tPA sequential strategiesIV-IA tPA sequential strategies ndash ndash IA tPA clot angioplasty fragmentationIA tPA clot angioplasty fragmentation ndash ndash Ultrasound-assisted tPA lysisUltrasound-assisted tPA lysis
rt-PA Trials NINDSrt-PA Trials NINDS
Acute stroke - 624 patientsAcute stroke - 624 patients Treat within 3 hrsTreat within 3 hrs Intravenous 09 mgkg rt-PA vs placeboIntravenous 09 mgkg rt-PA vs placebo Hemorrhage 64 tPA 06 placeboHemorrhage 64 tPA 06 placebo Neurologic recovery better with tPA 30 Neurologic recovery better with tPA 30
more like to have minimal or no disabilitymore like to have minimal or no disability
First proven approved treatment for First proven approved treatment for strokestroke
Limitations of tPALimitations of tPA Only 4 of acute strokes receive tPAOnly 4 of acute strokes receive tPA (Kleindorfer et al Stroke 2004 35 e27-e29)(Kleindorfer et al Stroke 2004 35 e27-e29)
Only 22 of patients present within 3 hoursOnly 22 of patients present within 3 hours1048707 1048707 51 of these ineligible due to51 of these ineligible due to
bull bull Mild severityMild severity bull bull Medical or surgical historyMedical or surgical history bull bull Blood testsBlood tests
Sustained recanalization only 13Sustained recanalization only 13 (Alexandrov et al NEJM 2004 351 2170-8)(Alexandrov et al NEJM 2004 351 2170-8)
Concern for hemorrhageConcern for hemorrhage tPA potentiates apoptotic injury tPA potentiates apoptotic injury (Liu et al Nature Med 2004 101379-83)(Liu et al Nature Med 2004 101379-83)
PROACT II IA Lysis TrialPROACT II IA Lysis Trial Baseline 24 hours 8 days
Baseline 60 minutes 120 minutes
9mg IAProurokinase
Desmoteplase Trials DEDAS Desmoteplase Trials DEDAS DIASDIAS
Trial OverviewTrial Overview Double blind randomized placebo Double blind randomized placebo
controlled trialscontrolled trials IV delivery 3-9 hour time windowIV delivery 3-9 hour time window Plasminogen activator ndash from Plasminogen activator ndash from vampire bat vampire bat
salivasaliva Selection based on PWI-DWI MismatchSelection based on PWI-DWI Mismatch
MRI InclusionMRI Inclusion PWI defect at least 2 cm AND ~20 larger PWI defect at least 2 cm AND ~20 larger
than DWIthan DWI PWI should be obvious even visible on PWI should be obvious even visible on
raw imagesraw imagesMRI ExclusionMRI Exclusion
DWI gt 13 MCADWI gt 13 MCA MRA ICA occlusionMRA ICA occlusion
Desmoteplase ndash DIAS Desmoteplase ndash DIAS ResultsResults
Mechanical Thrombolysis Mechanical Thrombolysis devicesdevices
mechanical thrombolysis potentially extends the treatment mechanical thrombolysis potentially extends the treatment window because they act promptly at the site of the thrombuswindow because they act promptly at the site of the thrombus
The devices can retrieve large clots that pharmaceutical agents The devices can retrieve large clots that pharmaceutical agents may not successfully lysemay not successfully lyse
Patients treated with IV tPA may be considered for treatment of Patients treated with IV tPA may be considered for treatment of residual clot with some of these devicesresidual clot with some of these devices
suction-creating saline jets suction-creating saline jets laser energy ultrasound laser energy ultrasound a corkscrew apparatus to treat strokesa corkscrew apparatus to treat strokes The AngioJet systemThe AngioJet system uses saline jets that are directed back into the catheter to uses saline jets that are directed back into the catheter to
create a low-pressure zone around the catheter tip inducing create a low-pressure zone around the catheter tip inducing suction suction
The clot is pulled into the exhaust lumen and removed from the The clot is pulled into the exhaust lumen and removed from the vessel Although US Food and Drug Administration (FDA) has vessel Although US Food and Drug Administration (FDA) has approved this device for use in arteriovenous dialysis grafts and approved this device for use in arteriovenous dialysis grafts and fistulae and for the treatment of coronary arteries saphenous fistulae and for the treatment of coronary arteries saphenous vein grafts and peripheral vessels clinical trials for the vein grafts and peripheral vessels clinical trials for the treatment of acute stroke are no longer in progress treatment of acute stroke are no longer in progress
Most devices are used in cerebral vessels that 2-5 mm
The Latis laser device The Latis laser device used laser energy to ablate clots used laser energy to ablate clots Arteries 2-5 mm in diameter could be Arteries 2-5 mm in diameter could be
treated including the ICA M1 or M2 treated including the ICA M1 or M2 branch of the MCA A1 branch of the branch of the MCA A1 branch of the anterior cerebral artery (ACA) basilar anterior cerebral artery (ACA) basilar artery posterior cerebral artery (PCA) artery posterior cerebral artery (PCA) and vertebral and vertebral
Patients could receive treatment as late Patients could receive treatment as late as 8 hours after symptom onset in the as 8 hours after symptom onset in the anterior circulation and within 24 hours in anterior circulation and within 24 hours in the posterior circulation the posterior circulation
Endovascular Photo Acoustic Endovascular Photo Acoustic Recanalization (EPAR) Recanalization (EPAR)
A laser power source generated energy for the A laser power source generated energy for the systemsystem
The energy was delivered by means of The energy was delivered by means of fiberoptics to the tip of the catheter at the fiberoptics to the tip of the catheter at the treatment sitetreatment site
Absorption of laser light by darkly pigmented Absorption of laser light by darkly pigmented materials (ie the clot) occurred inside the 1-mm materials (ie the clot) occurred inside the 1-mm catheter tipcatheter tip
the system was designed to minimize scattering the system was designed to minimize scattering of laser light of laser light
Absorption converted photo energy to acoustic Absorption converted photo energy to acoustic energy which then emulsified the clot inside the energy which then emulsified the clot inside the catheter tip catheter tip
EKOS ultrasound( the EKOS ultrasound( the Ultrasound Thrombolytic Ultrasound Thrombolytic
Infusion Catheter) Infusion Catheter) combines the use of a distal ultrasound transducer with combines the use of a distal ultrasound transducer with
infusion of a thrombolytic agent through the infusion of a thrombolytic agent through the microcathetermicrocatheter
Ultrasound changes the structure of the clot to Ultrasound changes the structure of the clot to temporarily increase its permeability while providing an temporarily increase its permeability while providing an acoustic pressure gradient to move the drug into the clot acoustic pressure gradient to move the drug into the clot to speed its dissolution to speed its dissolution
The EKOS catheter is placed in the proximal portion of the The EKOS catheter is placed in the proximal portion of the clot clot
After a 2-mg bolus of tPA was injected through the After a 2-mg bolus of tPA was injected through the catheter catheter
the patient received a continuous infusion of IA tPA 03 the patient received a continuous infusion of IA tPA 03 mgmin to a maximum of 20 mg and simultaneous mgmin to a maximum of 20 mg and simultaneous ultrasound transmission for as long as 60 minutes ultrasound transmission for as long as 60 minutes
One patient was treated with a total of 4 units of One patient was treated with a total of 4 units of recombinant reteplase (Retavase) hand-injected over 60 recombinant reteplase (Retavase) hand-injected over 60 minutes minutes
Penumbra system Penumbra system The Penumbra system (Penumbra Inc) provides a dual The Penumbra system (Penumbra Inc) provides a dual
approach to clot extraction using aspiration followed by approach to clot extraction using aspiration followed by clot retrieval with a ring device if needed clot retrieval with a ring device if needed
Mechanical Embolus Removal in Cerebral Ischemia Mechanical Embolus Removal in Cerebral Ischemia (MERCI)(MERCI)
a corkscrew-like apparatus to remove blood clots from a corkscrew-like apparatus to remove blood clots from the brain in patients experiencing an ischemic stroke the brain in patients experiencing an ischemic stroke
The corkscrew itself resides in the catheter tip which The corkscrew itself resides in the catheter tip which shields it from the wall of the vessel until it is ready to be shields it from the wall of the vessel until it is ready to be burrowed into the clot Once lodged in the clot the device burrowed into the clot Once lodged in the clot the device and clot are withdrawn from the vessel and clot are withdrawn from the vessel
Snarelike devicesSnarelike devices Snares such as the Neuronet snare (Guidant Snares such as the Neuronet snare (Guidant
Endovascular Santa Clara CA) have been developed Endovascular Santa Clara CA) have been developed specifically for use in the treatment of strokes specifically for use in the treatment of strokes
These devices are simple in design and do not require the These devices are simple in design and do not require the clot to be amenable to emulsification clot to be amenable to emulsification
X-Sizer deviceX-Sizer device a device with small moving blades at the a device with small moving blades at the
catheter tip catheter tip This device the X-Sizer device (EndiCor Medical This device the X-Sizer device (EndiCor Medical
San Clemente CA) can be used to excise the San Clemente CA) can be used to excise the thrombus and aspirate it thrombus and aspirate it
The device was being evaluated in randomized The device was being evaluated in randomized studies of coronary vessels and in a registry of studies of coronary vessels and in a registry of patients with acute myocardial infarctionpatients with acute myocardial infarction
Although the manufacturer had modified the Although the manufacturer had modified the device for use in cerebral vessels a safety and device for use in cerebral vessels a safety and feasibility study was indefinitely suspended after feasibility study was indefinitely suspended after only 1 patient was treated with the device in only 1 patient was treated with the device in Europe Europe
Suction thrombectomySuction thrombectomy This method of mechanical thrombolysis is one of the This method of mechanical thrombolysis is one of the
simplestsimplest In this readily available technique suction is applied with In this readily available technique suction is applied with
a syringe to remove thrombus in the ICA a syringe to remove thrombus in the ICA It requires no other devicesIt requires no other devices A catheter with a large inner diameter (Brite Tip Cordis A catheter with a large inner diameter (Brite Tip Cordis
Corporation Miami FL) was placed in the symptomatic Corporation Miami FL) was placed in the symptomatic vessel and navigated over a guidewire into the thrombusvessel and navigated over a guidewire into the thrombus
A 60-mL syringe was used to aspirate the thrombus A 60-mL syringe was used to aspirate the thrombus Each patient required angioplasty and stenting of carotid Each patient required angioplasty and stenting of carotid
bifurcation stenosis and received daily aspirin and bifurcation stenosis and received daily aspirin and ticlopidine after the procedure No complications ticlopidine after the procedure No complications occurred occurred
Summary Acute Stroke Summary Acute Stroke ImagingImaging
PhysiologyPhysiology importance collaterals importance collaterals
ndash ndashGrowing role for perfusion Growing role for perfusion assessmentassessment
tPAtPA guidelines amp limitations guidelines amp limitations Signs on CT amp MRSigns on CT amp MR follow physiology follow physiology Stroke trialsStroke trials PWI-DWI mismatch PWI-DWI mismatch
ndash ndashTreat based on physiology not timeTreat based on physiology not time ProtocolsProtocols should be fast and should be fast and
comprehensivecomprehensive
Penumbra stroke systemPenumbra stroke system This device combines two methods of clot This device combines two methods of clot
extraction aspiration and mechanical extraction aspiration and mechanical extraction extraction
First the clot is aspirated then a thrombus First the clot is aspirated then a thrombus removal ring can be used if necessary to removal ring can be used if necessary to remove remaining clot remove remaining clot
successful recanalizing 82successful recanalizing 82 Bridging therapyBridging therapy
06 mgkg IV rt-PA followed by IAT with IA rt-06 mgkg IV rt-PA followed by IAT with IA rt-PA (up to 20 mg)PA (up to 20 mg)
achieved a higher recanalization rateachieved a higher recanalization rate
Criteria for thrombolysis with rTPACriteria for thrombolysis with rTPA
Inclusion criteriaInclusion criteria Clinical signs and symptoms consistent with ischemic Clinical signs and symptoms consistent with ischemic
strokestroke Patient last seen normal within 3 hoursPatient last seen normal within 3 hours Measurable neurologic deficitMeasurable neurologic deficit
Exclusion criteriaExclusion criteria Any hemorrhage on neuroimaging (CT or MRI)Any hemorrhage on neuroimaging (CT or MRI) Symptoms suggestive of subarachnoid hemorrhageSymptoms suggestive of subarachnoid hemorrhage Seizure at stroke onset that is thought to contribute to Seizure at stroke onset that is thought to contribute to
neurologic deficitneurologic deficit Hypodensity greater than one third cerebral hemisphere Hypodensity greater than one third cerebral hemisphere
on CTon CT SBP greater than 185 mm Hg or DBP greater than 110 SBP greater than 185 mm Hg or DBP greater than 110
mm Hgmm Hg International normalized ratio (INR) greater than 17International normalized ratio (INR) greater than 17
Ischemic Stroke Ischemic Stroke Treatment ndash 2006Treatment ndash 2006
IV tissue plasminogen activator (tPA)IV tissue plasminogen activator (tPA) ndash ndash Only FDA-approved acute stroke drugOnly FDA-approved acute stroke drug ndash ndash 3 hour treatment window3 hour treatment window
MERCI - Concentric clot retrieval MERCI - Concentric clot retrieval devicedevice ndash ndash Rescue therapy - approved 2004Rescue therapy - approved 2004 ndash ndash Device approval (not outcomes-based)Device approval (not outcomes-based)
Off label approachesOff label approaches ndash ndash IV tPA after 3 hoursIV tPA after 3 hours ndash ndash IV-IA tPA sequential strategiesIV-IA tPA sequential strategies ndash ndash IA tPA clot angioplasty fragmentationIA tPA clot angioplasty fragmentation ndash ndash Ultrasound-assisted tPA lysisUltrasound-assisted tPA lysis
rt-PA Trials NINDSrt-PA Trials NINDS
Acute stroke - 624 patientsAcute stroke - 624 patients Treat within 3 hrsTreat within 3 hrs Intravenous 09 mgkg rt-PA vs placeboIntravenous 09 mgkg rt-PA vs placebo Hemorrhage 64 tPA 06 placeboHemorrhage 64 tPA 06 placebo Neurologic recovery better with tPA 30 Neurologic recovery better with tPA 30
more like to have minimal or no disabilitymore like to have minimal or no disability
First proven approved treatment for First proven approved treatment for strokestroke
Limitations of tPALimitations of tPA Only 4 of acute strokes receive tPAOnly 4 of acute strokes receive tPA (Kleindorfer et al Stroke 2004 35 e27-e29)(Kleindorfer et al Stroke 2004 35 e27-e29)
Only 22 of patients present within 3 hoursOnly 22 of patients present within 3 hours1048707 1048707 51 of these ineligible due to51 of these ineligible due to
bull bull Mild severityMild severity bull bull Medical or surgical historyMedical or surgical history bull bull Blood testsBlood tests
Sustained recanalization only 13Sustained recanalization only 13 (Alexandrov et al NEJM 2004 351 2170-8)(Alexandrov et al NEJM 2004 351 2170-8)
Concern for hemorrhageConcern for hemorrhage tPA potentiates apoptotic injury tPA potentiates apoptotic injury (Liu et al Nature Med 2004 101379-83)(Liu et al Nature Med 2004 101379-83)
PROACT II IA Lysis TrialPROACT II IA Lysis Trial Baseline 24 hours 8 days
Baseline 60 minutes 120 minutes
9mg IAProurokinase
Desmoteplase Trials DEDAS Desmoteplase Trials DEDAS DIASDIAS
Trial OverviewTrial Overview Double blind randomized placebo Double blind randomized placebo
controlled trialscontrolled trials IV delivery 3-9 hour time windowIV delivery 3-9 hour time window Plasminogen activator ndash from Plasminogen activator ndash from vampire bat vampire bat
salivasaliva Selection based on PWI-DWI MismatchSelection based on PWI-DWI Mismatch
MRI InclusionMRI Inclusion PWI defect at least 2 cm AND ~20 larger PWI defect at least 2 cm AND ~20 larger
than DWIthan DWI PWI should be obvious even visible on PWI should be obvious even visible on
raw imagesraw imagesMRI ExclusionMRI Exclusion
DWI gt 13 MCADWI gt 13 MCA MRA ICA occlusionMRA ICA occlusion
Desmoteplase ndash DIAS Desmoteplase ndash DIAS ResultsResults
Mechanical Thrombolysis Mechanical Thrombolysis devicesdevices
mechanical thrombolysis potentially extends the treatment mechanical thrombolysis potentially extends the treatment window because they act promptly at the site of the thrombuswindow because they act promptly at the site of the thrombus
The devices can retrieve large clots that pharmaceutical agents The devices can retrieve large clots that pharmaceutical agents may not successfully lysemay not successfully lyse
Patients treated with IV tPA may be considered for treatment of Patients treated with IV tPA may be considered for treatment of residual clot with some of these devicesresidual clot with some of these devices
suction-creating saline jets suction-creating saline jets laser energy ultrasound laser energy ultrasound a corkscrew apparatus to treat strokesa corkscrew apparatus to treat strokes The AngioJet systemThe AngioJet system uses saline jets that are directed back into the catheter to uses saline jets that are directed back into the catheter to
create a low-pressure zone around the catheter tip inducing create a low-pressure zone around the catheter tip inducing suction suction
The clot is pulled into the exhaust lumen and removed from the The clot is pulled into the exhaust lumen and removed from the vessel Although US Food and Drug Administration (FDA) has vessel Although US Food and Drug Administration (FDA) has approved this device for use in arteriovenous dialysis grafts and approved this device for use in arteriovenous dialysis grafts and fistulae and for the treatment of coronary arteries saphenous fistulae and for the treatment of coronary arteries saphenous vein grafts and peripheral vessels clinical trials for the vein grafts and peripheral vessels clinical trials for the treatment of acute stroke are no longer in progress treatment of acute stroke are no longer in progress
Most devices are used in cerebral vessels that 2-5 mm
The Latis laser device The Latis laser device used laser energy to ablate clots used laser energy to ablate clots Arteries 2-5 mm in diameter could be Arteries 2-5 mm in diameter could be
treated including the ICA M1 or M2 treated including the ICA M1 or M2 branch of the MCA A1 branch of the branch of the MCA A1 branch of the anterior cerebral artery (ACA) basilar anterior cerebral artery (ACA) basilar artery posterior cerebral artery (PCA) artery posterior cerebral artery (PCA) and vertebral and vertebral
Patients could receive treatment as late Patients could receive treatment as late as 8 hours after symptom onset in the as 8 hours after symptom onset in the anterior circulation and within 24 hours in anterior circulation and within 24 hours in the posterior circulation the posterior circulation
Endovascular Photo Acoustic Endovascular Photo Acoustic Recanalization (EPAR) Recanalization (EPAR)
A laser power source generated energy for the A laser power source generated energy for the systemsystem
The energy was delivered by means of The energy was delivered by means of fiberoptics to the tip of the catheter at the fiberoptics to the tip of the catheter at the treatment sitetreatment site
Absorption of laser light by darkly pigmented Absorption of laser light by darkly pigmented materials (ie the clot) occurred inside the 1-mm materials (ie the clot) occurred inside the 1-mm catheter tipcatheter tip
the system was designed to minimize scattering the system was designed to minimize scattering of laser light of laser light
Absorption converted photo energy to acoustic Absorption converted photo energy to acoustic energy which then emulsified the clot inside the energy which then emulsified the clot inside the catheter tip catheter tip
EKOS ultrasound( the EKOS ultrasound( the Ultrasound Thrombolytic Ultrasound Thrombolytic
Infusion Catheter) Infusion Catheter) combines the use of a distal ultrasound transducer with combines the use of a distal ultrasound transducer with
infusion of a thrombolytic agent through the infusion of a thrombolytic agent through the microcathetermicrocatheter
Ultrasound changes the structure of the clot to Ultrasound changes the structure of the clot to temporarily increase its permeability while providing an temporarily increase its permeability while providing an acoustic pressure gradient to move the drug into the clot acoustic pressure gradient to move the drug into the clot to speed its dissolution to speed its dissolution
The EKOS catheter is placed in the proximal portion of the The EKOS catheter is placed in the proximal portion of the clot clot
After a 2-mg bolus of tPA was injected through the After a 2-mg bolus of tPA was injected through the catheter catheter
the patient received a continuous infusion of IA tPA 03 the patient received a continuous infusion of IA tPA 03 mgmin to a maximum of 20 mg and simultaneous mgmin to a maximum of 20 mg and simultaneous ultrasound transmission for as long as 60 minutes ultrasound transmission for as long as 60 minutes
One patient was treated with a total of 4 units of One patient was treated with a total of 4 units of recombinant reteplase (Retavase) hand-injected over 60 recombinant reteplase (Retavase) hand-injected over 60 minutes minutes
Penumbra system Penumbra system The Penumbra system (Penumbra Inc) provides a dual The Penumbra system (Penumbra Inc) provides a dual
approach to clot extraction using aspiration followed by approach to clot extraction using aspiration followed by clot retrieval with a ring device if needed clot retrieval with a ring device if needed
Mechanical Embolus Removal in Cerebral Ischemia Mechanical Embolus Removal in Cerebral Ischemia (MERCI)(MERCI)
a corkscrew-like apparatus to remove blood clots from a corkscrew-like apparatus to remove blood clots from the brain in patients experiencing an ischemic stroke the brain in patients experiencing an ischemic stroke
The corkscrew itself resides in the catheter tip which The corkscrew itself resides in the catheter tip which shields it from the wall of the vessel until it is ready to be shields it from the wall of the vessel until it is ready to be burrowed into the clot Once lodged in the clot the device burrowed into the clot Once lodged in the clot the device and clot are withdrawn from the vessel and clot are withdrawn from the vessel
Snarelike devicesSnarelike devices Snares such as the Neuronet snare (Guidant Snares such as the Neuronet snare (Guidant
Endovascular Santa Clara CA) have been developed Endovascular Santa Clara CA) have been developed specifically for use in the treatment of strokes specifically for use in the treatment of strokes
These devices are simple in design and do not require the These devices are simple in design and do not require the clot to be amenable to emulsification clot to be amenable to emulsification
X-Sizer deviceX-Sizer device a device with small moving blades at the a device with small moving blades at the
catheter tip catheter tip This device the X-Sizer device (EndiCor Medical This device the X-Sizer device (EndiCor Medical
San Clemente CA) can be used to excise the San Clemente CA) can be used to excise the thrombus and aspirate it thrombus and aspirate it
The device was being evaluated in randomized The device was being evaluated in randomized studies of coronary vessels and in a registry of studies of coronary vessels and in a registry of patients with acute myocardial infarctionpatients with acute myocardial infarction
Although the manufacturer had modified the Although the manufacturer had modified the device for use in cerebral vessels a safety and device for use in cerebral vessels a safety and feasibility study was indefinitely suspended after feasibility study was indefinitely suspended after only 1 patient was treated with the device in only 1 patient was treated with the device in Europe Europe
Suction thrombectomySuction thrombectomy This method of mechanical thrombolysis is one of the This method of mechanical thrombolysis is one of the
simplestsimplest In this readily available technique suction is applied with In this readily available technique suction is applied with
a syringe to remove thrombus in the ICA a syringe to remove thrombus in the ICA It requires no other devicesIt requires no other devices A catheter with a large inner diameter (Brite Tip Cordis A catheter with a large inner diameter (Brite Tip Cordis
Corporation Miami FL) was placed in the symptomatic Corporation Miami FL) was placed in the symptomatic vessel and navigated over a guidewire into the thrombusvessel and navigated over a guidewire into the thrombus
A 60-mL syringe was used to aspirate the thrombus A 60-mL syringe was used to aspirate the thrombus Each patient required angioplasty and stenting of carotid Each patient required angioplasty and stenting of carotid
bifurcation stenosis and received daily aspirin and bifurcation stenosis and received daily aspirin and ticlopidine after the procedure No complications ticlopidine after the procedure No complications occurred occurred
Summary Acute Stroke Summary Acute Stroke ImagingImaging
PhysiologyPhysiology importance collaterals importance collaterals
ndash ndashGrowing role for perfusion Growing role for perfusion assessmentassessment
tPAtPA guidelines amp limitations guidelines amp limitations Signs on CT amp MRSigns on CT amp MR follow physiology follow physiology Stroke trialsStroke trials PWI-DWI mismatch PWI-DWI mismatch
ndash ndashTreat based on physiology not timeTreat based on physiology not time ProtocolsProtocols should be fast and should be fast and
comprehensivecomprehensive
Criteria for thrombolysis with rTPACriteria for thrombolysis with rTPA
Inclusion criteriaInclusion criteria Clinical signs and symptoms consistent with ischemic Clinical signs and symptoms consistent with ischemic
strokestroke Patient last seen normal within 3 hoursPatient last seen normal within 3 hours Measurable neurologic deficitMeasurable neurologic deficit
Exclusion criteriaExclusion criteria Any hemorrhage on neuroimaging (CT or MRI)Any hemorrhage on neuroimaging (CT or MRI) Symptoms suggestive of subarachnoid hemorrhageSymptoms suggestive of subarachnoid hemorrhage Seizure at stroke onset that is thought to contribute to Seizure at stroke onset that is thought to contribute to
neurologic deficitneurologic deficit Hypodensity greater than one third cerebral hemisphere Hypodensity greater than one third cerebral hemisphere
on CTon CT SBP greater than 185 mm Hg or DBP greater than 110 SBP greater than 185 mm Hg or DBP greater than 110
mm Hgmm Hg International normalized ratio (INR) greater than 17International normalized ratio (INR) greater than 17
Ischemic Stroke Ischemic Stroke Treatment ndash 2006Treatment ndash 2006
IV tissue plasminogen activator (tPA)IV tissue plasminogen activator (tPA) ndash ndash Only FDA-approved acute stroke drugOnly FDA-approved acute stroke drug ndash ndash 3 hour treatment window3 hour treatment window
MERCI - Concentric clot retrieval MERCI - Concentric clot retrieval devicedevice ndash ndash Rescue therapy - approved 2004Rescue therapy - approved 2004 ndash ndash Device approval (not outcomes-based)Device approval (not outcomes-based)
Off label approachesOff label approaches ndash ndash IV tPA after 3 hoursIV tPA after 3 hours ndash ndash IV-IA tPA sequential strategiesIV-IA tPA sequential strategies ndash ndash IA tPA clot angioplasty fragmentationIA tPA clot angioplasty fragmentation ndash ndash Ultrasound-assisted tPA lysisUltrasound-assisted tPA lysis
rt-PA Trials NINDSrt-PA Trials NINDS
Acute stroke - 624 patientsAcute stroke - 624 patients Treat within 3 hrsTreat within 3 hrs Intravenous 09 mgkg rt-PA vs placeboIntravenous 09 mgkg rt-PA vs placebo Hemorrhage 64 tPA 06 placeboHemorrhage 64 tPA 06 placebo Neurologic recovery better with tPA 30 Neurologic recovery better with tPA 30
more like to have minimal or no disabilitymore like to have minimal or no disability
First proven approved treatment for First proven approved treatment for strokestroke
Limitations of tPALimitations of tPA Only 4 of acute strokes receive tPAOnly 4 of acute strokes receive tPA (Kleindorfer et al Stroke 2004 35 e27-e29)(Kleindorfer et al Stroke 2004 35 e27-e29)
Only 22 of patients present within 3 hoursOnly 22 of patients present within 3 hours1048707 1048707 51 of these ineligible due to51 of these ineligible due to
bull bull Mild severityMild severity bull bull Medical or surgical historyMedical or surgical history bull bull Blood testsBlood tests
Sustained recanalization only 13Sustained recanalization only 13 (Alexandrov et al NEJM 2004 351 2170-8)(Alexandrov et al NEJM 2004 351 2170-8)
Concern for hemorrhageConcern for hemorrhage tPA potentiates apoptotic injury tPA potentiates apoptotic injury (Liu et al Nature Med 2004 101379-83)(Liu et al Nature Med 2004 101379-83)
PROACT II IA Lysis TrialPROACT II IA Lysis Trial Baseline 24 hours 8 days
Baseline 60 minutes 120 minutes
9mg IAProurokinase
Desmoteplase Trials DEDAS Desmoteplase Trials DEDAS DIASDIAS
Trial OverviewTrial Overview Double blind randomized placebo Double blind randomized placebo
controlled trialscontrolled trials IV delivery 3-9 hour time windowIV delivery 3-9 hour time window Plasminogen activator ndash from Plasminogen activator ndash from vampire bat vampire bat
salivasaliva Selection based on PWI-DWI MismatchSelection based on PWI-DWI Mismatch
MRI InclusionMRI Inclusion PWI defect at least 2 cm AND ~20 larger PWI defect at least 2 cm AND ~20 larger
than DWIthan DWI PWI should be obvious even visible on PWI should be obvious even visible on
raw imagesraw imagesMRI ExclusionMRI Exclusion
DWI gt 13 MCADWI gt 13 MCA MRA ICA occlusionMRA ICA occlusion
Desmoteplase ndash DIAS Desmoteplase ndash DIAS ResultsResults
Mechanical Thrombolysis Mechanical Thrombolysis devicesdevices
mechanical thrombolysis potentially extends the treatment mechanical thrombolysis potentially extends the treatment window because they act promptly at the site of the thrombuswindow because they act promptly at the site of the thrombus
The devices can retrieve large clots that pharmaceutical agents The devices can retrieve large clots that pharmaceutical agents may not successfully lysemay not successfully lyse
Patients treated with IV tPA may be considered for treatment of Patients treated with IV tPA may be considered for treatment of residual clot with some of these devicesresidual clot with some of these devices
suction-creating saline jets suction-creating saline jets laser energy ultrasound laser energy ultrasound a corkscrew apparatus to treat strokesa corkscrew apparatus to treat strokes The AngioJet systemThe AngioJet system uses saline jets that are directed back into the catheter to uses saline jets that are directed back into the catheter to
create a low-pressure zone around the catheter tip inducing create a low-pressure zone around the catheter tip inducing suction suction
The clot is pulled into the exhaust lumen and removed from the The clot is pulled into the exhaust lumen and removed from the vessel Although US Food and Drug Administration (FDA) has vessel Although US Food and Drug Administration (FDA) has approved this device for use in arteriovenous dialysis grafts and approved this device for use in arteriovenous dialysis grafts and fistulae and for the treatment of coronary arteries saphenous fistulae and for the treatment of coronary arteries saphenous vein grafts and peripheral vessels clinical trials for the vein grafts and peripheral vessels clinical trials for the treatment of acute stroke are no longer in progress treatment of acute stroke are no longer in progress
Most devices are used in cerebral vessels that 2-5 mm
The Latis laser device The Latis laser device used laser energy to ablate clots used laser energy to ablate clots Arteries 2-5 mm in diameter could be Arteries 2-5 mm in diameter could be
treated including the ICA M1 or M2 treated including the ICA M1 or M2 branch of the MCA A1 branch of the branch of the MCA A1 branch of the anterior cerebral artery (ACA) basilar anterior cerebral artery (ACA) basilar artery posterior cerebral artery (PCA) artery posterior cerebral artery (PCA) and vertebral and vertebral
Patients could receive treatment as late Patients could receive treatment as late as 8 hours after symptom onset in the as 8 hours after symptom onset in the anterior circulation and within 24 hours in anterior circulation and within 24 hours in the posterior circulation the posterior circulation
Endovascular Photo Acoustic Endovascular Photo Acoustic Recanalization (EPAR) Recanalization (EPAR)
A laser power source generated energy for the A laser power source generated energy for the systemsystem
The energy was delivered by means of The energy was delivered by means of fiberoptics to the tip of the catheter at the fiberoptics to the tip of the catheter at the treatment sitetreatment site
Absorption of laser light by darkly pigmented Absorption of laser light by darkly pigmented materials (ie the clot) occurred inside the 1-mm materials (ie the clot) occurred inside the 1-mm catheter tipcatheter tip
the system was designed to minimize scattering the system was designed to minimize scattering of laser light of laser light
Absorption converted photo energy to acoustic Absorption converted photo energy to acoustic energy which then emulsified the clot inside the energy which then emulsified the clot inside the catheter tip catheter tip
EKOS ultrasound( the EKOS ultrasound( the Ultrasound Thrombolytic Ultrasound Thrombolytic
Infusion Catheter) Infusion Catheter) combines the use of a distal ultrasound transducer with combines the use of a distal ultrasound transducer with
infusion of a thrombolytic agent through the infusion of a thrombolytic agent through the microcathetermicrocatheter
Ultrasound changes the structure of the clot to Ultrasound changes the structure of the clot to temporarily increase its permeability while providing an temporarily increase its permeability while providing an acoustic pressure gradient to move the drug into the clot acoustic pressure gradient to move the drug into the clot to speed its dissolution to speed its dissolution
The EKOS catheter is placed in the proximal portion of the The EKOS catheter is placed in the proximal portion of the clot clot
After a 2-mg bolus of tPA was injected through the After a 2-mg bolus of tPA was injected through the catheter catheter
the patient received a continuous infusion of IA tPA 03 the patient received a continuous infusion of IA tPA 03 mgmin to a maximum of 20 mg and simultaneous mgmin to a maximum of 20 mg and simultaneous ultrasound transmission for as long as 60 minutes ultrasound transmission for as long as 60 minutes
One patient was treated with a total of 4 units of One patient was treated with a total of 4 units of recombinant reteplase (Retavase) hand-injected over 60 recombinant reteplase (Retavase) hand-injected over 60 minutes minutes
Penumbra system Penumbra system The Penumbra system (Penumbra Inc) provides a dual The Penumbra system (Penumbra Inc) provides a dual
approach to clot extraction using aspiration followed by approach to clot extraction using aspiration followed by clot retrieval with a ring device if needed clot retrieval with a ring device if needed
Mechanical Embolus Removal in Cerebral Ischemia Mechanical Embolus Removal in Cerebral Ischemia (MERCI)(MERCI)
a corkscrew-like apparatus to remove blood clots from a corkscrew-like apparatus to remove blood clots from the brain in patients experiencing an ischemic stroke the brain in patients experiencing an ischemic stroke
The corkscrew itself resides in the catheter tip which The corkscrew itself resides in the catheter tip which shields it from the wall of the vessel until it is ready to be shields it from the wall of the vessel until it is ready to be burrowed into the clot Once lodged in the clot the device burrowed into the clot Once lodged in the clot the device and clot are withdrawn from the vessel and clot are withdrawn from the vessel
Snarelike devicesSnarelike devices Snares such as the Neuronet snare (Guidant Snares such as the Neuronet snare (Guidant
Endovascular Santa Clara CA) have been developed Endovascular Santa Clara CA) have been developed specifically for use in the treatment of strokes specifically for use in the treatment of strokes
These devices are simple in design and do not require the These devices are simple in design and do not require the clot to be amenable to emulsification clot to be amenable to emulsification
X-Sizer deviceX-Sizer device a device with small moving blades at the a device with small moving blades at the
catheter tip catheter tip This device the X-Sizer device (EndiCor Medical This device the X-Sizer device (EndiCor Medical
San Clemente CA) can be used to excise the San Clemente CA) can be used to excise the thrombus and aspirate it thrombus and aspirate it
The device was being evaluated in randomized The device was being evaluated in randomized studies of coronary vessels and in a registry of studies of coronary vessels and in a registry of patients with acute myocardial infarctionpatients with acute myocardial infarction
Although the manufacturer had modified the Although the manufacturer had modified the device for use in cerebral vessels a safety and device for use in cerebral vessels a safety and feasibility study was indefinitely suspended after feasibility study was indefinitely suspended after only 1 patient was treated with the device in only 1 patient was treated with the device in Europe Europe
Suction thrombectomySuction thrombectomy This method of mechanical thrombolysis is one of the This method of mechanical thrombolysis is one of the
simplestsimplest In this readily available technique suction is applied with In this readily available technique suction is applied with
a syringe to remove thrombus in the ICA a syringe to remove thrombus in the ICA It requires no other devicesIt requires no other devices A catheter with a large inner diameter (Brite Tip Cordis A catheter with a large inner diameter (Brite Tip Cordis
Corporation Miami FL) was placed in the symptomatic Corporation Miami FL) was placed in the symptomatic vessel and navigated over a guidewire into the thrombusvessel and navigated over a guidewire into the thrombus
A 60-mL syringe was used to aspirate the thrombus A 60-mL syringe was used to aspirate the thrombus Each patient required angioplasty and stenting of carotid Each patient required angioplasty and stenting of carotid
bifurcation stenosis and received daily aspirin and bifurcation stenosis and received daily aspirin and ticlopidine after the procedure No complications ticlopidine after the procedure No complications occurred occurred
Summary Acute Stroke Summary Acute Stroke ImagingImaging
PhysiologyPhysiology importance collaterals importance collaterals
ndash ndashGrowing role for perfusion Growing role for perfusion assessmentassessment
tPAtPA guidelines amp limitations guidelines amp limitations Signs on CT amp MRSigns on CT amp MR follow physiology follow physiology Stroke trialsStroke trials PWI-DWI mismatch PWI-DWI mismatch
ndash ndashTreat based on physiology not timeTreat based on physiology not time ProtocolsProtocols should be fast and should be fast and
comprehensivecomprehensive
Ischemic Stroke Ischemic Stroke Treatment ndash 2006Treatment ndash 2006
IV tissue plasminogen activator (tPA)IV tissue plasminogen activator (tPA) ndash ndash Only FDA-approved acute stroke drugOnly FDA-approved acute stroke drug ndash ndash 3 hour treatment window3 hour treatment window
MERCI - Concentric clot retrieval MERCI - Concentric clot retrieval devicedevice ndash ndash Rescue therapy - approved 2004Rescue therapy - approved 2004 ndash ndash Device approval (not outcomes-based)Device approval (not outcomes-based)
Off label approachesOff label approaches ndash ndash IV tPA after 3 hoursIV tPA after 3 hours ndash ndash IV-IA tPA sequential strategiesIV-IA tPA sequential strategies ndash ndash IA tPA clot angioplasty fragmentationIA tPA clot angioplasty fragmentation ndash ndash Ultrasound-assisted tPA lysisUltrasound-assisted tPA lysis
rt-PA Trials NINDSrt-PA Trials NINDS
Acute stroke - 624 patientsAcute stroke - 624 patients Treat within 3 hrsTreat within 3 hrs Intravenous 09 mgkg rt-PA vs placeboIntravenous 09 mgkg rt-PA vs placebo Hemorrhage 64 tPA 06 placeboHemorrhage 64 tPA 06 placebo Neurologic recovery better with tPA 30 Neurologic recovery better with tPA 30
more like to have minimal or no disabilitymore like to have minimal or no disability
First proven approved treatment for First proven approved treatment for strokestroke
Limitations of tPALimitations of tPA Only 4 of acute strokes receive tPAOnly 4 of acute strokes receive tPA (Kleindorfer et al Stroke 2004 35 e27-e29)(Kleindorfer et al Stroke 2004 35 e27-e29)
Only 22 of patients present within 3 hoursOnly 22 of patients present within 3 hours1048707 1048707 51 of these ineligible due to51 of these ineligible due to
bull bull Mild severityMild severity bull bull Medical or surgical historyMedical or surgical history bull bull Blood testsBlood tests
Sustained recanalization only 13Sustained recanalization only 13 (Alexandrov et al NEJM 2004 351 2170-8)(Alexandrov et al NEJM 2004 351 2170-8)
Concern for hemorrhageConcern for hemorrhage tPA potentiates apoptotic injury tPA potentiates apoptotic injury (Liu et al Nature Med 2004 101379-83)(Liu et al Nature Med 2004 101379-83)
PROACT II IA Lysis TrialPROACT II IA Lysis Trial Baseline 24 hours 8 days
Baseline 60 minutes 120 minutes
9mg IAProurokinase
Desmoteplase Trials DEDAS Desmoteplase Trials DEDAS DIASDIAS
Trial OverviewTrial Overview Double blind randomized placebo Double blind randomized placebo
controlled trialscontrolled trials IV delivery 3-9 hour time windowIV delivery 3-9 hour time window Plasminogen activator ndash from Plasminogen activator ndash from vampire bat vampire bat
salivasaliva Selection based on PWI-DWI MismatchSelection based on PWI-DWI Mismatch
MRI InclusionMRI Inclusion PWI defect at least 2 cm AND ~20 larger PWI defect at least 2 cm AND ~20 larger
than DWIthan DWI PWI should be obvious even visible on PWI should be obvious even visible on
raw imagesraw imagesMRI ExclusionMRI Exclusion
DWI gt 13 MCADWI gt 13 MCA MRA ICA occlusionMRA ICA occlusion
Desmoteplase ndash DIAS Desmoteplase ndash DIAS ResultsResults
Mechanical Thrombolysis Mechanical Thrombolysis devicesdevices
mechanical thrombolysis potentially extends the treatment mechanical thrombolysis potentially extends the treatment window because they act promptly at the site of the thrombuswindow because they act promptly at the site of the thrombus
The devices can retrieve large clots that pharmaceutical agents The devices can retrieve large clots that pharmaceutical agents may not successfully lysemay not successfully lyse
Patients treated with IV tPA may be considered for treatment of Patients treated with IV tPA may be considered for treatment of residual clot with some of these devicesresidual clot with some of these devices
suction-creating saline jets suction-creating saline jets laser energy ultrasound laser energy ultrasound a corkscrew apparatus to treat strokesa corkscrew apparatus to treat strokes The AngioJet systemThe AngioJet system uses saline jets that are directed back into the catheter to uses saline jets that are directed back into the catheter to
create a low-pressure zone around the catheter tip inducing create a low-pressure zone around the catheter tip inducing suction suction
The clot is pulled into the exhaust lumen and removed from the The clot is pulled into the exhaust lumen and removed from the vessel Although US Food and Drug Administration (FDA) has vessel Although US Food and Drug Administration (FDA) has approved this device for use in arteriovenous dialysis grafts and approved this device for use in arteriovenous dialysis grafts and fistulae and for the treatment of coronary arteries saphenous fistulae and for the treatment of coronary arteries saphenous vein grafts and peripheral vessels clinical trials for the vein grafts and peripheral vessels clinical trials for the treatment of acute stroke are no longer in progress treatment of acute stroke are no longer in progress
Most devices are used in cerebral vessels that 2-5 mm
The Latis laser device The Latis laser device used laser energy to ablate clots used laser energy to ablate clots Arteries 2-5 mm in diameter could be Arteries 2-5 mm in diameter could be
treated including the ICA M1 or M2 treated including the ICA M1 or M2 branch of the MCA A1 branch of the branch of the MCA A1 branch of the anterior cerebral artery (ACA) basilar anterior cerebral artery (ACA) basilar artery posterior cerebral artery (PCA) artery posterior cerebral artery (PCA) and vertebral and vertebral
Patients could receive treatment as late Patients could receive treatment as late as 8 hours after symptom onset in the as 8 hours after symptom onset in the anterior circulation and within 24 hours in anterior circulation and within 24 hours in the posterior circulation the posterior circulation
Endovascular Photo Acoustic Endovascular Photo Acoustic Recanalization (EPAR) Recanalization (EPAR)
A laser power source generated energy for the A laser power source generated energy for the systemsystem
The energy was delivered by means of The energy was delivered by means of fiberoptics to the tip of the catheter at the fiberoptics to the tip of the catheter at the treatment sitetreatment site
Absorption of laser light by darkly pigmented Absorption of laser light by darkly pigmented materials (ie the clot) occurred inside the 1-mm materials (ie the clot) occurred inside the 1-mm catheter tipcatheter tip
the system was designed to minimize scattering the system was designed to minimize scattering of laser light of laser light
Absorption converted photo energy to acoustic Absorption converted photo energy to acoustic energy which then emulsified the clot inside the energy which then emulsified the clot inside the catheter tip catheter tip
EKOS ultrasound( the EKOS ultrasound( the Ultrasound Thrombolytic Ultrasound Thrombolytic
Infusion Catheter) Infusion Catheter) combines the use of a distal ultrasound transducer with combines the use of a distal ultrasound transducer with
infusion of a thrombolytic agent through the infusion of a thrombolytic agent through the microcathetermicrocatheter
Ultrasound changes the structure of the clot to Ultrasound changes the structure of the clot to temporarily increase its permeability while providing an temporarily increase its permeability while providing an acoustic pressure gradient to move the drug into the clot acoustic pressure gradient to move the drug into the clot to speed its dissolution to speed its dissolution
The EKOS catheter is placed in the proximal portion of the The EKOS catheter is placed in the proximal portion of the clot clot
After a 2-mg bolus of tPA was injected through the After a 2-mg bolus of tPA was injected through the catheter catheter
the patient received a continuous infusion of IA tPA 03 the patient received a continuous infusion of IA tPA 03 mgmin to a maximum of 20 mg and simultaneous mgmin to a maximum of 20 mg and simultaneous ultrasound transmission for as long as 60 minutes ultrasound transmission for as long as 60 minutes
One patient was treated with a total of 4 units of One patient was treated with a total of 4 units of recombinant reteplase (Retavase) hand-injected over 60 recombinant reteplase (Retavase) hand-injected over 60 minutes minutes
Penumbra system Penumbra system The Penumbra system (Penumbra Inc) provides a dual The Penumbra system (Penumbra Inc) provides a dual
approach to clot extraction using aspiration followed by approach to clot extraction using aspiration followed by clot retrieval with a ring device if needed clot retrieval with a ring device if needed
Mechanical Embolus Removal in Cerebral Ischemia Mechanical Embolus Removal in Cerebral Ischemia (MERCI)(MERCI)
a corkscrew-like apparatus to remove blood clots from a corkscrew-like apparatus to remove blood clots from the brain in patients experiencing an ischemic stroke the brain in patients experiencing an ischemic stroke
The corkscrew itself resides in the catheter tip which The corkscrew itself resides in the catheter tip which shields it from the wall of the vessel until it is ready to be shields it from the wall of the vessel until it is ready to be burrowed into the clot Once lodged in the clot the device burrowed into the clot Once lodged in the clot the device and clot are withdrawn from the vessel and clot are withdrawn from the vessel
Snarelike devicesSnarelike devices Snares such as the Neuronet snare (Guidant Snares such as the Neuronet snare (Guidant
Endovascular Santa Clara CA) have been developed Endovascular Santa Clara CA) have been developed specifically for use in the treatment of strokes specifically for use in the treatment of strokes
These devices are simple in design and do not require the These devices are simple in design and do not require the clot to be amenable to emulsification clot to be amenable to emulsification
X-Sizer deviceX-Sizer device a device with small moving blades at the a device with small moving blades at the
catheter tip catheter tip This device the X-Sizer device (EndiCor Medical This device the X-Sizer device (EndiCor Medical
San Clemente CA) can be used to excise the San Clemente CA) can be used to excise the thrombus and aspirate it thrombus and aspirate it
The device was being evaluated in randomized The device was being evaluated in randomized studies of coronary vessels and in a registry of studies of coronary vessels and in a registry of patients with acute myocardial infarctionpatients with acute myocardial infarction
Although the manufacturer had modified the Although the manufacturer had modified the device for use in cerebral vessels a safety and device for use in cerebral vessels a safety and feasibility study was indefinitely suspended after feasibility study was indefinitely suspended after only 1 patient was treated with the device in only 1 patient was treated with the device in Europe Europe
Suction thrombectomySuction thrombectomy This method of mechanical thrombolysis is one of the This method of mechanical thrombolysis is one of the
simplestsimplest In this readily available technique suction is applied with In this readily available technique suction is applied with
a syringe to remove thrombus in the ICA a syringe to remove thrombus in the ICA It requires no other devicesIt requires no other devices A catheter with a large inner diameter (Brite Tip Cordis A catheter with a large inner diameter (Brite Tip Cordis
Corporation Miami FL) was placed in the symptomatic Corporation Miami FL) was placed in the symptomatic vessel and navigated over a guidewire into the thrombusvessel and navigated over a guidewire into the thrombus
A 60-mL syringe was used to aspirate the thrombus A 60-mL syringe was used to aspirate the thrombus Each patient required angioplasty and stenting of carotid Each patient required angioplasty and stenting of carotid
bifurcation stenosis and received daily aspirin and bifurcation stenosis and received daily aspirin and ticlopidine after the procedure No complications ticlopidine after the procedure No complications occurred occurred
Summary Acute Stroke Summary Acute Stroke ImagingImaging
PhysiologyPhysiology importance collaterals importance collaterals
ndash ndashGrowing role for perfusion Growing role for perfusion assessmentassessment
tPAtPA guidelines amp limitations guidelines amp limitations Signs on CT amp MRSigns on CT amp MR follow physiology follow physiology Stroke trialsStroke trials PWI-DWI mismatch PWI-DWI mismatch
ndash ndashTreat based on physiology not timeTreat based on physiology not time ProtocolsProtocols should be fast and should be fast and
comprehensivecomprehensive
rt-PA Trials NINDSrt-PA Trials NINDS
Acute stroke - 624 patientsAcute stroke - 624 patients Treat within 3 hrsTreat within 3 hrs Intravenous 09 mgkg rt-PA vs placeboIntravenous 09 mgkg rt-PA vs placebo Hemorrhage 64 tPA 06 placeboHemorrhage 64 tPA 06 placebo Neurologic recovery better with tPA 30 Neurologic recovery better with tPA 30
more like to have minimal or no disabilitymore like to have minimal or no disability
First proven approved treatment for First proven approved treatment for strokestroke
Limitations of tPALimitations of tPA Only 4 of acute strokes receive tPAOnly 4 of acute strokes receive tPA (Kleindorfer et al Stroke 2004 35 e27-e29)(Kleindorfer et al Stroke 2004 35 e27-e29)
Only 22 of patients present within 3 hoursOnly 22 of patients present within 3 hours1048707 1048707 51 of these ineligible due to51 of these ineligible due to
bull bull Mild severityMild severity bull bull Medical or surgical historyMedical or surgical history bull bull Blood testsBlood tests
Sustained recanalization only 13Sustained recanalization only 13 (Alexandrov et al NEJM 2004 351 2170-8)(Alexandrov et al NEJM 2004 351 2170-8)
Concern for hemorrhageConcern for hemorrhage tPA potentiates apoptotic injury tPA potentiates apoptotic injury (Liu et al Nature Med 2004 101379-83)(Liu et al Nature Med 2004 101379-83)
PROACT II IA Lysis TrialPROACT II IA Lysis Trial Baseline 24 hours 8 days
Baseline 60 minutes 120 minutes
9mg IAProurokinase
Desmoteplase Trials DEDAS Desmoteplase Trials DEDAS DIASDIAS
Trial OverviewTrial Overview Double blind randomized placebo Double blind randomized placebo
controlled trialscontrolled trials IV delivery 3-9 hour time windowIV delivery 3-9 hour time window Plasminogen activator ndash from Plasminogen activator ndash from vampire bat vampire bat
salivasaliva Selection based on PWI-DWI MismatchSelection based on PWI-DWI Mismatch
MRI InclusionMRI Inclusion PWI defect at least 2 cm AND ~20 larger PWI defect at least 2 cm AND ~20 larger
than DWIthan DWI PWI should be obvious even visible on PWI should be obvious even visible on
raw imagesraw imagesMRI ExclusionMRI Exclusion
DWI gt 13 MCADWI gt 13 MCA MRA ICA occlusionMRA ICA occlusion
Desmoteplase ndash DIAS Desmoteplase ndash DIAS ResultsResults
Mechanical Thrombolysis Mechanical Thrombolysis devicesdevices
mechanical thrombolysis potentially extends the treatment mechanical thrombolysis potentially extends the treatment window because they act promptly at the site of the thrombuswindow because they act promptly at the site of the thrombus
The devices can retrieve large clots that pharmaceutical agents The devices can retrieve large clots that pharmaceutical agents may not successfully lysemay not successfully lyse
Patients treated with IV tPA may be considered for treatment of Patients treated with IV tPA may be considered for treatment of residual clot with some of these devicesresidual clot with some of these devices
suction-creating saline jets suction-creating saline jets laser energy ultrasound laser energy ultrasound a corkscrew apparatus to treat strokesa corkscrew apparatus to treat strokes The AngioJet systemThe AngioJet system uses saline jets that are directed back into the catheter to uses saline jets that are directed back into the catheter to
create a low-pressure zone around the catheter tip inducing create a low-pressure zone around the catheter tip inducing suction suction
The clot is pulled into the exhaust lumen and removed from the The clot is pulled into the exhaust lumen and removed from the vessel Although US Food and Drug Administration (FDA) has vessel Although US Food and Drug Administration (FDA) has approved this device for use in arteriovenous dialysis grafts and approved this device for use in arteriovenous dialysis grafts and fistulae and for the treatment of coronary arteries saphenous fistulae and for the treatment of coronary arteries saphenous vein grafts and peripheral vessels clinical trials for the vein grafts and peripheral vessels clinical trials for the treatment of acute stroke are no longer in progress treatment of acute stroke are no longer in progress
Most devices are used in cerebral vessels that 2-5 mm
The Latis laser device The Latis laser device used laser energy to ablate clots used laser energy to ablate clots Arteries 2-5 mm in diameter could be Arteries 2-5 mm in diameter could be
treated including the ICA M1 or M2 treated including the ICA M1 or M2 branch of the MCA A1 branch of the branch of the MCA A1 branch of the anterior cerebral artery (ACA) basilar anterior cerebral artery (ACA) basilar artery posterior cerebral artery (PCA) artery posterior cerebral artery (PCA) and vertebral and vertebral
Patients could receive treatment as late Patients could receive treatment as late as 8 hours after symptom onset in the as 8 hours after symptom onset in the anterior circulation and within 24 hours in anterior circulation and within 24 hours in the posterior circulation the posterior circulation
Endovascular Photo Acoustic Endovascular Photo Acoustic Recanalization (EPAR) Recanalization (EPAR)
A laser power source generated energy for the A laser power source generated energy for the systemsystem
The energy was delivered by means of The energy was delivered by means of fiberoptics to the tip of the catheter at the fiberoptics to the tip of the catheter at the treatment sitetreatment site
Absorption of laser light by darkly pigmented Absorption of laser light by darkly pigmented materials (ie the clot) occurred inside the 1-mm materials (ie the clot) occurred inside the 1-mm catheter tipcatheter tip
the system was designed to minimize scattering the system was designed to minimize scattering of laser light of laser light
Absorption converted photo energy to acoustic Absorption converted photo energy to acoustic energy which then emulsified the clot inside the energy which then emulsified the clot inside the catheter tip catheter tip
EKOS ultrasound( the EKOS ultrasound( the Ultrasound Thrombolytic Ultrasound Thrombolytic
Infusion Catheter) Infusion Catheter) combines the use of a distal ultrasound transducer with combines the use of a distal ultrasound transducer with
infusion of a thrombolytic agent through the infusion of a thrombolytic agent through the microcathetermicrocatheter
Ultrasound changes the structure of the clot to Ultrasound changes the structure of the clot to temporarily increase its permeability while providing an temporarily increase its permeability while providing an acoustic pressure gradient to move the drug into the clot acoustic pressure gradient to move the drug into the clot to speed its dissolution to speed its dissolution
The EKOS catheter is placed in the proximal portion of the The EKOS catheter is placed in the proximal portion of the clot clot
After a 2-mg bolus of tPA was injected through the After a 2-mg bolus of tPA was injected through the catheter catheter
the patient received a continuous infusion of IA tPA 03 the patient received a continuous infusion of IA tPA 03 mgmin to a maximum of 20 mg and simultaneous mgmin to a maximum of 20 mg and simultaneous ultrasound transmission for as long as 60 minutes ultrasound transmission for as long as 60 minutes
One patient was treated with a total of 4 units of One patient was treated with a total of 4 units of recombinant reteplase (Retavase) hand-injected over 60 recombinant reteplase (Retavase) hand-injected over 60 minutes minutes
Penumbra system Penumbra system The Penumbra system (Penumbra Inc) provides a dual The Penumbra system (Penumbra Inc) provides a dual
approach to clot extraction using aspiration followed by approach to clot extraction using aspiration followed by clot retrieval with a ring device if needed clot retrieval with a ring device if needed
Mechanical Embolus Removal in Cerebral Ischemia Mechanical Embolus Removal in Cerebral Ischemia (MERCI)(MERCI)
a corkscrew-like apparatus to remove blood clots from a corkscrew-like apparatus to remove blood clots from the brain in patients experiencing an ischemic stroke the brain in patients experiencing an ischemic stroke
The corkscrew itself resides in the catheter tip which The corkscrew itself resides in the catheter tip which shields it from the wall of the vessel until it is ready to be shields it from the wall of the vessel until it is ready to be burrowed into the clot Once lodged in the clot the device burrowed into the clot Once lodged in the clot the device and clot are withdrawn from the vessel and clot are withdrawn from the vessel
Snarelike devicesSnarelike devices Snares such as the Neuronet snare (Guidant Snares such as the Neuronet snare (Guidant
Endovascular Santa Clara CA) have been developed Endovascular Santa Clara CA) have been developed specifically for use in the treatment of strokes specifically for use in the treatment of strokes
These devices are simple in design and do not require the These devices are simple in design and do not require the clot to be amenable to emulsification clot to be amenable to emulsification
X-Sizer deviceX-Sizer device a device with small moving blades at the a device with small moving blades at the
catheter tip catheter tip This device the X-Sizer device (EndiCor Medical This device the X-Sizer device (EndiCor Medical
San Clemente CA) can be used to excise the San Clemente CA) can be used to excise the thrombus and aspirate it thrombus and aspirate it
The device was being evaluated in randomized The device was being evaluated in randomized studies of coronary vessels and in a registry of studies of coronary vessels and in a registry of patients with acute myocardial infarctionpatients with acute myocardial infarction
Although the manufacturer had modified the Although the manufacturer had modified the device for use in cerebral vessels a safety and device for use in cerebral vessels a safety and feasibility study was indefinitely suspended after feasibility study was indefinitely suspended after only 1 patient was treated with the device in only 1 patient was treated with the device in Europe Europe
Suction thrombectomySuction thrombectomy This method of mechanical thrombolysis is one of the This method of mechanical thrombolysis is one of the
simplestsimplest In this readily available technique suction is applied with In this readily available technique suction is applied with
a syringe to remove thrombus in the ICA a syringe to remove thrombus in the ICA It requires no other devicesIt requires no other devices A catheter with a large inner diameter (Brite Tip Cordis A catheter with a large inner diameter (Brite Tip Cordis
Corporation Miami FL) was placed in the symptomatic Corporation Miami FL) was placed in the symptomatic vessel and navigated over a guidewire into the thrombusvessel and navigated over a guidewire into the thrombus
A 60-mL syringe was used to aspirate the thrombus A 60-mL syringe was used to aspirate the thrombus Each patient required angioplasty and stenting of carotid Each patient required angioplasty and stenting of carotid
bifurcation stenosis and received daily aspirin and bifurcation stenosis and received daily aspirin and ticlopidine after the procedure No complications ticlopidine after the procedure No complications occurred occurred
Summary Acute Stroke Summary Acute Stroke ImagingImaging
PhysiologyPhysiology importance collaterals importance collaterals
ndash ndashGrowing role for perfusion Growing role for perfusion assessmentassessment
tPAtPA guidelines amp limitations guidelines amp limitations Signs on CT amp MRSigns on CT amp MR follow physiology follow physiology Stroke trialsStroke trials PWI-DWI mismatch PWI-DWI mismatch
ndash ndashTreat based on physiology not timeTreat based on physiology not time ProtocolsProtocols should be fast and should be fast and
comprehensivecomprehensive
Limitations of tPALimitations of tPA Only 4 of acute strokes receive tPAOnly 4 of acute strokes receive tPA (Kleindorfer et al Stroke 2004 35 e27-e29)(Kleindorfer et al Stroke 2004 35 e27-e29)
Only 22 of patients present within 3 hoursOnly 22 of patients present within 3 hours1048707 1048707 51 of these ineligible due to51 of these ineligible due to
bull bull Mild severityMild severity bull bull Medical or surgical historyMedical or surgical history bull bull Blood testsBlood tests
Sustained recanalization only 13Sustained recanalization only 13 (Alexandrov et al NEJM 2004 351 2170-8)(Alexandrov et al NEJM 2004 351 2170-8)
Concern for hemorrhageConcern for hemorrhage tPA potentiates apoptotic injury tPA potentiates apoptotic injury (Liu et al Nature Med 2004 101379-83)(Liu et al Nature Med 2004 101379-83)
PROACT II IA Lysis TrialPROACT II IA Lysis Trial Baseline 24 hours 8 days
Baseline 60 minutes 120 minutes
9mg IAProurokinase
Desmoteplase Trials DEDAS Desmoteplase Trials DEDAS DIASDIAS
Trial OverviewTrial Overview Double blind randomized placebo Double blind randomized placebo
controlled trialscontrolled trials IV delivery 3-9 hour time windowIV delivery 3-9 hour time window Plasminogen activator ndash from Plasminogen activator ndash from vampire bat vampire bat
salivasaliva Selection based on PWI-DWI MismatchSelection based on PWI-DWI Mismatch
MRI InclusionMRI Inclusion PWI defect at least 2 cm AND ~20 larger PWI defect at least 2 cm AND ~20 larger
than DWIthan DWI PWI should be obvious even visible on PWI should be obvious even visible on
raw imagesraw imagesMRI ExclusionMRI Exclusion
DWI gt 13 MCADWI gt 13 MCA MRA ICA occlusionMRA ICA occlusion
Desmoteplase ndash DIAS Desmoteplase ndash DIAS ResultsResults
Mechanical Thrombolysis Mechanical Thrombolysis devicesdevices
mechanical thrombolysis potentially extends the treatment mechanical thrombolysis potentially extends the treatment window because they act promptly at the site of the thrombuswindow because they act promptly at the site of the thrombus
The devices can retrieve large clots that pharmaceutical agents The devices can retrieve large clots that pharmaceutical agents may not successfully lysemay not successfully lyse
Patients treated with IV tPA may be considered for treatment of Patients treated with IV tPA may be considered for treatment of residual clot with some of these devicesresidual clot with some of these devices
suction-creating saline jets suction-creating saline jets laser energy ultrasound laser energy ultrasound a corkscrew apparatus to treat strokesa corkscrew apparatus to treat strokes The AngioJet systemThe AngioJet system uses saline jets that are directed back into the catheter to uses saline jets that are directed back into the catheter to
create a low-pressure zone around the catheter tip inducing create a low-pressure zone around the catheter tip inducing suction suction
The clot is pulled into the exhaust lumen and removed from the The clot is pulled into the exhaust lumen and removed from the vessel Although US Food and Drug Administration (FDA) has vessel Although US Food and Drug Administration (FDA) has approved this device for use in arteriovenous dialysis grafts and approved this device for use in arteriovenous dialysis grafts and fistulae and for the treatment of coronary arteries saphenous fistulae and for the treatment of coronary arteries saphenous vein grafts and peripheral vessels clinical trials for the vein grafts and peripheral vessels clinical trials for the treatment of acute stroke are no longer in progress treatment of acute stroke are no longer in progress
Most devices are used in cerebral vessels that 2-5 mm
The Latis laser device The Latis laser device used laser energy to ablate clots used laser energy to ablate clots Arteries 2-5 mm in diameter could be Arteries 2-5 mm in diameter could be
treated including the ICA M1 or M2 treated including the ICA M1 or M2 branch of the MCA A1 branch of the branch of the MCA A1 branch of the anterior cerebral artery (ACA) basilar anterior cerebral artery (ACA) basilar artery posterior cerebral artery (PCA) artery posterior cerebral artery (PCA) and vertebral and vertebral
Patients could receive treatment as late Patients could receive treatment as late as 8 hours after symptom onset in the as 8 hours after symptom onset in the anterior circulation and within 24 hours in anterior circulation and within 24 hours in the posterior circulation the posterior circulation
Endovascular Photo Acoustic Endovascular Photo Acoustic Recanalization (EPAR) Recanalization (EPAR)
A laser power source generated energy for the A laser power source generated energy for the systemsystem
The energy was delivered by means of The energy was delivered by means of fiberoptics to the tip of the catheter at the fiberoptics to the tip of the catheter at the treatment sitetreatment site
Absorption of laser light by darkly pigmented Absorption of laser light by darkly pigmented materials (ie the clot) occurred inside the 1-mm materials (ie the clot) occurred inside the 1-mm catheter tipcatheter tip
the system was designed to minimize scattering the system was designed to minimize scattering of laser light of laser light
Absorption converted photo energy to acoustic Absorption converted photo energy to acoustic energy which then emulsified the clot inside the energy which then emulsified the clot inside the catheter tip catheter tip
EKOS ultrasound( the EKOS ultrasound( the Ultrasound Thrombolytic Ultrasound Thrombolytic
Infusion Catheter) Infusion Catheter) combines the use of a distal ultrasound transducer with combines the use of a distal ultrasound transducer with
infusion of a thrombolytic agent through the infusion of a thrombolytic agent through the microcathetermicrocatheter
Ultrasound changes the structure of the clot to Ultrasound changes the structure of the clot to temporarily increase its permeability while providing an temporarily increase its permeability while providing an acoustic pressure gradient to move the drug into the clot acoustic pressure gradient to move the drug into the clot to speed its dissolution to speed its dissolution
The EKOS catheter is placed in the proximal portion of the The EKOS catheter is placed in the proximal portion of the clot clot
After a 2-mg bolus of tPA was injected through the After a 2-mg bolus of tPA was injected through the catheter catheter
the patient received a continuous infusion of IA tPA 03 the patient received a continuous infusion of IA tPA 03 mgmin to a maximum of 20 mg and simultaneous mgmin to a maximum of 20 mg and simultaneous ultrasound transmission for as long as 60 minutes ultrasound transmission for as long as 60 minutes
One patient was treated with a total of 4 units of One patient was treated with a total of 4 units of recombinant reteplase (Retavase) hand-injected over 60 recombinant reteplase (Retavase) hand-injected over 60 minutes minutes
Penumbra system Penumbra system The Penumbra system (Penumbra Inc) provides a dual The Penumbra system (Penumbra Inc) provides a dual
approach to clot extraction using aspiration followed by approach to clot extraction using aspiration followed by clot retrieval with a ring device if needed clot retrieval with a ring device if needed
Mechanical Embolus Removal in Cerebral Ischemia Mechanical Embolus Removal in Cerebral Ischemia (MERCI)(MERCI)
a corkscrew-like apparatus to remove blood clots from a corkscrew-like apparatus to remove blood clots from the brain in patients experiencing an ischemic stroke the brain in patients experiencing an ischemic stroke
The corkscrew itself resides in the catheter tip which The corkscrew itself resides in the catheter tip which shields it from the wall of the vessel until it is ready to be shields it from the wall of the vessel until it is ready to be burrowed into the clot Once lodged in the clot the device burrowed into the clot Once lodged in the clot the device and clot are withdrawn from the vessel and clot are withdrawn from the vessel
Snarelike devicesSnarelike devices Snares such as the Neuronet snare (Guidant Snares such as the Neuronet snare (Guidant
Endovascular Santa Clara CA) have been developed Endovascular Santa Clara CA) have been developed specifically for use in the treatment of strokes specifically for use in the treatment of strokes
These devices are simple in design and do not require the These devices are simple in design and do not require the clot to be amenable to emulsification clot to be amenable to emulsification
X-Sizer deviceX-Sizer device a device with small moving blades at the a device with small moving blades at the
catheter tip catheter tip This device the X-Sizer device (EndiCor Medical This device the X-Sizer device (EndiCor Medical
San Clemente CA) can be used to excise the San Clemente CA) can be used to excise the thrombus and aspirate it thrombus and aspirate it
The device was being evaluated in randomized The device was being evaluated in randomized studies of coronary vessels and in a registry of studies of coronary vessels and in a registry of patients with acute myocardial infarctionpatients with acute myocardial infarction
Although the manufacturer had modified the Although the manufacturer had modified the device for use in cerebral vessels a safety and device for use in cerebral vessels a safety and feasibility study was indefinitely suspended after feasibility study was indefinitely suspended after only 1 patient was treated with the device in only 1 patient was treated with the device in Europe Europe
Suction thrombectomySuction thrombectomy This method of mechanical thrombolysis is one of the This method of mechanical thrombolysis is one of the
simplestsimplest In this readily available technique suction is applied with In this readily available technique suction is applied with
a syringe to remove thrombus in the ICA a syringe to remove thrombus in the ICA It requires no other devicesIt requires no other devices A catheter with a large inner diameter (Brite Tip Cordis A catheter with a large inner diameter (Brite Tip Cordis
Corporation Miami FL) was placed in the symptomatic Corporation Miami FL) was placed in the symptomatic vessel and navigated over a guidewire into the thrombusvessel and navigated over a guidewire into the thrombus
A 60-mL syringe was used to aspirate the thrombus A 60-mL syringe was used to aspirate the thrombus Each patient required angioplasty and stenting of carotid Each patient required angioplasty and stenting of carotid
bifurcation stenosis and received daily aspirin and bifurcation stenosis and received daily aspirin and ticlopidine after the procedure No complications ticlopidine after the procedure No complications occurred occurred
Summary Acute Stroke Summary Acute Stroke ImagingImaging
PhysiologyPhysiology importance collaterals importance collaterals
ndash ndashGrowing role for perfusion Growing role for perfusion assessmentassessment
tPAtPA guidelines amp limitations guidelines amp limitations Signs on CT amp MRSigns on CT amp MR follow physiology follow physiology Stroke trialsStroke trials PWI-DWI mismatch PWI-DWI mismatch
ndash ndashTreat based on physiology not timeTreat based on physiology not time ProtocolsProtocols should be fast and should be fast and
comprehensivecomprehensive
PROACT II IA Lysis TrialPROACT II IA Lysis Trial Baseline 24 hours 8 days
Baseline 60 minutes 120 minutes
9mg IAProurokinase
Desmoteplase Trials DEDAS Desmoteplase Trials DEDAS DIASDIAS
Trial OverviewTrial Overview Double blind randomized placebo Double blind randomized placebo
controlled trialscontrolled trials IV delivery 3-9 hour time windowIV delivery 3-9 hour time window Plasminogen activator ndash from Plasminogen activator ndash from vampire bat vampire bat
salivasaliva Selection based on PWI-DWI MismatchSelection based on PWI-DWI Mismatch
MRI InclusionMRI Inclusion PWI defect at least 2 cm AND ~20 larger PWI defect at least 2 cm AND ~20 larger
than DWIthan DWI PWI should be obvious even visible on PWI should be obvious even visible on
raw imagesraw imagesMRI ExclusionMRI Exclusion
DWI gt 13 MCADWI gt 13 MCA MRA ICA occlusionMRA ICA occlusion
Desmoteplase ndash DIAS Desmoteplase ndash DIAS ResultsResults
Mechanical Thrombolysis Mechanical Thrombolysis devicesdevices
mechanical thrombolysis potentially extends the treatment mechanical thrombolysis potentially extends the treatment window because they act promptly at the site of the thrombuswindow because they act promptly at the site of the thrombus
The devices can retrieve large clots that pharmaceutical agents The devices can retrieve large clots that pharmaceutical agents may not successfully lysemay not successfully lyse
Patients treated with IV tPA may be considered for treatment of Patients treated with IV tPA may be considered for treatment of residual clot with some of these devicesresidual clot with some of these devices
suction-creating saline jets suction-creating saline jets laser energy ultrasound laser energy ultrasound a corkscrew apparatus to treat strokesa corkscrew apparatus to treat strokes The AngioJet systemThe AngioJet system uses saline jets that are directed back into the catheter to uses saline jets that are directed back into the catheter to
create a low-pressure zone around the catheter tip inducing create a low-pressure zone around the catheter tip inducing suction suction
The clot is pulled into the exhaust lumen and removed from the The clot is pulled into the exhaust lumen and removed from the vessel Although US Food and Drug Administration (FDA) has vessel Although US Food and Drug Administration (FDA) has approved this device for use in arteriovenous dialysis grafts and approved this device for use in arteriovenous dialysis grafts and fistulae and for the treatment of coronary arteries saphenous fistulae and for the treatment of coronary arteries saphenous vein grafts and peripheral vessels clinical trials for the vein grafts and peripheral vessels clinical trials for the treatment of acute stroke are no longer in progress treatment of acute stroke are no longer in progress
Most devices are used in cerebral vessels that 2-5 mm
The Latis laser device The Latis laser device used laser energy to ablate clots used laser energy to ablate clots Arteries 2-5 mm in diameter could be Arteries 2-5 mm in diameter could be
treated including the ICA M1 or M2 treated including the ICA M1 or M2 branch of the MCA A1 branch of the branch of the MCA A1 branch of the anterior cerebral artery (ACA) basilar anterior cerebral artery (ACA) basilar artery posterior cerebral artery (PCA) artery posterior cerebral artery (PCA) and vertebral and vertebral
Patients could receive treatment as late Patients could receive treatment as late as 8 hours after symptom onset in the as 8 hours after symptom onset in the anterior circulation and within 24 hours in anterior circulation and within 24 hours in the posterior circulation the posterior circulation
Endovascular Photo Acoustic Endovascular Photo Acoustic Recanalization (EPAR) Recanalization (EPAR)
A laser power source generated energy for the A laser power source generated energy for the systemsystem
The energy was delivered by means of The energy was delivered by means of fiberoptics to the tip of the catheter at the fiberoptics to the tip of the catheter at the treatment sitetreatment site
Absorption of laser light by darkly pigmented Absorption of laser light by darkly pigmented materials (ie the clot) occurred inside the 1-mm materials (ie the clot) occurred inside the 1-mm catheter tipcatheter tip
the system was designed to minimize scattering the system was designed to minimize scattering of laser light of laser light
Absorption converted photo energy to acoustic Absorption converted photo energy to acoustic energy which then emulsified the clot inside the energy which then emulsified the clot inside the catheter tip catheter tip
EKOS ultrasound( the EKOS ultrasound( the Ultrasound Thrombolytic Ultrasound Thrombolytic
Infusion Catheter) Infusion Catheter) combines the use of a distal ultrasound transducer with combines the use of a distal ultrasound transducer with
infusion of a thrombolytic agent through the infusion of a thrombolytic agent through the microcathetermicrocatheter
Ultrasound changes the structure of the clot to Ultrasound changes the structure of the clot to temporarily increase its permeability while providing an temporarily increase its permeability while providing an acoustic pressure gradient to move the drug into the clot acoustic pressure gradient to move the drug into the clot to speed its dissolution to speed its dissolution
The EKOS catheter is placed in the proximal portion of the The EKOS catheter is placed in the proximal portion of the clot clot
After a 2-mg bolus of tPA was injected through the After a 2-mg bolus of tPA was injected through the catheter catheter
the patient received a continuous infusion of IA tPA 03 the patient received a continuous infusion of IA tPA 03 mgmin to a maximum of 20 mg and simultaneous mgmin to a maximum of 20 mg and simultaneous ultrasound transmission for as long as 60 minutes ultrasound transmission for as long as 60 minutes
One patient was treated with a total of 4 units of One patient was treated with a total of 4 units of recombinant reteplase (Retavase) hand-injected over 60 recombinant reteplase (Retavase) hand-injected over 60 minutes minutes
Penumbra system Penumbra system The Penumbra system (Penumbra Inc) provides a dual The Penumbra system (Penumbra Inc) provides a dual
approach to clot extraction using aspiration followed by approach to clot extraction using aspiration followed by clot retrieval with a ring device if needed clot retrieval with a ring device if needed
Mechanical Embolus Removal in Cerebral Ischemia Mechanical Embolus Removal in Cerebral Ischemia (MERCI)(MERCI)
a corkscrew-like apparatus to remove blood clots from a corkscrew-like apparatus to remove blood clots from the brain in patients experiencing an ischemic stroke the brain in patients experiencing an ischemic stroke
The corkscrew itself resides in the catheter tip which The corkscrew itself resides in the catheter tip which shields it from the wall of the vessel until it is ready to be shields it from the wall of the vessel until it is ready to be burrowed into the clot Once lodged in the clot the device burrowed into the clot Once lodged in the clot the device and clot are withdrawn from the vessel and clot are withdrawn from the vessel
Snarelike devicesSnarelike devices Snares such as the Neuronet snare (Guidant Snares such as the Neuronet snare (Guidant
Endovascular Santa Clara CA) have been developed Endovascular Santa Clara CA) have been developed specifically for use in the treatment of strokes specifically for use in the treatment of strokes
These devices are simple in design and do not require the These devices are simple in design and do not require the clot to be amenable to emulsification clot to be amenable to emulsification
X-Sizer deviceX-Sizer device a device with small moving blades at the a device with small moving blades at the
catheter tip catheter tip This device the X-Sizer device (EndiCor Medical This device the X-Sizer device (EndiCor Medical
San Clemente CA) can be used to excise the San Clemente CA) can be used to excise the thrombus and aspirate it thrombus and aspirate it
The device was being evaluated in randomized The device was being evaluated in randomized studies of coronary vessels and in a registry of studies of coronary vessels and in a registry of patients with acute myocardial infarctionpatients with acute myocardial infarction
Although the manufacturer had modified the Although the manufacturer had modified the device for use in cerebral vessels a safety and device for use in cerebral vessels a safety and feasibility study was indefinitely suspended after feasibility study was indefinitely suspended after only 1 patient was treated with the device in only 1 patient was treated with the device in Europe Europe
Suction thrombectomySuction thrombectomy This method of mechanical thrombolysis is one of the This method of mechanical thrombolysis is one of the
simplestsimplest In this readily available technique suction is applied with In this readily available technique suction is applied with
a syringe to remove thrombus in the ICA a syringe to remove thrombus in the ICA It requires no other devicesIt requires no other devices A catheter with a large inner diameter (Brite Tip Cordis A catheter with a large inner diameter (Brite Tip Cordis
Corporation Miami FL) was placed in the symptomatic Corporation Miami FL) was placed in the symptomatic vessel and navigated over a guidewire into the thrombusvessel and navigated over a guidewire into the thrombus
A 60-mL syringe was used to aspirate the thrombus A 60-mL syringe was used to aspirate the thrombus Each patient required angioplasty and stenting of carotid Each patient required angioplasty and stenting of carotid
bifurcation stenosis and received daily aspirin and bifurcation stenosis and received daily aspirin and ticlopidine after the procedure No complications ticlopidine after the procedure No complications occurred occurred
Summary Acute Stroke Summary Acute Stroke ImagingImaging
PhysiologyPhysiology importance collaterals importance collaterals
ndash ndashGrowing role for perfusion Growing role for perfusion assessmentassessment
tPAtPA guidelines amp limitations guidelines amp limitations Signs on CT amp MRSigns on CT amp MR follow physiology follow physiology Stroke trialsStroke trials PWI-DWI mismatch PWI-DWI mismatch
ndash ndashTreat based on physiology not timeTreat based on physiology not time ProtocolsProtocols should be fast and should be fast and
comprehensivecomprehensive
Desmoteplase Trials DEDAS Desmoteplase Trials DEDAS DIASDIAS
Trial OverviewTrial Overview Double blind randomized placebo Double blind randomized placebo
controlled trialscontrolled trials IV delivery 3-9 hour time windowIV delivery 3-9 hour time window Plasminogen activator ndash from Plasminogen activator ndash from vampire bat vampire bat
salivasaliva Selection based on PWI-DWI MismatchSelection based on PWI-DWI Mismatch
MRI InclusionMRI Inclusion PWI defect at least 2 cm AND ~20 larger PWI defect at least 2 cm AND ~20 larger
than DWIthan DWI PWI should be obvious even visible on PWI should be obvious even visible on
raw imagesraw imagesMRI ExclusionMRI Exclusion
DWI gt 13 MCADWI gt 13 MCA MRA ICA occlusionMRA ICA occlusion
Desmoteplase ndash DIAS Desmoteplase ndash DIAS ResultsResults
Mechanical Thrombolysis Mechanical Thrombolysis devicesdevices
mechanical thrombolysis potentially extends the treatment mechanical thrombolysis potentially extends the treatment window because they act promptly at the site of the thrombuswindow because they act promptly at the site of the thrombus
The devices can retrieve large clots that pharmaceutical agents The devices can retrieve large clots that pharmaceutical agents may not successfully lysemay not successfully lyse
Patients treated with IV tPA may be considered for treatment of Patients treated with IV tPA may be considered for treatment of residual clot with some of these devicesresidual clot with some of these devices
suction-creating saline jets suction-creating saline jets laser energy ultrasound laser energy ultrasound a corkscrew apparatus to treat strokesa corkscrew apparatus to treat strokes The AngioJet systemThe AngioJet system uses saline jets that are directed back into the catheter to uses saline jets that are directed back into the catheter to
create a low-pressure zone around the catheter tip inducing create a low-pressure zone around the catheter tip inducing suction suction
The clot is pulled into the exhaust lumen and removed from the The clot is pulled into the exhaust lumen and removed from the vessel Although US Food and Drug Administration (FDA) has vessel Although US Food and Drug Administration (FDA) has approved this device for use in arteriovenous dialysis grafts and approved this device for use in arteriovenous dialysis grafts and fistulae and for the treatment of coronary arteries saphenous fistulae and for the treatment of coronary arteries saphenous vein grafts and peripheral vessels clinical trials for the vein grafts and peripheral vessels clinical trials for the treatment of acute stroke are no longer in progress treatment of acute stroke are no longer in progress
Most devices are used in cerebral vessels that 2-5 mm
The Latis laser device The Latis laser device used laser energy to ablate clots used laser energy to ablate clots Arteries 2-5 mm in diameter could be Arteries 2-5 mm in diameter could be
treated including the ICA M1 or M2 treated including the ICA M1 or M2 branch of the MCA A1 branch of the branch of the MCA A1 branch of the anterior cerebral artery (ACA) basilar anterior cerebral artery (ACA) basilar artery posterior cerebral artery (PCA) artery posterior cerebral artery (PCA) and vertebral and vertebral
Patients could receive treatment as late Patients could receive treatment as late as 8 hours after symptom onset in the as 8 hours after symptom onset in the anterior circulation and within 24 hours in anterior circulation and within 24 hours in the posterior circulation the posterior circulation
Endovascular Photo Acoustic Endovascular Photo Acoustic Recanalization (EPAR) Recanalization (EPAR)
A laser power source generated energy for the A laser power source generated energy for the systemsystem
The energy was delivered by means of The energy was delivered by means of fiberoptics to the tip of the catheter at the fiberoptics to the tip of the catheter at the treatment sitetreatment site
Absorption of laser light by darkly pigmented Absorption of laser light by darkly pigmented materials (ie the clot) occurred inside the 1-mm materials (ie the clot) occurred inside the 1-mm catheter tipcatheter tip
the system was designed to minimize scattering the system was designed to minimize scattering of laser light of laser light
Absorption converted photo energy to acoustic Absorption converted photo energy to acoustic energy which then emulsified the clot inside the energy which then emulsified the clot inside the catheter tip catheter tip
EKOS ultrasound( the EKOS ultrasound( the Ultrasound Thrombolytic Ultrasound Thrombolytic
Infusion Catheter) Infusion Catheter) combines the use of a distal ultrasound transducer with combines the use of a distal ultrasound transducer with
infusion of a thrombolytic agent through the infusion of a thrombolytic agent through the microcathetermicrocatheter
Ultrasound changes the structure of the clot to Ultrasound changes the structure of the clot to temporarily increase its permeability while providing an temporarily increase its permeability while providing an acoustic pressure gradient to move the drug into the clot acoustic pressure gradient to move the drug into the clot to speed its dissolution to speed its dissolution
The EKOS catheter is placed in the proximal portion of the The EKOS catheter is placed in the proximal portion of the clot clot
After a 2-mg bolus of tPA was injected through the After a 2-mg bolus of tPA was injected through the catheter catheter
the patient received a continuous infusion of IA tPA 03 the patient received a continuous infusion of IA tPA 03 mgmin to a maximum of 20 mg and simultaneous mgmin to a maximum of 20 mg and simultaneous ultrasound transmission for as long as 60 minutes ultrasound transmission for as long as 60 minutes
One patient was treated with a total of 4 units of One patient was treated with a total of 4 units of recombinant reteplase (Retavase) hand-injected over 60 recombinant reteplase (Retavase) hand-injected over 60 minutes minutes
Penumbra system Penumbra system The Penumbra system (Penumbra Inc) provides a dual The Penumbra system (Penumbra Inc) provides a dual
approach to clot extraction using aspiration followed by approach to clot extraction using aspiration followed by clot retrieval with a ring device if needed clot retrieval with a ring device if needed
Mechanical Embolus Removal in Cerebral Ischemia Mechanical Embolus Removal in Cerebral Ischemia (MERCI)(MERCI)
a corkscrew-like apparatus to remove blood clots from a corkscrew-like apparatus to remove blood clots from the brain in patients experiencing an ischemic stroke the brain in patients experiencing an ischemic stroke
The corkscrew itself resides in the catheter tip which The corkscrew itself resides in the catheter tip which shields it from the wall of the vessel until it is ready to be shields it from the wall of the vessel until it is ready to be burrowed into the clot Once lodged in the clot the device burrowed into the clot Once lodged in the clot the device and clot are withdrawn from the vessel and clot are withdrawn from the vessel
Snarelike devicesSnarelike devices Snares such as the Neuronet snare (Guidant Snares such as the Neuronet snare (Guidant
Endovascular Santa Clara CA) have been developed Endovascular Santa Clara CA) have been developed specifically for use in the treatment of strokes specifically for use in the treatment of strokes
These devices are simple in design and do not require the These devices are simple in design and do not require the clot to be amenable to emulsification clot to be amenable to emulsification
X-Sizer deviceX-Sizer device a device with small moving blades at the a device with small moving blades at the
catheter tip catheter tip This device the X-Sizer device (EndiCor Medical This device the X-Sizer device (EndiCor Medical
San Clemente CA) can be used to excise the San Clemente CA) can be used to excise the thrombus and aspirate it thrombus and aspirate it
The device was being evaluated in randomized The device was being evaluated in randomized studies of coronary vessels and in a registry of studies of coronary vessels and in a registry of patients with acute myocardial infarctionpatients with acute myocardial infarction
Although the manufacturer had modified the Although the manufacturer had modified the device for use in cerebral vessels a safety and device for use in cerebral vessels a safety and feasibility study was indefinitely suspended after feasibility study was indefinitely suspended after only 1 patient was treated with the device in only 1 patient was treated with the device in Europe Europe
Suction thrombectomySuction thrombectomy This method of mechanical thrombolysis is one of the This method of mechanical thrombolysis is one of the
simplestsimplest In this readily available technique suction is applied with In this readily available technique suction is applied with
a syringe to remove thrombus in the ICA a syringe to remove thrombus in the ICA It requires no other devicesIt requires no other devices A catheter with a large inner diameter (Brite Tip Cordis A catheter with a large inner diameter (Brite Tip Cordis
Corporation Miami FL) was placed in the symptomatic Corporation Miami FL) was placed in the symptomatic vessel and navigated over a guidewire into the thrombusvessel and navigated over a guidewire into the thrombus
A 60-mL syringe was used to aspirate the thrombus A 60-mL syringe was used to aspirate the thrombus Each patient required angioplasty and stenting of carotid Each patient required angioplasty and stenting of carotid
bifurcation stenosis and received daily aspirin and bifurcation stenosis and received daily aspirin and ticlopidine after the procedure No complications ticlopidine after the procedure No complications occurred occurred
Summary Acute Stroke Summary Acute Stroke ImagingImaging
PhysiologyPhysiology importance collaterals importance collaterals
ndash ndashGrowing role for perfusion Growing role for perfusion assessmentassessment
tPAtPA guidelines amp limitations guidelines amp limitations Signs on CT amp MRSigns on CT amp MR follow physiology follow physiology Stroke trialsStroke trials PWI-DWI mismatch PWI-DWI mismatch
ndash ndashTreat based on physiology not timeTreat based on physiology not time ProtocolsProtocols should be fast and should be fast and
comprehensivecomprehensive
Desmoteplase ndash DIAS Desmoteplase ndash DIAS ResultsResults
Mechanical Thrombolysis Mechanical Thrombolysis devicesdevices
mechanical thrombolysis potentially extends the treatment mechanical thrombolysis potentially extends the treatment window because they act promptly at the site of the thrombuswindow because they act promptly at the site of the thrombus
The devices can retrieve large clots that pharmaceutical agents The devices can retrieve large clots that pharmaceutical agents may not successfully lysemay not successfully lyse
Patients treated with IV tPA may be considered for treatment of Patients treated with IV tPA may be considered for treatment of residual clot with some of these devicesresidual clot with some of these devices
suction-creating saline jets suction-creating saline jets laser energy ultrasound laser energy ultrasound a corkscrew apparatus to treat strokesa corkscrew apparatus to treat strokes The AngioJet systemThe AngioJet system uses saline jets that are directed back into the catheter to uses saline jets that are directed back into the catheter to
create a low-pressure zone around the catheter tip inducing create a low-pressure zone around the catheter tip inducing suction suction
The clot is pulled into the exhaust lumen and removed from the The clot is pulled into the exhaust lumen and removed from the vessel Although US Food and Drug Administration (FDA) has vessel Although US Food and Drug Administration (FDA) has approved this device for use in arteriovenous dialysis grafts and approved this device for use in arteriovenous dialysis grafts and fistulae and for the treatment of coronary arteries saphenous fistulae and for the treatment of coronary arteries saphenous vein grafts and peripheral vessels clinical trials for the vein grafts and peripheral vessels clinical trials for the treatment of acute stroke are no longer in progress treatment of acute stroke are no longer in progress
Most devices are used in cerebral vessels that 2-5 mm
The Latis laser device The Latis laser device used laser energy to ablate clots used laser energy to ablate clots Arteries 2-5 mm in diameter could be Arteries 2-5 mm in diameter could be
treated including the ICA M1 or M2 treated including the ICA M1 or M2 branch of the MCA A1 branch of the branch of the MCA A1 branch of the anterior cerebral artery (ACA) basilar anterior cerebral artery (ACA) basilar artery posterior cerebral artery (PCA) artery posterior cerebral artery (PCA) and vertebral and vertebral
Patients could receive treatment as late Patients could receive treatment as late as 8 hours after symptom onset in the as 8 hours after symptom onset in the anterior circulation and within 24 hours in anterior circulation and within 24 hours in the posterior circulation the posterior circulation
Endovascular Photo Acoustic Endovascular Photo Acoustic Recanalization (EPAR) Recanalization (EPAR)
A laser power source generated energy for the A laser power source generated energy for the systemsystem
The energy was delivered by means of The energy was delivered by means of fiberoptics to the tip of the catheter at the fiberoptics to the tip of the catheter at the treatment sitetreatment site
Absorption of laser light by darkly pigmented Absorption of laser light by darkly pigmented materials (ie the clot) occurred inside the 1-mm materials (ie the clot) occurred inside the 1-mm catheter tipcatheter tip
the system was designed to minimize scattering the system was designed to minimize scattering of laser light of laser light
Absorption converted photo energy to acoustic Absorption converted photo energy to acoustic energy which then emulsified the clot inside the energy which then emulsified the clot inside the catheter tip catheter tip
EKOS ultrasound( the EKOS ultrasound( the Ultrasound Thrombolytic Ultrasound Thrombolytic
Infusion Catheter) Infusion Catheter) combines the use of a distal ultrasound transducer with combines the use of a distal ultrasound transducer with
infusion of a thrombolytic agent through the infusion of a thrombolytic agent through the microcathetermicrocatheter
Ultrasound changes the structure of the clot to Ultrasound changes the structure of the clot to temporarily increase its permeability while providing an temporarily increase its permeability while providing an acoustic pressure gradient to move the drug into the clot acoustic pressure gradient to move the drug into the clot to speed its dissolution to speed its dissolution
The EKOS catheter is placed in the proximal portion of the The EKOS catheter is placed in the proximal portion of the clot clot
After a 2-mg bolus of tPA was injected through the After a 2-mg bolus of tPA was injected through the catheter catheter
the patient received a continuous infusion of IA tPA 03 the patient received a continuous infusion of IA tPA 03 mgmin to a maximum of 20 mg and simultaneous mgmin to a maximum of 20 mg and simultaneous ultrasound transmission for as long as 60 minutes ultrasound transmission for as long as 60 minutes
One patient was treated with a total of 4 units of One patient was treated with a total of 4 units of recombinant reteplase (Retavase) hand-injected over 60 recombinant reteplase (Retavase) hand-injected over 60 minutes minutes
Penumbra system Penumbra system The Penumbra system (Penumbra Inc) provides a dual The Penumbra system (Penumbra Inc) provides a dual
approach to clot extraction using aspiration followed by approach to clot extraction using aspiration followed by clot retrieval with a ring device if needed clot retrieval with a ring device if needed
Mechanical Embolus Removal in Cerebral Ischemia Mechanical Embolus Removal in Cerebral Ischemia (MERCI)(MERCI)
a corkscrew-like apparatus to remove blood clots from a corkscrew-like apparatus to remove blood clots from the brain in patients experiencing an ischemic stroke the brain in patients experiencing an ischemic stroke
The corkscrew itself resides in the catheter tip which The corkscrew itself resides in the catheter tip which shields it from the wall of the vessel until it is ready to be shields it from the wall of the vessel until it is ready to be burrowed into the clot Once lodged in the clot the device burrowed into the clot Once lodged in the clot the device and clot are withdrawn from the vessel and clot are withdrawn from the vessel
Snarelike devicesSnarelike devices Snares such as the Neuronet snare (Guidant Snares such as the Neuronet snare (Guidant
Endovascular Santa Clara CA) have been developed Endovascular Santa Clara CA) have been developed specifically for use in the treatment of strokes specifically for use in the treatment of strokes
These devices are simple in design and do not require the These devices are simple in design and do not require the clot to be amenable to emulsification clot to be amenable to emulsification
X-Sizer deviceX-Sizer device a device with small moving blades at the a device with small moving blades at the
catheter tip catheter tip This device the X-Sizer device (EndiCor Medical This device the X-Sizer device (EndiCor Medical
San Clemente CA) can be used to excise the San Clemente CA) can be used to excise the thrombus and aspirate it thrombus and aspirate it
The device was being evaluated in randomized The device was being evaluated in randomized studies of coronary vessels and in a registry of studies of coronary vessels and in a registry of patients with acute myocardial infarctionpatients with acute myocardial infarction
Although the manufacturer had modified the Although the manufacturer had modified the device for use in cerebral vessels a safety and device for use in cerebral vessels a safety and feasibility study was indefinitely suspended after feasibility study was indefinitely suspended after only 1 patient was treated with the device in only 1 patient was treated with the device in Europe Europe
Suction thrombectomySuction thrombectomy This method of mechanical thrombolysis is one of the This method of mechanical thrombolysis is one of the
simplestsimplest In this readily available technique suction is applied with In this readily available technique suction is applied with
a syringe to remove thrombus in the ICA a syringe to remove thrombus in the ICA It requires no other devicesIt requires no other devices A catheter with a large inner diameter (Brite Tip Cordis A catheter with a large inner diameter (Brite Tip Cordis
Corporation Miami FL) was placed in the symptomatic Corporation Miami FL) was placed in the symptomatic vessel and navigated over a guidewire into the thrombusvessel and navigated over a guidewire into the thrombus
A 60-mL syringe was used to aspirate the thrombus A 60-mL syringe was used to aspirate the thrombus Each patient required angioplasty and stenting of carotid Each patient required angioplasty and stenting of carotid
bifurcation stenosis and received daily aspirin and bifurcation stenosis and received daily aspirin and ticlopidine after the procedure No complications ticlopidine after the procedure No complications occurred occurred
Summary Acute Stroke Summary Acute Stroke ImagingImaging
PhysiologyPhysiology importance collaterals importance collaterals
ndash ndashGrowing role for perfusion Growing role for perfusion assessmentassessment
tPAtPA guidelines amp limitations guidelines amp limitations Signs on CT amp MRSigns on CT amp MR follow physiology follow physiology Stroke trialsStroke trials PWI-DWI mismatch PWI-DWI mismatch
ndash ndashTreat based on physiology not timeTreat based on physiology not time ProtocolsProtocols should be fast and should be fast and
comprehensivecomprehensive
Mechanical Thrombolysis Mechanical Thrombolysis devicesdevices
mechanical thrombolysis potentially extends the treatment mechanical thrombolysis potentially extends the treatment window because they act promptly at the site of the thrombuswindow because they act promptly at the site of the thrombus
The devices can retrieve large clots that pharmaceutical agents The devices can retrieve large clots that pharmaceutical agents may not successfully lysemay not successfully lyse
Patients treated with IV tPA may be considered for treatment of Patients treated with IV tPA may be considered for treatment of residual clot with some of these devicesresidual clot with some of these devices
suction-creating saline jets suction-creating saline jets laser energy ultrasound laser energy ultrasound a corkscrew apparatus to treat strokesa corkscrew apparatus to treat strokes The AngioJet systemThe AngioJet system uses saline jets that are directed back into the catheter to uses saline jets that are directed back into the catheter to
create a low-pressure zone around the catheter tip inducing create a low-pressure zone around the catheter tip inducing suction suction
The clot is pulled into the exhaust lumen and removed from the The clot is pulled into the exhaust lumen and removed from the vessel Although US Food and Drug Administration (FDA) has vessel Although US Food and Drug Administration (FDA) has approved this device for use in arteriovenous dialysis grafts and approved this device for use in arteriovenous dialysis grafts and fistulae and for the treatment of coronary arteries saphenous fistulae and for the treatment of coronary arteries saphenous vein grafts and peripheral vessels clinical trials for the vein grafts and peripheral vessels clinical trials for the treatment of acute stroke are no longer in progress treatment of acute stroke are no longer in progress
Most devices are used in cerebral vessels that 2-5 mm
The Latis laser device The Latis laser device used laser energy to ablate clots used laser energy to ablate clots Arteries 2-5 mm in diameter could be Arteries 2-5 mm in diameter could be
treated including the ICA M1 or M2 treated including the ICA M1 or M2 branch of the MCA A1 branch of the branch of the MCA A1 branch of the anterior cerebral artery (ACA) basilar anterior cerebral artery (ACA) basilar artery posterior cerebral artery (PCA) artery posterior cerebral artery (PCA) and vertebral and vertebral
Patients could receive treatment as late Patients could receive treatment as late as 8 hours after symptom onset in the as 8 hours after symptom onset in the anterior circulation and within 24 hours in anterior circulation and within 24 hours in the posterior circulation the posterior circulation
Endovascular Photo Acoustic Endovascular Photo Acoustic Recanalization (EPAR) Recanalization (EPAR)
A laser power source generated energy for the A laser power source generated energy for the systemsystem
The energy was delivered by means of The energy was delivered by means of fiberoptics to the tip of the catheter at the fiberoptics to the tip of the catheter at the treatment sitetreatment site
Absorption of laser light by darkly pigmented Absorption of laser light by darkly pigmented materials (ie the clot) occurred inside the 1-mm materials (ie the clot) occurred inside the 1-mm catheter tipcatheter tip
the system was designed to minimize scattering the system was designed to minimize scattering of laser light of laser light
Absorption converted photo energy to acoustic Absorption converted photo energy to acoustic energy which then emulsified the clot inside the energy which then emulsified the clot inside the catheter tip catheter tip
EKOS ultrasound( the EKOS ultrasound( the Ultrasound Thrombolytic Ultrasound Thrombolytic
Infusion Catheter) Infusion Catheter) combines the use of a distal ultrasound transducer with combines the use of a distal ultrasound transducer with
infusion of a thrombolytic agent through the infusion of a thrombolytic agent through the microcathetermicrocatheter
Ultrasound changes the structure of the clot to Ultrasound changes the structure of the clot to temporarily increase its permeability while providing an temporarily increase its permeability while providing an acoustic pressure gradient to move the drug into the clot acoustic pressure gradient to move the drug into the clot to speed its dissolution to speed its dissolution
The EKOS catheter is placed in the proximal portion of the The EKOS catheter is placed in the proximal portion of the clot clot
After a 2-mg bolus of tPA was injected through the After a 2-mg bolus of tPA was injected through the catheter catheter
the patient received a continuous infusion of IA tPA 03 the patient received a continuous infusion of IA tPA 03 mgmin to a maximum of 20 mg and simultaneous mgmin to a maximum of 20 mg and simultaneous ultrasound transmission for as long as 60 minutes ultrasound transmission for as long as 60 minutes
One patient was treated with a total of 4 units of One patient was treated with a total of 4 units of recombinant reteplase (Retavase) hand-injected over 60 recombinant reteplase (Retavase) hand-injected over 60 minutes minutes
Penumbra system Penumbra system The Penumbra system (Penumbra Inc) provides a dual The Penumbra system (Penumbra Inc) provides a dual
approach to clot extraction using aspiration followed by approach to clot extraction using aspiration followed by clot retrieval with a ring device if needed clot retrieval with a ring device if needed
Mechanical Embolus Removal in Cerebral Ischemia Mechanical Embolus Removal in Cerebral Ischemia (MERCI)(MERCI)
a corkscrew-like apparatus to remove blood clots from a corkscrew-like apparatus to remove blood clots from the brain in patients experiencing an ischemic stroke the brain in patients experiencing an ischemic stroke
The corkscrew itself resides in the catheter tip which The corkscrew itself resides in the catheter tip which shields it from the wall of the vessel until it is ready to be shields it from the wall of the vessel until it is ready to be burrowed into the clot Once lodged in the clot the device burrowed into the clot Once lodged in the clot the device and clot are withdrawn from the vessel and clot are withdrawn from the vessel
Snarelike devicesSnarelike devices Snares such as the Neuronet snare (Guidant Snares such as the Neuronet snare (Guidant
Endovascular Santa Clara CA) have been developed Endovascular Santa Clara CA) have been developed specifically for use in the treatment of strokes specifically for use in the treatment of strokes
These devices are simple in design and do not require the These devices are simple in design and do not require the clot to be amenable to emulsification clot to be amenable to emulsification
X-Sizer deviceX-Sizer device a device with small moving blades at the a device with small moving blades at the
catheter tip catheter tip This device the X-Sizer device (EndiCor Medical This device the X-Sizer device (EndiCor Medical
San Clemente CA) can be used to excise the San Clemente CA) can be used to excise the thrombus and aspirate it thrombus and aspirate it
The device was being evaluated in randomized The device was being evaluated in randomized studies of coronary vessels and in a registry of studies of coronary vessels and in a registry of patients with acute myocardial infarctionpatients with acute myocardial infarction
Although the manufacturer had modified the Although the manufacturer had modified the device for use in cerebral vessels a safety and device for use in cerebral vessels a safety and feasibility study was indefinitely suspended after feasibility study was indefinitely suspended after only 1 patient was treated with the device in only 1 patient was treated with the device in Europe Europe
Suction thrombectomySuction thrombectomy This method of mechanical thrombolysis is one of the This method of mechanical thrombolysis is one of the
simplestsimplest In this readily available technique suction is applied with In this readily available technique suction is applied with
a syringe to remove thrombus in the ICA a syringe to remove thrombus in the ICA It requires no other devicesIt requires no other devices A catheter with a large inner diameter (Brite Tip Cordis A catheter with a large inner diameter (Brite Tip Cordis
Corporation Miami FL) was placed in the symptomatic Corporation Miami FL) was placed in the symptomatic vessel and navigated over a guidewire into the thrombusvessel and navigated over a guidewire into the thrombus
A 60-mL syringe was used to aspirate the thrombus A 60-mL syringe was used to aspirate the thrombus Each patient required angioplasty and stenting of carotid Each patient required angioplasty and stenting of carotid
bifurcation stenosis and received daily aspirin and bifurcation stenosis and received daily aspirin and ticlopidine after the procedure No complications ticlopidine after the procedure No complications occurred occurred
Summary Acute Stroke Summary Acute Stroke ImagingImaging
PhysiologyPhysiology importance collaterals importance collaterals
ndash ndashGrowing role for perfusion Growing role for perfusion assessmentassessment
tPAtPA guidelines amp limitations guidelines amp limitations Signs on CT amp MRSigns on CT amp MR follow physiology follow physiology Stroke trialsStroke trials PWI-DWI mismatch PWI-DWI mismatch
ndash ndashTreat based on physiology not timeTreat based on physiology not time ProtocolsProtocols should be fast and should be fast and
comprehensivecomprehensive
The Latis laser device The Latis laser device used laser energy to ablate clots used laser energy to ablate clots Arteries 2-5 mm in diameter could be Arteries 2-5 mm in diameter could be
treated including the ICA M1 or M2 treated including the ICA M1 or M2 branch of the MCA A1 branch of the branch of the MCA A1 branch of the anterior cerebral artery (ACA) basilar anterior cerebral artery (ACA) basilar artery posterior cerebral artery (PCA) artery posterior cerebral artery (PCA) and vertebral and vertebral
Patients could receive treatment as late Patients could receive treatment as late as 8 hours after symptom onset in the as 8 hours after symptom onset in the anterior circulation and within 24 hours in anterior circulation and within 24 hours in the posterior circulation the posterior circulation
Endovascular Photo Acoustic Endovascular Photo Acoustic Recanalization (EPAR) Recanalization (EPAR)
A laser power source generated energy for the A laser power source generated energy for the systemsystem
The energy was delivered by means of The energy was delivered by means of fiberoptics to the tip of the catheter at the fiberoptics to the tip of the catheter at the treatment sitetreatment site
Absorption of laser light by darkly pigmented Absorption of laser light by darkly pigmented materials (ie the clot) occurred inside the 1-mm materials (ie the clot) occurred inside the 1-mm catheter tipcatheter tip
the system was designed to minimize scattering the system was designed to minimize scattering of laser light of laser light
Absorption converted photo energy to acoustic Absorption converted photo energy to acoustic energy which then emulsified the clot inside the energy which then emulsified the clot inside the catheter tip catheter tip
EKOS ultrasound( the EKOS ultrasound( the Ultrasound Thrombolytic Ultrasound Thrombolytic
Infusion Catheter) Infusion Catheter) combines the use of a distal ultrasound transducer with combines the use of a distal ultrasound transducer with
infusion of a thrombolytic agent through the infusion of a thrombolytic agent through the microcathetermicrocatheter
Ultrasound changes the structure of the clot to Ultrasound changes the structure of the clot to temporarily increase its permeability while providing an temporarily increase its permeability while providing an acoustic pressure gradient to move the drug into the clot acoustic pressure gradient to move the drug into the clot to speed its dissolution to speed its dissolution
The EKOS catheter is placed in the proximal portion of the The EKOS catheter is placed in the proximal portion of the clot clot
After a 2-mg bolus of tPA was injected through the After a 2-mg bolus of tPA was injected through the catheter catheter
the patient received a continuous infusion of IA tPA 03 the patient received a continuous infusion of IA tPA 03 mgmin to a maximum of 20 mg and simultaneous mgmin to a maximum of 20 mg and simultaneous ultrasound transmission for as long as 60 minutes ultrasound transmission for as long as 60 minutes
One patient was treated with a total of 4 units of One patient was treated with a total of 4 units of recombinant reteplase (Retavase) hand-injected over 60 recombinant reteplase (Retavase) hand-injected over 60 minutes minutes
Penumbra system Penumbra system The Penumbra system (Penumbra Inc) provides a dual The Penumbra system (Penumbra Inc) provides a dual
approach to clot extraction using aspiration followed by approach to clot extraction using aspiration followed by clot retrieval with a ring device if needed clot retrieval with a ring device if needed
Mechanical Embolus Removal in Cerebral Ischemia Mechanical Embolus Removal in Cerebral Ischemia (MERCI)(MERCI)
a corkscrew-like apparatus to remove blood clots from a corkscrew-like apparatus to remove blood clots from the brain in patients experiencing an ischemic stroke the brain in patients experiencing an ischemic stroke
The corkscrew itself resides in the catheter tip which The corkscrew itself resides in the catheter tip which shields it from the wall of the vessel until it is ready to be shields it from the wall of the vessel until it is ready to be burrowed into the clot Once lodged in the clot the device burrowed into the clot Once lodged in the clot the device and clot are withdrawn from the vessel and clot are withdrawn from the vessel
Snarelike devicesSnarelike devices Snares such as the Neuronet snare (Guidant Snares such as the Neuronet snare (Guidant
Endovascular Santa Clara CA) have been developed Endovascular Santa Clara CA) have been developed specifically for use in the treatment of strokes specifically for use in the treatment of strokes
These devices are simple in design and do not require the These devices are simple in design and do not require the clot to be amenable to emulsification clot to be amenable to emulsification
X-Sizer deviceX-Sizer device a device with small moving blades at the a device with small moving blades at the
catheter tip catheter tip This device the X-Sizer device (EndiCor Medical This device the X-Sizer device (EndiCor Medical
San Clemente CA) can be used to excise the San Clemente CA) can be used to excise the thrombus and aspirate it thrombus and aspirate it
The device was being evaluated in randomized The device was being evaluated in randomized studies of coronary vessels and in a registry of studies of coronary vessels and in a registry of patients with acute myocardial infarctionpatients with acute myocardial infarction
Although the manufacturer had modified the Although the manufacturer had modified the device for use in cerebral vessels a safety and device for use in cerebral vessels a safety and feasibility study was indefinitely suspended after feasibility study was indefinitely suspended after only 1 patient was treated with the device in only 1 patient was treated with the device in Europe Europe
Suction thrombectomySuction thrombectomy This method of mechanical thrombolysis is one of the This method of mechanical thrombolysis is one of the
simplestsimplest In this readily available technique suction is applied with In this readily available technique suction is applied with
a syringe to remove thrombus in the ICA a syringe to remove thrombus in the ICA It requires no other devicesIt requires no other devices A catheter with a large inner diameter (Brite Tip Cordis A catheter with a large inner diameter (Brite Tip Cordis
Corporation Miami FL) was placed in the symptomatic Corporation Miami FL) was placed in the symptomatic vessel and navigated over a guidewire into the thrombusvessel and navigated over a guidewire into the thrombus
A 60-mL syringe was used to aspirate the thrombus A 60-mL syringe was used to aspirate the thrombus Each patient required angioplasty and stenting of carotid Each patient required angioplasty and stenting of carotid
bifurcation stenosis and received daily aspirin and bifurcation stenosis and received daily aspirin and ticlopidine after the procedure No complications ticlopidine after the procedure No complications occurred occurred
Summary Acute Stroke Summary Acute Stroke ImagingImaging
PhysiologyPhysiology importance collaterals importance collaterals
ndash ndashGrowing role for perfusion Growing role for perfusion assessmentassessment
tPAtPA guidelines amp limitations guidelines amp limitations Signs on CT amp MRSigns on CT amp MR follow physiology follow physiology Stroke trialsStroke trials PWI-DWI mismatch PWI-DWI mismatch
ndash ndashTreat based on physiology not timeTreat based on physiology not time ProtocolsProtocols should be fast and should be fast and
comprehensivecomprehensive
Endovascular Photo Acoustic Endovascular Photo Acoustic Recanalization (EPAR) Recanalization (EPAR)
A laser power source generated energy for the A laser power source generated energy for the systemsystem
The energy was delivered by means of The energy was delivered by means of fiberoptics to the tip of the catheter at the fiberoptics to the tip of the catheter at the treatment sitetreatment site
Absorption of laser light by darkly pigmented Absorption of laser light by darkly pigmented materials (ie the clot) occurred inside the 1-mm materials (ie the clot) occurred inside the 1-mm catheter tipcatheter tip
the system was designed to minimize scattering the system was designed to minimize scattering of laser light of laser light
Absorption converted photo energy to acoustic Absorption converted photo energy to acoustic energy which then emulsified the clot inside the energy which then emulsified the clot inside the catheter tip catheter tip
EKOS ultrasound( the EKOS ultrasound( the Ultrasound Thrombolytic Ultrasound Thrombolytic
Infusion Catheter) Infusion Catheter) combines the use of a distal ultrasound transducer with combines the use of a distal ultrasound transducer with
infusion of a thrombolytic agent through the infusion of a thrombolytic agent through the microcathetermicrocatheter
Ultrasound changes the structure of the clot to Ultrasound changes the structure of the clot to temporarily increase its permeability while providing an temporarily increase its permeability while providing an acoustic pressure gradient to move the drug into the clot acoustic pressure gradient to move the drug into the clot to speed its dissolution to speed its dissolution
The EKOS catheter is placed in the proximal portion of the The EKOS catheter is placed in the proximal portion of the clot clot
After a 2-mg bolus of tPA was injected through the After a 2-mg bolus of tPA was injected through the catheter catheter
the patient received a continuous infusion of IA tPA 03 the patient received a continuous infusion of IA tPA 03 mgmin to a maximum of 20 mg and simultaneous mgmin to a maximum of 20 mg and simultaneous ultrasound transmission for as long as 60 minutes ultrasound transmission for as long as 60 minutes
One patient was treated with a total of 4 units of One patient was treated with a total of 4 units of recombinant reteplase (Retavase) hand-injected over 60 recombinant reteplase (Retavase) hand-injected over 60 minutes minutes
Penumbra system Penumbra system The Penumbra system (Penumbra Inc) provides a dual The Penumbra system (Penumbra Inc) provides a dual
approach to clot extraction using aspiration followed by approach to clot extraction using aspiration followed by clot retrieval with a ring device if needed clot retrieval with a ring device if needed
Mechanical Embolus Removal in Cerebral Ischemia Mechanical Embolus Removal in Cerebral Ischemia (MERCI)(MERCI)
a corkscrew-like apparatus to remove blood clots from a corkscrew-like apparatus to remove blood clots from the brain in patients experiencing an ischemic stroke the brain in patients experiencing an ischemic stroke
The corkscrew itself resides in the catheter tip which The corkscrew itself resides in the catheter tip which shields it from the wall of the vessel until it is ready to be shields it from the wall of the vessel until it is ready to be burrowed into the clot Once lodged in the clot the device burrowed into the clot Once lodged in the clot the device and clot are withdrawn from the vessel and clot are withdrawn from the vessel
Snarelike devicesSnarelike devices Snares such as the Neuronet snare (Guidant Snares such as the Neuronet snare (Guidant
Endovascular Santa Clara CA) have been developed Endovascular Santa Clara CA) have been developed specifically for use in the treatment of strokes specifically for use in the treatment of strokes
These devices are simple in design and do not require the These devices are simple in design and do not require the clot to be amenable to emulsification clot to be amenable to emulsification
X-Sizer deviceX-Sizer device a device with small moving blades at the a device with small moving blades at the
catheter tip catheter tip This device the X-Sizer device (EndiCor Medical This device the X-Sizer device (EndiCor Medical
San Clemente CA) can be used to excise the San Clemente CA) can be used to excise the thrombus and aspirate it thrombus and aspirate it
The device was being evaluated in randomized The device was being evaluated in randomized studies of coronary vessels and in a registry of studies of coronary vessels and in a registry of patients with acute myocardial infarctionpatients with acute myocardial infarction
Although the manufacturer had modified the Although the manufacturer had modified the device for use in cerebral vessels a safety and device for use in cerebral vessels a safety and feasibility study was indefinitely suspended after feasibility study was indefinitely suspended after only 1 patient was treated with the device in only 1 patient was treated with the device in Europe Europe
Suction thrombectomySuction thrombectomy This method of mechanical thrombolysis is one of the This method of mechanical thrombolysis is one of the
simplestsimplest In this readily available technique suction is applied with In this readily available technique suction is applied with
a syringe to remove thrombus in the ICA a syringe to remove thrombus in the ICA It requires no other devicesIt requires no other devices A catheter with a large inner diameter (Brite Tip Cordis A catheter with a large inner diameter (Brite Tip Cordis
Corporation Miami FL) was placed in the symptomatic Corporation Miami FL) was placed in the symptomatic vessel and navigated over a guidewire into the thrombusvessel and navigated over a guidewire into the thrombus
A 60-mL syringe was used to aspirate the thrombus A 60-mL syringe was used to aspirate the thrombus Each patient required angioplasty and stenting of carotid Each patient required angioplasty and stenting of carotid
bifurcation stenosis and received daily aspirin and bifurcation stenosis and received daily aspirin and ticlopidine after the procedure No complications ticlopidine after the procedure No complications occurred occurred
Summary Acute Stroke Summary Acute Stroke ImagingImaging
PhysiologyPhysiology importance collaterals importance collaterals
ndash ndashGrowing role for perfusion Growing role for perfusion assessmentassessment
tPAtPA guidelines amp limitations guidelines amp limitations Signs on CT amp MRSigns on CT amp MR follow physiology follow physiology Stroke trialsStroke trials PWI-DWI mismatch PWI-DWI mismatch
ndash ndashTreat based on physiology not timeTreat based on physiology not time ProtocolsProtocols should be fast and should be fast and
comprehensivecomprehensive
EKOS ultrasound( the EKOS ultrasound( the Ultrasound Thrombolytic Ultrasound Thrombolytic
Infusion Catheter) Infusion Catheter) combines the use of a distal ultrasound transducer with combines the use of a distal ultrasound transducer with
infusion of a thrombolytic agent through the infusion of a thrombolytic agent through the microcathetermicrocatheter
Ultrasound changes the structure of the clot to Ultrasound changes the structure of the clot to temporarily increase its permeability while providing an temporarily increase its permeability while providing an acoustic pressure gradient to move the drug into the clot acoustic pressure gradient to move the drug into the clot to speed its dissolution to speed its dissolution
The EKOS catheter is placed in the proximal portion of the The EKOS catheter is placed in the proximal portion of the clot clot
After a 2-mg bolus of tPA was injected through the After a 2-mg bolus of tPA was injected through the catheter catheter
the patient received a continuous infusion of IA tPA 03 the patient received a continuous infusion of IA tPA 03 mgmin to a maximum of 20 mg and simultaneous mgmin to a maximum of 20 mg and simultaneous ultrasound transmission for as long as 60 minutes ultrasound transmission for as long as 60 minutes
One patient was treated with a total of 4 units of One patient was treated with a total of 4 units of recombinant reteplase (Retavase) hand-injected over 60 recombinant reteplase (Retavase) hand-injected over 60 minutes minutes
Penumbra system Penumbra system The Penumbra system (Penumbra Inc) provides a dual The Penumbra system (Penumbra Inc) provides a dual
approach to clot extraction using aspiration followed by approach to clot extraction using aspiration followed by clot retrieval with a ring device if needed clot retrieval with a ring device if needed
Mechanical Embolus Removal in Cerebral Ischemia Mechanical Embolus Removal in Cerebral Ischemia (MERCI)(MERCI)
a corkscrew-like apparatus to remove blood clots from a corkscrew-like apparatus to remove blood clots from the brain in patients experiencing an ischemic stroke the brain in patients experiencing an ischemic stroke
The corkscrew itself resides in the catheter tip which The corkscrew itself resides in the catheter tip which shields it from the wall of the vessel until it is ready to be shields it from the wall of the vessel until it is ready to be burrowed into the clot Once lodged in the clot the device burrowed into the clot Once lodged in the clot the device and clot are withdrawn from the vessel and clot are withdrawn from the vessel
Snarelike devicesSnarelike devices Snares such as the Neuronet snare (Guidant Snares such as the Neuronet snare (Guidant
Endovascular Santa Clara CA) have been developed Endovascular Santa Clara CA) have been developed specifically for use in the treatment of strokes specifically for use in the treatment of strokes
These devices are simple in design and do not require the These devices are simple in design and do not require the clot to be amenable to emulsification clot to be amenable to emulsification
X-Sizer deviceX-Sizer device a device with small moving blades at the a device with small moving blades at the
catheter tip catheter tip This device the X-Sizer device (EndiCor Medical This device the X-Sizer device (EndiCor Medical
San Clemente CA) can be used to excise the San Clemente CA) can be used to excise the thrombus and aspirate it thrombus and aspirate it
The device was being evaluated in randomized The device was being evaluated in randomized studies of coronary vessels and in a registry of studies of coronary vessels and in a registry of patients with acute myocardial infarctionpatients with acute myocardial infarction
Although the manufacturer had modified the Although the manufacturer had modified the device for use in cerebral vessels a safety and device for use in cerebral vessels a safety and feasibility study was indefinitely suspended after feasibility study was indefinitely suspended after only 1 patient was treated with the device in only 1 patient was treated with the device in Europe Europe
Suction thrombectomySuction thrombectomy This method of mechanical thrombolysis is one of the This method of mechanical thrombolysis is one of the
simplestsimplest In this readily available technique suction is applied with In this readily available technique suction is applied with
a syringe to remove thrombus in the ICA a syringe to remove thrombus in the ICA It requires no other devicesIt requires no other devices A catheter with a large inner diameter (Brite Tip Cordis A catheter with a large inner diameter (Brite Tip Cordis
Corporation Miami FL) was placed in the symptomatic Corporation Miami FL) was placed in the symptomatic vessel and navigated over a guidewire into the thrombusvessel and navigated over a guidewire into the thrombus
A 60-mL syringe was used to aspirate the thrombus A 60-mL syringe was used to aspirate the thrombus Each patient required angioplasty and stenting of carotid Each patient required angioplasty and stenting of carotid
bifurcation stenosis and received daily aspirin and bifurcation stenosis and received daily aspirin and ticlopidine after the procedure No complications ticlopidine after the procedure No complications occurred occurred
Summary Acute Stroke Summary Acute Stroke ImagingImaging
PhysiologyPhysiology importance collaterals importance collaterals
ndash ndashGrowing role for perfusion Growing role for perfusion assessmentassessment
tPAtPA guidelines amp limitations guidelines amp limitations Signs on CT amp MRSigns on CT amp MR follow physiology follow physiology Stroke trialsStroke trials PWI-DWI mismatch PWI-DWI mismatch
ndash ndashTreat based on physiology not timeTreat based on physiology not time ProtocolsProtocols should be fast and should be fast and
comprehensivecomprehensive
Penumbra system Penumbra system The Penumbra system (Penumbra Inc) provides a dual The Penumbra system (Penumbra Inc) provides a dual
approach to clot extraction using aspiration followed by approach to clot extraction using aspiration followed by clot retrieval with a ring device if needed clot retrieval with a ring device if needed
Mechanical Embolus Removal in Cerebral Ischemia Mechanical Embolus Removal in Cerebral Ischemia (MERCI)(MERCI)
a corkscrew-like apparatus to remove blood clots from a corkscrew-like apparatus to remove blood clots from the brain in patients experiencing an ischemic stroke the brain in patients experiencing an ischemic stroke
The corkscrew itself resides in the catheter tip which The corkscrew itself resides in the catheter tip which shields it from the wall of the vessel until it is ready to be shields it from the wall of the vessel until it is ready to be burrowed into the clot Once lodged in the clot the device burrowed into the clot Once lodged in the clot the device and clot are withdrawn from the vessel and clot are withdrawn from the vessel
Snarelike devicesSnarelike devices Snares such as the Neuronet snare (Guidant Snares such as the Neuronet snare (Guidant
Endovascular Santa Clara CA) have been developed Endovascular Santa Clara CA) have been developed specifically for use in the treatment of strokes specifically for use in the treatment of strokes
These devices are simple in design and do not require the These devices are simple in design and do not require the clot to be amenable to emulsification clot to be amenable to emulsification
X-Sizer deviceX-Sizer device a device with small moving blades at the a device with small moving blades at the
catheter tip catheter tip This device the X-Sizer device (EndiCor Medical This device the X-Sizer device (EndiCor Medical
San Clemente CA) can be used to excise the San Clemente CA) can be used to excise the thrombus and aspirate it thrombus and aspirate it
The device was being evaluated in randomized The device was being evaluated in randomized studies of coronary vessels and in a registry of studies of coronary vessels and in a registry of patients with acute myocardial infarctionpatients with acute myocardial infarction
Although the manufacturer had modified the Although the manufacturer had modified the device for use in cerebral vessels a safety and device for use in cerebral vessels a safety and feasibility study was indefinitely suspended after feasibility study was indefinitely suspended after only 1 patient was treated with the device in only 1 patient was treated with the device in Europe Europe
Suction thrombectomySuction thrombectomy This method of mechanical thrombolysis is one of the This method of mechanical thrombolysis is one of the
simplestsimplest In this readily available technique suction is applied with In this readily available technique suction is applied with
a syringe to remove thrombus in the ICA a syringe to remove thrombus in the ICA It requires no other devicesIt requires no other devices A catheter with a large inner diameter (Brite Tip Cordis A catheter with a large inner diameter (Brite Tip Cordis
Corporation Miami FL) was placed in the symptomatic Corporation Miami FL) was placed in the symptomatic vessel and navigated over a guidewire into the thrombusvessel and navigated over a guidewire into the thrombus
A 60-mL syringe was used to aspirate the thrombus A 60-mL syringe was used to aspirate the thrombus Each patient required angioplasty and stenting of carotid Each patient required angioplasty and stenting of carotid
bifurcation stenosis and received daily aspirin and bifurcation stenosis and received daily aspirin and ticlopidine after the procedure No complications ticlopidine after the procedure No complications occurred occurred
Summary Acute Stroke Summary Acute Stroke ImagingImaging
PhysiologyPhysiology importance collaterals importance collaterals
ndash ndashGrowing role for perfusion Growing role for perfusion assessmentassessment
tPAtPA guidelines amp limitations guidelines amp limitations Signs on CT amp MRSigns on CT amp MR follow physiology follow physiology Stroke trialsStroke trials PWI-DWI mismatch PWI-DWI mismatch
ndash ndashTreat based on physiology not timeTreat based on physiology not time ProtocolsProtocols should be fast and should be fast and
comprehensivecomprehensive
X-Sizer deviceX-Sizer device a device with small moving blades at the a device with small moving blades at the
catheter tip catheter tip This device the X-Sizer device (EndiCor Medical This device the X-Sizer device (EndiCor Medical
San Clemente CA) can be used to excise the San Clemente CA) can be used to excise the thrombus and aspirate it thrombus and aspirate it
The device was being evaluated in randomized The device was being evaluated in randomized studies of coronary vessels and in a registry of studies of coronary vessels and in a registry of patients with acute myocardial infarctionpatients with acute myocardial infarction
Although the manufacturer had modified the Although the manufacturer had modified the device for use in cerebral vessels a safety and device for use in cerebral vessels a safety and feasibility study was indefinitely suspended after feasibility study was indefinitely suspended after only 1 patient was treated with the device in only 1 patient was treated with the device in Europe Europe
Suction thrombectomySuction thrombectomy This method of mechanical thrombolysis is one of the This method of mechanical thrombolysis is one of the
simplestsimplest In this readily available technique suction is applied with In this readily available technique suction is applied with
a syringe to remove thrombus in the ICA a syringe to remove thrombus in the ICA It requires no other devicesIt requires no other devices A catheter with a large inner diameter (Brite Tip Cordis A catheter with a large inner diameter (Brite Tip Cordis
Corporation Miami FL) was placed in the symptomatic Corporation Miami FL) was placed in the symptomatic vessel and navigated over a guidewire into the thrombusvessel and navigated over a guidewire into the thrombus
A 60-mL syringe was used to aspirate the thrombus A 60-mL syringe was used to aspirate the thrombus Each patient required angioplasty and stenting of carotid Each patient required angioplasty and stenting of carotid
bifurcation stenosis and received daily aspirin and bifurcation stenosis and received daily aspirin and ticlopidine after the procedure No complications ticlopidine after the procedure No complications occurred occurred
Summary Acute Stroke Summary Acute Stroke ImagingImaging
PhysiologyPhysiology importance collaterals importance collaterals
ndash ndashGrowing role for perfusion Growing role for perfusion assessmentassessment
tPAtPA guidelines amp limitations guidelines amp limitations Signs on CT amp MRSigns on CT amp MR follow physiology follow physiology Stroke trialsStroke trials PWI-DWI mismatch PWI-DWI mismatch
ndash ndashTreat based on physiology not timeTreat based on physiology not time ProtocolsProtocols should be fast and should be fast and
comprehensivecomprehensive
Suction thrombectomySuction thrombectomy This method of mechanical thrombolysis is one of the This method of mechanical thrombolysis is one of the
simplestsimplest In this readily available technique suction is applied with In this readily available technique suction is applied with
a syringe to remove thrombus in the ICA a syringe to remove thrombus in the ICA It requires no other devicesIt requires no other devices A catheter with a large inner diameter (Brite Tip Cordis A catheter with a large inner diameter (Brite Tip Cordis
Corporation Miami FL) was placed in the symptomatic Corporation Miami FL) was placed in the symptomatic vessel and navigated over a guidewire into the thrombusvessel and navigated over a guidewire into the thrombus
A 60-mL syringe was used to aspirate the thrombus A 60-mL syringe was used to aspirate the thrombus Each patient required angioplasty and stenting of carotid Each patient required angioplasty and stenting of carotid
bifurcation stenosis and received daily aspirin and bifurcation stenosis and received daily aspirin and ticlopidine after the procedure No complications ticlopidine after the procedure No complications occurred occurred
Summary Acute Stroke Summary Acute Stroke ImagingImaging
PhysiologyPhysiology importance collaterals importance collaterals
ndash ndashGrowing role for perfusion Growing role for perfusion assessmentassessment
tPAtPA guidelines amp limitations guidelines amp limitations Signs on CT amp MRSigns on CT amp MR follow physiology follow physiology Stroke trialsStroke trials PWI-DWI mismatch PWI-DWI mismatch
ndash ndashTreat based on physiology not timeTreat based on physiology not time ProtocolsProtocols should be fast and should be fast and
comprehensivecomprehensive
Summary Acute Stroke Summary Acute Stroke ImagingImaging
PhysiologyPhysiology importance collaterals importance collaterals
ndash ndashGrowing role for perfusion Growing role for perfusion assessmentassessment
tPAtPA guidelines amp limitations guidelines amp limitations Signs on CT amp MRSigns on CT amp MR follow physiology follow physiology Stroke trialsStroke trials PWI-DWI mismatch PWI-DWI mismatch
ndash ndashTreat based on physiology not timeTreat based on physiology not time ProtocolsProtocols should be fast and should be fast and
comprehensivecomprehensive