disseminated intravascular coagulation keith lewis, md
TRANSCRIPT
DIC
An acquired syndrome An acquired syndrome characterized by characterized by systemicsystemic intravascularintravascular coagulationcoagulation
Coagulation is Coagulation is alwaysalways the the initial event.initial event.
Most morbidity and Most morbidity and mortality depends on extent mortality depends on extent of intravascular thrombosisof intravascular thrombosis
Multiple causesMultiple causes
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ThrombosisThrombosis
FibrinFibrin
Red Blood CellRed Blood Cell
PlateletPlatelet
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Hemostasis Review
Coagulation cascadeCoagulation cascade Vascular EndotheliumVascular Endothelium Anticlotting MechanismsAnticlotting Mechanisms Fibrinolytic SystemFibrinolytic System PlateletsPlatelets Blood Flow DynamicsBlood Flow Dynamics
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HemostasisHemostasisSubendothelialSubendothelial matrix matrix
PlateletsPlatelets
HemostaticHemostatic plug plug
FibrinFibrin
Endothelial cellEndothelial cell
RBCRBCWBCWBC
WBCWBC
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Vascular Endothelium
Vascular endothelium Vascular endothelium expressesexpresses: : ThrombomodulinThrombomodulin Tissue Plasminogen Tissue Plasminogen
ActivatorActivator Tissue Tissue
thromboplastin/Tissue thromboplastin/Tissue factorfactor
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HemostasisHemostasisSubendothelialSubendothelial matrix matrix
PlateletsPlatelets
HemostaticHemostatic plug plug
FibrinFibrin
Endothelial cellEndothelial cell
RBCRBCWBCWBC
WBCWBC
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Coagulation Intrinsic PathwayIntrinsic Pathway Extrinsic PathwayExtrinsic Pathway Common PathwayCommon Pathway Contact PathwayContact Pathway Tissue Factor PathwayTissue Factor Pathway
Primary factor in DICPrimary factor in DIC
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Contact Tissue Factor + VIITissue Factor + VII
XIIIXIIIaa
XIIIXIII
ThrombinThrombin
FibrinFibrin(strong)(strong)
FibrinogenFibrinogen FibrinFibrin(weak)(weak)
IXIX
XIXI
XIXIaa
IXIXaa
XXaaVVaa
XIIXIIaa
ProthrombinProthrombin
TF-VIITF-VIIaa
(Prothrombinase)(Prothrombinase)
PLPL
PLPL(Tenase)(Tenase)
VIIIVIIIaa
PLPL
XX
Intrinsic Pathway
HKHKaa
Extrinsic Pathway
Common Pathway
TF Pathway
Coagulation PathwaysCoagulation Pathways
Protein C, ProteinS, Antithrombin III
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Anticlotting Mechanisms Antithrombin III (ATIII):Antithrombin III (ATIII):
The major inhibitor of the The major inhibitor of the coagulation cascade.coagulation cascade.
Inhibits ThrombinInhibits Thrombin Inhibits activated Factors IX, X, Inhibits activated Factors IX, X,
XI, and XII.XI, and XII. Activity is enhanced by heparin.Activity is enhanced by heparin.
Tissue factor pathway inhibitor Tissue factor pathway inhibitor TFPITFPI
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Contact Tissue Factor + VIITissue Factor + VII
XIIIXIIIaa
XIIIXIII
ThrombinThrombin
FibrinFibrin(strong)(strong)
FibrinogenFibrinogen FibrinFibrin(weak)(weak)
IXIX
XIXI
XIXIaa
IXIXaa
XXaaVVaa
XIIXIIaa
ProthrombinProthrombin
TF-VIITF-VIIaa
(Prothrombinase)(Prothrombinase)
PLPL
PLPL
(Tenase)(Tenase)
VIIIVIIIaa
PLPL
XX
Intrinsic Pathway
HKHKaa
Extrinsic Pathway
Common Pathway
TF Pathway
Coagulation PathwaysCoagulation Pathways
Protein C, ProteinS, Antithrombin III
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Anticlotting Mechanisms
Protein CProtein C Activated by Activated by
Thrombin/ThrombomodulinThrombin/Thrombomodulin Anticoagulant and fibrinolytic Anticoagulant and fibrinolytic
activity.activity. Vitamin K and Protein S are Vitamin K and Protein S are
cofactorscofactors
Protein SProtein S
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Contact Tissue Factor + VIITissue Factor + VII
XIIIXIIIaa
XIIIXIII
ThrombinThrombin
FibrinFibrin(strong)(strong)
FibrinogenFibrinogen FibrinFibrin(weak)(weak)
IXIX
XIXI
XIXIaa
IXIXaa
XXaaVVaa
XIIXIIaa
ProthrombinProthrombin
TF-VIITF-VIIaa
(Prothrombinase)(Prothrombinase)
PLPL
PLPL
(Tenase)(Tenase)
VIIIVIIIaa
PLPL
XX
Intrinsic Pathway
HKHKaa
Extrinsic Pathway
Common Pathway
TF Pathway
Coagulation PathwaysCoagulation Pathways
Protein C, ProteinS, Antithrombin III
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Fibrinolytic System PlasminPlasmin
Produced from Produced from Plasminogen by Tissue Plasminogen by Tissue Plasminogen activator Plasminogen activator (TPA)(TPA)
Degrades Fibrin and Degrades Fibrin and Fibrinogen (Fibrin Fibrinogen (Fibrin degradation products, degradation products, FDP)FDP)
Degrades Degrades Factors V, VIII, Factors V, VIII, IX, XI, and XII.IX, XI, and XII.
Activity is inhibited by Activity is inhibited by Antiplasmin.Antiplasmin.
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FibrinolysisFibrinolysisPlasminogen
Plasmin
Fibrin, fibrinogenFibrin, fibrinogen
ActivationActivationExtrinsic: t-PA,Extrinsic: t-PA, urokinase urokinase
Intrinsic: factor XIIa, HMWK,Intrinsic: factor XIIa, HMWK, kallikrein kallikrein
Exogenous:Exogenous: streptokinase streptokinase
Fibrin, fibrinogenFibrin, fibrinogendegradation productsdegradation products
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Fibrinolytic Inhibitors AntiplasminAntiplasmin
Inactivates plasmin rapidly.Inactivates plasmin rapidly. Acts slowly on plasmin Acts slowly on plasmin
sequestered in the fibrin clot.sequestered in the fibrin clot. Inactivates factors XI and XII Inactivates factors XI and XII
slowly.slowly.
Plasminogen -Activator Plasminogen -Activator Inhibitor-1(PAI-1)Inhibitor-1(PAI-1) Inhibits the function of TPAInhibits the function of TPA Also has some inhibitory Also has some inhibitory
activity against urokinase, activity against urokinase, plasmin, thrombin, activated plasmin, thrombin, activated Protein C, factors and XII, and Protein C, factors and XII, and kallikreinkallikrein
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FibrinolysisFibrinolysisPlasminogen
Plasmin
Fibrin, fibrinogenFibrin, fibrinogen
ActivationActivationExtrinsic: t-PA,Extrinsic: t-PA, urokinase urokinase
Intrinsic: factor XIIa, HMWK,Intrinsic: factor XIIa, HMWK, kallikrein kallikrein
Exogenous:Exogenous: streptokinase streptokinase
Fibrin, fibrinogenFibrin, fibrinogendegradation productsdegradation products
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Hemostatic Balance
ATIIIClotting Factors
Tissue factor*
PAI-1
AntiplasminTFPI
Prot. C
Prot. S
ProcoagulantProcoagulant AnticoagulantAnticoagulant
Fibrinolytic System
DIC
An acquired syndrome An acquired syndrome characterized by characterized by systemicsystemic intravascularintravascular coagulationcoagulation
Coagulation is Coagulation is alwaysalways the the initial eventinitial event
SYSTEMIC ACTIVATION OF COAGULATION
Intravascular deposition of
fibrin
Depletion of platelets and coagulation
factors
Thrombosis of small and midsize
vesselsBleeding
Organ failure DEATHDEATH
Pathophysiology of DIC
Activation of Blood CoagulationActivation of Blood Coagulation Suppression of Physiologic Anticoagulant Suppression of Physiologic Anticoagulant
PathwaysPathways Impaired FibrinolysisImpaired Fibrinolysis CytokinesCytokines
Pathophysiology of DIC
Activation of Blood CoagulationActivation of Blood Coagulation Tissue factor/factor VIIa mediated thrombin generation via the Tissue factor/factor VIIa mediated thrombin generation via the
extrinsic pathwayextrinsic pathway complex activates factor IX and Xcomplex activates factor IX and X
TF TF endothelial cellsendothelial cells monocytesmonocytes Extravascular:Extravascular:
• lunglung
• kidneykidney
• epithelial cellsepithelial cells
Pathophysiology of DIC
Suppression of Physiologic Anticoagulant Suppression of Physiologic Anticoagulant PathwaysPathways reduced antithrombin III levels reduced antithrombin III levels reduced activity of the protein C-protein S systemreduced activity of the protein C-protein S system Insufficient regulation of tissue factor activity by Insufficient regulation of tissue factor activity by
tissue factor pathway inhibitor (TFPI)tissue factor pathway inhibitor (TFPI) inhibits TF/FVIIa/Fxa complex activity inhibits TF/FVIIa/Fxa complex activity
Pathophysiology of DIC Impaired FibrinolysisImpaired Fibrinolysis
relatively suppressed at time of maximal activation of relatively suppressed at time of maximal activation of coagulation due to increased plasminogen activator inhibitor coagulation due to increased plasminogen activator inhibitor type 1type 1
Pathophysiology of DIC - Cytokines
CytokinesCytokines IL-6, and IL-1 mediates coagulation activation in DICIL-6, and IL-1 mediates coagulation activation in DIC TNF-TNF-
mediates dysregulation of physiologic anticoagulant pathways and mediates dysregulation of physiologic anticoagulant pathways and fibrinolysisfibrinolysis
modulates IL-6 activitymodulates IL-6 activity
IL-10 may modulate the activation of coagulationIL-10 may modulate the activation of coagulation
CoagulationInflamation
Diagnosis of DIC
Presence of disease associated with DICPresence of disease associated with DIC Appropriate clinical settingAppropriate clinical setting
Clinical evidence of thrombosis, hemorrhage or both.Clinical evidence of thrombosis, hemorrhage or both. Laboratory studiesLaboratory studies
no single test is accurateno single test is accurate serial test are more helpful than single testserial test are more helpful than single test
Conditions Associated With DIC
MalignancyMalignancy LeukemiaLeukemia Metastatic diseaseMetastatic disease
CardiovascularCardiovascular Post cardiac arrestPost cardiac arrest Acute MIAcute MI Prosthetic devicesProsthetic devices
Hypothermia/HyperthermiaHypothermia/Hyperthermia
PulmonaryPulmonary ARDS/RDSARDS/RDS Pulmonary embolismPulmonary embolism
Severe acidosisSevere acidosis Severe anoxiaSevere anoxia Collagen vascular diseaseCollagen vascular disease AnaphylaxisAnaphylaxis
Conditions Associated With DIC
Infectious/SepticemiaInfectious/Septicemia BacterialBacterial
Gm - / Gm +Gm - / Gm +
ViralViral CMVCMV VaricellaVaricella HepatitisHepatitis
FungalFungal
Intravascular hemolysisIntravascular hemolysis Acute Liver DiseaseAcute Liver Disease
Tissue InjuryTissue Injury traumatrauma extensive surgeryextensive surgery tissue necrosistissue necrosis head traumahead trauma
ObstetricObstetric Amniotic fluid emboliAmniotic fluid emboli Placental abruptionPlacental abruption EclampsiaEclampsia Missed abortionMissed abortion
Clinical Manifestations of DIC
ORGAN ISCHEMIC HEMOR.Skin Pur. Fulminans
GangreneAcral cyanosis
PetechiaeEchymosisOozing
CNS Delirium/ComaInfarcts
Intracranialbleeding
Renal Oliguria/AzotemiaCortical Necrosis
Hematuria
Cardiovascular MyocardialDysfxn
Pulmonary Dyspnea/HypoxiaInfarct
Hemorrhagiclung
GIEndocrine
Ulcers, InfarctsAdrenal infarcts
Massivehemorrhage.
Ischemic Findingsare earliest!
Bleeding is the most obvious
clinical finding
Microscopic findings in DIC
FragmentsFragments SchistocytesSchistocytes Paucity of plateletsPaucity of platelets
Laboratory Tests Used in DIC
D-dimerD-dimer** Antithrombin IIIAntithrombin III* * F. 1+2*F. 1+2* Fibrinopeptide A*Fibrinopeptide A* Platelet factor 4*Platelet factor 4* Fibrin Degradation ProdFibrin Degradation Prod Platelet countPlatelet count Protamine testProtamine test
Thrombin timeThrombin time FibrinogenFibrinogen Prothrombin timeProthrombin time Activated PTTActivated PTT Protamine testProtamine test Reptilase timeReptilase time Coagulation factor levelsCoagulation factor levels
*Most reliable test*Most reliable test
Laboratory diagnosis ThrombocytopeniaThrombocytopenia
plat count <100,000 or rapidly decliningplat count <100,000 or rapidly declining Prolonged clotting times (PT, APTT)Prolonged clotting times (PT, APTT) Presence of Fibrin degradation products or positive Presence of Fibrin degradation products or positive
D-dimerD-dimer Low levels of coagulation inhibitorsLow levels of coagulation inhibitors
AT III, protein CAT III, protein C Low levels of coagulation factorsLow levels of coagulation factors
Factors V,VIII,X,XIIIFactors V,VIII,X,XIII Fibrinogen levels Fibrinogen levels notnot useful diagnostically useful diagnostically
Differential Diagnosis
Severe liver failureSevere liver failure Vitamin K deficiencyVitamin K deficiency Liver diseaseLiver disease Thrombotic thrombocytopenic purpuraThrombotic thrombocytopenic purpura Congenital abnormalities of fibrinogenCongenital abnormalities of fibrinogen HELLP syndromeHELLP syndrome
Treatment of DIC
Stop the triggering processStop the triggering process . . The only proven treatment!The only proven treatment!
Supportive therapySupportive therapy No specific treatmentsNo specific treatments
Plasma and platelet substitution therapyPlasma and platelet substitution therapy AnticoagulantsAnticoagulants Physiologic coagulation inhibitorsPhysiologic coagulation inhibitors
Plasma therapy IndicationsIndications
Active bleedingActive bleeding Patient requiring invasive proceduresPatient requiring invasive procedures Patient at high risk for bleeding complicationsPatient at high risk for bleeding complications
Prophylactic therapy has no proven benefit.Prophylactic therapy has no proven benefit. Cons:Cons: Fresh frozen plasma(FFP):Fresh frozen plasma(FFP):
provides clotting factors, fibrinogen, inhibitors, and platelets in provides clotting factors, fibrinogen, inhibitors, and platelets in balanced amounts.balanced amounts.
Usual dose is 10-15 ml/kgUsual dose is 10-15 ml/kg
Platelet therapy
IndicationsIndications Active bleedingActive bleeding Patient requiring invasive proceduresPatient requiring invasive procedures Patient at high risk for bleeding complicationsPatient at high risk for bleeding complications
PlateletsPlatelets approximate dose 1 unit/10kgapproximate dose 1 unit/10kg
Blood
Replaced as needed to maintain adequate oxygen Replaced as needed to maintain adequate oxygen delivery.delivery. Blood loss due to bleedingBlood loss due to bleeding RBC destruction (hemolysis)RBC destruction (hemolysis)
Coagulation Inhibitor Therapy
Antithrombin IIIAntithrombin III Protein C concentrateProtein C concentrate Tissue Factor Pathway Inhibitor (TFPI)Tissue Factor Pathway Inhibitor (TFPI) HeparinHeparin
The major inhibitor of the coagulation cascadeThe major inhibitor of the coagulation cascade Levels are decreased in DIC.Levels are decreased in DIC. Anticoagulant and antiinflammatory propertiesAnticoagulant and antiinflammatory properties
Therapeutic goal is to achieve supranormal levels of ATIII (>125-150%).Therapeutic goal is to achieve supranormal levels of ATIII (>125-150%). Experimental data indicated a beneficial effect in preventing or attenuating DIC in Experimental data indicated a beneficial effect in preventing or attenuating DIC in
septic shockseptic shock reduced DIC scores, DIC duration, and some improvement in organ functionreduced DIC scores, DIC duration, and some improvement in organ function
Clinical trials have shown laboratory evidence of attenuation of DIC and trends Clinical trials have shown laboratory evidence of attenuation of DIC and trends toward improved outcomes.toward improved outcomes.
A clear benefit has not been established in clinical trialsA clear benefit has not been established in clinical trials..
Antithrombin III
Protein C Concentrates
Inhibits Factor Va, VIIa and PAI-1 in conjunction with Inhibits Factor Va, VIIa and PAI-1 in conjunction with thrombomodulin.thrombomodulin.
Protein S is a cofactorProtein S is a cofactor Therapeutic use in DIC is experimental and is based on studies Therapeutic use in DIC is experimental and is based on studies
that show:that show: Patients with congenital deficiency are prone to thromboembolic disease.Patients with congenital deficiency are prone to thromboembolic disease. Protein C levels are low in DIC due to sepsis.Protein C levels are low in DIC due to sepsis. Levels correlate with outcome.Levels correlate with outcome. Clinical trials show significantly decreased morbidity and mortality in Clinical trials show significantly decreased morbidity and mortality in
DIC due to sepsis.DIC due to sepsis.
Tissue Factor Pathway Inhibitor
Tissue factor is expressed on endothelial cells and Tissue factor is expressed on endothelial cells and macrophagesmacrophages
TFPI complexes with TF, Factor VIIa,and Factor Xa to TFPI complexes with TF, Factor VIIa,and Factor Xa to inhibit generation of thrombin from prothrombininhibit generation of thrombin from prothrombin
TF inhibition may also have antiinflammatory effectsTF inhibition may also have antiinflammatory effects Clinical studies using recombinant TFPI are promising.Clinical studies using recombinant TFPI are promising.
Heparin
Use is very controversial. Data is mixed.Use is very controversial. Data is mixed. May be indicated in patients with clinical evidence May be indicated in patients with clinical evidence
of fibrin deposition or significant thrombosis.of fibrin deposition or significant thrombosis. Generally contraindicated in patients with Generally contraindicated in patients with
significant bleeding and CNS insults.significant bleeding and CNS insults. Dosing and route of administration varies.Dosing and route of administration varies. Requires normal levels of ATIII.Requires normal levels of ATIII.
Antifibrinolytic Therapy
Rarely indicated in DICRarely indicated in DIC Fibrinolysis is needed to clear thrombi from the micro circulation.Fibrinolysis is needed to clear thrombi from the micro circulation. Use can lead to fatal disseminated thrombosis.Use can lead to fatal disseminated thrombosis.
May be indicated for May be indicated for life threateninglife threatening bleeding under the bleeding under the following conditions:following conditions: bleeding has not responded to other therapies and:bleeding has not responded to other therapies and: laboratory evidence of overwhelming fibrinolysis.laboratory evidence of overwhelming fibrinolysis. evidence that the intravascular coagulation has ceased.evidence that the intravascular coagulation has ceased.
Agents: tranexamic acid, EACAAgents: tranexamic acid, EACA
Summary
DIC is a syndrome characterized DIC is a syndrome characterized systemic intravascular systemic intravascular coagulation.coagulation.
Coagulation is the initial event and the extent of intravascular Coagulation is the initial event and the extent of intravascular thrombosis has the greatest impact on morbidity and mortality.thrombosis has the greatest impact on morbidity and mortality.
Important link between inflammation and coagulation. Important link between inflammation and coagulation. Morbidity and mortality remain high.Morbidity and mortality remain high. The only proven treatment is reversal or control of the The only proven treatment is reversal or control of the
underlying cause.underlying cause.