Thrombotic DiseasesThrombotic Diseases

Ahmad Shihada SilmiAhmad Shihada SilmiFaculty of SciencesFaculty of Sciences

IUGIUGMED TECH DEPMED TECH DEPRoom B326Room B326

Thrombotic disordersThrombotic disorders

Congenital and acquired Congenital and acquired diseases characterized by diseases characterized by formation of thrombus that formation of thrombus that obstructs vascular blood obstructs vascular blood flow locally or detaches flow locally or detaches and embolizes to occlude and embolizes to occlude blood flow downstream blood flow downstream (thromboembolism)(thromboembolism)

Thrombus FormationThrombus Formation

Clot is a Thrombus formed in an arterial or Clot is a Thrombus formed in an arterial or venous vessel venous vessel

thrombophlebitis - Both inflammation and thrombophlebitis - Both inflammation and clots are presentclots are present

Some thrombus can be superficial but itrsquos Some thrombus can be superficial but itrsquos the DVT thatrsquos a concern the DVT thatrsquos a concern embolism to embolism to lungslungs

ClassificationClassification

1 1 Familial ndash physiologicalFamilial ndash physiological

2 Non-familial (acquired) ndash physiological or 2 Non-familial (acquired) ndash physiological or pathologicalpathological

AcquiredProthrombotic

Stimulus

One or moreInherited

ProthromboticMutation(s)

Thrombosis

AcquiredProthrombotic

Stimulus

One or moreInherited

ProthromboticMutation(s)

Thrombosis

Factor V LeidenProthrombin 20210AProtein C deficiencyProtein S deficiencyAntithrombin deficiencyHyperhomocysteinemia

Antiphospholipid antibodiesMalignancyImmobilizationSurgeryPregnancyEstrogenHeparin-induced thrombocytopenia

Dr Rudolph Virchow1821-1902

AbnormalBlood Flow

AbnormalVessel Wall

AbnormalBlood

The Hypercoagulable State(thrombophilia)

Mechanisms of ThrombosisMechanisms of Thrombosis

Clinical associations with thrombotic Clinical associations with thrombotic diseasedisease

ImmobilityImmobilityObesityObesity

SmokingSmokingCancerCancer

PregnancyPregnancyEstrogen therapyEstrogen therapy

Types of ThrombosisTypes of Thrombosis

ArterialArterial platelet-based (white) thrombus platelet-based (white) thrombus

Platelet-VWF interactions criticalPlatelet-VWF interactions critical

Associated with end-stage atherosclerosisAssociated with end-stage atherosclerosis

Venous Fibrin-based (red) thrombus

Coagulation factors critical

Venous stasis

Thrombus FormationThrombus Formation

bull Arterial formation - begins w platelet adhesion to arterial vessel wall Adenosine diphosphate (ADP) released from platelets more platelet aggregation Bld flow inhibited fibrin platelets amp RBCrsquos surround clot build up of size structure occludes bld vessels tissue ischemia

bull The result of Arterial Thrombus is localized tissue injury from lack of perfusion

Thrombus FormationThrombus Formation

Venous FormationVenous Formation - Usually from slow bld flow - Usually from slow bld flow - Can occur rapidly Stagnation of the blood flow initiate - Can occur rapidly Stagnation of the blood flow initiate

the coagulation cascadethe coagulation cascade production of fibrin production of fibrinenmeshes enmeshes RBCrsquos amp platelets to form the thrombus Venous RBCrsquos amp platelets to form the thrombus Venous thrombus has a long tail that can break off to produce an thrombus has a long tail that can break off to produce an embolus These travel to faraway sites then lodge embolus These travel to faraway sites then lodge in in lung (capillary level) lung (capillary level) inadequate O2 amp CO2 exchange inadequate O2 amp CO2 exchange occur (ie pulmonary embolism amp cerebral embolism)occur (ie pulmonary embolism amp cerebral embolism)

Oral amp parenteral anticoagulants (HeparinWarfarin) Oral amp parenteral anticoagulants (HeparinWarfarin) primarily act by preventing venous thrombosisprimarily act by preventing venous thrombosis

Antiplatelet drugs primarily act by preventing arterial Antiplatelet drugs primarily act by preventing arterial thrombosisthrombosis

Types of ThrombosisTypes of Thrombosis

Occlusive Thrombus occurs when the Occlusive Thrombus occurs when the entire lumen of blood vessel is occupied by entire lumen of blood vessel is occupied by coagulated material amp blood flow is coagulated material amp blood flow is obstructedobstructed

Mural Thrombosis occurs when the Mural Thrombosis occurs when the thrombus adheres to one site of the blood thrombus adheres to one site of the blood vessel only amp blood is restricted but not vessel only amp blood is restricted but not arrested arrested

Thrombosis

Hereditarythrombophilia

Acquiredthrombophilia

SurgerytraumaImmobility

Inflammation

Malignancy

Estrogens

Risk Factors for ThrombosisRisk Factors for Thrombosis

Atherosclerosis

THROMBOEMBOLIC DISORDERSTHROMBOEMBOLIC DISORDERS

Venous thromboembolismVenous thromboembolism

Arterial thromboembolismArterial thromboembolism

Risk Factors forRisk Factors forVenous ThrombosisVenous Thrombosis

AcquiredAcquired InheritedInherited MixedunknownMixedunknown

Venous Thrombosis Venous system low flow amp pressure Thrombi are fibrin rich Function of age biologic conditions genetic

ampenvironmental factors and their interactions Venous thromboembolism (VTE) ndash Deep vein thrombosis (DVT) ndash Pulmonary embolism (PE) ndash Superficial portal cerebral or retinal vein thrombosis Reasons for coagulation testing ndash Risk for recurrence of thrombosis ndash Treatment considerations (duration amp intensity) ndash Genetic counseling for affected family members ndash Prophylaxis for high risk situations

The most common is (DVT) deep venous The most common is (DVT) deep venous thrombosis of the lower limbs The main thrombosis of the lower limbs The main site where there is maximum stasis and low site where there is maximum stasis and low blood flow blood flow

Propagation of thrombus is associated with Propagation of thrombus is associated with red cell entrapmenthelliphellipred thrombusred cell entrapmenthelliphellipred thrombus

Venus thrombi may become dislodged or Venus thrombi may become dislodged or fragment resulting in the formation of fragment resulting in the formation of circulating thrombi This may result in circulating thrombi This may result in pulmonary embolismpulmonary embolism

Venous Thrombosis

Pulmonary embolismPulmonary embolism

Presents with acute chest painPresents with acute chest pain Breathlessness with shockBreathlessness with shock Cough amp hemopysisCough amp hemopysis May be fatalMay be fatal

Venous Thrombosis symptoms

Typically presents with pain swelling Typically presents with pain swelling discoloration amp warmth in the affected areadiscoloration amp warmth in the affected area

However However

(these symptoms may be absent amp non of (these symptoms may be absent amp non of them is specific)them is specific)

Hematologic manifestationsHematologic manifestations

Cutaneous manifestationsCutaneous manifestations

Genetic Risk Factors(Familial)

11 FV- Leiden (APCR activated prot C resistance)FV- Leiden (APCR activated prot C resistance)

22 Protein C (deficiency)Protein C (deficiency)

33 Protein S (deficiency)Protein S (deficiency)

44 Antithrombin III (deficiency)Antithrombin III (deficiency)

55 Abnormal Prothrombin (PT 20210 A)Abnormal Prothrombin (PT 20210 A)

66 Sticky platelet syndromeSticky platelet syndrome

Risk FactorsmdashAcquiredRisk FactorsmdashAcquired

Advancing ageAdvancing age Prior ThrombosisPrior Thrombosis ImmobilizationImmobilization Major surgeryMajor surgery MalignancyMalignancy EstrogensEstrogens

Antiphospholipid Antiphospholipid antibody syndromeantibody syndrome

Myeloproliferative Myeloproliferative DisordersDisorders

Heparin-induced Heparin-induced thrombocytopenia thrombocytopenia (HIT)(HIT)

ProlongedProlonged air travel air travel

Risk FactorsmdashMixedUnknownRisk FactorsmdashMixedUnknown

HyperhomocysteinemiaHyperhomocysteinemia High levels of factor VIIIHigh levels of factor VIII Acquired Protein C resistance in the absence of Acquired Protein C resistance in the absence of

Factor V LeidenFactor V Leiden High levels of Factor IX XIHigh levels of Factor IX XI

11 FV- LeidenFV- Leiden

One of the most common causes for thrombophilia One of the most common causes for thrombophilia ndash 20 of clinical disease (AT PC and PS ndash 5) + ndash 20 of clinical disease (AT PC and PS ndash 5) + risk factorrisk factor

Activated PC inhibits F Va and F VIIIaActivated PC inhibits F Va and F VIIIa Inability of APC to inhibit the above complex due Inability of APC to inhibit the above complex due

to mutated FVto mutated FV Heterozygous 5-10 times increased risk for TEHeterozygous 5-10 times increased risk for TE Homozygous 50-100 timesHomozygous 50-100 times

Factor Va

Arg 306 Arg 506 Arg 1765

Arginine CGA

Glutamine CAA

Factor Va resistant to APC cleavage

Factor V Leiden

Relative Risk forVenous Thrombosis

Factor V Leiden Heterozygote x 7

Factor V Leiden Homozygote x 80

Oral Contraceptives x 3

Oral Contraceptives + Factor V Leiden x 35

Leiden Study Group Data

22 Protein C DeficiencyProtein C Deficiency

Common cause (increasing TE with age)Common cause (increasing TE with age) Needs TM from endothelium wallNeeds TM from endothelium wall Heterozygous 50 of level of normal Heterozygous 50 of level of normal

individualsindividuals Homozygous babies are born with Homozygous babies are born with

undetected levels (thrombi in microvascular undetected levels (thrombi in microvascular of skin DIC necrosis purpura of skin DIC necrosis purpura fulminans)fulminans)

33 Protein S DeficiencyProtein S Deficiency

Non-enzymatic co-factor for PCNon-enzymatic co-factor for PC Binds to TM-PCBinds to TM-PC Same properties as PCSame properties as PC Two forms free in plasma and bound to C4b Two forms free in plasma and bound to C4b

binding protein (60) Only free fraction binding protein (60) Only free fraction functions as co-factor for APCfunctions as co-factor for APC

Sometimes difficult to get accurate measures of Sometimes difficult to get accurate measures of PS because of the latterPS because of the latter

Like PC can be acquired liver disease Warfarin Like PC can be acquired liver disease Warfarin pregnancy cancer DIC and chemopregnancy cancer DIC and chemo

44 Antithrombin III DeficiencyAntithrombin III Deficiency

Common cause (incidence 12000 ndash 15000 Common cause (incidence 12000 ndash 15000 heterozygotes 50 DVT) Quantitative vs heterozygotes 50 DVT) Quantitative vs Qualitative disorder (Acquired DIC cirrhosis Qualitative disorder (Acquired DIC cirrhosis NS)NS)

Bind to and inactivate thrombin Factors IXa Xa Bind to and inactivate thrombin Factors IXa Xa XIa and XIIa (ATheparin complex - rate of XIa and XIIa (ATheparin complex - rate of inhibition 1000-fold increased)inhibition 1000-fold increased)

Not necessarily a risk factor to be involved in Not necessarily a risk factor to be involved in heterozygotes to give TEheterozygotes to give TE

Increased incidence with ageing 80 at 55 yearsIncreased incidence with ageing 80 at 55 years

55 Abnormal ProthrombinAbnormal Prothrombin (PT 20210 A) (PT 20210 A)

CommonCommon Increased levels of prothrombin enhanced Increased levels of prothrombin enhanced

thrombin formationthrombin formation Only way for diagnosis DNA-PCR Only way for diagnosis DNA-PCR

techniquetechnique

66 Sticky Platelet SyndromeSticky Platelet Syndrome

Especially in arterial thrombosis (MI) and Especially in arterial thrombosis (MI) and development of recurrent TE while on Warfarindevelopment of recurrent TE while on Warfarin

3 Forms3 Forms If on aspirin it should be stopped 14 days prior to If on aspirin it should be stopped 14 days prior to

testingtesting

Also rememberAlso remember

PC PS and AT III are inhibitors of clottingPC PS and AT III are inhibitors of clotting

Non-familial (Acquired)Non-familial (Acquired)11 Antiphospholipid SyndromeAntiphospholipid Syndrome Antibodies directed against phospholipid cell membrane = Antibodies directed against phospholipid cell membrane =

APA (Antiphospholipid Ab)APA (Antiphospholipid Ab) APA ACA or LAAPA ACA or LA Primary (PAPS) or secondary (autoimmune disorders eg Primary (PAPS) or secondary (autoimmune disorders eg

SLE)SLE) ACA (Anticardiolipin Ab) IgM + IgGACA (Anticardiolipin Ab) IgM + IgG IgG the clinically important oneIgG the clinically important one IgM pregnancy infection (viral) trauma and post-opIgM pregnancy infection (viral) trauma and post-op LA (Lupus anticoagulant) Ab which affect clotting tests (LA-LA (Lupus anticoagulant) Ab which affect clotting tests (LA-

PTT RVV Kaolin)PTT RVV Kaolin) PAPS = TE miscarriage IUDPAPS = TE miscarriage IUD

Antiphospholipid Syndrome1048734 Antiphospholipid syndrome (APS) ndash Syndrome characterized by venous andor arterial thrombosis thrombocytopenia or recurrent fetal loss associated with antibodies to phospho-lipid- protein Complexes

1048734 Antiphospholipid antibodies (aPL)ndash IgG IgM or IgA antibodies that are directed to target proteins such as cardiolipin beta2-Glycoprotein I (β2GPI)or Prothrombin all of which bind to phospholipidsndash Lupus anticoagulant (LA) bull Antiphospholipid antibodies identified by in vitro phospholipid dependent clot-based assays antibodies are targeted against Prothrombin or β2GPI and prolong clotting times

Antiphospholipd Antibodies

Lupus Anticoagulant

Conditions where screening for APS Conditions where screening for APS is indicatedis indicated

The first thrombotic event below the age of 40The first thrombotic event below the age of 40 History of recurrent TEDHistory of recurrent TED Recurrent fetal loss in the 1Recurrent fetal loss in the 1stst or the 2 or the 2ndnd trimester trimester Patient with SLEPatient with SLE Pre-hormone replacement therapyPre-hormone replacement therapy

Non-familial (Acquired) continuedNon-familial (Acquired) continued

22 TPA (Tissue Plasminogen Activator) TPA (Tissue Plasminogen Activator) decreased levels impaired fibrinolysisdecreased levels impaired fibrinolysis

33 PAI (Plasminogen Activator Inhibitor) PAI (Plasminogen Activator Inhibitor) increased levels decreased TPAincreased levels decreased TPA

44 DysfibrinogenemiaDysfibrinogenemia55 F XII deficiency Hageman factorF XII deficiency Hageman factor66 Fibrinogen (increased)Fibrinogen (increased)77 F VIII (increased)F VIII (increased)88 PlasminogenPlasminogen99 Hyperhomocyteinemia ndash enzyme (folate)Hyperhomocyteinemia ndash enzyme (folate)

Investigation (Thrombotic Profile)Investigation (Thrombotic Profile)

NB Patients can be on Warfarin but not HeparinNB Patients can be on Warfarin but not Heparin FBC PLT amp ESRFBC PLT amp ESR PT aPTT TT amp FibrinogenPT aPTT TT amp Fibrinogen PC amp PSPC amp PS AT IIIAT III APCR (if + screening submit for PCR)APCR (if + screening submit for PCR) PT 20210A (PCR)PT 20210A (PCR) Lupus anticoagulant (RVVT KT LA-PTT) Lupus anticoagulant (RVVT KT LA-PTT) Cardiolipin antibodies (antiphospholipid syndrome)Cardiolipin antibodies (antiphospholipid syndrome) Sticky platelet syndrome (aspirin)Sticky platelet syndrome (aspirin) ANA screeningANA screening PNH screeningPNH screening

When to testWhen to test Younger lt 50 years recurrent TE unusual sites Younger lt 50 years recurrent TE unusual sites

TE on WarfarinTE on Warfarin Not ideal to test after acute episode (inhibitors of Not ideal to test after acute episode (inhibitors of

clotting may be low)clotting may be low) Ideal test after 6 weeks after settlement of Ideal test after 6 weeks after settlement of

hemostasishemostasis Most patients are on Warfarin then (PC amp PS are Most patients are on Warfarin then (PC amp PS are

Vit K dependent may be falsely low)Vit K dependent may be falsely low) My view if long-term Warfarin is planned do My view if long-term Warfarin is planned do

immediately according to duration of treatment it immediately according to duration of treatment it can be done after cessation of treatmentcan be done after cessation of treatment

When to test (continued)When to test (continued)

Practical (my experience) before treatment ndash if AT Practical (my experience) before treatment ndash if AT PS PC are low PS PC are low repeat after Rx has been stopped repeat after Rx has been stopped

SPS platelet aggregation studies (problem SPS platelet aggregation studies (problem sometimes aspirin cannot be stopped)sometimes aspirin cannot be stopped)

Remember the effect of the vessel wall on clotting Remember the effect of the vessel wall on clotting especially in arterial thrombosisespecially in arterial thrombosis

Every woman on contraception HRTEvery woman on contraception HRT

Arterial ThrombosisArterial Thrombosis

Arterial Thrombosis

Arterial ThrombosisArterial Thrombosis

Results as sever oResults as sever o2 2 starvation of the left starvation of the left ventricle of the heartventricle of the heart

This leads to myocardial ischemia amp may This leads to myocardial ischemia amp may progress to myocardial infarction or progress to myocardial infarction or ischemic left ventricular fibrillation amp ischemic left ventricular fibrillation amp sudden deathsudden death

Similar episodes involving the cerebral Similar episodes involving the cerebral circulation result in transient ischemic circulation result in transient ischemic attacks amp thrombotic stroke attacks amp thrombotic stroke

Myocardial Infarction SymptomMyocardial Infarction Symptom

Crushing tightness of the chest with Crushing tightness of the chest with sweating nausea breathlessness amp sweating nausea breathlessness amp collapsecollapse

Chest pain may radiates to the arm throat amp Chest pain may radiates to the arm throat amp jawjaw

Chest pain may confused with sever Chest pain may confused with sever indigestion in itrsquos early stagesindigestion in itrsquos early stages

Transient Ischemic attacksTransient Ischemic attacks

Itrsquos usually accompanied with neurological Itrsquos usually accompanied with neurological dysfunction or loss of visiondysfunction or loss of vision

Completed thrombotic strokeCompleted thrombotic stroke

Itrsquos accompanied by similar symptoms Itrsquos accompanied by similar symptoms which persist for more than 24 hours that which persist for more than 24 hours that may be severely amp permanently disablingmay be severely amp permanently disabling

Risk factors for arterial amp venous thrombosisRisk factors for arterial amp venous thrombosis

Venous thrombosisVenous thrombosisArterial thrombosisArterial thrombosisIncreasing ageIncreasing ageIncreasing ageIncreasing age

ObesityObesityObesityObesity

ImmobilityImmobilityLack of exerciseLack of exercise

Pregnancy rdquopost partomrdquoPregnancy rdquopost partomrdquoHigh fat low fiber dietHigh fat low fiber diet

MalignancyMalignancySmokingSmoking

Lupus anticoagulantLupus anticoagulantHyperlipidemiaHyperlipidemia

Nephrotic syndromeNephrotic syndromeHypertensionHypertension

PolycythemiaPolycythemiaElevated factor VII II concElevated factor VII II conc

goutgoutGenetic factorGenetic factor

Prophylaxis amp treatment of Prophylaxis amp treatment of thrombosisthrombosis

Prevent the risk factorsPrevent the risk factors SmokingSmoking ObesityObesity Lack of exerciseLack of exercise Poor dietPoor diet

Only when this proves to be impossibleOnly when this proves to be impossible

(Pharmacological intervention is required) (Pharmacological intervention is required)

Thrombotic disordersThrombotic disorders

Congenital and acquired Congenital and acquired diseases characterized by diseases characterized by formation of thrombus that formation of thrombus that obstructs vascular blood obstructs vascular blood flow locally or detaches flow locally or detaches and embolizes to occlude and embolizes to occlude blood flow downstream blood flow downstream (thromboembolism)(thromboembolism)

Thrombus FormationThrombus Formation

Clot is a Thrombus formed in an arterial or Clot is a Thrombus formed in an arterial or venous vessel venous vessel

thrombophlebitis - Both inflammation and thrombophlebitis - Both inflammation and clots are presentclots are present

Some thrombus can be superficial but itrsquos Some thrombus can be superficial but itrsquos the DVT thatrsquos a concern the DVT thatrsquos a concern embolism to embolism to lungslungs

ClassificationClassification

1 1 Familial ndash physiologicalFamilial ndash physiological

2 Non-familial (acquired) ndash physiological or 2 Non-familial (acquired) ndash physiological or pathologicalpathological

AcquiredProthrombotic

Stimulus

One or moreInherited

ProthromboticMutation(s)

Thrombosis

AcquiredProthrombotic

Stimulus

One or moreInherited

ProthromboticMutation(s)

Thrombosis

Factor V LeidenProthrombin 20210AProtein C deficiencyProtein S deficiencyAntithrombin deficiencyHyperhomocysteinemia

Antiphospholipid antibodiesMalignancyImmobilizationSurgeryPregnancyEstrogenHeparin-induced thrombocytopenia

Dr Rudolph Virchow1821-1902

AbnormalBlood Flow

AbnormalVessel Wall

AbnormalBlood

The Hypercoagulable State(thrombophilia)

Mechanisms of ThrombosisMechanisms of Thrombosis

Clinical associations with thrombotic Clinical associations with thrombotic diseasedisease

ImmobilityImmobilityObesityObesity

SmokingSmokingCancerCancer

PregnancyPregnancyEstrogen therapyEstrogen therapy

Types of ThrombosisTypes of Thrombosis

ArterialArterial platelet-based (white) thrombus platelet-based (white) thrombus

Platelet-VWF interactions criticalPlatelet-VWF interactions critical

Associated with end-stage atherosclerosisAssociated with end-stage atherosclerosis

Venous Fibrin-based (red) thrombus

Coagulation factors critical

Venous stasis

Thrombus FormationThrombus Formation

bull Arterial formation - begins w platelet adhesion to arterial vessel wall Adenosine diphosphate (ADP) released from platelets more platelet aggregation Bld flow inhibited fibrin platelets amp RBCrsquos surround clot build up of size structure occludes bld vessels tissue ischemia

bull The result of Arterial Thrombus is localized tissue injury from lack of perfusion

Thrombus FormationThrombus Formation

Venous FormationVenous Formation - Usually from slow bld flow - Usually from slow bld flow - Can occur rapidly Stagnation of the blood flow initiate - Can occur rapidly Stagnation of the blood flow initiate

the coagulation cascadethe coagulation cascade production of fibrin production of fibrinenmeshes enmeshes RBCrsquos amp platelets to form the thrombus Venous RBCrsquos amp platelets to form the thrombus Venous thrombus has a long tail that can break off to produce an thrombus has a long tail that can break off to produce an embolus These travel to faraway sites then lodge embolus These travel to faraway sites then lodge in in lung (capillary level) lung (capillary level) inadequate O2 amp CO2 exchange inadequate O2 amp CO2 exchange occur (ie pulmonary embolism amp cerebral embolism)occur (ie pulmonary embolism amp cerebral embolism)

Oral amp parenteral anticoagulants (HeparinWarfarin) Oral amp parenteral anticoagulants (HeparinWarfarin) primarily act by preventing venous thrombosisprimarily act by preventing venous thrombosis

Antiplatelet drugs primarily act by preventing arterial Antiplatelet drugs primarily act by preventing arterial thrombosisthrombosis

Types of ThrombosisTypes of Thrombosis

Occlusive Thrombus occurs when the Occlusive Thrombus occurs when the entire lumen of blood vessel is occupied by entire lumen of blood vessel is occupied by coagulated material amp blood flow is coagulated material amp blood flow is obstructedobstructed

Mural Thrombosis occurs when the Mural Thrombosis occurs when the thrombus adheres to one site of the blood thrombus adheres to one site of the blood vessel only amp blood is restricted but not vessel only amp blood is restricted but not arrested arrested

Thrombosis

Hereditarythrombophilia

Acquiredthrombophilia

SurgerytraumaImmobility

Inflammation

Malignancy

Estrogens

Risk Factors for ThrombosisRisk Factors for Thrombosis

Atherosclerosis

THROMBOEMBOLIC DISORDERSTHROMBOEMBOLIC DISORDERS

Venous thromboembolismVenous thromboembolism

Arterial thromboembolismArterial thromboembolism

Risk Factors forRisk Factors forVenous ThrombosisVenous Thrombosis

AcquiredAcquired InheritedInherited MixedunknownMixedunknown

Venous Thrombosis Venous system low flow amp pressure Thrombi are fibrin rich Function of age biologic conditions genetic

ampenvironmental factors and their interactions Venous thromboembolism (VTE) ndash Deep vein thrombosis (DVT) ndash Pulmonary embolism (PE) ndash Superficial portal cerebral or retinal vein thrombosis Reasons for coagulation testing ndash Risk for recurrence of thrombosis ndash Treatment considerations (duration amp intensity) ndash Genetic counseling for affected family members ndash Prophylaxis for high risk situations

The most common is (DVT) deep venous The most common is (DVT) deep venous thrombosis of the lower limbs The main thrombosis of the lower limbs The main site where there is maximum stasis and low site where there is maximum stasis and low blood flow blood flow

Propagation of thrombus is associated with Propagation of thrombus is associated with red cell entrapmenthelliphellipred thrombusred cell entrapmenthelliphellipred thrombus

Venus thrombi may become dislodged or Venus thrombi may become dislodged or fragment resulting in the formation of fragment resulting in the formation of circulating thrombi This may result in circulating thrombi This may result in pulmonary embolismpulmonary embolism

Venous Thrombosis

Pulmonary embolismPulmonary embolism

Presents with acute chest painPresents with acute chest pain Breathlessness with shockBreathlessness with shock Cough amp hemopysisCough amp hemopysis May be fatalMay be fatal

Venous Thrombosis symptoms

Typically presents with pain swelling Typically presents with pain swelling discoloration amp warmth in the affected areadiscoloration amp warmth in the affected area

However However

(these symptoms may be absent amp non of (these symptoms may be absent amp non of them is specific)them is specific)

Hematologic manifestationsHematologic manifestations

Cutaneous manifestationsCutaneous manifestations

Genetic Risk Factors(Familial)

11 FV- Leiden (APCR activated prot C resistance)FV- Leiden (APCR activated prot C resistance)

22 Protein C (deficiency)Protein C (deficiency)

33 Protein S (deficiency)Protein S (deficiency)

44 Antithrombin III (deficiency)Antithrombin III (deficiency)

55 Abnormal Prothrombin (PT 20210 A)Abnormal Prothrombin (PT 20210 A)

66 Sticky platelet syndromeSticky platelet syndrome

Risk FactorsmdashAcquiredRisk FactorsmdashAcquired

Advancing ageAdvancing age Prior ThrombosisPrior Thrombosis ImmobilizationImmobilization Major surgeryMajor surgery MalignancyMalignancy EstrogensEstrogens

Antiphospholipid Antiphospholipid antibody syndromeantibody syndrome

Myeloproliferative Myeloproliferative DisordersDisorders

Heparin-induced Heparin-induced thrombocytopenia thrombocytopenia (HIT)(HIT)

ProlongedProlonged air travel air travel

Risk FactorsmdashMixedUnknownRisk FactorsmdashMixedUnknown

HyperhomocysteinemiaHyperhomocysteinemia High levels of factor VIIIHigh levels of factor VIII Acquired Protein C resistance in the absence of Acquired Protein C resistance in the absence of

Factor V LeidenFactor V Leiden High levels of Factor IX XIHigh levels of Factor IX XI

11 FV- LeidenFV- Leiden

One of the most common causes for thrombophilia One of the most common causes for thrombophilia ndash 20 of clinical disease (AT PC and PS ndash 5) + ndash 20 of clinical disease (AT PC and PS ndash 5) + risk factorrisk factor

Activated PC inhibits F Va and F VIIIaActivated PC inhibits F Va and F VIIIa Inability of APC to inhibit the above complex due Inability of APC to inhibit the above complex due

to mutated FVto mutated FV Heterozygous 5-10 times increased risk for TEHeterozygous 5-10 times increased risk for TE Homozygous 50-100 timesHomozygous 50-100 times

Factor Va

Arg 306 Arg 506 Arg 1765

Arginine CGA

Glutamine CAA

Factor Va resistant to APC cleavage

Factor V Leiden

Relative Risk forVenous Thrombosis

Factor V Leiden Heterozygote x 7

Factor V Leiden Homozygote x 80

Oral Contraceptives x 3

Oral Contraceptives + Factor V Leiden x 35

Leiden Study Group Data

22 Protein C DeficiencyProtein C Deficiency

Common cause (increasing TE with age)Common cause (increasing TE with age) Needs TM from endothelium wallNeeds TM from endothelium wall Heterozygous 50 of level of normal Heterozygous 50 of level of normal

individualsindividuals Homozygous babies are born with Homozygous babies are born with

undetected levels (thrombi in microvascular undetected levels (thrombi in microvascular of skin DIC necrosis purpura of skin DIC necrosis purpura fulminans)fulminans)

33 Protein S DeficiencyProtein S Deficiency

Non-enzymatic co-factor for PCNon-enzymatic co-factor for PC Binds to TM-PCBinds to TM-PC Same properties as PCSame properties as PC Two forms free in plasma and bound to C4b Two forms free in plasma and bound to C4b

binding protein (60) Only free fraction binding protein (60) Only free fraction functions as co-factor for APCfunctions as co-factor for APC

Sometimes difficult to get accurate measures of Sometimes difficult to get accurate measures of PS because of the latterPS because of the latter

Like PC can be acquired liver disease Warfarin Like PC can be acquired liver disease Warfarin pregnancy cancer DIC and chemopregnancy cancer DIC and chemo

44 Antithrombin III DeficiencyAntithrombin III Deficiency

Common cause (incidence 12000 ndash 15000 Common cause (incidence 12000 ndash 15000 heterozygotes 50 DVT) Quantitative vs heterozygotes 50 DVT) Quantitative vs Qualitative disorder (Acquired DIC cirrhosis Qualitative disorder (Acquired DIC cirrhosis NS)NS)

Bind to and inactivate thrombin Factors IXa Xa Bind to and inactivate thrombin Factors IXa Xa XIa and XIIa (ATheparin complex - rate of XIa and XIIa (ATheparin complex - rate of inhibition 1000-fold increased)inhibition 1000-fold increased)

Not necessarily a risk factor to be involved in Not necessarily a risk factor to be involved in heterozygotes to give TEheterozygotes to give TE

Increased incidence with ageing 80 at 55 yearsIncreased incidence with ageing 80 at 55 years

55 Abnormal ProthrombinAbnormal Prothrombin (PT 20210 A) (PT 20210 A)

CommonCommon Increased levels of prothrombin enhanced Increased levels of prothrombin enhanced

thrombin formationthrombin formation Only way for diagnosis DNA-PCR Only way for diagnosis DNA-PCR

techniquetechnique

66 Sticky Platelet SyndromeSticky Platelet Syndrome

Especially in arterial thrombosis (MI) and Especially in arterial thrombosis (MI) and development of recurrent TE while on Warfarindevelopment of recurrent TE while on Warfarin

3 Forms3 Forms If on aspirin it should be stopped 14 days prior to If on aspirin it should be stopped 14 days prior to

testingtesting

Also rememberAlso remember

PC PS and AT III are inhibitors of clottingPC PS and AT III are inhibitors of clotting

Non-familial (Acquired)Non-familial (Acquired)11 Antiphospholipid SyndromeAntiphospholipid Syndrome Antibodies directed against phospholipid cell membrane = Antibodies directed against phospholipid cell membrane =

APA (Antiphospholipid Ab)APA (Antiphospholipid Ab) APA ACA or LAAPA ACA or LA Primary (PAPS) or secondary (autoimmune disorders eg Primary (PAPS) or secondary (autoimmune disorders eg

SLE)SLE) ACA (Anticardiolipin Ab) IgM + IgGACA (Anticardiolipin Ab) IgM + IgG IgG the clinically important oneIgG the clinically important one IgM pregnancy infection (viral) trauma and post-opIgM pregnancy infection (viral) trauma and post-op LA (Lupus anticoagulant) Ab which affect clotting tests (LA-LA (Lupus anticoagulant) Ab which affect clotting tests (LA-

PTT RVV Kaolin)PTT RVV Kaolin) PAPS = TE miscarriage IUDPAPS = TE miscarriage IUD

Antiphospholipid Syndrome1048734 Antiphospholipid syndrome (APS) ndash Syndrome characterized by venous andor arterial thrombosis thrombocytopenia or recurrent fetal loss associated with antibodies to phospho-lipid- protein Complexes

1048734 Antiphospholipid antibodies (aPL)ndash IgG IgM or IgA antibodies that are directed to target proteins such as cardiolipin beta2-Glycoprotein I (β2GPI)or Prothrombin all of which bind to phospholipidsndash Lupus anticoagulant (LA) bull Antiphospholipid antibodies identified by in vitro phospholipid dependent clot-based assays antibodies are targeted against Prothrombin or β2GPI and prolong clotting times

Antiphospholipd Antibodies

Lupus Anticoagulant

Conditions where screening for APS Conditions where screening for APS is indicatedis indicated

The first thrombotic event below the age of 40The first thrombotic event below the age of 40 History of recurrent TEDHistory of recurrent TED Recurrent fetal loss in the 1Recurrent fetal loss in the 1stst or the 2 or the 2ndnd trimester trimester Patient with SLEPatient with SLE Pre-hormone replacement therapyPre-hormone replacement therapy

Non-familial (Acquired) continuedNon-familial (Acquired) continued

22 TPA (Tissue Plasminogen Activator) TPA (Tissue Plasminogen Activator) decreased levels impaired fibrinolysisdecreased levels impaired fibrinolysis

33 PAI (Plasminogen Activator Inhibitor) PAI (Plasminogen Activator Inhibitor) increased levels decreased TPAincreased levels decreased TPA

44 DysfibrinogenemiaDysfibrinogenemia55 F XII deficiency Hageman factorF XII deficiency Hageman factor66 Fibrinogen (increased)Fibrinogen (increased)77 F VIII (increased)F VIII (increased)88 PlasminogenPlasminogen99 Hyperhomocyteinemia ndash enzyme (folate)Hyperhomocyteinemia ndash enzyme (folate)

Investigation (Thrombotic Profile)Investigation (Thrombotic Profile)

NB Patients can be on Warfarin but not HeparinNB Patients can be on Warfarin but not Heparin FBC PLT amp ESRFBC PLT amp ESR PT aPTT TT amp FibrinogenPT aPTT TT amp Fibrinogen PC amp PSPC amp PS AT IIIAT III APCR (if + screening submit for PCR)APCR (if + screening submit for PCR) PT 20210A (PCR)PT 20210A (PCR) Lupus anticoagulant (RVVT KT LA-PTT) Lupus anticoagulant (RVVT KT LA-PTT) Cardiolipin antibodies (antiphospholipid syndrome)Cardiolipin antibodies (antiphospholipid syndrome) Sticky platelet syndrome (aspirin)Sticky platelet syndrome (aspirin) ANA screeningANA screening PNH screeningPNH screening

When to testWhen to test Younger lt 50 years recurrent TE unusual sites Younger lt 50 years recurrent TE unusual sites

TE on WarfarinTE on Warfarin Not ideal to test after acute episode (inhibitors of Not ideal to test after acute episode (inhibitors of

clotting may be low)clotting may be low) Ideal test after 6 weeks after settlement of Ideal test after 6 weeks after settlement of

hemostasishemostasis Most patients are on Warfarin then (PC amp PS are Most patients are on Warfarin then (PC amp PS are

Vit K dependent may be falsely low)Vit K dependent may be falsely low) My view if long-term Warfarin is planned do My view if long-term Warfarin is planned do

immediately according to duration of treatment it immediately according to duration of treatment it can be done after cessation of treatmentcan be done after cessation of treatment

When to test (continued)When to test (continued)

Practical (my experience) before treatment ndash if AT Practical (my experience) before treatment ndash if AT PS PC are low PS PC are low repeat after Rx has been stopped repeat after Rx has been stopped

SPS platelet aggregation studies (problem SPS platelet aggregation studies (problem sometimes aspirin cannot be stopped)sometimes aspirin cannot be stopped)

Remember the effect of the vessel wall on clotting Remember the effect of the vessel wall on clotting especially in arterial thrombosisespecially in arterial thrombosis

Every woman on contraception HRTEvery woman on contraception HRT

Arterial ThrombosisArterial Thrombosis

Arterial Thrombosis

Arterial ThrombosisArterial Thrombosis

Results as sever oResults as sever o2 2 starvation of the left starvation of the left ventricle of the heartventricle of the heart

This leads to myocardial ischemia amp may This leads to myocardial ischemia amp may progress to myocardial infarction or progress to myocardial infarction or ischemic left ventricular fibrillation amp ischemic left ventricular fibrillation amp sudden deathsudden death

Similar episodes involving the cerebral Similar episodes involving the cerebral circulation result in transient ischemic circulation result in transient ischemic attacks amp thrombotic stroke attacks amp thrombotic stroke

Myocardial Infarction SymptomMyocardial Infarction Symptom

Crushing tightness of the chest with Crushing tightness of the chest with sweating nausea breathlessness amp sweating nausea breathlessness amp collapsecollapse

Chest pain may radiates to the arm throat amp Chest pain may radiates to the arm throat amp jawjaw

Chest pain may confused with sever Chest pain may confused with sever indigestion in itrsquos early stagesindigestion in itrsquos early stages

Transient Ischemic attacksTransient Ischemic attacks

Itrsquos usually accompanied with neurological Itrsquos usually accompanied with neurological dysfunction or loss of visiondysfunction or loss of vision

Completed thrombotic strokeCompleted thrombotic stroke

Itrsquos accompanied by similar symptoms Itrsquos accompanied by similar symptoms which persist for more than 24 hours that which persist for more than 24 hours that may be severely amp permanently disablingmay be severely amp permanently disabling

Risk factors for arterial amp venous thrombosisRisk factors for arterial amp venous thrombosis

Venous thrombosisVenous thrombosisArterial thrombosisArterial thrombosisIncreasing ageIncreasing ageIncreasing ageIncreasing age

ObesityObesityObesityObesity

ImmobilityImmobilityLack of exerciseLack of exercise

Pregnancy rdquopost partomrdquoPregnancy rdquopost partomrdquoHigh fat low fiber dietHigh fat low fiber diet

MalignancyMalignancySmokingSmoking

Lupus anticoagulantLupus anticoagulantHyperlipidemiaHyperlipidemia

Nephrotic syndromeNephrotic syndromeHypertensionHypertension

PolycythemiaPolycythemiaElevated factor VII II concElevated factor VII II conc

goutgoutGenetic factorGenetic factor

Prophylaxis amp treatment of Prophylaxis amp treatment of thrombosisthrombosis

Prevent the risk factorsPrevent the risk factors SmokingSmoking ObesityObesity Lack of exerciseLack of exercise Poor dietPoor diet

Only when this proves to be impossibleOnly when this proves to be impossible

(Pharmacological intervention is required) (Pharmacological intervention is required)

Thrombus FormationThrombus Formation

Clot is a Thrombus formed in an arterial or Clot is a Thrombus formed in an arterial or venous vessel venous vessel

thrombophlebitis - Both inflammation and thrombophlebitis - Both inflammation and clots are presentclots are present

Some thrombus can be superficial but itrsquos Some thrombus can be superficial but itrsquos the DVT thatrsquos a concern the DVT thatrsquos a concern embolism to embolism to lungslungs

ClassificationClassification

1 1 Familial ndash physiologicalFamilial ndash physiological

2 Non-familial (acquired) ndash physiological or 2 Non-familial (acquired) ndash physiological or pathologicalpathological

AcquiredProthrombotic

Stimulus

One or moreInherited

ProthromboticMutation(s)

Thrombosis

AcquiredProthrombotic

Stimulus

One or moreInherited

ProthromboticMutation(s)

Thrombosis

Factor V LeidenProthrombin 20210AProtein C deficiencyProtein S deficiencyAntithrombin deficiencyHyperhomocysteinemia

Antiphospholipid antibodiesMalignancyImmobilizationSurgeryPregnancyEstrogenHeparin-induced thrombocytopenia

Dr Rudolph Virchow1821-1902

AbnormalBlood Flow

AbnormalVessel Wall

AbnormalBlood

The Hypercoagulable State(thrombophilia)

Mechanisms of ThrombosisMechanisms of Thrombosis

Clinical associations with thrombotic Clinical associations with thrombotic diseasedisease

ImmobilityImmobilityObesityObesity

SmokingSmokingCancerCancer

PregnancyPregnancyEstrogen therapyEstrogen therapy

Types of ThrombosisTypes of Thrombosis

ArterialArterial platelet-based (white) thrombus platelet-based (white) thrombus

Platelet-VWF interactions criticalPlatelet-VWF interactions critical

Associated with end-stage atherosclerosisAssociated with end-stage atherosclerosis

Venous Fibrin-based (red) thrombus

Coagulation factors critical

Venous stasis

Thrombus FormationThrombus Formation

bull Arterial formation - begins w platelet adhesion to arterial vessel wall Adenosine diphosphate (ADP) released from platelets more platelet aggregation Bld flow inhibited fibrin platelets amp RBCrsquos surround clot build up of size structure occludes bld vessels tissue ischemia

bull The result of Arterial Thrombus is localized tissue injury from lack of perfusion

Thrombus FormationThrombus Formation

Venous FormationVenous Formation - Usually from slow bld flow - Usually from slow bld flow - Can occur rapidly Stagnation of the blood flow initiate - Can occur rapidly Stagnation of the blood flow initiate

the coagulation cascadethe coagulation cascade production of fibrin production of fibrinenmeshes enmeshes RBCrsquos amp platelets to form the thrombus Venous RBCrsquos amp platelets to form the thrombus Venous thrombus has a long tail that can break off to produce an thrombus has a long tail that can break off to produce an embolus These travel to faraway sites then lodge embolus These travel to faraway sites then lodge in in lung (capillary level) lung (capillary level) inadequate O2 amp CO2 exchange inadequate O2 amp CO2 exchange occur (ie pulmonary embolism amp cerebral embolism)occur (ie pulmonary embolism amp cerebral embolism)

Oral amp parenteral anticoagulants (HeparinWarfarin) Oral amp parenteral anticoagulants (HeparinWarfarin) primarily act by preventing venous thrombosisprimarily act by preventing venous thrombosis

Antiplatelet drugs primarily act by preventing arterial Antiplatelet drugs primarily act by preventing arterial thrombosisthrombosis

Types of ThrombosisTypes of Thrombosis

Occlusive Thrombus occurs when the Occlusive Thrombus occurs when the entire lumen of blood vessel is occupied by entire lumen of blood vessel is occupied by coagulated material amp blood flow is coagulated material amp blood flow is obstructedobstructed

Mural Thrombosis occurs when the Mural Thrombosis occurs when the thrombus adheres to one site of the blood thrombus adheres to one site of the blood vessel only amp blood is restricted but not vessel only amp blood is restricted but not arrested arrested

Thrombosis

Hereditarythrombophilia

Acquiredthrombophilia

SurgerytraumaImmobility

Inflammation

Malignancy

Estrogens

Risk Factors for ThrombosisRisk Factors for Thrombosis

Atherosclerosis

THROMBOEMBOLIC DISORDERSTHROMBOEMBOLIC DISORDERS

Venous thromboembolismVenous thromboembolism

Arterial thromboembolismArterial thromboembolism

Risk Factors forRisk Factors forVenous ThrombosisVenous Thrombosis

AcquiredAcquired InheritedInherited MixedunknownMixedunknown

Venous Thrombosis Venous system low flow amp pressure Thrombi are fibrin rich Function of age biologic conditions genetic

ampenvironmental factors and their interactions Venous thromboembolism (VTE) ndash Deep vein thrombosis (DVT) ndash Pulmonary embolism (PE) ndash Superficial portal cerebral or retinal vein thrombosis Reasons for coagulation testing ndash Risk for recurrence of thrombosis ndash Treatment considerations (duration amp intensity) ndash Genetic counseling for affected family members ndash Prophylaxis for high risk situations

The most common is (DVT) deep venous The most common is (DVT) deep venous thrombosis of the lower limbs The main thrombosis of the lower limbs The main site where there is maximum stasis and low site where there is maximum stasis and low blood flow blood flow

Propagation of thrombus is associated with Propagation of thrombus is associated with red cell entrapmenthelliphellipred thrombusred cell entrapmenthelliphellipred thrombus

Venus thrombi may become dislodged or Venus thrombi may become dislodged or fragment resulting in the formation of fragment resulting in the formation of circulating thrombi This may result in circulating thrombi This may result in pulmonary embolismpulmonary embolism

Venous Thrombosis

Pulmonary embolismPulmonary embolism

Presents with acute chest painPresents with acute chest pain Breathlessness with shockBreathlessness with shock Cough amp hemopysisCough amp hemopysis May be fatalMay be fatal

Venous Thrombosis symptoms

Typically presents with pain swelling Typically presents with pain swelling discoloration amp warmth in the affected areadiscoloration amp warmth in the affected area

However However

(these symptoms may be absent amp non of (these symptoms may be absent amp non of them is specific)them is specific)

Hematologic manifestationsHematologic manifestations

Cutaneous manifestationsCutaneous manifestations

Genetic Risk Factors(Familial)

11 FV- Leiden (APCR activated prot C resistance)FV- Leiden (APCR activated prot C resistance)

22 Protein C (deficiency)Protein C (deficiency)

33 Protein S (deficiency)Protein S (deficiency)

44 Antithrombin III (deficiency)Antithrombin III (deficiency)

55 Abnormal Prothrombin (PT 20210 A)Abnormal Prothrombin (PT 20210 A)

66 Sticky platelet syndromeSticky platelet syndrome

Risk FactorsmdashAcquiredRisk FactorsmdashAcquired

Advancing ageAdvancing age Prior ThrombosisPrior Thrombosis ImmobilizationImmobilization Major surgeryMajor surgery MalignancyMalignancy EstrogensEstrogens

Antiphospholipid Antiphospholipid antibody syndromeantibody syndrome

Myeloproliferative Myeloproliferative DisordersDisorders

Heparin-induced Heparin-induced thrombocytopenia thrombocytopenia (HIT)(HIT)

ProlongedProlonged air travel air travel

Risk FactorsmdashMixedUnknownRisk FactorsmdashMixedUnknown

HyperhomocysteinemiaHyperhomocysteinemia High levels of factor VIIIHigh levels of factor VIII Acquired Protein C resistance in the absence of Acquired Protein C resistance in the absence of

Factor V LeidenFactor V Leiden High levels of Factor IX XIHigh levels of Factor IX XI

11 FV- LeidenFV- Leiden

One of the most common causes for thrombophilia One of the most common causes for thrombophilia ndash 20 of clinical disease (AT PC and PS ndash 5) + ndash 20 of clinical disease (AT PC and PS ndash 5) + risk factorrisk factor

Activated PC inhibits F Va and F VIIIaActivated PC inhibits F Va and F VIIIa Inability of APC to inhibit the above complex due Inability of APC to inhibit the above complex due

to mutated FVto mutated FV Heterozygous 5-10 times increased risk for TEHeterozygous 5-10 times increased risk for TE Homozygous 50-100 timesHomozygous 50-100 times

Factor Va

Arg 306 Arg 506 Arg 1765

Arginine CGA

Glutamine CAA

Factor Va resistant to APC cleavage

Factor V Leiden

Relative Risk forVenous Thrombosis

Factor V Leiden Heterozygote x 7

Factor V Leiden Homozygote x 80

Oral Contraceptives x 3

Oral Contraceptives + Factor V Leiden x 35

Leiden Study Group Data

22 Protein C DeficiencyProtein C Deficiency

Common cause (increasing TE with age)Common cause (increasing TE with age) Needs TM from endothelium wallNeeds TM from endothelium wall Heterozygous 50 of level of normal Heterozygous 50 of level of normal

individualsindividuals Homozygous babies are born with Homozygous babies are born with

undetected levels (thrombi in microvascular undetected levels (thrombi in microvascular of skin DIC necrosis purpura of skin DIC necrosis purpura fulminans)fulminans)

33 Protein S DeficiencyProtein S Deficiency

Non-enzymatic co-factor for PCNon-enzymatic co-factor for PC Binds to TM-PCBinds to TM-PC Same properties as PCSame properties as PC Two forms free in plasma and bound to C4b Two forms free in plasma and bound to C4b

binding protein (60) Only free fraction binding protein (60) Only free fraction functions as co-factor for APCfunctions as co-factor for APC

Sometimes difficult to get accurate measures of Sometimes difficult to get accurate measures of PS because of the latterPS because of the latter

Like PC can be acquired liver disease Warfarin Like PC can be acquired liver disease Warfarin pregnancy cancer DIC and chemopregnancy cancer DIC and chemo

44 Antithrombin III DeficiencyAntithrombin III Deficiency

Common cause (incidence 12000 ndash 15000 Common cause (incidence 12000 ndash 15000 heterozygotes 50 DVT) Quantitative vs heterozygotes 50 DVT) Quantitative vs Qualitative disorder (Acquired DIC cirrhosis Qualitative disorder (Acquired DIC cirrhosis NS)NS)

Bind to and inactivate thrombin Factors IXa Xa Bind to and inactivate thrombin Factors IXa Xa XIa and XIIa (ATheparin complex - rate of XIa and XIIa (ATheparin complex - rate of inhibition 1000-fold increased)inhibition 1000-fold increased)

Not necessarily a risk factor to be involved in Not necessarily a risk factor to be involved in heterozygotes to give TEheterozygotes to give TE

Increased incidence with ageing 80 at 55 yearsIncreased incidence with ageing 80 at 55 years

55 Abnormal ProthrombinAbnormal Prothrombin (PT 20210 A) (PT 20210 A)

CommonCommon Increased levels of prothrombin enhanced Increased levels of prothrombin enhanced

thrombin formationthrombin formation Only way for diagnosis DNA-PCR Only way for diagnosis DNA-PCR

techniquetechnique

66 Sticky Platelet SyndromeSticky Platelet Syndrome

Especially in arterial thrombosis (MI) and Especially in arterial thrombosis (MI) and development of recurrent TE while on Warfarindevelopment of recurrent TE while on Warfarin

3 Forms3 Forms If on aspirin it should be stopped 14 days prior to If on aspirin it should be stopped 14 days prior to

testingtesting

Also rememberAlso remember

PC PS and AT III are inhibitors of clottingPC PS and AT III are inhibitors of clotting

Non-familial (Acquired)Non-familial (Acquired)11 Antiphospholipid SyndromeAntiphospholipid Syndrome Antibodies directed against phospholipid cell membrane = Antibodies directed against phospholipid cell membrane =

APA (Antiphospholipid Ab)APA (Antiphospholipid Ab) APA ACA or LAAPA ACA or LA Primary (PAPS) or secondary (autoimmune disorders eg Primary (PAPS) or secondary (autoimmune disorders eg

SLE)SLE) ACA (Anticardiolipin Ab) IgM + IgGACA (Anticardiolipin Ab) IgM + IgG IgG the clinically important oneIgG the clinically important one IgM pregnancy infection (viral) trauma and post-opIgM pregnancy infection (viral) trauma and post-op LA (Lupus anticoagulant) Ab which affect clotting tests (LA-LA (Lupus anticoagulant) Ab which affect clotting tests (LA-

PTT RVV Kaolin)PTT RVV Kaolin) PAPS = TE miscarriage IUDPAPS = TE miscarriage IUD

Antiphospholipid Syndrome1048734 Antiphospholipid syndrome (APS) ndash Syndrome characterized by venous andor arterial thrombosis thrombocytopenia or recurrent fetal loss associated with antibodies to phospho-lipid- protein Complexes

1048734 Antiphospholipid antibodies (aPL)ndash IgG IgM or IgA antibodies that are directed to target proteins such as cardiolipin beta2-Glycoprotein I (β2GPI)or Prothrombin all of which bind to phospholipidsndash Lupus anticoagulant (LA) bull Antiphospholipid antibodies identified by in vitro phospholipid dependent clot-based assays antibodies are targeted against Prothrombin or β2GPI and prolong clotting times

Antiphospholipd Antibodies

Lupus Anticoagulant

Conditions where screening for APS Conditions where screening for APS is indicatedis indicated

The first thrombotic event below the age of 40The first thrombotic event below the age of 40 History of recurrent TEDHistory of recurrent TED Recurrent fetal loss in the 1Recurrent fetal loss in the 1stst or the 2 or the 2ndnd trimester trimester Patient with SLEPatient with SLE Pre-hormone replacement therapyPre-hormone replacement therapy

Non-familial (Acquired) continuedNon-familial (Acquired) continued

22 TPA (Tissue Plasminogen Activator) TPA (Tissue Plasminogen Activator) decreased levels impaired fibrinolysisdecreased levels impaired fibrinolysis

33 PAI (Plasminogen Activator Inhibitor) PAI (Plasminogen Activator Inhibitor) increased levels decreased TPAincreased levels decreased TPA

44 DysfibrinogenemiaDysfibrinogenemia55 F XII deficiency Hageman factorF XII deficiency Hageman factor66 Fibrinogen (increased)Fibrinogen (increased)77 F VIII (increased)F VIII (increased)88 PlasminogenPlasminogen99 Hyperhomocyteinemia ndash enzyme (folate)Hyperhomocyteinemia ndash enzyme (folate)

Investigation (Thrombotic Profile)Investigation (Thrombotic Profile)

NB Patients can be on Warfarin but not HeparinNB Patients can be on Warfarin but not Heparin FBC PLT amp ESRFBC PLT amp ESR PT aPTT TT amp FibrinogenPT aPTT TT amp Fibrinogen PC amp PSPC amp PS AT IIIAT III APCR (if + screening submit for PCR)APCR (if + screening submit for PCR) PT 20210A (PCR)PT 20210A (PCR) Lupus anticoagulant (RVVT KT LA-PTT) Lupus anticoagulant (RVVT KT LA-PTT) Cardiolipin antibodies (antiphospholipid syndrome)Cardiolipin antibodies (antiphospholipid syndrome) Sticky platelet syndrome (aspirin)Sticky platelet syndrome (aspirin) ANA screeningANA screening PNH screeningPNH screening

When to testWhen to test Younger lt 50 years recurrent TE unusual sites Younger lt 50 years recurrent TE unusual sites

TE on WarfarinTE on Warfarin Not ideal to test after acute episode (inhibitors of Not ideal to test after acute episode (inhibitors of

clotting may be low)clotting may be low) Ideal test after 6 weeks after settlement of Ideal test after 6 weeks after settlement of

hemostasishemostasis Most patients are on Warfarin then (PC amp PS are Most patients are on Warfarin then (PC amp PS are

Vit K dependent may be falsely low)Vit K dependent may be falsely low) My view if long-term Warfarin is planned do My view if long-term Warfarin is planned do

immediately according to duration of treatment it immediately according to duration of treatment it can be done after cessation of treatmentcan be done after cessation of treatment

When to test (continued)When to test (continued)

Practical (my experience) before treatment ndash if AT Practical (my experience) before treatment ndash if AT PS PC are low PS PC are low repeat after Rx has been stopped repeat after Rx has been stopped

SPS platelet aggregation studies (problem SPS platelet aggregation studies (problem sometimes aspirin cannot be stopped)sometimes aspirin cannot be stopped)

Remember the effect of the vessel wall on clotting Remember the effect of the vessel wall on clotting especially in arterial thrombosisespecially in arterial thrombosis

Every woman on contraception HRTEvery woman on contraception HRT

Arterial ThrombosisArterial Thrombosis

Arterial Thrombosis

Arterial ThrombosisArterial Thrombosis

Results as sever oResults as sever o2 2 starvation of the left starvation of the left ventricle of the heartventricle of the heart

This leads to myocardial ischemia amp may This leads to myocardial ischemia amp may progress to myocardial infarction or progress to myocardial infarction or ischemic left ventricular fibrillation amp ischemic left ventricular fibrillation amp sudden deathsudden death

Similar episodes involving the cerebral Similar episodes involving the cerebral circulation result in transient ischemic circulation result in transient ischemic attacks amp thrombotic stroke attacks amp thrombotic stroke

Myocardial Infarction SymptomMyocardial Infarction Symptom

Crushing tightness of the chest with Crushing tightness of the chest with sweating nausea breathlessness amp sweating nausea breathlessness amp collapsecollapse

Chest pain may radiates to the arm throat amp Chest pain may radiates to the arm throat amp jawjaw

Chest pain may confused with sever Chest pain may confused with sever indigestion in itrsquos early stagesindigestion in itrsquos early stages

Transient Ischemic attacksTransient Ischemic attacks

Itrsquos usually accompanied with neurological Itrsquos usually accompanied with neurological dysfunction or loss of visiondysfunction or loss of vision

Completed thrombotic strokeCompleted thrombotic stroke

Itrsquos accompanied by similar symptoms Itrsquos accompanied by similar symptoms which persist for more than 24 hours that which persist for more than 24 hours that may be severely amp permanently disablingmay be severely amp permanently disabling

Risk factors for arterial amp venous thrombosisRisk factors for arterial amp venous thrombosis

Venous thrombosisVenous thrombosisArterial thrombosisArterial thrombosisIncreasing ageIncreasing ageIncreasing ageIncreasing age

ObesityObesityObesityObesity

ImmobilityImmobilityLack of exerciseLack of exercise

Pregnancy rdquopost partomrdquoPregnancy rdquopost partomrdquoHigh fat low fiber dietHigh fat low fiber diet

MalignancyMalignancySmokingSmoking

Lupus anticoagulantLupus anticoagulantHyperlipidemiaHyperlipidemia

Nephrotic syndromeNephrotic syndromeHypertensionHypertension

PolycythemiaPolycythemiaElevated factor VII II concElevated factor VII II conc

goutgoutGenetic factorGenetic factor

Prophylaxis amp treatment of Prophylaxis amp treatment of thrombosisthrombosis

Prevent the risk factorsPrevent the risk factors SmokingSmoking ObesityObesity Lack of exerciseLack of exercise Poor dietPoor diet

Only when this proves to be impossibleOnly when this proves to be impossible

(Pharmacological intervention is required) (Pharmacological intervention is required)

ClassificationClassification

1 1 Familial ndash physiologicalFamilial ndash physiological

2 Non-familial (acquired) ndash physiological or 2 Non-familial (acquired) ndash physiological or pathologicalpathological

AcquiredProthrombotic

Stimulus

One or moreInherited

ProthromboticMutation(s)

Thrombosis

AcquiredProthrombotic

Stimulus

One or moreInherited

ProthromboticMutation(s)

Thrombosis

Factor V LeidenProthrombin 20210AProtein C deficiencyProtein S deficiencyAntithrombin deficiencyHyperhomocysteinemia

Antiphospholipid antibodiesMalignancyImmobilizationSurgeryPregnancyEstrogenHeparin-induced thrombocytopenia

Dr Rudolph Virchow1821-1902

AbnormalBlood Flow

AbnormalVessel Wall

AbnormalBlood

The Hypercoagulable State(thrombophilia)

Mechanisms of ThrombosisMechanisms of Thrombosis

Clinical associations with thrombotic Clinical associations with thrombotic diseasedisease

ImmobilityImmobilityObesityObesity

SmokingSmokingCancerCancer

PregnancyPregnancyEstrogen therapyEstrogen therapy

Types of ThrombosisTypes of Thrombosis

ArterialArterial platelet-based (white) thrombus platelet-based (white) thrombus

Platelet-VWF interactions criticalPlatelet-VWF interactions critical

Associated with end-stage atherosclerosisAssociated with end-stage atherosclerosis

Venous Fibrin-based (red) thrombus

Coagulation factors critical

Venous stasis

Thrombus FormationThrombus Formation

bull Arterial formation - begins w platelet adhesion to arterial vessel wall Adenosine diphosphate (ADP) released from platelets more platelet aggregation Bld flow inhibited fibrin platelets amp RBCrsquos surround clot build up of size structure occludes bld vessels tissue ischemia

bull The result of Arterial Thrombus is localized tissue injury from lack of perfusion

Thrombus FormationThrombus Formation

Venous FormationVenous Formation - Usually from slow bld flow - Usually from slow bld flow - Can occur rapidly Stagnation of the blood flow initiate - Can occur rapidly Stagnation of the blood flow initiate

the coagulation cascadethe coagulation cascade production of fibrin production of fibrinenmeshes enmeshes RBCrsquos amp platelets to form the thrombus Venous RBCrsquos amp platelets to form the thrombus Venous thrombus has a long tail that can break off to produce an thrombus has a long tail that can break off to produce an embolus These travel to faraway sites then lodge embolus These travel to faraway sites then lodge in in lung (capillary level) lung (capillary level) inadequate O2 amp CO2 exchange inadequate O2 amp CO2 exchange occur (ie pulmonary embolism amp cerebral embolism)occur (ie pulmonary embolism amp cerebral embolism)

Oral amp parenteral anticoagulants (HeparinWarfarin) Oral amp parenteral anticoagulants (HeparinWarfarin) primarily act by preventing venous thrombosisprimarily act by preventing venous thrombosis

Antiplatelet drugs primarily act by preventing arterial Antiplatelet drugs primarily act by preventing arterial thrombosisthrombosis

Types of ThrombosisTypes of Thrombosis

Occlusive Thrombus occurs when the Occlusive Thrombus occurs when the entire lumen of blood vessel is occupied by entire lumen of blood vessel is occupied by coagulated material amp blood flow is coagulated material amp blood flow is obstructedobstructed

Mural Thrombosis occurs when the Mural Thrombosis occurs when the thrombus adheres to one site of the blood thrombus adheres to one site of the blood vessel only amp blood is restricted but not vessel only amp blood is restricted but not arrested arrested

Thrombosis

Hereditarythrombophilia

Acquiredthrombophilia

SurgerytraumaImmobility

Inflammation

Malignancy

Estrogens

Risk Factors for ThrombosisRisk Factors for Thrombosis

Atherosclerosis

THROMBOEMBOLIC DISORDERSTHROMBOEMBOLIC DISORDERS

Venous thromboembolismVenous thromboembolism

Arterial thromboembolismArterial thromboembolism

Risk Factors forRisk Factors forVenous ThrombosisVenous Thrombosis

AcquiredAcquired InheritedInherited MixedunknownMixedunknown

Venous Thrombosis Venous system low flow amp pressure Thrombi are fibrin rich Function of age biologic conditions genetic

ampenvironmental factors and their interactions Venous thromboembolism (VTE) ndash Deep vein thrombosis (DVT) ndash Pulmonary embolism (PE) ndash Superficial portal cerebral or retinal vein thrombosis Reasons for coagulation testing ndash Risk for recurrence of thrombosis ndash Treatment considerations (duration amp intensity) ndash Genetic counseling for affected family members ndash Prophylaxis for high risk situations

The most common is (DVT) deep venous The most common is (DVT) deep venous thrombosis of the lower limbs The main thrombosis of the lower limbs The main site where there is maximum stasis and low site where there is maximum stasis and low blood flow blood flow

Propagation of thrombus is associated with Propagation of thrombus is associated with red cell entrapmenthelliphellipred thrombusred cell entrapmenthelliphellipred thrombus

Venus thrombi may become dislodged or Venus thrombi may become dislodged or fragment resulting in the formation of fragment resulting in the formation of circulating thrombi This may result in circulating thrombi This may result in pulmonary embolismpulmonary embolism

Venous Thrombosis

Pulmonary embolismPulmonary embolism

Presents with acute chest painPresents with acute chest pain Breathlessness with shockBreathlessness with shock Cough amp hemopysisCough amp hemopysis May be fatalMay be fatal

Venous Thrombosis symptoms

Typically presents with pain swelling Typically presents with pain swelling discoloration amp warmth in the affected areadiscoloration amp warmth in the affected area

However However

(these symptoms may be absent amp non of (these symptoms may be absent amp non of them is specific)them is specific)

Hematologic manifestationsHematologic manifestations

Cutaneous manifestationsCutaneous manifestations

Genetic Risk Factors(Familial)

11 FV- Leiden (APCR activated prot C resistance)FV- Leiden (APCR activated prot C resistance)

22 Protein C (deficiency)Protein C (deficiency)

33 Protein S (deficiency)Protein S (deficiency)

44 Antithrombin III (deficiency)Antithrombin III (deficiency)

55 Abnormal Prothrombin (PT 20210 A)Abnormal Prothrombin (PT 20210 A)

66 Sticky platelet syndromeSticky platelet syndrome

Risk FactorsmdashAcquiredRisk FactorsmdashAcquired

Advancing ageAdvancing age Prior ThrombosisPrior Thrombosis ImmobilizationImmobilization Major surgeryMajor surgery MalignancyMalignancy EstrogensEstrogens

Antiphospholipid Antiphospholipid antibody syndromeantibody syndrome

Myeloproliferative Myeloproliferative DisordersDisorders

Heparin-induced Heparin-induced thrombocytopenia thrombocytopenia (HIT)(HIT)

ProlongedProlonged air travel air travel

Risk FactorsmdashMixedUnknownRisk FactorsmdashMixedUnknown

HyperhomocysteinemiaHyperhomocysteinemia High levels of factor VIIIHigh levels of factor VIII Acquired Protein C resistance in the absence of Acquired Protein C resistance in the absence of

Factor V LeidenFactor V Leiden High levels of Factor IX XIHigh levels of Factor IX XI

11 FV- LeidenFV- Leiden

One of the most common causes for thrombophilia One of the most common causes for thrombophilia ndash 20 of clinical disease (AT PC and PS ndash 5) + ndash 20 of clinical disease (AT PC and PS ndash 5) + risk factorrisk factor

Activated PC inhibits F Va and F VIIIaActivated PC inhibits F Va and F VIIIa Inability of APC to inhibit the above complex due Inability of APC to inhibit the above complex due

to mutated FVto mutated FV Heterozygous 5-10 times increased risk for TEHeterozygous 5-10 times increased risk for TE Homozygous 50-100 timesHomozygous 50-100 times

Factor Va

Arg 306 Arg 506 Arg 1765

Arginine CGA

Glutamine CAA

Factor Va resistant to APC cleavage

Factor V Leiden

Relative Risk forVenous Thrombosis

Factor V Leiden Heterozygote x 7

Factor V Leiden Homozygote x 80

Oral Contraceptives x 3

Oral Contraceptives + Factor V Leiden x 35

Leiden Study Group Data

22 Protein C DeficiencyProtein C Deficiency

Common cause (increasing TE with age)Common cause (increasing TE with age) Needs TM from endothelium wallNeeds TM from endothelium wall Heterozygous 50 of level of normal Heterozygous 50 of level of normal

individualsindividuals Homozygous babies are born with Homozygous babies are born with

undetected levels (thrombi in microvascular undetected levels (thrombi in microvascular of skin DIC necrosis purpura of skin DIC necrosis purpura fulminans)fulminans)

33 Protein S DeficiencyProtein S Deficiency

Non-enzymatic co-factor for PCNon-enzymatic co-factor for PC Binds to TM-PCBinds to TM-PC Same properties as PCSame properties as PC Two forms free in plasma and bound to C4b Two forms free in plasma and bound to C4b

binding protein (60) Only free fraction binding protein (60) Only free fraction functions as co-factor for APCfunctions as co-factor for APC

Sometimes difficult to get accurate measures of Sometimes difficult to get accurate measures of PS because of the latterPS because of the latter

Like PC can be acquired liver disease Warfarin Like PC can be acquired liver disease Warfarin pregnancy cancer DIC and chemopregnancy cancer DIC and chemo

44 Antithrombin III DeficiencyAntithrombin III Deficiency

Common cause (incidence 12000 ndash 15000 Common cause (incidence 12000 ndash 15000 heterozygotes 50 DVT) Quantitative vs heterozygotes 50 DVT) Quantitative vs Qualitative disorder (Acquired DIC cirrhosis Qualitative disorder (Acquired DIC cirrhosis NS)NS)

Bind to and inactivate thrombin Factors IXa Xa Bind to and inactivate thrombin Factors IXa Xa XIa and XIIa (ATheparin complex - rate of XIa and XIIa (ATheparin complex - rate of inhibition 1000-fold increased)inhibition 1000-fold increased)

Not necessarily a risk factor to be involved in Not necessarily a risk factor to be involved in heterozygotes to give TEheterozygotes to give TE

Increased incidence with ageing 80 at 55 yearsIncreased incidence with ageing 80 at 55 years

55 Abnormal ProthrombinAbnormal Prothrombin (PT 20210 A) (PT 20210 A)

CommonCommon Increased levels of prothrombin enhanced Increased levels of prothrombin enhanced

thrombin formationthrombin formation Only way for diagnosis DNA-PCR Only way for diagnosis DNA-PCR

techniquetechnique

66 Sticky Platelet SyndromeSticky Platelet Syndrome

Especially in arterial thrombosis (MI) and Especially in arterial thrombosis (MI) and development of recurrent TE while on Warfarindevelopment of recurrent TE while on Warfarin

3 Forms3 Forms If on aspirin it should be stopped 14 days prior to If on aspirin it should be stopped 14 days prior to

testingtesting

Also rememberAlso remember

PC PS and AT III are inhibitors of clottingPC PS and AT III are inhibitors of clotting

Non-familial (Acquired)Non-familial (Acquired)11 Antiphospholipid SyndromeAntiphospholipid Syndrome Antibodies directed against phospholipid cell membrane = Antibodies directed against phospholipid cell membrane =

APA (Antiphospholipid Ab)APA (Antiphospholipid Ab) APA ACA or LAAPA ACA or LA Primary (PAPS) or secondary (autoimmune disorders eg Primary (PAPS) or secondary (autoimmune disorders eg

SLE)SLE) ACA (Anticardiolipin Ab) IgM + IgGACA (Anticardiolipin Ab) IgM + IgG IgG the clinically important oneIgG the clinically important one IgM pregnancy infection (viral) trauma and post-opIgM pregnancy infection (viral) trauma and post-op LA (Lupus anticoagulant) Ab which affect clotting tests (LA-LA (Lupus anticoagulant) Ab which affect clotting tests (LA-

PTT RVV Kaolin)PTT RVV Kaolin) PAPS = TE miscarriage IUDPAPS = TE miscarriage IUD

Antiphospholipid Syndrome1048734 Antiphospholipid syndrome (APS) ndash Syndrome characterized by venous andor arterial thrombosis thrombocytopenia or recurrent fetal loss associated with antibodies to phospho-lipid- protein Complexes

1048734 Antiphospholipid antibodies (aPL)ndash IgG IgM or IgA antibodies that are directed to target proteins such as cardiolipin beta2-Glycoprotein I (β2GPI)or Prothrombin all of which bind to phospholipidsndash Lupus anticoagulant (LA) bull Antiphospholipid antibodies identified by in vitro phospholipid dependent clot-based assays antibodies are targeted against Prothrombin or β2GPI and prolong clotting times

Antiphospholipd Antibodies

Lupus Anticoagulant

Conditions where screening for APS Conditions where screening for APS is indicatedis indicated

The first thrombotic event below the age of 40The first thrombotic event below the age of 40 History of recurrent TEDHistory of recurrent TED Recurrent fetal loss in the 1Recurrent fetal loss in the 1stst or the 2 or the 2ndnd trimester trimester Patient with SLEPatient with SLE Pre-hormone replacement therapyPre-hormone replacement therapy

Non-familial (Acquired) continuedNon-familial (Acquired) continued

22 TPA (Tissue Plasminogen Activator) TPA (Tissue Plasminogen Activator) decreased levels impaired fibrinolysisdecreased levels impaired fibrinolysis

33 PAI (Plasminogen Activator Inhibitor) PAI (Plasminogen Activator Inhibitor) increased levels decreased TPAincreased levels decreased TPA

44 DysfibrinogenemiaDysfibrinogenemia55 F XII deficiency Hageman factorF XII deficiency Hageman factor66 Fibrinogen (increased)Fibrinogen (increased)77 F VIII (increased)F VIII (increased)88 PlasminogenPlasminogen99 Hyperhomocyteinemia ndash enzyme (folate)Hyperhomocyteinemia ndash enzyme (folate)

Investigation (Thrombotic Profile)Investigation (Thrombotic Profile)

NB Patients can be on Warfarin but not HeparinNB Patients can be on Warfarin but not Heparin FBC PLT amp ESRFBC PLT amp ESR PT aPTT TT amp FibrinogenPT aPTT TT amp Fibrinogen PC amp PSPC amp PS AT IIIAT III APCR (if + screening submit for PCR)APCR (if + screening submit for PCR) PT 20210A (PCR)PT 20210A (PCR) Lupus anticoagulant (RVVT KT LA-PTT) Lupus anticoagulant (RVVT KT LA-PTT) Cardiolipin antibodies (antiphospholipid syndrome)Cardiolipin antibodies (antiphospholipid syndrome) Sticky platelet syndrome (aspirin)Sticky platelet syndrome (aspirin) ANA screeningANA screening PNH screeningPNH screening

When to testWhen to test Younger lt 50 years recurrent TE unusual sites Younger lt 50 years recurrent TE unusual sites

TE on WarfarinTE on Warfarin Not ideal to test after acute episode (inhibitors of Not ideal to test after acute episode (inhibitors of

clotting may be low)clotting may be low) Ideal test after 6 weeks after settlement of Ideal test after 6 weeks after settlement of

hemostasishemostasis Most patients are on Warfarin then (PC amp PS are Most patients are on Warfarin then (PC amp PS are

Vit K dependent may be falsely low)Vit K dependent may be falsely low) My view if long-term Warfarin is planned do My view if long-term Warfarin is planned do

immediately according to duration of treatment it immediately according to duration of treatment it can be done after cessation of treatmentcan be done after cessation of treatment

When to test (continued)When to test (continued)

Practical (my experience) before treatment ndash if AT Practical (my experience) before treatment ndash if AT PS PC are low PS PC are low repeat after Rx has been stopped repeat after Rx has been stopped

SPS platelet aggregation studies (problem SPS platelet aggregation studies (problem sometimes aspirin cannot be stopped)sometimes aspirin cannot be stopped)

Remember the effect of the vessel wall on clotting Remember the effect of the vessel wall on clotting especially in arterial thrombosisespecially in arterial thrombosis

Every woman on contraception HRTEvery woman on contraception HRT

Arterial ThrombosisArterial Thrombosis

Arterial Thrombosis

Arterial ThrombosisArterial Thrombosis

Results as sever oResults as sever o2 2 starvation of the left starvation of the left ventricle of the heartventricle of the heart

This leads to myocardial ischemia amp may This leads to myocardial ischemia amp may progress to myocardial infarction or progress to myocardial infarction or ischemic left ventricular fibrillation amp ischemic left ventricular fibrillation amp sudden deathsudden death

Similar episodes involving the cerebral Similar episodes involving the cerebral circulation result in transient ischemic circulation result in transient ischemic attacks amp thrombotic stroke attacks amp thrombotic stroke

Myocardial Infarction SymptomMyocardial Infarction Symptom

Crushing tightness of the chest with Crushing tightness of the chest with sweating nausea breathlessness amp sweating nausea breathlessness amp collapsecollapse

Chest pain may radiates to the arm throat amp Chest pain may radiates to the arm throat amp jawjaw

Chest pain may confused with sever Chest pain may confused with sever indigestion in itrsquos early stagesindigestion in itrsquos early stages

Transient Ischemic attacksTransient Ischemic attacks

Itrsquos usually accompanied with neurological Itrsquos usually accompanied with neurological dysfunction or loss of visiondysfunction or loss of vision

Completed thrombotic strokeCompleted thrombotic stroke

Itrsquos accompanied by similar symptoms Itrsquos accompanied by similar symptoms which persist for more than 24 hours that which persist for more than 24 hours that may be severely amp permanently disablingmay be severely amp permanently disabling

Risk factors for arterial amp venous thrombosisRisk factors for arterial amp venous thrombosis

Venous thrombosisVenous thrombosisArterial thrombosisArterial thrombosisIncreasing ageIncreasing ageIncreasing ageIncreasing age

ObesityObesityObesityObesity

ImmobilityImmobilityLack of exerciseLack of exercise

Pregnancy rdquopost partomrdquoPregnancy rdquopost partomrdquoHigh fat low fiber dietHigh fat low fiber diet

MalignancyMalignancySmokingSmoking

Lupus anticoagulantLupus anticoagulantHyperlipidemiaHyperlipidemia

Nephrotic syndromeNephrotic syndromeHypertensionHypertension

PolycythemiaPolycythemiaElevated factor VII II concElevated factor VII II conc

goutgoutGenetic factorGenetic factor

Prophylaxis amp treatment of Prophylaxis amp treatment of thrombosisthrombosis

Prevent the risk factorsPrevent the risk factors SmokingSmoking ObesityObesity Lack of exerciseLack of exercise Poor dietPoor diet

Only when this proves to be impossibleOnly when this proves to be impossible

(Pharmacological intervention is required) (Pharmacological intervention is required)

AcquiredProthrombotic

Stimulus

One or moreInherited

ProthromboticMutation(s)

Thrombosis

AcquiredProthrombotic

Stimulus

One or moreInherited

ProthromboticMutation(s)

Thrombosis

Factor V LeidenProthrombin 20210AProtein C deficiencyProtein S deficiencyAntithrombin deficiencyHyperhomocysteinemia

Antiphospholipid antibodiesMalignancyImmobilizationSurgeryPregnancyEstrogenHeparin-induced thrombocytopenia

Dr Rudolph Virchow1821-1902

AbnormalBlood Flow

AbnormalVessel Wall

AbnormalBlood

The Hypercoagulable State(thrombophilia)

Mechanisms of ThrombosisMechanisms of Thrombosis

Clinical associations with thrombotic Clinical associations with thrombotic diseasedisease

ImmobilityImmobilityObesityObesity

SmokingSmokingCancerCancer

PregnancyPregnancyEstrogen therapyEstrogen therapy

Types of ThrombosisTypes of Thrombosis

ArterialArterial platelet-based (white) thrombus platelet-based (white) thrombus

Platelet-VWF interactions criticalPlatelet-VWF interactions critical

Associated with end-stage atherosclerosisAssociated with end-stage atherosclerosis

Venous Fibrin-based (red) thrombus

Coagulation factors critical

Venous stasis

Thrombus FormationThrombus Formation

bull Arterial formation - begins w platelet adhesion to arterial vessel wall Adenosine diphosphate (ADP) released from platelets more platelet aggregation Bld flow inhibited fibrin platelets amp RBCrsquos surround clot build up of size structure occludes bld vessels tissue ischemia

bull The result of Arterial Thrombus is localized tissue injury from lack of perfusion

Thrombus FormationThrombus Formation

Venous FormationVenous Formation - Usually from slow bld flow - Usually from slow bld flow - Can occur rapidly Stagnation of the blood flow initiate - Can occur rapidly Stagnation of the blood flow initiate

the coagulation cascadethe coagulation cascade production of fibrin production of fibrinenmeshes enmeshes RBCrsquos amp platelets to form the thrombus Venous RBCrsquos amp platelets to form the thrombus Venous thrombus has a long tail that can break off to produce an thrombus has a long tail that can break off to produce an embolus These travel to faraway sites then lodge embolus These travel to faraway sites then lodge in in lung (capillary level) lung (capillary level) inadequate O2 amp CO2 exchange inadequate O2 amp CO2 exchange occur (ie pulmonary embolism amp cerebral embolism)occur (ie pulmonary embolism amp cerebral embolism)

Oral amp parenteral anticoagulants (HeparinWarfarin) Oral amp parenteral anticoagulants (HeparinWarfarin) primarily act by preventing venous thrombosisprimarily act by preventing venous thrombosis

Antiplatelet drugs primarily act by preventing arterial Antiplatelet drugs primarily act by preventing arterial thrombosisthrombosis

Types of ThrombosisTypes of Thrombosis

Occlusive Thrombus occurs when the Occlusive Thrombus occurs when the entire lumen of blood vessel is occupied by entire lumen of blood vessel is occupied by coagulated material amp blood flow is coagulated material amp blood flow is obstructedobstructed

Mural Thrombosis occurs when the Mural Thrombosis occurs when the thrombus adheres to one site of the blood thrombus adheres to one site of the blood vessel only amp blood is restricted but not vessel only amp blood is restricted but not arrested arrested

Thrombosis

Hereditarythrombophilia

Acquiredthrombophilia

SurgerytraumaImmobility

Inflammation

Malignancy

Estrogens

Risk Factors for ThrombosisRisk Factors for Thrombosis

Atherosclerosis

THROMBOEMBOLIC DISORDERSTHROMBOEMBOLIC DISORDERS

Venous thromboembolismVenous thromboembolism

Arterial thromboembolismArterial thromboembolism

Risk Factors forRisk Factors forVenous ThrombosisVenous Thrombosis

AcquiredAcquired InheritedInherited MixedunknownMixedunknown

Venous Thrombosis Venous system low flow amp pressure Thrombi are fibrin rich Function of age biologic conditions genetic

ampenvironmental factors and their interactions Venous thromboembolism (VTE) ndash Deep vein thrombosis (DVT) ndash Pulmonary embolism (PE) ndash Superficial portal cerebral or retinal vein thrombosis Reasons for coagulation testing ndash Risk for recurrence of thrombosis ndash Treatment considerations (duration amp intensity) ndash Genetic counseling for affected family members ndash Prophylaxis for high risk situations

The most common is (DVT) deep venous The most common is (DVT) deep venous thrombosis of the lower limbs The main thrombosis of the lower limbs The main site where there is maximum stasis and low site where there is maximum stasis and low blood flow blood flow

Propagation of thrombus is associated with Propagation of thrombus is associated with red cell entrapmenthelliphellipred thrombusred cell entrapmenthelliphellipred thrombus

Venus thrombi may become dislodged or Venus thrombi may become dislodged or fragment resulting in the formation of fragment resulting in the formation of circulating thrombi This may result in circulating thrombi This may result in pulmonary embolismpulmonary embolism

Venous Thrombosis

Pulmonary embolismPulmonary embolism

Presents with acute chest painPresents with acute chest pain Breathlessness with shockBreathlessness with shock Cough amp hemopysisCough amp hemopysis May be fatalMay be fatal

Venous Thrombosis symptoms

Typically presents with pain swelling Typically presents with pain swelling discoloration amp warmth in the affected areadiscoloration amp warmth in the affected area

However However

(these symptoms may be absent amp non of (these symptoms may be absent amp non of them is specific)them is specific)

Hematologic manifestationsHematologic manifestations

Cutaneous manifestationsCutaneous manifestations

Genetic Risk Factors(Familial)

11 FV- Leiden (APCR activated prot C resistance)FV- Leiden (APCR activated prot C resistance)

22 Protein C (deficiency)Protein C (deficiency)

33 Protein S (deficiency)Protein S (deficiency)

44 Antithrombin III (deficiency)Antithrombin III (deficiency)

55 Abnormal Prothrombin (PT 20210 A)Abnormal Prothrombin (PT 20210 A)

66 Sticky platelet syndromeSticky platelet syndrome

Risk FactorsmdashAcquiredRisk FactorsmdashAcquired

Advancing ageAdvancing age Prior ThrombosisPrior Thrombosis ImmobilizationImmobilization Major surgeryMajor surgery MalignancyMalignancy EstrogensEstrogens

Antiphospholipid Antiphospholipid antibody syndromeantibody syndrome

Myeloproliferative Myeloproliferative DisordersDisorders

Heparin-induced Heparin-induced thrombocytopenia thrombocytopenia (HIT)(HIT)

ProlongedProlonged air travel air travel

Risk FactorsmdashMixedUnknownRisk FactorsmdashMixedUnknown

HyperhomocysteinemiaHyperhomocysteinemia High levels of factor VIIIHigh levels of factor VIII Acquired Protein C resistance in the absence of Acquired Protein C resistance in the absence of

Factor V LeidenFactor V Leiden High levels of Factor IX XIHigh levels of Factor IX XI

11 FV- LeidenFV- Leiden

One of the most common causes for thrombophilia One of the most common causes for thrombophilia ndash 20 of clinical disease (AT PC and PS ndash 5) + ndash 20 of clinical disease (AT PC and PS ndash 5) + risk factorrisk factor

Activated PC inhibits F Va and F VIIIaActivated PC inhibits F Va and F VIIIa Inability of APC to inhibit the above complex due Inability of APC to inhibit the above complex due

to mutated FVto mutated FV Heterozygous 5-10 times increased risk for TEHeterozygous 5-10 times increased risk for TE Homozygous 50-100 timesHomozygous 50-100 times

Factor Va

Arg 306 Arg 506 Arg 1765

Arginine CGA

Glutamine CAA

Factor Va resistant to APC cleavage

Factor V Leiden

Relative Risk forVenous Thrombosis

Factor V Leiden Heterozygote x 7

Factor V Leiden Homozygote x 80

Oral Contraceptives x 3

Oral Contraceptives + Factor V Leiden x 35

Leiden Study Group Data

22 Protein C DeficiencyProtein C Deficiency

Common cause (increasing TE with age)Common cause (increasing TE with age) Needs TM from endothelium wallNeeds TM from endothelium wall Heterozygous 50 of level of normal Heterozygous 50 of level of normal

individualsindividuals Homozygous babies are born with Homozygous babies are born with

undetected levels (thrombi in microvascular undetected levels (thrombi in microvascular of skin DIC necrosis purpura of skin DIC necrosis purpura fulminans)fulminans)

33 Protein S DeficiencyProtein S Deficiency

Non-enzymatic co-factor for PCNon-enzymatic co-factor for PC Binds to TM-PCBinds to TM-PC Same properties as PCSame properties as PC Two forms free in plasma and bound to C4b Two forms free in plasma and bound to C4b

binding protein (60) Only free fraction binding protein (60) Only free fraction functions as co-factor for APCfunctions as co-factor for APC

Sometimes difficult to get accurate measures of Sometimes difficult to get accurate measures of PS because of the latterPS because of the latter

Like PC can be acquired liver disease Warfarin Like PC can be acquired liver disease Warfarin pregnancy cancer DIC and chemopregnancy cancer DIC and chemo

44 Antithrombin III DeficiencyAntithrombin III Deficiency

Common cause (incidence 12000 ndash 15000 Common cause (incidence 12000 ndash 15000 heterozygotes 50 DVT) Quantitative vs heterozygotes 50 DVT) Quantitative vs Qualitative disorder (Acquired DIC cirrhosis Qualitative disorder (Acquired DIC cirrhosis NS)NS)

Bind to and inactivate thrombin Factors IXa Xa Bind to and inactivate thrombin Factors IXa Xa XIa and XIIa (ATheparin complex - rate of XIa and XIIa (ATheparin complex - rate of inhibition 1000-fold increased)inhibition 1000-fold increased)

Not necessarily a risk factor to be involved in Not necessarily a risk factor to be involved in heterozygotes to give TEheterozygotes to give TE

Increased incidence with ageing 80 at 55 yearsIncreased incidence with ageing 80 at 55 years

55 Abnormal ProthrombinAbnormal Prothrombin (PT 20210 A) (PT 20210 A)

CommonCommon Increased levels of prothrombin enhanced Increased levels of prothrombin enhanced

thrombin formationthrombin formation Only way for diagnosis DNA-PCR Only way for diagnosis DNA-PCR

techniquetechnique

66 Sticky Platelet SyndromeSticky Platelet Syndrome

Especially in arterial thrombosis (MI) and Especially in arterial thrombosis (MI) and development of recurrent TE while on Warfarindevelopment of recurrent TE while on Warfarin

3 Forms3 Forms If on aspirin it should be stopped 14 days prior to If on aspirin it should be stopped 14 days prior to

testingtesting

Also rememberAlso remember

PC PS and AT III are inhibitors of clottingPC PS and AT III are inhibitors of clotting

Non-familial (Acquired)Non-familial (Acquired)11 Antiphospholipid SyndromeAntiphospholipid Syndrome Antibodies directed against phospholipid cell membrane = Antibodies directed against phospholipid cell membrane =

APA (Antiphospholipid Ab)APA (Antiphospholipid Ab) APA ACA or LAAPA ACA or LA Primary (PAPS) or secondary (autoimmune disorders eg Primary (PAPS) or secondary (autoimmune disorders eg

SLE)SLE) ACA (Anticardiolipin Ab) IgM + IgGACA (Anticardiolipin Ab) IgM + IgG IgG the clinically important oneIgG the clinically important one IgM pregnancy infection (viral) trauma and post-opIgM pregnancy infection (viral) trauma and post-op LA (Lupus anticoagulant) Ab which affect clotting tests (LA-LA (Lupus anticoagulant) Ab which affect clotting tests (LA-

PTT RVV Kaolin)PTT RVV Kaolin) PAPS = TE miscarriage IUDPAPS = TE miscarriage IUD

Antiphospholipid Syndrome1048734 Antiphospholipid syndrome (APS) ndash Syndrome characterized by venous andor arterial thrombosis thrombocytopenia or recurrent fetal loss associated with antibodies to phospho-lipid- protein Complexes

1048734 Antiphospholipid antibodies (aPL)ndash IgG IgM or IgA antibodies that are directed to target proteins such as cardiolipin beta2-Glycoprotein I (β2GPI)or Prothrombin all of which bind to phospholipidsndash Lupus anticoagulant (LA) bull Antiphospholipid antibodies identified by in vitro phospholipid dependent clot-based assays antibodies are targeted against Prothrombin or β2GPI and prolong clotting times

Antiphospholipd Antibodies

Lupus Anticoagulant

Conditions where screening for APS Conditions where screening for APS is indicatedis indicated

The first thrombotic event below the age of 40The first thrombotic event below the age of 40 History of recurrent TEDHistory of recurrent TED Recurrent fetal loss in the 1Recurrent fetal loss in the 1stst or the 2 or the 2ndnd trimester trimester Patient with SLEPatient with SLE Pre-hormone replacement therapyPre-hormone replacement therapy

Non-familial (Acquired) continuedNon-familial (Acquired) continued

22 TPA (Tissue Plasminogen Activator) TPA (Tissue Plasminogen Activator) decreased levels impaired fibrinolysisdecreased levels impaired fibrinolysis

33 PAI (Plasminogen Activator Inhibitor) PAI (Plasminogen Activator Inhibitor) increased levels decreased TPAincreased levels decreased TPA

44 DysfibrinogenemiaDysfibrinogenemia55 F XII deficiency Hageman factorF XII deficiency Hageman factor66 Fibrinogen (increased)Fibrinogen (increased)77 F VIII (increased)F VIII (increased)88 PlasminogenPlasminogen99 Hyperhomocyteinemia ndash enzyme (folate)Hyperhomocyteinemia ndash enzyme (folate)

Investigation (Thrombotic Profile)Investigation (Thrombotic Profile)

NB Patients can be on Warfarin but not HeparinNB Patients can be on Warfarin but not Heparin FBC PLT amp ESRFBC PLT amp ESR PT aPTT TT amp FibrinogenPT aPTT TT amp Fibrinogen PC amp PSPC amp PS AT IIIAT III APCR (if + screening submit for PCR)APCR (if + screening submit for PCR) PT 20210A (PCR)PT 20210A (PCR) Lupus anticoagulant (RVVT KT LA-PTT) Lupus anticoagulant (RVVT KT LA-PTT) Cardiolipin antibodies (antiphospholipid syndrome)Cardiolipin antibodies (antiphospholipid syndrome) Sticky platelet syndrome (aspirin)Sticky platelet syndrome (aspirin) ANA screeningANA screening PNH screeningPNH screening

When to testWhen to test Younger lt 50 years recurrent TE unusual sites Younger lt 50 years recurrent TE unusual sites

TE on WarfarinTE on Warfarin Not ideal to test after acute episode (inhibitors of Not ideal to test after acute episode (inhibitors of

clotting may be low)clotting may be low) Ideal test after 6 weeks after settlement of Ideal test after 6 weeks after settlement of

hemostasishemostasis Most patients are on Warfarin then (PC amp PS are Most patients are on Warfarin then (PC amp PS are

Vit K dependent may be falsely low)Vit K dependent may be falsely low) My view if long-term Warfarin is planned do My view if long-term Warfarin is planned do

immediately according to duration of treatment it immediately according to duration of treatment it can be done after cessation of treatmentcan be done after cessation of treatment

When to test (continued)When to test (continued)

Practical (my experience) before treatment ndash if AT Practical (my experience) before treatment ndash if AT PS PC are low PS PC are low repeat after Rx has been stopped repeat after Rx has been stopped

SPS platelet aggregation studies (problem SPS platelet aggregation studies (problem sometimes aspirin cannot be stopped)sometimes aspirin cannot be stopped)

Remember the effect of the vessel wall on clotting Remember the effect of the vessel wall on clotting especially in arterial thrombosisespecially in arterial thrombosis

Every woman on contraception HRTEvery woman on contraception HRT

Arterial ThrombosisArterial Thrombosis

Arterial Thrombosis

Arterial ThrombosisArterial Thrombosis

Results as sever oResults as sever o2 2 starvation of the left starvation of the left ventricle of the heartventricle of the heart

This leads to myocardial ischemia amp may This leads to myocardial ischemia amp may progress to myocardial infarction or progress to myocardial infarction or ischemic left ventricular fibrillation amp ischemic left ventricular fibrillation amp sudden deathsudden death

Similar episodes involving the cerebral Similar episodes involving the cerebral circulation result in transient ischemic circulation result in transient ischemic attacks amp thrombotic stroke attacks amp thrombotic stroke

Myocardial Infarction SymptomMyocardial Infarction Symptom

Crushing tightness of the chest with Crushing tightness of the chest with sweating nausea breathlessness amp sweating nausea breathlessness amp collapsecollapse

Chest pain may radiates to the arm throat amp Chest pain may radiates to the arm throat amp jawjaw

Chest pain may confused with sever Chest pain may confused with sever indigestion in itrsquos early stagesindigestion in itrsquos early stages

Transient Ischemic attacksTransient Ischemic attacks

Itrsquos usually accompanied with neurological Itrsquos usually accompanied with neurological dysfunction or loss of visiondysfunction or loss of vision

Completed thrombotic strokeCompleted thrombotic stroke

Itrsquos accompanied by similar symptoms Itrsquos accompanied by similar symptoms which persist for more than 24 hours that which persist for more than 24 hours that may be severely amp permanently disablingmay be severely amp permanently disabling

Risk factors for arterial amp venous thrombosisRisk factors for arterial amp venous thrombosis

Venous thrombosisVenous thrombosisArterial thrombosisArterial thrombosisIncreasing ageIncreasing ageIncreasing ageIncreasing age

ObesityObesityObesityObesity

ImmobilityImmobilityLack of exerciseLack of exercise

Pregnancy rdquopost partomrdquoPregnancy rdquopost partomrdquoHigh fat low fiber dietHigh fat low fiber diet

MalignancyMalignancySmokingSmoking

Lupus anticoagulantLupus anticoagulantHyperlipidemiaHyperlipidemia

Nephrotic syndromeNephrotic syndromeHypertensionHypertension

PolycythemiaPolycythemiaElevated factor VII II concElevated factor VII II conc

goutgoutGenetic factorGenetic factor

Prophylaxis amp treatment of Prophylaxis amp treatment of thrombosisthrombosis

Prevent the risk factorsPrevent the risk factors SmokingSmoking ObesityObesity Lack of exerciseLack of exercise Poor dietPoor diet

Only when this proves to be impossibleOnly when this proves to be impossible

(Pharmacological intervention is required) (Pharmacological intervention is required)

Dr Rudolph Virchow1821-1902

AbnormalBlood Flow

AbnormalVessel Wall

AbnormalBlood

The Hypercoagulable State(thrombophilia)

Mechanisms of ThrombosisMechanisms of Thrombosis

Clinical associations with thrombotic Clinical associations with thrombotic diseasedisease

ImmobilityImmobilityObesityObesity

SmokingSmokingCancerCancer

PregnancyPregnancyEstrogen therapyEstrogen therapy

Types of ThrombosisTypes of Thrombosis

ArterialArterial platelet-based (white) thrombus platelet-based (white) thrombus

Platelet-VWF interactions criticalPlatelet-VWF interactions critical

Associated with end-stage atherosclerosisAssociated with end-stage atherosclerosis

Venous Fibrin-based (red) thrombus

Coagulation factors critical

Venous stasis

Thrombus FormationThrombus Formation

bull Arterial formation - begins w platelet adhesion to arterial vessel wall Adenosine diphosphate (ADP) released from platelets more platelet aggregation Bld flow inhibited fibrin platelets amp RBCrsquos surround clot build up of size structure occludes bld vessels tissue ischemia

bull The result of Arterial Thrombus is localized tissue injury from lack of perfusion

Thrombus FormationThrombus Formation

Venous FormationVenous Formation - Usually from slow bld flow - Usually from slow bld flow - Can occur rapidly Stagnation of the blood flow initiate - Can occur rapidly Stagnation of the blood flow initiate

the coagulation cascadethe coagulation cascade production of fibrin production of fibrinenmeshes enmeshes RBCrsquos amp platelets to form the thrombus Venous RBCrsquos amp platelets to form the thrombus Venous thrombus has a long tail that can break off to produce an thrombus has a long tail that can break off to produce an embolus These travel to faraway sites then lodge embolus These travel to faraway sites then lodge in in lung (capillary level) lung (capillary level) inadequate O2 amp CO2 exchange inadequate O2 amp CO2 exchange occur (ie pulmonary embolism amp cerebral embolism)occur (ie pulmonary embolism amp cerebral embolism)

Oral amp parenteral anticoagulants (HeparinWarfarin) Oral amp parenteral anticoagulants (HeparinWarfarin) primarily act by preventing venous thrombosisprimarily act by preventing venous thrombosis

Antiplatelet drugs primarily act by preventing arterial Antiplatelet drugs primarily act by preventing arterial thrombosisthrombosis

Types of ThrombosisTypes of Thrombosis

Occlusive Thrombus occurs when the Occlusive Thrombus occurs when the entire lumen of blood vessel is occupied by entire lumen of blood vessel is occupied by coagulated material amp blood flow is coagulated material amp blood flow is obstructedobstructed

Mural Thrombosis occurs when the Mural Thrombosis occurs when the thrombus adheres to one site of the blood thrombus adheres to one site of the blood vessel only amp blood is restricted but not vessel only amp blood is restricted but not arrested arrested

Thrombosis

Hereditarythrombophilia

Acquiredthrombophilia

SurgerytraumaImmobility

Inflammation

Malignancy

Estrogens

Risk Factors for ThrombosisRisk Factors for Thrombosis

Atherosclerosis

THROMBOEMBOLIC DISORDERSTHROMBOEMBOLIC DISORDERS

Venous thromboembolismVenous thromboembolism

Arterial thromboembolismArterial thromboembolism

Risk Factors forRisk Factors forVenous ThrombosisVenous Thrombosis

AcquiredAcquired InheritedInherited MixedunknownMixedunknown

Venous Thrombosis Venous system low flow amp pressure Thrombi are fibrin rich Function of age biologic conditions genetic

ampenvironmental factors and their interactions Venous thromboembolism (VTE) ndash Deep vein thrombosis (DVT) ndash Pulmonary embolism (PE) ndash Superficial portal cerebral or retinal vein thrombosis Reasons for coagulation testing ndash Risk for recurrence of thrombosis ndash Treatment considerations (duration amp intensity) ndash Genetic counseling for affected family members ndash Prophylaxis for high risk situations

The most common is (DVT) deep venous The most common is (DVT) deep venous thrombosis of the lower limbs The main thrombosis of the lower limbs The main site where there is maximum stasis and low site where there is maximum stasis and low blood flow blood flow

Propagation of thrombus is associated with Propagation of thrombus is associated with red cell entrapmenthelliphellipred thrombusred cell entrapmenthelliphellipred thrombus

Venus thrombi may become dislodged or Venus thrombi may become dislodged or fragment resulting in the formation of fragment resulting in the formation of circulating thrombi This may result in circulating thrombi This may result in pulmonary embolismpulmonary embolism

Venous Thrombosis

Pulmonary embolismPulmonary embolism

Presents with acute chest painPresents with acute chest pain Breathlessness with shockBreathlessness with shock Cough amp hemopysisCough amp hemopysis May be fatalMay be fatal

Venous Thrombosis symptoms

Typically presents with pain swelling Typically presents with pain swelling discoloration amp warmth in the affected areadiscoloration amp warmth in the affected area

However However

(these symptoms may be absent amp non of (these symptoms may be absent amp non of them is specific)them is specific)

Hematologic manifestationsHematologic manifestations

Cutaneous manifestationsCutaneous manifestations

Genetic Risk Factors(Familial)

11 FV- Leiden (APCR activated prot C resistance)FV- Leiden (APCR activated prot C resistance)

22 Protein C (deficiency)Protein C (deficiency)

33 Protein S (deficiency)Protein S (deficiency)

44 Antithrombin III (deficiency)Antithrombin III (deficiency)

55 Abnormal Prothrombin (PT 20210 A)Abnormal Prothrombin (PT 20210 A)

66 Sticky platelet syndromeSticky platelet syndrome

Risk FactorsmdashAcquiredRisk FactorsmdashAcquired

Advancing ageAdvancing age Prior ThrombosisPrior Thrombosis ImmobilizationImmobilization Major surgeryMajor surgery MalignancyMalignancy EstrogensEstrogens

Antiphospholipid Antiphospholipid antibody syndromeantibody syndrome

Myeloproliferative Myeloproliferative DisordersDisorders

Heparin-induced Heparin-induced thrombocytopenia thrombocytopenia (HIT)(HIT)

ProlongedProlonged air travel air travel

Risk FactorsmdashMixedUnknownRisk FactorsmdashMixedUnknown

HyperhomocysteinemiaHyperhomocysteinemia High levels of factor VIIIHigh levels of factor VIII Acquired Protein C resistance in the absence of Acquired Protein C resistance in the absence of

Factor V LeidenFactor V Leiden High levels of Factor IX XIHigh levels of Factor IX XI

11 FV- LeidenFV- Leiden

One of the most common causes for thrombophilia One of the most common causes for thrombophilia ndash 20 of clinical disease (AT PC and PS ndash 5) + ndash 20 of clinical disease (AT PC and PS ndash 5) + risk factorrisk factor

Activated PC inhibits F Va and F VIIIaActivated PC inhibits F Va and F VIIIa Inability of APC to inhibit the above complex due Inability of APC to inhibit the above complex due

to mutated FVto mutated FV Heterozygous 5-10 times increased risk for TEHeterozygous 5-10 times increased risk for TE Homozygous 50-100 timesHomozygous 50-100 times

Factor Va

Arg 306 Arg 506 Arg 1765

Arginine CGA

Glutamine CAA

Factor Va resistant to APC cleavage

Factor V Leiden

Relative Risk forVenous Thrombosis

Factor V Leiden Heterozygote x 7

Factor V Leiden Homozygote x 80

Oral Contraceptives x 3

Oral Contraceptives + Factor V Leiden x 35

Leiden Study Group Data

22 Protein C DeficiencyProtein C Deficiency

Common cause (increasing TE with age)Common cause (increasing TE with age) Needs TM from endothelium wallNeeds TM from endothelium wall Heterozygous 50 of level of normal Heterozygous 50 of level of normal

individualsindividuals Homozygous babies are born with Homozygous babies are born with

undetected levels (thrombi in microvascular undetected levels (thrombi in microvascular of skin DIC necrosis purpura of skin DIC necrosis purpura fulminans)fulminans)

33 Protein S DeficiencyProtein S Deficiency

Non-enzymatic co-factor for PCNon-enzymatic co-factor for PC Binds to TM-PCBinds to TM-PC Same properties as PCSame properties as PC Two forms free in plasma and bound to C4b Two forms free in plasma and bound to C4b

binding protein (60) Only free fraction binding protein (60) Only free fraction functions as co-factor for APCfunctions as co-factor for APC

Sometimes difficult to get accurate measures of Sometimes difficult to get accurate measures of PS because of the latterPS because of the latter

Like PC can be acquired liver disease Warfarin Like PC can be acquired liver disease Warfarin pregnancy cancer DIC and chemopregnancy cancer DIC and chemo

44 Antithrombin III DeficiencyAntithrombin III Deficiency

Common cause (incidence 12000 ndash 15000 Common cause (incidence 12000 ndash 15000 heterozygotes 50 DVT) Quantitative vs heterozygotes 50 DVT) Quantitative vs Qualitative disorder (Acquired DIC cirrhosis Qualitative disorder (Acquired DIC cirrhosis NS)NS)

Bind to and inactivate thrombin Factors IXa Xa Bind to and inactivate thrombin Factors IXa Xa XIa and XIIa (ATheparin complex - rate of XIa and XIIa (ATheparin complex - rate of inhibition 1000-fold increased)inhibition 1000-fold increased)

Not necessarily a risk factor to be involved in Not necessarily a risk factor to be involved in heterozygotes to give TEheterozygotes to give TE

Increased incidence with ageing 80 at 55 yearsIncreased incidence with ageing 80 at 55 years

55 Abnormal ProthrombinAbnormal Prothrombin (PT 20210 A) (PT 20210 A)

CommonCommon Increased levels of prothrombin enhanced Increased levels of prothrombin enhanced

thrombin formationthrombin formation Only way for diagnosis DNA-PCR Only way for diagnosis DNA-PCR

techniquetechnique

66 Sticky Platelet SyndromeSticky Platelet Syndrome

Especially in arterial thrombosis (MI) and Especially in arterial thrombosis (MI) and development of recurrent TE while on Warfarindevelopment of recurrent TE while on Warfarin

3 Forms3 Forms If on aspirin it should be stopped 14 days prior to If on aspirin it should be stopped 14 days prior to

testingtesting

Also rememberAlso remember

PC PS and AT III are inhibitors of clottingPC PS and AT III are inhibitors of clotting

Non-familial (Acquired)Non-familial (Acquired)11 Antiphospholipid SyndromeAntiphospholipid Syndrome Antibodies directed against phospholipid cell membrane = Antibodies directed against phospholipid cell membrane =

APA (Antiphospholipid Ab)APA (Antiphospholipid Ab) APA ACA or LAAPA ACA or LA Primary (PAPS) or secondary (autoimmune disorders eg Primary (PAPS) or secondary (autoimmune disorders eg

SLE)SLE) ACA (Anticardiolipin Ab) IgM + IgGACA (Anticardiolipin Ab) IgM + IgG IgG the clinically important oneIgG the clinically important one IgM pregnancy infection (viral) trauma and post-opIgM pregnancy infection (viral) trauma and post-op LA (Lupus anticoagulant) Ab which affect clotting tests (LA-LA (Lupus anticoagulant) Ab which affect clotting tests (LA-

PTT RVV Kaolin)PTT RVV Kaolin) PAPS = TE miscarriage IUDPAPS = TE miscarriage IUD

Antiphospholipid Syndrome1048734 Antiphospholipid syndrome (APS) ndash Syndrome characterized by venous andor arterial thrombosis thrombocytopenia or recurrent fetal loss associated with antibodies to phospho-lipid- protein Complexes

1048734 Antiphospholipid antibodies (aPL)ndash IgG IgM or IgA antibodies that are directed to target proteins such as cardiolipin beta2-Glycoprotein I (β2GPI)or Prothrombin all of which bind to phospholipidsndash Lupus anticoagulant (LA) bull Antiphospholipid antibodies identified by in vitro phospholipid dependent clot-based assays antibodies are targeted against Prothrombin or β2GPI and prolong clotting times

Antiphospholipd Antibodies

Lupus Anticoagulant

Conditions where screening for APS Conditions where screening for APS is indicatedis indicated

The first thrombotic event below the age of 40The first thrombotic event below the age of 40 History of recurrent TEDHistory of recurrent TED Recurrent fetal loss in the 1Recurrent fetal loss in the 1stst or the 2 or the 2ndnd trimester trimester Patient with SLEPatient with SLE Pre-hormone replacement therapyPre-hormone replacement therapy

Non-familial (Acquired) continuedNon-familial (Acquired) continued

22 TPA (Tissue Plasminogen Activator) TPA (Tissue Plasminogen Activator) decreased levels impaired fibrinolysisdecreased levels impaired fibrinolysis

33 PAI (Plasminogen Activator Inhibitor) PAI (Plasminogen Activator Inhibitor) increased levels decreased TPAincreased levels decreased TPA

44 DysfibrinogenemiaDysfibrinogenemia55 F XII deficiency Hageman factorF XII deficiency Hageman factor66 Fibrinogen (increased)Fibrinogen (increased)77 F VIII (increased)F VIII (increased)88 PlasminogenPlasminogen99 Hyperhomocyteinemia ndash enzyme (folate)Hyperhomocyteinemia ndash enzyme (folate)

Investigation (Thrombotic Profile)Investigation (Thrombotic Profile)

NB Patients can be on Warfarin but not HeparinNB Patients can be on Warfarin but not Heparin FBC PLT amp ESRFBC PLT amp ESR PT aPTT TT amp FibrinogenPT aPTT TT amp Fibrinogen PC amp PSPC amp PS AT IIIAT III APCR (if + screening submit for PCR)APCR (if + screening submit for PCR) PT 20210A (PCR)PT 20210A (PCR) Lupus anticoagulant (RVVT KT LA-PTT) Lupus anticoagulant (RVVT KT LA-PTT) Cardiolipin antibodies (antiphospholipid syndrome)Cardiolipin antibodies (antiphospholipid syndrome) Sticky platelet syndrome (aspirin)Sticky platelet syndrome (aspirin) ANA screeningANA screening PNH screeningPNH screening

When to testWhen to test Younger lt 50 years recurrent TE unusual sites Younger lt 50 years recurrent TE unusual sites

TE on WarfarinTE on Warfarin Not ideal to test after acute episode (inhibitors of Not ideal to test after acute episode (inhibitors of

clotting may be low)clotting may be low) Ideal test after 6 weeks after settlement of Ideal test after 6 weeks after settlement of

hemostasishemostasis Most patients are on Warfarin then (PC amp PS are Most patients are on Warfarin then (PC amp PS are

Vit K dependent may be falsely low)Vit K dependent may be falsely low) My view if long-term Warfarin is planned do My view if long-term Warfarin is planned do

immediately according to duration of treatment it immediately according to duration of treatment it can be done after cessation of treatmentcan be done after cessation of treatment

When to test (continued)When to test (continued)

Practical (my experience) before treatment ndash if AT Practical (my experience) before treatment ndash if AT PS PC are low PS PC are low repeat after Rx has been stopped repeat after Rx has been stopped

SPS platelet aggregation studies (problem SPS platelet aggregation studies (problem sometimes aspirin cannot be stopped)sometimes aspirin cannot be stopped)

Remember the effect of the vessel wall on clotting Remember the effect of the vessel wall on clotting especially in arterial thrombosisespecially in arterial thrombosis

Every woman on contraception HRTEvery woman on contraception HRT

Arterial ThrombosisArterial Thrombosis

Arterial Thrombosis

Arterial ThrombosisArterial Thrombosis

Results as sever oResults as sever o2 2 starvation of the left starvation of the left ventricle of the heartventricle of the heart

This leads to myocardial ischemia amp may This leads to myocardial ischemia amp may progress to myocardial infarction or progress to myocardial infarction or ischemic left ventricular fibrillation amp ischemic left ventricular fibrillation amp sudden deathsudden death

Similar episodes involving the cerebral Similar episodes involving the cerebral circulation result in transient ischemic circulation result in transient ischemic attacks amp thrombotic stroke attacks amp thrombotic stroke

Myocardial Infarction SymptomMyocardial Infarction Symptom

Crushing tightness of the chest with Crushing tightness of the chest with sweating nausea breathlessness amp sweating nausea breathlessness amp collapsecollapse

Chest pain may radiates to the arm throat amp Chest pain may radiates to the arm throat amp jawjaw

Chest pain may confused with sever Chest pain may confused with sever indigestion in itrsquos early stagesindigestion in itrsquos early stages

Transient Ischemic attacksTransient Ischemic attacks

Itrsquos usually accompanied with neurological Itrsquos usually accompanied with neurological dysfunction or loss of visiondysfunction or loss of vision

Completed thrombotic strokeCompleted thrombotic stroke

Itrsquos accompanied by similar symptoms Itrsquos accompanied by similar symptoms which persist for more than 24 hours that which persist for more than 24 hours that may be severely amp permanently disablingmay be severely amp permanently disabling

Risk factors for arterial amp venous thrombosisRisk factors for arterial amp venous thrombosis

Venous thrombosisVenous thrombosisArterial thrombosisArterial thrombosisIncreasing ageIncreasing ageIncreasing ageIncreasing age

ObesityObesityObesityObesity

ImmobilityImmobilityLack of exerciseLack of exercise

Pregnancy rdquopost partomrdquoPregnancy rdquopost partomrdquoHigh fat low fiber dietHigh fat low fiber diet

MalignancyMalignancySmokingSmoking

Lupus anticoagulantLupus anticoagulantHyperlipidemiaHyperlipidemia

Nephrotic syndromeNephrotic syndromeHypertensionHypertension

PolycythemiaPolycythemiaElevated factor VII II concElevated factor VII II conc

goutgoutGenetic factorGenetic factor

Prophylaxis amp treatment of Prophylaxis amp treatment of thrombosisthrombosis

Prevent the risk factorsPrevent the risk factors SmokingSmoking ObesityObesity Lack of exerciseLack of exercise Poor dietPoor diet

Only when this proves to be impossibleOnly when this proves to be impossible

(Pharmacological intervention is required) (Pharmacological intervention is required)

Mechanisms of ThrombosisMechanisms of Thrombosis

Clinical associations with thrombotic Clinical associations with thrombotic diseasedisease

ImmobilityImmobilityObesityObesity

SmokingSmokingCancerCancer

PregnancyPregnancyEstrogen therapyEstrogen therapy

Types of ThrombosisTypes of Thrombosis

ArterialArterial platelet-based (white) thrombus platelet-based (white) thrombus

Platelet-VWF interactions criticalPlatelet-VWF interactions critical

Associated with end-stage atherosclerosisAssociated with end-stage atherosclerosis

Venous Fibrin-based (red) thrombus

Coagulation factors critical

Venous stasis

Thrombus FormationThrombus Formation

bull Arterial formation - begins w platelet adhesion to arterial vessel wall Adenosine diphosphate (ADP) released from platelets more platelet aggregation Bld flow inhibited fibrin platelets amp RBCrsquos surround clot build up of size structure occludes bld vessels tissue ischemia

bull The result of Arterial Thrombus is localized tissue injury from lack of perfusion

Thrombus FormationThrombus Formation

Venous FormationVenous Formation - Usually from slow bld flow - Usually from slow bld flow - Can occur rapidly Stagnation of the blood flow initiate - Can occur rapidly Stagnation of the blood flow initiate

the coagulation cascadethe coagulation cascade production of fibrin production of fibrinenmeshes enmeshes RBCrsquos amp platelets to form the thrombus Venous RBCrsquos amp platelets to form the thrombus Venous thrombus has a long tail that can break off to produce an thrombus has a long tail that can break off to produce an embolus These travel to faraway sites then lodge embolus These travel to faraway sites then lodge in in lung (capillary level) lung (capillary level) inadequate O2 amp CO2 exchange inadequate O2 amp CO2 exchange occur (ie pulmonary embolism amp cerebral embolism)occur (ie pulmonary embolism amp cerebral embolism)

Oral amp parenteral anticoagulants (HeparinWarfarin) Oral amp parenteral anticoagulants (HeparinWarfarin) primarily act by preventing venous thrombosisprimarily act by preventing venous thrombosis

Antiplatelet drugs primarily act by preventing arterial Antiplatelet drugs primarily act by preventing arterial thrombosisthrombosis

Types of ThrombosisTypes of Thrombosis

Occlusive Thrombus occurs when the Occlusive Thrombus occurs when the entire lumen of blood vessel is occupied by entire lumen of blood vessel is occupied by coagulated material amp blood flow is coagulated material amp blood flow is obstructedobstructed

Mural Thrombosis occurs when the Mural Thrombosis occurs when the thrombus adheres to one site of the blood thrombus adheres to one site of the blood vessel only amp blood is restricted but not vessel only amp blood is restricted but not arrested arrested

Thrombosis

Hereditarythrombophilia

Acquiredthrombophilia

SurgerytraumaImmobility

Inflammation

Malignancy

Estrogens

Risk Factors for ThrombosisRisk Factors for Thrombosis

Atherosclerosis

THROMBOEMBOLIC DISORDERSTHROMBOEMBOLIC DISORDERS

Venous thromboembolismVenous thromboembolism

Arterial thromboembolismArterial thromboembolism

Risk Factors forRisk Factors forVenous ThrombosisVenous Thrombosis

AcquiredAcquired InheritedInherited MixedunknownMixedunknown

Venous Thrombosis Venous system low flow amp pressure Thrombi are fibrin rich Function of age biologic conditions genetic

ampenvironmental factors and their interactions Venous thromboembolism (VTE) ndash Deep vein thrombosis (DVT) ndash Pulmonary embolism (PE) ndash Superficial portal cerebral or retinal vein thrombosis Reasons for coagulation testing ndash Risk for recurrence of thrombosis ndash Treatment considerations (duration amp intensity) ndash Genetic counseling for affected family members ndash Prophylaxis for high risk situations

The most common is (DVT) deep venous The most common is (DVT) deep venous thrombosis of the lower limbs The main thrombosis of the lower limbs The main site where there is maximum stasis and low site where there is maximum stasis and low blood flow blood flow

Propagation of thrombus is associated with Propagation of thrombus is associated with red cell entrapmenthelliphellipred thrombusred cell entrapmenthelliphellipred thrombus

Venus thrombi may become dislodged or Venus thrombi may become dislodged or fragment resulting in the formation of fragment resulting in the formation of circulating thrombi This may result in circulating thrombi This may result in pulmonary embolismpulmonary embolism

Venous Thrombosis

Pulmonary embolismPulmonary embolism

Presents with acute chest painPresents with acute chest pain Breathlessness with shockBreathlessness with shock Cough amp hemopysisCough amp hemopysis May be fatalMay be fatal

Venous Thrombosis symptoms

Typically presents with pain swelling Typically presents with pain swelling discoloration amp warmth in the affected areadiscoloration amp warmth in the affected area

However However

(these symptoms may be absent amp non of (these symptoms may be absent amp non of them is specific)them is specific)

Hematologic manifestationsHematologic manifestations

Cutaneous manifestationsCutaneous manifestations

Genetic Risk Factors(Familial)

11 FV- Leiden (APCR activated prot C resistance)FV- Leiden (APCR activated prot C resistance)

22 Protein C (deficiency)Protein C (deficiency)

33 Protein S (deficiency)Protein S (deficiency)

44 Antithrombin III (deficiency)Antithrombin III (deficiency)

55 Abnormal Prothrombin (PT 20210 A)Abnormal Prothrombin (PT 20210 A)

66 Sticky platelet syndromeSticky platelet syndrome

Risk FactorsmdashAcquiredRisk FactorsmdashAcquired

Advancing ageAdvancing age Prior ThrombosisPrior Thrombosis ImmobilizationImmobilization Major surgeryMajor surgery MalignancyMalignancy EstrogensEstrogens

Antiphospholipid Antiphospholipid antibody syndromeantibody syndrome

Myeloproliferative Myeloproliferative DisordersDisorders

Heparin-induced Heparin-induced thrombocytopenia thrombocytopenia (HIT)(HIT)

ProlongedProlonged air travel air travel

Risk FactorsmdashMixedUnknownRisk FactorsmdashMixedUnknown

HyperhomocysteinemiaHyperhomocysteinemia High levels of factor VIIIHigh levels of factor VIII Acquired Protein C resistance in the absence of Acquired Protein C resistance in the absence of

Factor V LeidenFactor V Leiden High levels of Factor IX XIHigh levels of Factor IX XI

11 FV- LeidenFV- Leiden

One of the most common causes for thrombophilia One of the most common causes for thrombophilia ndash 20 of clinical disease (AT PC and PS ndash 5) + ndash 20 of clinical disease (AT PC and PS ndash 5) + risk factorrisk factor

Activated PC inhibits F Va and F VIIIaActivated PC inhibits F Va and F VIIIa Inability of APC to inhibit the above complex due Inability of APC to inhibit the above complex due

to mutated FVto mutated FV Heterozygous 5-10 times increased risk for TEHeterozygous 5-10 times increased risk for TE Homozygous 50-100 timesHomozygous 50-100 times

Factor Va

Arg 306 Arg 506 Arg 1765

Arginine CGA

Glutamine CAA

Factor Va resistant to APC cleavage

Factor V Leiden

Relative Risk forVenous Thrombosis

Factor V Leiden Heterozygote x 7

Factor V Leiden Homozygote x 80

Oral Contraceptives x 3

Oral Contraceptives + Factor V Leiden x 35

Leiden Study Group Data

22 Protein C DeficiencyProtein C Deficiency

Common cause (increasing TE with age)Common cause (increasing TE with age) Needs TM from endothelium wallNeeds TM from endothelium wall Heterozygous 50 of level of normal Heterozygous 50 of level of normal

individualsindividuals Homozygous babies are born with Homozygous babies are born with

undetected levels (thrombi in microvascular undetected levels (thrombi in microvascular of skin DIC necrosis purpura of skin DIC necrosis purpura fulminans)fulminans)

33 Protein S DeficiencyProtein S Deficiency

Non-enzymatic co-factor for PCNon-enzymatic co-factor for PC Binds to TM-PCBinds to TM-PC Same properties as PCSame properties as PC Two forms free in plasma and bound to C4b Two forms free in plasma and bound to C4b

binding protein (60) Only free fraction binding protein (60) Only free fraction functions as co-factor for APCfunctions as co-factor for APC

Sometimes difficult to get accurate measures of Sometimes difficult to get accurate measures of PS because of the latterPS because of the latter

Like PC can be acquired liver disease Warfarin Like PC can be acquired liver disease Warfarin pregnancy cancer DIC and chemopregnancy cancer DIC and chemo

44 Antithrombin III DeficiencyAntithrombin III Deficiency

Common cause (incidence 12000 ndash 15000 Common cause (incidence 12000 ndash 15000 heterozygotes 50 DVT) Quantitative vs heterozygotes 50 DVT) Quantitative vs Qualitative disorder (Acquired DIC cirrhosis Qualitative disorder (Acquired DIC cirrhosis NS)NS)

Bind to and inactivate thrombin Factors IXa Xa Bind to and inactivate thrombin Factors IXa Xa XIa and XIIa (ATheparin complex - rate of XIa and XIIa (ATheparin complex - rate of inhibition 1000-fold increased)inhibition 1000-fold increased)

Not necessarily a risk factor to be involved in Not necessarily a risk factor to be involved in heterozygotes to give TEheterozygotes to give TE

Increased incidence with ageing 80 at 55 yearsIncreased incidence with ageing 80 at 55 years

55 Abnormal ProthrombinAbnormal Prothrombin (PT 20210 A) (PT 20210 A)

CommonCommon Increased levels of prothrombin enhanced Increased levels of prothrombin enhanced

thrombin formationthrombin formation Only way for diagnosis DNA-PCR Only way for diagnosis DNA-PCR

techniquetechnique

66 Sticky Platelet SyndromeSticky Platelet Syndrome

Especially in arterial thrombosis (MI) and Especially in arterial thrombosis (MI) and development of recurrent TE while on Warfarindevelopment of recurrent TE while on Warfarin

3 Forms3 Forms If on aspirin it should be stopped 14 days prior to If on aspirin it should be stopped 14 days prior to

testingtesting

Also rememberAlso remember

PC PS and AT III are inhibitors of clottingPC PS and AT III are inhibitors of clotting

Non-familial (Acquired)Non-familial (Acquired)11 Antiphospholipid SyndromeAntiphospholipid Syndrome Antibodies directed against phospholipid cell membrane = Antibodies directed against phospholipid cell membrane =

APA (Antiphospholipid Ab)APA (Antiphospholipid Ab) APA ACA or LAAPA ACA or LA Primary (PAPS) or secondary (autoimmune disorders eg Primary (PAPS) or secondary (autoimmune disorders eg

SLE)SLE) ACA (Anticardiolipin Ab) IgM + IgGACA (Anticardiolipin Ab) IgM + IgG IgG the clinically important oneIgG the clinically important one IgM pregnancy infection (viral) trauma and post-opIgM pregnancy infection (viral) trauma and post-op LA (Lupus anticoagulant) Ab which affect clotting tests (LA-LA (Lupus anticoagulant) Ab which affect clotting tests (LA-

PTT RVV Kaolin)PTT RVV Kaolin) PAPS = TE miscarriage IUDPAPS = TE miscarriage IUD

Antiphospholipid Syndrome1048734 Antiphospholipid syndrome (APS) ndash Syndrome characterized by venous andor arterial thrombosis thrombocytopenia or recurrent fetal loss associated with antibodies to phospho-lipid- protein Complexes

1048734 Antiphospholipid antibodies (aPL)ndash IgG IgM or IgA antibodies that are directed to target proteins such as cardiolipin beta2-Glycoprotein I (β2GPI)or Prothrombin all of which bind to phospholipidsndash Lupus anticoagulant (LA) bull Antiphospholipid antibodies identified by in vitro phospholipid dependent clot-based assays antibodies are targeted against Prothrombin or β2GPI and prolong clotting times

Antiphospholipd Antibodies

Lupus Anticoagulant

Conditions where screening for APS Conditions where screening for APS is indicatedis indicated

The first thrombotic event below the age of 40The first thrombotic event below the age of 40 History of recurrent TEDHistory of recurrent TED Recurrent fetal loss in the 1Recurrent fetal loss in the 1stst or the 2 or the 2ndnd trimester trimester Patient with SLEPatient with SLE Pre-hormone replacement therapyPre-hormone replacement therapy

Non-familial (Acquired) continuedNon-familial (Acquired) continued

22 TPA (Tissue Plasminogen Activator) TPA (Tissue Plasminogen Activator) decreased levels impaired fibrinolysisdecreased levels impaired fibrinolysis

33 PAI (Plasminogen Activator Inhibitor) PAI (Plasminogen Activator Inhibitor) increased levels decreased TPAincreased levels decreased TPA

44 DysfibrinogenemiaDysfibrinogenemia55 F XII deficiency Hageman factorF XII deficiency Hageman factor66 Fibrinogen (increased)Fibrinogen (increased)77 F VIII (increased)F VIII (increased)88 PlasminogenPlasminogen99 Hyperhomocyteinemia ndash enzyme (folate)Hyperhomocyteinemia ndash enzyme (folate)

Investigation (Thrombotic Profile)Investigation (Thrombotic Profile)

NB Patients can be on Warfarin but not HeparinNB Patients can be on Warfarin but not Heparin FBC PLT amp ESRFBC PLT amp ESR PT aPTT TT amp FibrinogenPT aPTT TT amp Fibrinogen PC amp PSPC amp PS AT IIIAT III APCR (if + screening submit for PCR)APCR (if + screening submit for PCR) PT 20210A (PCR)PT 20210A (PCR) Lupus anticoagulant (RVVT KT LA-PTT) Lupus anticoagulant (RVVT KT LA-PTT) Cardiolipin antibodies (antiphospholipid syndrome)Cardiolipin antibodies (antiphospholipid syndrome) Sticky platelet syndrome (aspirin)Sticky platelet syndrome (aspirin) ANA screeningANA screening PNH screeningPNH screening

When to testWhen to test Younger lt 50 years recurrent TE unusual sites Younger lt 50 years recurrent TE unusual sites

TE on WarfarinTE on Warfarin Not ideal to test after acute episode (inhibitors of Not ideal to test after acute episode (inhibitors of

clotting may be low)clotting may be low) Ideal test after 6 weeks after settlement of Ideal test after 6 weeks after settlement of

hemostasishemostasis Most patients are on Warfarin then (PC amp PS are Most patients are on Warfarin then (PC amp PS are

Vit K dependent may be falsely low)Vit K dependent may be falsely low) My view if long-term Warfarin is planned do My view if long-term Warfarin is planned do

immediately according to duration of treatment it immediately according to duration of treatment it can be done after cessation of treatmentcan be done after cessation of treatment

When to test (continued)When to test (continued)

Practical (my experience) before treatment ndash if AT Practical (my experience) before treatment ndash if AT PS PC are low PS PC are low repeat after Rx has been stopped repeat after Rx has been stopped

SPS platelet aggregation studies (problem SPS platelet aggregation studies (problem sometimes aspirin cannot be stopped)sometimes aspirin cannot be stopped)

Remember the effect of the vessel wall on clotting Remember the effect of the vessel wall on clotting especially in arterial thrombosisespecially in arterial thrombosis

Every woman on contraception HRTEvery woman on contraception HRT

Arterial ThrombosisArterial Thrombosis

Arterial Thrombosis

Arterial ThrombosisArterial Thrombosis

Results as sever oResults as sever o2 2 starvation of the left starvation of the left ventricle of the heartventricle of the heart

This leads to myocardial ischemia amp may This leads to myocardial ischemia amp may progress to myocardial infarction or progress to myocardial infarction or ischemic left ventricular fibrillation amp ischemic left ventricular fibrillation amp sudden deathsudden death

Similar episodes involving the cerebral Similar episodes involving the cerebral circulation result in transient ischemic circulation result in transient ischemic attacks amp thrombotic stroke attacks amp thrombotic stroke

Myocardial Infarction SymptomMyocardial Infarction Symptom

Crushing tightness of the chest with Crushing tightness of the chest with sweating nausea breathlessness amp sweating nausea breathlessness amp collapsecollapse

Chest pain may radiates to the arm throat amp Chest pain may radiates to the arm throat amp jawjaw

Chest pain may confused with sever Chest pain may confused with sever indigestion in itrsquos early stagesindigestion in itrsquos early stages

Transient Ischemic attacksTransient Ischemic attacks

Itrsquos usually accompanied with neurological Itrsquos usually accompanied with neurological dysfunction or loss of visiondysfunction or loss of vision

Completed thrombotic strokeCompleted thrombotic stroke

Itrsquos accompanied by similar symptoms Itrsquos accompanied by similar symptoms which persist for more than 24 hours that which persist for more than 24 hours that may be severely amp permanently disablingmay be severely amp permanently disabling

Risk factors for arterial amp venous thrombosisRisk factors for arterial amp venous thrombosis

Venous thrombosisVenous thrombosisArterial thrombosisArterial thrombosisIncreasing ageIncreasing ageIncreasing ageIncreasing age

ObesityObesityObesityObesity

ImmobilityImmobilityLack of exerciseLack of exercise

Pregnancy rdquopost partomrdquoPregnancy rdquopost partomrdquoHigh fat low fiber dietHigh fat low fiber diet

MalignancyMalignancySmokingSmoking

Lupus anticoagulantLupus anticoagulantHyperlipidemiaHyperlipidemia

Nephrotic syndromeNephrotic syndromeHypertensionHypertension

PolycythemiaPolycythemiaElevated factor VII II concElevated factor VII II conc

goutgoutGenetic factorGenetic factor

Prophylaxis amp treatment of Prophylaxis amp treatment of thrombosisthrombosis

Prevent the risk factorsPrevent the risk factors SmokingSmoking ObesityObesity Lack of exerciseLack of exercise Poor dietPoor diet

Only when this proves to be impossibleOnly when this proves to be impossible

(Pharmacological intervention is required) (Pharmacological intervention is required)

Types of ThrombosisTypes of Thrombosis

ArterialArterial platelet-based (white) thrombus platelet-based (white) thrombus

Platelet-VWF interactions criticalPlatelet-VWF interactions critical

Associated with end-stage atherosclerosisAssociated with end-stage atherosclerosis

Venous Fibrin-based (red) thrombus

Coagulation factors critical

Venous stasis

Thrombus FormationThrombus Formation

bull Arterial formation - begins w platelet adhesion to arterial vessel wall Adenosine diphosphate (ADP) released from platelets more platelet aggregation Bld flow inhibited fibrin platelets amp RBCrsquos surround clot build up of size structure occludes bld vessels tissue ischemia

bull The result of Arterial Thrombus is localized tissue injury from lack of perfusion

Thrombus FormationThrombus Formation

Venous FormationVenous Formation - Usually from slow bld flow - Usually from slow bld flow - Can occur rapidly Stagnation of the blood flow initiate - Can occur rapidly Stagnation of the blood flow initiate

the coagulation cascadethe coagulation cascade production of fibrin production of fibrinenmeshes enmeshes RBCrsquos amp platelets to form the thrombus Venous RBCrsquos amp platelets to form the thrombus Venous thrombus has a long tail that can break off to produce an thrombus has a long tail that can break off to produce an embolus These travel to faraway sites then lodge embolus These travel to faraway sites then lodge in in lung (capillary level) lung (capillary level) inadequate O2 amp CO2 exchange inadequate O2 amp CO2 exchange occur (ie pulmonary embolism amp cerebral embolism)occur (ie pulmonary embolism amp cerebral embolism)

Oral amp parenteral anticoagulants (HeparinWarfarin) Oral amp parenteral anticoagulants (HeparinWarfarin) primarily act by preventing venous thrombosisprimarily act by preventing venous thrombosis

Antiplatelet drugs primarily act by preventing arterial Antiplatelet drugs primarily act by preventing arterial thrombosisthrombosis

Types of ThrombosisTypes of Thrombosis

Occlusive Thrombus occurs when the Occlusive Thrombus occurs when the entire lumen of blood vessel is occupied by entire lumen of blood vessel is occupied by coagulated material amp blood flow is coagulated material amp blood flow is obstructedobstructed

Mural Thrombosis occurs when the Mural Thrombosis occurs when the thrombus adheres to one site of the blood thrombus adheres to one site of the blood vessel only amp blood is restricted but not vessel only amp blood is restricted but not arrested arrested

Thrombosis

Hereditarythrombophilia

Acquiredthrombophilia

SurgerytraumaImmobility

Inflammation

Malignancy

Estrogens

Risk Factors for ThrombosisRisk Factors for Thrombosis

Atherosclerosis

THROMBOEMBOLIC DISORDERSTHROMBOEMBOLIC DISORDERS

Venous thromboembolismVenous thromboembolism

Arterial thromboembolismArterial thromboembolism

Risk Factors forRisk Factors forVenous ThrombosisVenous Thrombosis

AcquiredAcquired InheritedInherited MixedunknownMixedunknown

Venous Thrombosis Venous system low flow amp pressure Thrombi are fibrin rich Function of age biologic conditions genetic

ampenvironmental factors and their interactions Venous thromboembolism (VTE) ndash Deep vein thrombosis (DVT) ndash Pulmonary embolism (PE) ndash Superficial portal cerebral or retinal vein thrombosis Reasons for coagulation testing ndash Risk for recurrence of thrombosis ndash Treatment considerations (duration amp intensity) ndash Genetic counseling for affected family members ndash Prophylaxis for high risk situations

The most common is (DVT) deep venous The most common is (DVT) deep venous thrombosis of the lower limbs The main thrombosis of the lower limbs The main site where there is maximum stasis and low site where there is maximum stasis and low blood flow blood flow

Propagation of thrombus is associated with Propagation of thrombus is associated with red cell entrapmenthelliphellipred thrombusred cell entrapmenthelliphellipred thrombus

Venus thrombi may become dislodged or Venus thrombi may become dislodged or fragment resulting in the formation of fragment resulting in the formation of circulating thrombi This may result in circulating thrombi This may result in pulmonary embolismpulmonary embolism

Venous Thrombosis

Pulmonary embolismPulmonary embolism

Presents with acute chest painPresents with acute chest pain Breathlessness with shockBreathlessness with shock Cough amp hemopysisCough amp hemopysis May be fatalMay be fatal

Venous Thrombosis symptoms

Typically presents with pain swelling Typically presents with pain swelling discoloration amp warmth in the affected areadiscoloration amp warmth in the affected area

However However

(these symptoms may be absent amp non of (these symptoms may be absent amp non of them is specific)them is specific)

Hematologic manifestationsHematologic manifestations

Cutaneous manifestationsCutaneous manifestations

Genetic Risk Factors(Familial)

11 FV- Leiden (APCR activated prot C resistance)FV- Leiden (APCR activated prot C resistance)

22 Protein C (deficiency)Protein C (deficiency)

33 Protein S (deficiency)Protein S (deficiency)

44 Antithrombin III (deficiency)Antithrombin III (deficiency)

55 Abnormal Prothrombin (PT 20210 A)Abnormal Prothrombin (PT 20210 A)

66 Sticky platelet syndromeSticky platelet syndrome

Risk FactorsmdashAcquiredRisk FactorsmdashAcquired

Advancing ageAdvancing age Prior ThrombosisPrior Thrombosis ImmobilizationImmobilization Major surgeryMajor surgery MalignancyMalignancy EstrogensEstrogens

Antiphospholipid Antiphospholipid antibody syndromeantibody syndrome

Myeloproliferative Myeloproliferative DisordersDisorders

Heparin-induced Heparin-induced thrombocytopenia thrombocytopenia (HIT)(HIT)

ProlongedProlonged air travel air travel

Risk FactorsmdashMixedUnknownRisk FactorsmdashMixedUnknown

HyperhomocysteinemiaHyperhomocysteinemia High levels of factor VIIIHigh levels of factor VIII Acquired Protein C resistance in the absence of Acquired Protein C resistance in the absence of

Factor V LeidenFactor V Leiden High levels of Factor IX XIHigh levels of Factor IX XI

11 FV- LeidenFV- Leiden

One of the most common causes for thrombophilia One of the most common causes for thrombophilia ndash 20 of clinical disease (AT PC and PS ndash 5) + ndash 20 of clinical disease (AT PC and PS ndash 5) + risk factorrisk factor

Activated PC inhibits F Va and F VIIIaActivated PC inhibits F Va and F VIIIa Inability of APC to inhibit the above complex due Inability of APC to inhibit the above complex due

to mutated FVto mutated FV Heterozygous 5-10 times increased risk for TEHeterozygous 5-10 times increased risk for TE Homozygous 50-100 timesHomozygous 50-100 times

Factor Va

Arg 306 Arg 506 Arg 1765

Arginine CGA

Glutamine CAA

Factor Va resistant to APC cleavage

Factor V Leiden

Relative Risk forVenous Thrombosis

Factor V Leiden Heterozygote x 7

Factor V Leiden Homozygote x 80

Oral Contraceptives x 3

Oral Contraceptives + Factor V Leiden x 35

Leiden Study Group Data

22 Protein C DeficiencyProtein C Deficiency

Common cause (increasing TE with age)Common cause (increasing TE with age) Needs TM from endothelium wallNeeds TM from endothelium wall Heterozygous 50 of level of normal Heterozygous 50 of level of normal

individualsindividuals Homozygous babies are born with Homozygous babies are born with

undetected levels (thrombi in microvascular undetected levels (thrombi in microvascular of skin DIC necrosis purpura of skin DIC necrosis purpura fulminans)fulminans)

33 Protein S DeficiencyProtein S Deficiency

Non-enzymatic co-factor for PCNon-enzymatic co-factor for PC Binds to TM-PCBinds to TM-PC Same properties as PCSame properties as PC Two forms free in plasma and bound to C4b Two forms free in plasma and bound to C4b

binding protein (60) Only free fraction binding protein (60) Only free fraction functions as co-factor for APCfunctions as co-factor for APC

Sometimes difficult to get accurate measures of Sometimes difficult to get accurate measures of PS because of the latterPS because of the latter

Like PC can be acquired liver disease Warfarin Like PC can be acquired liver disease Warfarin pregnancy cancer DIC and chemopregnancy cancer DIC and chemo

44 Antithrombin III DeficiencyAntithrombin III Deficiency

Common cause (incidence 12000 ndash 15000 Common cause (incidence 12000 ndash 15000 heterozygotes 50 DVT) Quantitative vs heterozygotes 50 DVT) Quantitative vs Qualitative disorder (Acquired DIC cirrhosis Qualitative disorder (Acquired DIC cirrhosis NS)NS)

Bind to and inactivate thrombin Factors IXa Xa Bind to and inactivate thrombin Factors IXa Xa XIa and XIIa (ATheparin complex - rate of XIa and XIIa (ATheparin complex - rate of inhibition 1000-fold increased)inhibition 1000-fold increased)

Not necessarily a risk factor to be involved in Not necessarily a risk factor to be involved in heterozygotes to give TEheterozygotes to give TE

Increased incidence with ageing 80 at 55 yearsIncreased incidence with ageing 80 at 55 years

55 Abnormal ProthrombinAbnormal Prothrombin (PT 20210 A) (PT 20210 A)

CommonCommon Increased levels of prothrombin enhanced Increased levels of prothrombin enhanced

thrombin formationthrombin formation Only way for diagnosis DNA-PCR Only way for diagnosis DNA-PCR

techniquetechnique

66 Sticky Platelet SyndromeSticky Platelet Syndrome

Especially in arterial thrombosis (MI) and Especially in arterial thrombosis (MI) and development of recurrent TE while on Warfarindevelopment of recurrent TE while on Warfarin

3 Forms3 Forms If on aspirin it should be stopped 14 days prior to If on aspirin it should be stopped 14 days prior to

testingtesting

Also rememberAlso remember

PC PS and AT III are inhibitors of clottingPC PS and AT III are inhibitors of clotting

Non-familial (Acquired)Non-familial (Acquired)11 Antiphospholipid SyndromeAntiphospholipid Syndrome Antibodies directed against phospholipid cell membrane = Antibodies directed against phospholipid cell membrane =

APA (Antiphospholipid Ab)APA (Antiphospholipid Ab) APA ACA or LAAPA ACA or LA Primary (PAPS) or secondary (autoimmune disorders eg Primary (PAPS) or secondary (autoimmune disorders eg

SLE)SLE) ACA (Anticardiolipin Ab) IgM + IgGACA (Anticardiolipin Ab) IgM + IgG IgG the clinically important oneIgG the clinically important one IgM pregnancy infection (viral) trauma and post-opIgM pregnancy infection (viral) trauma and post-op LA (Lupus anticoagulant) Ab which affect clotting tests (LA-LA (Lupus anticoagulant) Ab which affect clotting tests (LA-

PTT RVV Kaolin)PTT RVV Kaolin) PAPS = TE miscarriage IUDPAPS = TE miscarriage IUD

Antiphospholipid Syndrome1048734 Antiphospholipid syndrome (APS) ndash Syndrome characterized by venous andor arterial thrombosis thrombocytopenia or recurrent fetal loss associated with antibodies to phospho-lipid- protein Complexes

1048734 Antiphospholipid antibodies (aPL)ndash IgG IgM or IgA antibodies that are directed to target proteins such as cardiolipin beta2-Glycoprotein I (β2GPI)or Prothrombin all of which bind to phospholipidsndash Lupus anticoagulant (LA) bull Antiphospholipid antibodies identified by in vitro phospholipid dependent clot-based assays antibodies are targeted against Prothrombin or β2GPI and prolong clotting times

Antiphospholipd Antibodies

Lupus Anticoagulant

Conditions where screening for APS Conditions where screening for APS is indicatedis indicated

The first thrombotic event below the age of 40The first thrombotic event below the age of 40 History of recurrent TEDHistory of recurrent TED Recurrent fetal loss in the 1Recurrent fetal loss in the 1stst or the 2 or the 2ndnd trimester trimester Patient with SLEPatient with SLE Pre-hormone replacement therapyPre-hormone replacement therapy

Non-familial (Acquired) continuedNon-familial (Acquired) continued

22 TPA (Tissue Plasminogen Activator) TPA (Tissue Plasminogen Activator) decreased levels impaired fibrinolysisdecreased levels impaired fibrinolysis

33 PAI (Plasminogen Activator Inhibitor) PAI (Plasminogen Activator Inhibitor) increased levels decreased TPAincreased levels decreased TPA

44 DysfibrinogenemiaDysfibrinogenemia55 F XII deficiency Hageman factorF XII deficiency Hageman factor66 Fibrinogen (increased)Fibrinogen (increased)77 F VIII (increased)F VIII (increased)88 PlasminogenPlasminogen99 Hyperhomocyteinemia ndash enzyme (folate)Hyperhomocyteinemia ndash enzyme (folate)

Investigation (Thrombotic Profile)Investigation (Thrombotic Profile)

NB Patients can be on Warfarin but not HeparinNB Patients can be on Warfarin but not Heparin FBC PLT amp ESRFBC PLT amp ESR PT aPTT TT amp FibrinogenPT aPTT TT amp Fibrinogen PC amp PSPC amp PS AT IIIAT III APCR (if + screening submit for PCR)APCR (if + screening submit for PCR) PT 20210A (PCR)PT 20210A (PCR) Lupus anticoagulant (RVVT KT LA-PTT) Lupus anticoagulant (RVVT KT LA-PTT) Cardiolipin antibodies (antiphospholipid syndrome)Cardiolipin antibodies (antiphospholipid syndrome) Sticky platelet syndrome (aspirin)Sticky platelet syndrome (aspirin) ANA screeningANA screening PNH screeningPNH screening

When to testWhen to test Younger lt 50 years recurrent TE unusual sites Younger lt 50 years recurrent TE unusual sites

TE on WarfarinTE on Warfarin Not ideal to test after acute episode (inhibitors of Not ideal to test after acute episode (inhibitors of

clotting may be low)clotting may be low) Ideal test after 6 weeks after settlement of Ideal test after 6 weeks after settlement of

hemostasishemostasis Most patients are on Warfarin then (PC amp PS are Most patients are on Warfarin then (PC amp PS are

Vit K dependent may be falsely low)Vit K dependent may be falsely low) My view if long-term Warfarin is planned do My view if long-term Warfarin is planned do

immediately according to duration of treatment it immediately according to duration of treatment it can be done after cessation of treatmentcan be done after cessation of treatment

When to test (continued)When to test (continued)

Practical (my experience) before treatment ndash if AT Practical (my experience) before treatment ndash if AT PS PC are low PS PC are low repeat after Rx has been stopped repeat after Rx has been stopped

SPS platelet aggregation studies (problem SPS platelet aggregation studies (problem sometimes aspirin cannot be stopped)sometimes aspirin cannot be stopped)

Remember the effect of the vessel wall on clotting Remember the effect of the vessel wall on clotting especially in arterial thrombosisespecially in arterial thrombosis

Every woman on contraception HRTEvery woman on contraception HRT

Arterial ThrombosisArterial Thrombosis

Arterial Thrombosis

Arterial ThrombosisArterial Thrombosis

Results as sever oResults as sever o2 2 starvation of the left starvation of the left ventricle of the heartventricle of the heart

This leads to myocardial ischemia amp may This leads to myocardial ischemia amp may progress to myocardial infarction or progress to myocardial infarction or ischemic left ventricular fibrillation amp ischemic left ventricular fibrillation amp sudden deathsudden death

Similar episodes involving the cerebral Similar episodes involving the cerebral circulation result in transient ischemic circulation result in transient ischemic attacks amp thrombotic stroke attacks amp thrombotic stroke

Myocardial Infarction SymptomMyocardial Infarction Symptom

Crushing tightness of the chest with Crushing tightness of the chest with sweating nausea breathlessness amp sweating nausea breathlessness amp collapsecollapse

Chest pain may radiates to the arm throat amp Chest pain may radiates to the arm throat amp jawjaw

Chest pain may confused with sever Chest pain may confused with sever indigestion in itrsquos early stagesindigestion in itrsquos early stages

Transient Ischemic attacksTransient Ischemic attacks

Itrsquos usually accompanied with neurological Itrsquos usually accompanied with neurological dysfunction or loss of visiondysfunction or loss of vision

Completed thrombotic strokeCompleted thrombotic stroke

Itrsquos accompanied by similar symptoms Itrsquos accompanied by similar symptoms which persist for more than 24 hours that which persist for more than 24 hours that may be severely amp permanently disablingmay be severely amp permanently disabling

Risk factors for arterial amp venous thrombosisRisk factors for arterial amp venous thrombosis

Venous thrombosisVenous thrombosisArterial thrombosisArterial thrombosisIncreasing ageIncreasing ageIncreasing ageIncreasing age

ObesityObesityObesityObesity

ImmobilityImmobilityLack of exerciseLack of exercise

Pregnancy rdquopost partomrdquoPregnancy rdquopost partomrdquoHigh fat low fiber dietHigh fat low fiber diet

MalignancyMalignancySmokingSmoking

Lupus anticoagulantLupus anticoagulantHyperlipidemiaHyperlipidemia

Nephrotic syndromeNephrotic syndromeHypertensionHypertension

PolycythemiaPolycythemiaElevated factor VII II concElevated factor VII II conc

goutgoutGenetic factorGenetic factor

Prophylaxis amp treatment of Prophylaxis amp treatment of thrombosisthrombosis

Prevent the risk factorsPrevent the risk factors SmokingSmoking ObesityObesity Lack of exerciseLack of exercise Poor dietPoor diet

Only when this proves to be impossibleOnly when this proves to be impossible

(Pharmacological intervention is required) (Pharmacological intervention is required)

Thrombus FormationThrombus Formation

bull Arterial formation - begins w platelet adhesion to arterial vessel wall Adenosine diphosphate (ADP) released from platelets more platelet aggregation Bld flow inhibited fibrin platelets amp RBCrsquos surround clot build up of size structure occludes bld vessels tissue ischemia

bull The result of Arterial Thrombus is localized tissue injury from lack of perfusion

Thrombus FormationThrombus Formation

Venous FormationVenous Formation - Usually from slow bld flow - Usually from slow bld flow - Can occur rapidly Stagnation of the blood flow initiate - Can occur rapidly Stagnation of the blood flow initiate

the coagulation cascadethe coagulation cascade production of fibrin production of fibrinenmeshes enmeshes RBCrsquos amp platelets to form the thrombus Venous RBCrsquos amp platelets to form the thrombus Venous thrombus has a long tail that can break off to produce an thrombus has a long tail that can break off to produce an embolus These travel to faraway sites then lodge embolus These travel to faraway sites then lodge in in lung (capillary level) lung (capillary level) inadequate O2 amp CO2 exchange inadequate O2 amp CO2 exchange occur (ie pulmonary embolism amp cerebral embolism)occur (ie pulmonary embolism amp cerebral embolism)

Oral amp parenteral anticoagulants (HeparinWarfarin) Oral amp parenteral anticoagulants (HeparinWarfarin) primarily act by preventing venous thrombosisprimarily act by preventing venous thrombosis

Antiplatelet drugs primarily act by preventing arterial Antiplatelet drugs primarily act by preventing arterial thrombosisthrombosis

Types of ThrombosisTypes of Thrombosis

Occlusive Thrombus occurs when the Occlusive Thrombus occurs when the entire lumen of blood vessel is occupied by entire lumen of blood vessel is occupied by coagulated material amp blood flow is coagulated material amp blood flow is obstructedobstructed

Mural Thrombosis occurs when the Mural Thrombosis occurs when the thrombus adheres to one site of the blood thrombus adheres to one site of the blood vessel only amp blood is restricted but not vessel only amp blood is restricted but not arrested arrested

Thrombosis

Hereditarythrombophilia

Acquiredthrombophilia

SurgerytraumaImmobility

Inflammation

Malignancy

Estrogens

Risk Factors for ThrombosisRisk Factors for Thrombosis

Atherosclerosis

THROMBOEMBOLIC DISORDERSTHROMBOEMBOLIC DISORDERS

Venous thromboembolismVenous thromboembolism

Arterial thromboembolismArterial thromboembolism

Risk Factors forRisk Factors forVenous ThrombosisVenous Thrombosis

AcquiredAcquired InheritedInherited MixedunknownMixedunknown

Venous Thrombosis Venous system low flow amp pressure Thrombi are fibrin rich Function of age biologic conditions genetic

ampenvironmental factors and their interactions Venous thromboembolism (VTE) ndash Deep vein thrombosis (DVT) ndash Pulmonary embolism (PE) ndash Superficial portal cerebral or retinal vein thrombosis Reasons for coagulation testing ndash Risk for recurrence of thrombosis ndash Treatment considerations (duration amp intensity) ndash Genetic counseling for affected family members ndash Prophylaxis for high risk situations

The most common is (DVT) deep venous The most common is (DVT) deep venous thrombosis of the lower limbs The main thrombosis of the lower limbs The main site where there is maximum stasis and low site where there is maximum stasis and low blood flow blood flow

Propagation of thrombus is associated with Propagation of thrombus is associated with red cell entrapmenthelliphellipred thrombusred cell entrapmenthelliphellipred thrombus

Venus thrombi may become dislodged or Venus thrombi may become dislodged or fragment resulting in the formation of fragment resulting in the formation of circulating thrombi This may result in circulating thrombi This may result in pulmonary embolismpulmonary embolism

Venous Thrombosis

Pulmonary embolismPulmonary embolism

Presents with acute chest painPresents with acute chest pain Breathlessness with shockBreathlessness with shock Cough amp hemopysisCough amp hemopysis May be fatalMay be fatal

Venous Thrombosis symptoms

Typically presents with pain swelling Typically presents with pain swelling discoloration amp warmth in the affected areadiscoloration amp warmth in the affected area

However However

(these symptoms may be absent amp non of (these symptoms may be absent amp non of them is specific)them is specific)

Hematologic manifestationsHematologic manifestations

Cutaneous manifestationsCutaneous manifestations

Genetic Risk Factors(Familial)

11 FV- Leiden (APCR activated prot C resistance)FV- Leiden (APCR activated prot C resistance)

22 Protein C (deficiency)Protein C (deficiency)

33 Protein S (deficiency)Protein S (deficiency)

44 Antithrombin III (deficiency)Antithrombin III (deficiency)

55 Abnormal Prothrombin (PT 20210 A)Abnormal Prothrombin (PT 20210 A)

66 Sticky platelet syndromeSticky platelet syndrome

Risk FactorsmdashAcquiredRisk FactorsmdashAcquired

Advancing ageAdvancing age Prior ThrombosisPrior Thrombosis ImmobilizationImmobilization Major surgeryMajor surgery MalignancyMalignancy EstrogensEstrogens

Antiphospholipid Antiphospholipid antibody syndromeantibody syndrome

Myeloproliferative Myeloproliferative DisordersDisorders

Heparin-induced Heparin-induced thrombocytopenia thrombocytopenia (HIT)(HIT)

ProlongedProlonged air travel air travel

Risk FactorsmdashMixedUnknownRisk FactorsmdashMixedUnknown

HyperhomocysteinemiaHyperhomocysteinemia High levels of factor VIIIHigh levels of factor VIII Acquired Protein C resistance in the absence of Acquired Protein C resistance in the absence of

Factor V LeidenFactor V Leiden High levels of Factor IX XIHigh levels of Factor IX XI

11 FV- LeidenFV- Leiden

One of the most common causes for thrombophilia One of the most common causes for thrombophilia ndash 20 of clinical disease (AT PC and PS ndash 5) + ndash 20 of clinical disease (AT PC and PS ndash 5) + risk factorrisk factor

Activated PC inhibits F Va and F VIIIaActivated PC inhibits F Va and F VIIIa Inability of APC to inhibit the above complex due Inability of APC to inhibit the above complex due

to mutated FVto mutated FV Heterozygous 5-10 times increased risk for TEHeterozygous 5-10 times increased risk for TE Homozygous 50-100 timesHomozygous 50-100 times

Factor Va

Arg 306 Arg 506 Arg 1765

Arginine CGA

Glutamine CAA

Factor Va resistant to APC cleavage

Factor V Leiden

Relative Risk forVenous Thrombosis

Factor V Leiden Heterozygote x 7

Factor V Leiden Homozygote x 80

Oral Contraceptives x 3

Oral Contraceptives + Factor V Leiden x 35

Leiden Study Group Data

22 Protein C DeficiencyProtein C Deficiency

Common cause (increasing TE with age)Common cause (increasing TE with age) Needs TM from endothelium wallNeeds TM from endothelium wall Heterozygous 50 of level of normal Heterozygous 50 of level of normal

individualsindividuals Homozygous babies are born with Homozygous babies are born with

undetected levels (thrombi in microvascular undetected levels (thrombi in microvascular of skin DIC necrosis purpura of skin DIC necrosis purpura fulminans)fulminans)

33 Protein S DeficiencyProtein S Deficiency

Non-enzymatic co-factor for PCNon-enzymatic co-factor for PC Binds to TM-PCBinds to TM-PC Same properties as PCSame properties as PC Two forms free in plasma and bound to C4b Two forms free in plasma and bound to C4b

binding protein (60) Only free fraction binding protein (60) Only free fraction functions as co-factor for APCfunctions as co-factor for APC

Sometimes difficult to get accurate measures of Sometimes difficult to get accurate measures of PS because of the latterPS because of the latter

Like PC can be acquired liver disease Warfarin Like PC can be acquired liver disease Warfarin pregnancy cancer DIC and chemopregnancy cancer DIC and chemo

44 Antithrombin III DeficiencyAntithrombin III Deficiency

Common cause (incidence 12000 ndash 15000 Common cause (incidence 12000 ndash 15000 heterozygotes 50 DVT) Quantitative vs heterozygotes 50 DVT) Quantitative vs Qualitative disorder (Acquired DIC cirrhosis Qualitative disorder (Acquired DIC cirrhosis NS)NS)

Bind to and inactivate thrombin Factors IXa Xa Bind to and inactivate thrombin Factors IXa Xa XIa and XIIa (ATheparin complex - rate of XIa and XIIa (ATheparin complex - rate of inhibition 1000-fold increased)inhibition 1000-fold increased)

Not necessarily a risk factor to be involved in Not necessarily a risk factor to be involved in heterozygotes to give TEheterozygotes to give TE

Increased incidence with ageing 80 at 55 yearsIncreased incidence with ageing 80 at 55 years

55 Abnormal ProthrombinAbnormal Prothrombin (PT 20210 A) (PT 20210 A)

CommonCommon Increased levels of prothrombin enhanced Increased levels of prothrombin enhanced

thrombin formationthrombin formation Only way for diagnosis DNA-PCR Only way for diagnosis DNA-PCR

techniquetechnique

66 Sticky Platelet SyndromeSticky Platelet Syndrome

Especially in arterial thrombosis (MI) and Especially in arterial thrombosis (MI) and development of recurrent TE while on Warfarindevelopment of recurrent TE while on Warfarin

3 Forms3 Forms If on aspirin it should be stopped 14 days prior to If on aspirin it should be stopped 14 days prior to

testingtesting

Also rememberAlso remember

PC PS and AT III are inhibitors of clottingPC PS and AT III are inhibitors of clotting

Non-familial (Acquired)Non-familial (Acquired)11 Antiphospholipid SyndromeAntiphospholipid Syndrome Antibodies directed against phospholipid cell membrane = Antibodies directed against phospholipid cell membrane =

APA (Antiphospholipid Ab)APA (Antiphospholipid Ab) APA ACA or LAAPA ACA or LA Primary (PAPS) or secondary (autoimmune disorders eg Primary (PAPS) or secondary (autoimmune disorders eg

SLE)SLE) ACA (Anticardiolipin Ab) IgM + IgGACA (Anticardiolipin Ab) IgM + IgG IgG the clinically important oneIgG the clinically important one IgM pregnancy infection (viral) trauma and post-opIgM pregnancy infection (viral) trauma and post-op LA (Lupus anticoagulant) Ab which affect clotting tests (LA-LA (Lupus anticoagulant) Ab which affect clotting tests (LA-

PTT RVV Kaolin)PTT RVV Kaolin) PAPS = TE miscarriage IUDPAPS = TE miscarriage IUD

Antiphospholipid Syndrome1048734 Antiphospholipid syndrome (APS) ndash Syndrome characterized by venous andor arterial thrombosis thrombocytopenia or recurrent fetal loss associated with antibodies to phospho-lipid- protein Complexes

1048734 Antiphospholipid antibodies (aPL)ndash IgG IgM or IgA antibodies that are directed to target proteins such as cardiolipin beta2-Glycoprotein I (β2GPI)or Prothrombin all of which bind to phospholipidsndash Lupus anticoagulant (LA) bull Antiphospholipid antibodies identified by in vitro phospholipid dependent clot-based assays antibodies are targeted against Prothrombin or β2GPI and prolong clotting times

Antiphospholipd Antibodies

Lupus Anticoagulant

Conditions where screening for APS Conditions where screening for APS is indicatedis indicated

The first thrombotic event below the age of 40The first thrombotic event below the age of 40 History of recurrent TEDHistory of recurrent TED Recurrent fetal loss in the 1Recurrent fetal loss in the 1stst or the 2 or the 2ndnd trimester trimester Patient with SLEPatient with SLE Pre-hormone replacement therapyPre-hormone replacement therapy

Non-familial (Acquired) continuedNon-familial (Acquired) continued

22 TPA (Tissue Plasminogen Activator) TPA (Tissue Plasminogen Activator) decreased levels impaired fibrinolysisdecreased levels impaired fibrinolysis

33 PAI (Plasminogen Activator Inhibitor) PAI (Plasminogen Activator Inhibitor) increased levels decreased TPAincreased levels decreased TPA

44 DysfibrinogenemiaDysfibrinogenemia55 F XII deficiency Hageman factorF XII deficiency Hageman factor66 Fibrinogen (increased)Fibrinogen (increased)77 F VIII (increased)F VIII (increased)88 PlasminogenPlasminogen99 Hyperhomocyteinemia ndash enzyme (folate)Hyperhomocyteinemia ndash enzyme (folate)

Investigation (Thrombotic Profile)Investigation (Thrombotic Profile)

NB Patients can be on Warfarin but not HeparinNB Patients can be on Warfarin but not Heparin FBC PLT amp ESRFBC PLT amp ESR PT aPTT TT amp FibrinogenPT aPTT TT amp Fibrinogen PC amp PSPC amp PS AT IIIAT III APCR (if + screening submit for PCR)APCR (if + screening submit for PCR) PT 20210A (PCR)PT 20210A (PCR) Lupus anticoagulant (RVVT KT LA-PTT) Lupus anticoagulant (RVVT KT LA-PTT) Cardiolipin antibodies (antiphospholipid syndrome)Cardiolipin antibodies (antiphospholipid syndrome) Sticky platelet syndrome (aspirin)Sticky platelet syndrome (aspirin) ANA screeningANA screening PNH screeningPNH screening

When to testWhen to test Younger lt 50 years recurrent TE unusual sites Younger lt 50 years recurrent TE unusual sites

TE on WarfarinTE on Warfarin Not ideal to test after acute episode (inhibitors of Not ideal to test after acute episode (inhibitors of

clotting may be low)clotting may be low) Ideal test after 6 weeks after settlement of Ideal test after 6 weeks after settlement of

hemostasishemostasis Most patients are on Warfarin then (PC amp PS are Most patients are on Warfarin then (PC amp PS are

Vit K dependent may be falsely low)Vit K dependent may be falsely low) My view if long-term Warfarin is planned do My view if long-term Warfarin is planned do

immediately according to duration of treatment it immediately according to duration of treatment it can be done after cessation of treatmentcan be done after cessation of treatment

When to test (continued)When to test (continued)

Practical (my experience) before treatment ndash if AT Practical (my experience) before treatment ndash if AT PS PC are low PS PC are low repeat after Rx has been stopped repeat after Rx has been stopped

SPS platelet aggregation studies (problem SPS platelet aggregation studies (problem sometimes aspirin cannot be stopped)sometimes aspirin cannot be stopped)

Remember the effect of the vessel wall on clotting Remember the effect of the vessel wall on clotting especially in arterial thrombosisespecially in arterial thrombosis

Every woman on contraception HRTEvery woman on contraception HRT

Arterial ThrombosisArterial Thrombosis

Arterial Thrombosis

Arterial ThrombosisArterial Thrombosis

Results as sever oResults as sever o2 2 starvation of the left starvation of the left ventricle of the heartventricle of the heart

This leads to myocardial ischemia amp may This leads to myocardial ischemia amp may progress to myocardial infarction or progress to myocardial infarction or ischemic left ventricular fibrillation amp ischemic left ventricular fibrillation amp sudden deathsudden death

Similar episodes involving the cerebral Similar episodes involving the cerebral circulation result in transient ischemic circulation result in transient ischemic attacks amp thrombotic stroke attacks amp thrombotic stroke

Myocardial Infarction SymptomMyocardial Infarction Symptom

Crushing tightness of the chest with Crushing tightness of the chest with sweating nausea breathlessness amp sweating nausea breathlessness amp collapsecollapse

Chest pain may radiates to the arm throat amp Chest pain may radiates to the arm throat amp jawjaw

Chest pain may confused with sever Chest pain may confused with sever indigestion in itrsquos early stagesindigestion in itrsquos early stages

Transient Ischemic attacksTransient Ischemic attacks

Itrsquos usually accompanied with neurological Itrsquos usually accompanied with neurological dysfunction or loss of visiondysfunction or loss of vision

Completed thrombotic strokeCompleted thrombotic stroke

Itrsquos accompanied by similar symptoms Itrsquos accompanied by similar symptoms which persist for more than 24 hours that which persist for more than 24 hours that may be severely amp permanently disablingmay be severely amp permanently disabling

Risk factors for arterial amp venous thrombosisRisk factors for arterial amp venous thrombosis

Venous thrombosisVenous thrombosisArterial thrombosisArterial thrombosisIncreasing ageIncreasing ageIncreasing ageIncreasing age

ObesityObesityObesityObesity

ImmobilityImmobilityLack of exerciseLack of exercise

Pregnancy rdquopost partomrdquoPregnancy rdquopost partomrdquoHigh fat low fiber dietHigh fat low fiber diet

MalignancyMalignancySmokingSmoking

Lupus anticoagulantLupus anticoagulantHyperlipidemiaHyperlipidemia

Nephrotic syndromeNephrotic syndromeHypertensionHypertension

PolycythemiaPolycythemiaElevated factor VII II concElevated factor VII II conc

goutgoutGenetic factorGenetic factor

Prophylaxis amp treatment of Prophylaxis amp treatment of thrombosisthrombosis

Prevent the risk factorsPrevent the risk factors SmokingSmoking ObesityObesity Lack of exerciseLack of exercise Poor dietPoor diet

Only when this proves to be impossibleOnly when this proves to be impossible

(Pharmacological intervention is required) (Pharmacological intervention is required)

Thrombus FormationThrombus Formation

Venous FormationVenous Formation - Usually from slow bld flow - Usually from slow bld flow - Can occur rapidly Stagnation of the blood flow initiate - Can occur rapidly Stagnation of the blood flow initiate

the coagulation cascadethe coagulation cascade production of fibrin production of fibrinenmeshes enmeshes RBCrsquos amp platelets to form the thrombus Venous RBCrsquos amp platelets to form the thrombus Venous thrombus has a long tail that can break off to produce an thrombus has a long tail that can break off to produce an embolus These travel to faraway sites then lodge embolus These travel to faraway sites then lodge in in lung (capillary level) lung (capillary level) inadequate O2 amp CO2 exchange inadequate O2 amp CO2 exchange occur (ie pulmonary embolism amp cerebral embolism)occur (ie pulmonary embolism amp cerebral embolism)

Oral amp parenteral anticoagulants (HeparinWarfarin) Oral amp parenteral anticoagulants (HeparinWarfarin) primarily act by preventing venous thrombosisprimarily act by preventing venous thrombosis

Antiplatelet drugs primarily act by preventing arterial Antiplatelet drugs primarily act by preventing arterial thrombosisthrombosis

Types of ThrombosisTypes of Thrombosis

Occlusive Thrombus occurs when the Occlusive Thrombus occurs when the entire lumen of blood vessel is occupied by entire lumen of blood vessel is occupied by coagulated material amp blood flow is coagulated material amp blood flow is obstructedobstructed

Mural Thrombosis occurs when the Mural Thrombosis occurs when the thrombus adheres to one site of the blood thrombus adheres to one site of the blood vessel only amp blood is restricted but not vessel only amp blood is restricted but not arrested arrested

Thrombosis

Hereditarythrombophilia

Acquiredthrombophilia

SurgerytraumaImmobility

Inflammation

Malignancy

Estrogens

Risk Factors for ThrombosisRisk Factors for Thrombosis

Atherosclerosis

THROMBOEMBOLIC DISORDERSTHROMBOEMBOLIC DISORDERS

Venous thromboembolismVenous thromboembolism

Arterial thromboembolismArterial thromboembolism

Risk Factors forRisk Factors forVenous ThrombosisVenous Thrombosis

AcquiredAcquired InheritedInherited MixedunknownMixedunknown

Venous Thrombosis Venous system low flow amp pressure Thrombi are fibrin rich Function of age biologic conditions genetic

ampenvironmental factors and their interactions Venous thromboembolism (VTE) ndash Deep vein thrombosis (DVT) ndash Pulmonary embolism (PE) ndash Superficial portal cerebral or retinal vein thrombosis Reasons for coagulation testing ndash Risk for recurrence of thrombosis ndash Treatment considerations (duration amp intensity) ndash Genetic counseling for affected family members ndash Prophylaxis for high risk situations

The most common is (DVT) deep venous The most common is (DVT) deep venous thrombosis of the lower limbs The main thrombosis of the lower limbs The main site where there is maximum stasis and low site where there is maximum stasis and low blood flow blood flow

Propagation of thrombus is associated with Propagation of thrombus is associated with red cell entrapmenthelliphellipred thrombusred cell entrapmenthelliphellipred thrombus

Venus thrombi may become dislodged or Venus thrombi may become dislodged or fragment resulting in the formation of fragment resulting in the formation of circulating thrombi This may result in circulating thrombi This may result in pulmonary embolismpulmonary embolism

Venous Thrombosis

Pulmonary embolismPulmonary embolism

Presents with acute chest painPresents with acute chest pain Breathlessness with shockBreathlessness with shock Cough amp hemopysisCough amp hemopysis May be fatalMay be fatal

Venous Thrombosis symptoms

Typically presents with pain swelling Typically presents with pain swelling discoloration amp warmth in the affected areadiscoloration amp warmth in the affected area

However However

(these symptoms may be absent amp non of (these symptoms may be absent amp non of them is specific)them is specific)

Hematologic manifestationsHematologic manifestations

Cutaneous manifestationsCutaneous manifestations

Genetic Risk Factors(Familial)

11 FV- Leiden (APCR activated prot C resistance)FV- Leiden (APCR activated prot C resistance)

22 Protein C (deficiency)Protein C (deficiency)

33 Protein S (deficiency)Protein S (deficiency)

44 Antithrombin III (deficiency)Antithrombin III (deficiency)

55 Abnormal Prothrombin (PT 20210 A)Abnormal Prothrombin (PT 20210 A)

66 Sticky platelet syndromeSticky platelet syndrome

Risk FactorsmdashAcquiredRisk FactorsmdashAcquired

Advancing ageAdvancing age Prior ThrombosisPrior Thrombosis ImmobilizationImmobilization Major surgeryMajor surgery MalignancyMalignancy EstrogensEstrogens

Antiphospholipid Antiphospholipid antibody syndromeantibody syndrome

Myeloproliferative Myeloproliferative DisordersDisorders

Heparin-induced Heparin-induced thrombocytopenia thrombocytopenia (HIT)(HIT)

ProlongedProlonged air travel air travel

Risk FactorsmdashMixedUnknownRisk FactorsmdashMixedUnknown

HyperhomocysteinemiaHyperhomocysteinemia High levels of factor VIIIHigh levels of factor VIII Acquired Protein C resistance in the absence of Acquired Protein C resistance in the absence of

Factor V LeidenFactor V Leiden High levels of Factor IX XIHigh levels of Factor IX XI

11 FV- LeidenFV- Leiden

One of the most common causes for thrombophilia One of the most common causes for thrombophilia ndash 20 of clinical disease (AT PC and PS ndash 5) + ndash 20 of clinical disease (AT PC and PS ndash 5) + risk factorrisk factor

Activated PC inhibits F Va and F VIIIaActivated PC inhibits F Va and F VIIIa Inability of APC to inhibit the above complex due Inability of APC to inhibit the above complex due

to mutated FVto mutated FV Heterozygous 5-10 times increased risk for TEHeterozygous 5-10 times increased risk for TE Homozygous 50-100 timesHomozygous 50-100 times

Factor Va

Arg 306 Arg 506 Arg 1765

Arginine CGA

Glutamine CAA

Factor Va resistant to APC cleavage

Factor V Leiden

Relative Risk forVenous Thrombosis

Factor V Leiden Heterozygote x 7

Factor V Leiden Homozygote x 80

Oral Contraceptives x 3

Oral Contraceptives + Factor V Leiden x 35

Leiden Study Group Data

22 Protein C DeficiencyProtein C Deficiency

Common cause (increasing TE with age)Common cause (increasing TE with age) Needs TM from endothelium wallNeeds TM from endothelium wall Heterozygous 50 of level of normal Heterozygous 50 of level of normal

individualsindividuals Homozygous babies are born with Homozygous babies are born with

undetected levels (thrombi in microvascular undetected levels (thrombi in microvascular of skin DIC necrosis purpura of skin DIC necrosis purpura fulminans)fulminans)

33 Protein S DeficiencyProtein S Deficiency

Non-enzymatic co-factor for PCNon-enzymatic co-factor for PC Binds to TM-PCBinds to TM-PC Same properties as PCSame properties as PC Two forms free in plasma and bound to C4b Two forms free in plasma and bound to C4b

binding protein (60) Only free fraction binding protein (60) Only free fraction functions as co-factor for APCfunctions as co-factor for APC

Sometimes difficult to get accurate measures of Sometimes difficult to get accurate measures of PS because of the latterPS because of the latter

Like PC can be acquired liver disease Warfarin Like PC can be acquired liver disease Warfarin pregnancy cancer DIC and chemopregnancy cancer DIC and chemo

44 Antithrombin III DeficiencyAntithrombin III Deficiency

Common cause (incidence 12000 ndash 15000 Common cause (incidence 12000 ndash 15000 heterozygotes 50 DVT) Quantitative vs heterozygotes 50 DVT) Quantitative vs Qualitative disorder (Acquired DIC cirrhosis Qualitative disorder (Acquired DIC cirrhosis NS)NS)

Bind to and inactivate thrombin Factors IXa Xa Bind to and inactivate thrombin Factors IXa Xa XIa and XIIa (ATheparin complex - rate of XIa and XIIa (ATheparin complex - rate of inhibition 1000-fold increased)inhibition 1000-fold increased)

Not necessarily a risk factor to be involved in Not necessarily a risk factor to be involved in heterozygotes to give TEheterozygotes to give TE

Increased incidence with ageing 80 at 55 yearsIncreased incidence with ageing 80 at 55 years

55 Abnormal ProthrombinAbnormal Prothrombin (PT 20210 A) (PT 20210 A)

CommonCommon Increased levels of prothrombin enhanced Increased levels of prothrombin enhanced

thrombin formationthrombin formation Only way for diagnosis DNA-PCR Only way for diagnosis DNA-PCR

techniquetechnique

66 Sticky Platelet SyndromeSticky Platelet Syndrome

Especially in arterial thrombosis (MI) and Especially in arterial thrombosis (MI) and development of recurrent TE while on Warfarindevelopment of recurrent TE while on Warfarin

3 Forms3 Forms If on aspirin it should be stopped 14 days prior to If on aspirin it should be stopped 14 days prior to

testingtesting

Also rememberAlso remember

PC PS and AT III are inhibitors of clottingPC PS and AT III are inhibitors of clotting

Non-familial (Acquired)Non-familial (Acquired)11 Antiphospholipid SyndromeAntiphospholipid Syndrome Antibodies directed against phospholipid cell membrane = Antibodies directed against phospholipid cell membrane =

APA (Antiphospholipid Ab)APA (Antiphospholipid Ab) APA ACA or LAAPA ACA or LA Primary (PAPS) or secondary (autoimmune disorders eg Primary (PAPS) or secondary (autoimmune disorders eg

SLE)SLE) ACA (Anticardiolipin Ab) IgM + IgGACA (Anticardiolipin Ab) IgM + IgG IgG the clinically important oneIgG the clinically important one IgM pregnancy infection (viral) trauma and post-opIgM pregnancy infection (viral) trauma and post-op LA (Lupus anticoagulant) Ab which affect clotting tests (LA-LA (Lupus anticoagulant) Ab which affect clotting tests (LA-

PTT RVV Kaolin)PTT RVV Kaolin) PAPS = TE miscarriage IUDPAPS = TE miscarriage IUD

Antiphospholipid Syndrome1048734 Antiphospholipid syndrome (APS) ndash Syndrome characterized by venous andor arterial thrombosis thrombocytopenia or recurrent fetal loss associated with antibodies to phospho-lipid- protein Complexes

1048734 Antiphospholipid antibodies (aPL)ndash IgG IgM or IgA antibodies that are directed to target proteins such as cardiolipin beta2-Glycoprotein I (β2GPI)or Prothrombin all of which bind to phospholipidsndash Lupus anticoagulant (LA) bull Antiphospholipid antibodies identified by in vitro phospholipid dependent clot-based assays antibodies are targeted against Prothrombin or β2GPI and prolong clotting times

Antiphospholipd Antibodies

Lupus Anticoagulant

Conditions where screening for APS Conditions where screening for APS is indicatedis indicated

The first thrombotic event below the age of 40The first thrombotic event below the age of 40 History of recurrent TEDHistory of recurrent TED Recurrent fetal loss in the 1Recurrent fetal loss in the 1stst or the 2 or the 2ndnd trimester trimester Patient with SLEPatient with SLE Pre-hormone replacement therapyPre-hormone replacement therapy

Non-familial (Acquired) continuedNon-familial (Acquired) continued

22 TPA (Tissue Plasminogen Activator) TPA (Tissue Plasminogen Activator) decreased levels impaired fibrinolysisdecreased levels impaired fibrinolysis

33 PAI (Plasminogen Activator Inhibitor) PAI (Plasminogen Activator Inhibitor) increased levels decreased TPAincreased levels decreased TPA

44 DysfibrinogenemiaDysfibrinogenemia55 F XII deficiency Hageman factorF XII deficiency Hageman factor66 Fibrinogen (increased)Fibrinogen (increased)77 F VIII (increased)F VIII (increased)88 PlasminogenPlasminogen99 Hyperhomocyteinemia ndash enzyme (folate)Hyperhomocyteinemia ndash enzyme (folate)

Investigation (Thrombotic Profile)Investigation (Thrombotic Profile)

NB Patients can be on Warfarin but not HeparinNB Patients can be on Warfarin but not Heparin FBC PLT amp ESRFBC PLT amp ESR PT aPTT TT amp FibrinogenPT aPTT TT amp Fibrinogen PC amp PSPC amp PS AT IIIAT III APCR (if + screening submit for PCR)APCR (if + screening submit for PCR) PT 20210A (PCR)PT 20210A (PCR) Lupus anticoagulant (RVVT KT LA-PTT) Lupus anticoagulant (RVVT KT LA-PTT) Cardiolipin antibodies (antiphospholipid syndrome)Cardiolipin antibodies (antiphospholipid syndrome) Sticky platelet syndrome (aspirin)Sticky platelet syndrome (aspirin) ANA screeningANA screening PNH screeningPNH screening

When to testWhen to test Younger lt 50 years recurrent TE unusual sites Younger lt 50 years recurrent TE unusual sites

TE on WarfarinTE on Warfarin Not ideal to test after acute episode (inhibitors of Not ideal to test after acute episode (inhibitors of

clotting may be low)clotting may be low) Ideal test after 6 weeks after settlement of Ideal test after 6 weeks after settlement of

hemostasishemostasis Most patients are on Warfarin then (PC amp PS are Most patients are on Warfarin then (PC amp PS are

Vit K dependent may be falsely low)Vit K dependent may be falsely low) My view if long-term Warfarin is planned do My view if long-term Warfarin is planned do

immediately according to duration of treatment it immediately according to duration of treatment it can be done after cessation of treatmentcan be done after cessation of treatment

When to test (continued)When to test (continued)

Practical (my experience) before treatment ndash if AT Practical (my experience) before treatment ndash if AT PS PC are low PS PC are low repeat after Rx has been stopped repeat after Rx has been stopped

SPS platelet aggregation studies (problem SPS platelet aggregation studies (problem sometimes aspirin cannot be stopped)sometimes aspirin cannot be stopped)

Remember the effect of the vessel wall on clotting Remember the effect of the vessel wall on clotting especially in arterial thrombosisespecially in arterial thrombosis

Every woman on contraception HRTEvery woman on contraception HRT

Arterial ThrombosisArterial Thrombosis

Arterial Thrombosis

Arterial ThrombosisArterial Thrombosis

Results as sever oResults as sever o2 2 starvation of the left starvation of the left ventricle of the heartventricle of the heart

This leads to myocardial ischemia amp may This leads to myocardial ischemia amp may progress to myocardial infarction or progress to myocardial infarction or ischemic left ventricular fibrillation amp ischemic left ventricular fibrillation amp sudden deathsudden death

Similar episodes involving the cerebral Similar episodes involving the cerebral circulation result in transient ischemic circulation result in transient ischemic attacks amp thrombotic stroke attacks amp thrombotic stroke

Myocardial Infarction SymptomMyocardial Infarction Symptom

Crushing tightness of the chest with Crushing tightness of the chest with sweating nausea breathlessness amp sweating nausea breathlessness amp collapsecollapse

Chest pain may radiates to the arm throat amp Chest pain may radiates to the arm throat amp jawjaw

Chest pain may confused with sever Chest pain may confused with sever indigestion in itrsquos early stagesindigestion in itrsquos early stages

Transient Ischemic attacksTransient Ischemic attacks

Itrsquos usually accompanied with neurological Itrsquos usually accompanied with neurological dysfunction or loss of visiondysfunction or loss of vision

Completed thrombotic strokeCompleted thrombotic stroke

Itrsquos accompanied by similar symptoms Itrsquos accompanied by similar symptoms which persist for more than 24 hours that which persist for more than 24 hours that may be severely amp permanently disablingmay be severely amp permanently disabling

Risk factors for arterial amp venous thrombosisRisk factors for arterial amp venous thrombosis

Venous thrombosisVenous thrombosisArterial thrombosisArterial thrombosisIncreasing ageIncreasing ageIncreasing ageIncreasing age

ObesityObesityObesityObesity

ImmobilityImmobilityLack of exerciseLack of exercise

Pregnancy rdquopost partomrdquoPregnancy rdquopost partomrdquoHigh fat low fiber dietHigh fat low fiber diet

MalignancyMalignancySmokingSmoking

Lupus anticoagulantLupus anticoagulantHyperlipidemiaHyperlipidemia

Nephrotic syndromeNephrotic syndromeHypertensionHypertension

PolycythemiaPolycythemiaElevated factor VII II concElevated factor VII II conc

goutgoutGenetic factorGenetic factor

Prophylaxis amp treatment of Prophylaxis amp treatment of thrombosisthrombosis

Prevent the risk factorsPrevent the risk factors SmokingSmoking ObesityObesity Lack of exerciseLack of exercise Poor dietPoor diet

Only when this proves to be impossibleOnly when this proves to be impossible

(Pharmacological intervention is required) (Pharmacological intervention is required)

Types of ThrombosisTypes of Thrombosis

Occlusive Thrombus occurs when the Occlusive Thrombus occurs when the entire lumen of blood vessel is occupied by entire lumen of blood vessel is occupied by coagulated material amp blood flow is coagulated material amp blood flow is obstructedobstructed

Mural Thrombosis occurs when the Mural Thrombosis occurs when the thrombus adheres to one site of the blood thrombus adheres to one site of the blood vessel only amp blood is restricted but not vessel only amp blood is restricted but not arrested arrested

Thrombosis

Hereditarythrombophilia

Acquiredthrombophilia

SurgerytraumaImmobility

Inflammation

Malignancy

Estrogens

Risk Factors for ThrombosisRisk Factors for Thrombosis

Atherosclerosis

THROMBOEMBOLIC DISORDERSTHROMBOEMBOLIC DISORDERS

Venous thromboembolismVenous thromboembolism

Arterial thromboembolismArterial thromboembolism

Risk Factors forRisk Factors forVenous ThrombosisVenous Thrombosis

AcquiredAcquired InheritedInherited MixedunknownMixedunknown

Venous Thrombosis Venous system low flow amp pressure Thrombi are fibrin rich Function of age biologic conditions genetic

ampenvironmental factors and their interactions Venous thromboembolism (VTE) ndash Deep vein thrombosis (DVT) ndash Pulmonary embolism (PE) ndash Superficial portal cerebral or retinal vein thrombosis Reasons for coagulation testing ndash Risk for recurrence of thrombosis ndash Treatment considerations (duration amp intensity) ndash Genetic counseling for affected family members ndash Prophylaxis for high risk situations

The most common is (DVT) deep venous The most common is (DVT) deep venous thrombosis of the lower limbs The main thrombosis of the lower limbs The main site where there is maximum stasis and low site where there is maximum stasis and low blood flow blood flow

Propagation of thrombus is associated with Propagation of thrombus is associated with red cell entrapmenthelliphellipred thrombusred cell entrapmenthelliphellipred thrombus

Venus thrombi may become dislodged or Venus thrombi may become dislodged or fragment resulting in the formation of fragment resulting in the formation of circulating thrombi This may result in circulating thrombi This may result in pulmonary embolismpulmonary embolism

Venous Thrombosis

Pulmonary embolismPulmonary embolism

Presents with acute chest painPresents with acute chest pain Breathlessness with shockBreathlessness with shock Cough amp hemopysisCough amp hemopysis May be fatalMay be fatal

Venous Thrombosis symptoms

Typically presents with pain swelling Typically presents with pain swelling discoloration amp warmth in the affected areadiscoloration amp warmth in the affected area

However However

(these symptoms may be absent amp non of (these symptoms may be absent amp non of them is specific)them is specific)

Hematologic manifestationsHematologic manifestations

Cutaneous manifestationsCutaneous manifestations

Genetic Risk Factors(Familial)

11 FV- Leiden (APCR activated prot C resistance)FV- Leiden (APCR activated prot C resistance)

22 Protein C (deficiency)Protein C (deficiency)

33 Protein S (deficiency)Protein S (deficiency)

44 Antithrombin III (deficiency)Antithrombin III (deficiency)

55 Abnormal Prothrombin (PT 20210 A)Abnormal Prothrombin (PT 20210 A)

66 Sticky platelet syndromeSticky platelet syndrome

Risk FactorsmdashAcquiredRisk FactorsmdashAcquired

Advancing ageAdvancing age Prior ThrombosisPrior Thrombosis ImmobilizationImmobilization Major surgeryMajor surgery MalignancyMalignancy EstrogensEstrogens

Antiphospholipid Antiphospholipid antibody syndromeantibody syndrome

Myeloproliferative Myeloproliferative DisordersDisorders

Heparin-induced Heparin-induced thrombocytopenia thrombocytopenia (HIT)(HIT)

ProlongedProlonged air travel air travel

Risk FactorsmdashMixedUnknownRisk FactorsmdashMixedUnknown

HyperhomocysteinemiaHyperhomocysteinemia High levels of factor VIIIHigh levels of factor VIII Acquired Protein C resistance in the absence of Acquired Protein C resistance in the absence of

Factor V LeidenFactor V Leiden High levels of Factor IX XIHigh levels of Factor IX XI

11 FV- LeidenFV- Leiden

One of the most common causes for thrombophilia One of the most common causes for thrombophilia ndash 20 of clinical disease (AT PC and PS ndash 5) + ndash 20 of clinical disease (AT PC and PS ndash 5) + risk factorrisk factor

Activated PC inhibits F Va and F VIIIaActivated PC inhibits F Va and F VIIIa Inability of APC to inhibit the above complex due Inability of APC to inhibit the above complex due

to mutated FVto mutated FV Heterozygous 5-10 times increased risk for TEHeterozygous 5-10 times increased risk for TE Homozygous 50-100 timesHomozygous 50-100 times

Factor Va

Arg 306 Arg 506 Arg 1765

Arginine CGA

Glutamine CAA

Factor Va resistant to APC cleavage

Factor V Leiden

Relative Risk forVenous Thrombosis

Factor V Leiden Heterozygote x 7

Factor V Leiden Homozygote x 80

Oral Contraceptives x 3

Oral Contraceptives + Factor V Leiden x 35

Leiden Study Group Data

22 Protein C DeficiencyProtein C Deficiency

Common cause (increasing TE with age)Common cause (increasing TE with age) Needs TM from endothelium wallNeeds TM from endothelium wall Heterozygous 50 of level of normal Heterozygous 50 of level of normal

individualsindividuals Homozygous babies are born with Homozygous babies are born with

undetected levels (thrombi in microvascular undetected levels (thrombi in microvascular of skin DIC necrosis purpura of skin DIC necrosis purpura fulminans)fulminans)

33 Protein S DeficiencyProtein S Deficiency

Non-enzymatic co-factor for PCNon-enzymatic co-factor for PC Binds to TM-PCBinds to TM-PC Same properties as PCSame properties as PC Two forms free in plasma and bound to C4b Two forms free in plasma and bound to C4b

binding protein (60) Only free fraction binding protein (60) Only free fraction functions as co-factor for APCfunctions as co-factor for APC

Sometimes difficult to get accurate measures of Sometimes difficult to get accurate measures of PS because of the latterPS because of the latter

Like PC can be acquired liver disease Warfarin Like PC can be acquired liver disease Warfarin pregnancy cancer DIC and chemopregnancy cancer DIC and chemo

44 Antithrombin III DeficiencyAntithrombin III Deficiency

Common cause (incidence 12000 ndash 15000 Common cause (incidence 12000 ndash 15000 heterozygotes 50 DVT) Quantitative vs heterozygotes 50 DVT) Quantitative vs Qualitative disorder (Acquired DIC cirrhosis Qualitative disorder (Acquired DIC cirrhosis NS)NS)

Bind to and inactivate thrombin Factors IXa Xa Bind to and inactivate thrombin Factors IXa Xa XIa and XIIa (ATheparin complex - rate of XIa and XIIa (ATheparin complex - rate of inhibition 1000-fold increased)inhibition 1000-fold increased)

Not necessarily a risk factor to be involved in Not necessarily a risk factor to be involved in heterozygotes to give TEheterozygotes to give TE

Increased incidence with ageing 80 at 55 yearsIncreased incidence with ageing 80 at 55 years

55 Abnormal ProthrombinAbnormal Prothrombin (PT 20210 A) (PT 20210 A)

CommonCommon Increased levels of prothrombin enhanced Increased levels of prothrombin enhanced

thrombin formationthrombin formation Only way for diagnosis DNA-PCR Only way for diagnosis DNA-PCR

techniquetechnique

66 Sticky Platelet SyndromeSticky Platelet Syndrome

Especially in arterial thrombosis (MI) and Especially in arterial thrombosis (MI) and development of recurrent TE while on Warfarindevelopment of recurrent TE while on Warfarin

3 Forms3 Forms If on aspirin it should be stopped 14 days prior to If on aspirin it should be stopped 14 days prior to

testingtesting

Also rememberAlso remember

PC PS and AT III are inhibitors of clottingPC PS and AT III are inhibitors of clotting

Non-familial (Acquired)Non-familial (Acquired)11 Antiphospholipid SyndromeAntiphospholipid Syndrome Antibodies directed against phospholipid cell membrane = Antibodies directed against phospholipid cell membrane =

APA (Antiphospholipid Ab)APA (Antiphospholipid Ab) APA ACA or LAAPA ACA or LA Primary (PAPS) or secondary (autoimmune disorders eg Primary (PAPS) or secondary (autoimmune disorders eg

SLE)SLE) ACA (Anticardiolipin Ab) IgM + IgGACA (Anticardiolipin Ab) IgM + IgG IgG the clinically important oneIgG the clinically important one IgM pregnancy infection (viral) trauma and post-opIgM pregnancy infection (viral) trauma and post-op LA (Lupus anticoagulant) Ab which affect clotting tests (LA-LA (Lupus anticoagulant) Ab which affect clotting tests (LA-

PTT RVV Kaolin)PTT RVV Kaolin) PAPS = TE miscarriage IUDPAPS = TE miscarriage IUD

Antiphospholipid Syndrome1048734 Antiphospholipid syndrome (APS) ndash Syndrome characterized by venous andor arterial thrombosis thrombocytopenia or recurrent fetal loss associated with antibodies to phospho-lipid- protein Complexes

1048734 Antiphospholipid antibodies (aPL)ndash IgG IgM or IgA antibodies that are directed to target proteins such as cardiolipin beta2-Glycoprotein I (β2GPI)or Prothrombin all of which bind to phospholipidsndash Lupus anticoagulant (LA) bull Antiphospholipid antibodies identified by in vitro phospholipid dependent clot-based assays antibodies are targeted against Prothrombin or β2GPI and prolong clotting times

Antiphospholipd Antibodies

Lupus Anticoagulant

Conditions where screening for APS Conditions where screening for APS is indicatedis indicated

The first thrombotic event below the age of 40The first thrombotic event below the age of 40 History of recurrent TEDHistory of recurrent TED Recurrent fetal loss in the 1Recurrent fetal loss in the 1stst or the 2 or the 2ndnd trimester trimester Patient with SLEPatient with SLE Pre-hormone replacement therapyPre-hormone replacement therapy

Non-familial (Acquired) continuedNon-familial (Acquired) continued

22 TPA (Tissue Plasminogen Activator) TPA (Tissue Plasminogen Activator) decreased levels impaired fibrinolysisdecreased levels impaired fibrinolysis

33 PAI (Plasminogen Activator Inhibitor) PAI (Plasminogen Activator Inhibitor) increased levels decreased TPAincreased levels decreased TPA

44 DysfibrinogenemiaDysfibrinogenemia55 F XII deficiency Hageman factorF XII deficiency Hageman factor66 Fibrinogen (increased)Fibrinogen (increased)77 F VIII (increased)F VIII (increased)88 PlasminogenPlasminogen99 Hyperhomocyteinemia ndash enzyme (folate)Hyperhomocyteinemia ndash enzyme (folate)

Investigation (Thrombotic Profile)Investigation (Thrombotic Profile)

NB Patients can be on Warfarin but not HeparinNB Patients can be on Warfarin but not Heparin FBC PLT amp ESRFBC PLT amp ESR PT aPTT TT amp FibrinogenPT aPTT TT amp Fibrinogen PC amp PSPC amp PS AT IIIAT III APCR (if + screening submit for PCR)APCR (if + screening submit for PCR) PT 20210A (PCR)PT 20210A (PCR) Lupus anticoagulant (RVVT KT LA-PTT) Lupus anticoagulant (RVVT KT LA-PTT) Cardiolipin antibodies (antiphospholipid syndrome)Cardiolipin antibodies (antiphospholipid syndrome) Sticky platelet syndrome (aspirin)Sticky platelet syndrome (aspirin) ANA screeningANA screening PNH screeningPNH screening

When to testWhen to test Younger lt 50 years recurrent TE unusual sites Younger lt 50 years recurrent TE unusual sites

TE on WarfarinTE on Warfarin Not ideal to test after acute episode (inhibitors of Not ideal to test after acute episode (inhibitors of

clotting may be low)clotting may be low) Ideal test after 6 weeks after settlement of Ideal test after 6 weeks after settlement of

hemostasishemostasis Most patients are on Warfarin then (PC amp PS are Most patients are on Warfarin then (PC amp PS are

Vit K dependent may be falsely low)Vit K dependent may be falsely low) My view if long-term Warfarin is planned do My view if long-term Warfarin is planned do

immediately according to duration of treatment it immediately according to duration of treatment it can be done after cessation of treatmentcan be done after cessation of treatment

When to test (continued)When to test (continued)

Practical (my experience) before treatment ndash if AT Practical (my experience) before treatment ndash if AT PS PC are low PS PC are low repeat after Rx has been stopped repeat after Rx has been stopped

SPS platelet aggregation studies (problem SPS platelet aggregation studies (problem sometimes aspirin cannot be stopped)sometimes aspirin cannot be stopped)

Remember the effect of the vessel wall on clotting Remember the effect of the vessel wall on clotting especially in arterial thrombosisespecially in arterial thrombosis

Every woman on contraception HRTEvery woman on contraception HRT

Arterial ThrombosisArterial Thrombosis

Arterial Thrombosis

Arterial ThrombosisArterial Thrombosis

Results as sever oResults as sever o2 2 starvation of the left starvation of the left ventricle of the heartventricle of the heart

This leads to myocardial ischemia amp may This leads to myocardial ischemia amp may progress to myocardial infarction or progress to myocardial infarction or ischemic left ventricular fibrillation amp ischemic left ventricular fibrillation amp sudden deathsudden death

Similar episodes involving the cerebral Similar episodes involving the cerebral circulation result in transient ischemic circulation result in transient ischemic attacks amp thrombotic stroke attacks amp thrombotic stroke

Myocardial Infarction SymptomMyocardial Infarction Symptom

Crushing tightness of the chest with Crushing tightness of the chest with sweating nausea breathlessness amp sweating nausea breathlessness amp collapsecollapse

Chest pain may radiates to the arm throat amp Chest pain may radiates to the arm throat amp jawjaw

Chest pain may confused with sever Chest pain may confused with sever indigestion in itrsquos early stagesindigestion in itrsquos early stages

Transient Ischemic attacksTransient Ischemic attacks

Itrsquos usually accompanied with neurological Itrsquos usually accompanied with neurological dysfunction or loss of visiondysfunction or loss of vision

Completed thrombotic strokeCompleted thrombotic stroke

Itrsquos accompanied by similar symptoms Itrsquos accompanied by similar symptoms which persist for more than 24 hours that which persist for more than 24 hours that may be severely amp permanently disablingmay be severely amp permanently disabling

Risk factors for arterial amp venous thrombosisRisk factors for arterial amp venous thrombosis

Venous thrombosisVenous thrombosisArterial thrombosisArterial thrombosisIncreasing ageIncreasing ageIncreasing ageIncreasing age

ObesityObesityObesityObesity

ImmobilityImmobilityLack of exerciseLack of exercise

Pregnancy rdquopost partomrdquoPregnancy rdquopost partomrdquoHigh fat low fiber dietHigh fat low fiber diet

MalignancyMalignancySmokingSmoking

Lupus anticoagulantLupus anticoagulantHyperlipidemiaHyperlipidemia

Nephrotic syndromeNephrotic syndromeHypertensionHypertension

PolycythemiaPolycythemiaElevated factor VII II concElevated factor VII II conc

goutgoutGenetic factorGenetic factor

Prophylaxis amp treatment of Prophylaxis amp treatment of thrombosisthrombosis

Prevent the risk factorsPrevent the risk factors SmokingSmoking ObesityObesity Lack of exerciseLack of exercise Poor dietPoor diet

Only when this proves to be impossibleOnly when this proves to be impossible

(Pharmacological intervention is required) (Pharmacological intervention is required)

Thrombosis

Hereditarythrombophilia

Acquiredthrombophilia

SurgerytraumaImmobility

Inflammation

Malignancy

Estrogens

Risk Factors for ThrombosisRisk Factors for Thrombosis

Atherosclerosis

THROMBOEMBOLIC DISORDERSTHROMBOEMBOLIC DISORDERS

Venous thromboembolismVenous thromboembolism

Arterial thromboembolismArterial thromboembolism

Risk Factors forRisk Factors forVenous ThrombosisVenous Thrombosis

AcquiredAcquired InheritedInherited MixedunknownMixedunknown

Venous Thrombosis Venous system low flow amp pressure Thrombi are fibrin rich Function of age biologic conditions genetic

ampenvironmental factors and their interactions Venous thromboembolism (VTE) ndash Deep vein thrombosis (DVT) ndash Pulmonary embolism (PE) ndash Superficial portal cerebral or retinal vein thrombosis Reasons for coagulation testing ndash Risk for recurrence of thrombosis ndash Treatment considerations (duration amp intensity) ndash Genetic counseling for affected family members ndash Prophylaxis for high risk situations

The most common is (DVT) deep venous The most common is (DVT) deep venous thrombosis of the lower limbs The main thrombosis of the lower limbs The main site where there is maximum stasis and low site where there is maximum stasis and low blood flow blood flow

Propagation of thrombus is associated with Propagation of thrombus is associated with red cell entrapmenthelliphellipred thrombusred cell entrapmenthelliphellipred thrombus

Venus thrombi may become dislodged or Venus thrombi may become dislodged or fragment resulting in the formation of fragment resulting in the formation of circulating thrombi This may result in circulating thrombi This may result in pulmonary embolismpulmonary embolism

Venous Thrombosis

Pulmonary embolismPulmonary embolism

Presents with acute chest painPresents with acute chest pain Breathlessness with shockBreathlessness with shock Cough amp hemopysisCough amp hemopysis May be fatalMay be fatal

Venous Thrombosis symptoms

Typically presents with pain swelling Typically presents with pain swelling discoloration amp warmth in the affected areadiscoloration amp warmth in the affected area

However However

(these symptoms may be absent amp non of (these symptoms may be absent amp non of them is specific)them is specific)

Hematologic manifestationsHematologic manifestations

Cutaneous manifestationsCutaneous manifestations

Genetic Risk Factors(Familial)

11 FV- Leiden (APCR activated prot C resistance)FV- Leiden (APCR activated prot C resistance)

22 Protein C (deficiency)Protein C (deficiency)

33 Protein S (deficiency)Protein S (deficiency)

44 Antithrombin III (deficiency)Antithrombin III (deficiency)

55 Abnormal Prothrombin (PT 20210 A)Abnormal Prothrombin (PT 20210 A)

66 Sticky platelet syndromeSticky platelet syndrome

Risk FactorsmdashAcquiredRisk FactorsmdashAcquired

Advancing ageAdvancing age Prior ThrombosisPrior Thrombosis ImmobilizationImmobilization Major surgeryMajor surgery MalignancyMalignancy EstrogensEstrogens

Antiphospholipid Antiphospholipid antibody syndromeantibody syndrome

Myeloproliferative Myeloproliferative DisordersDisorders

Heparin-induced Heparin-induced thrombocytopenia thrombocytopenia (HIT)(HIT)

ProlongedProlonged air travel air travel

Risk FactorsmdashMixedUnknownRisk FactorsmdashMixedUnknown

HyperhomocysteinemiaHyperhomocysteinemia High levels of factor VIIIHigh levels of factor VIII Acquired Protein C resistance in the absence of Acquired Protein C resistance in the absence of

Factor V LeidenFactor V Leiden High levels of Factor IX XIHigh levels of Factor IX XI

11 FV- LeidenFV- Leiden

One of the most common causes for thrombophilia One of the most common causes for thrombophilia ndash 20 of clinical disease (AT PC and PS ndash 5) + ndash 20 of clinical disease (AT PC and PS ndash 5) + risk factorrisk factor

Activated PC inhibits F Va and F VIIIaActivated PC inhibits F Va and F VIIIa Inability of APC to inhibit the above complex due Inability of APC to inhibit the above complex due

to mutated FVto mutated FV Heterozygous 5-10 times increased risk for TEHeterozygous 5-10 times increased risk for TE Homozygous 50-100 timesHomozygous 50-100 times

Factor Va

Arg 306 Arg 506 Arg 1765

Arginine CGA

Glutamine CAA

Factor Va resistant to APC cleavage

Factor V Leiden

Relative Risk forVenous Thrombosis

Factor V Leiden Heterozygote x 7

Factor V Leiden Homozygote x 80

Oral Contraceptives x 3

Oral Contraceptives + Factor V Leiden x 35

Leiden Study Group Data

22 Protein C DeficiencyProtein C Deficiency

Common cause (increasing TE with age)Common cause (increasing TE with age) Needs TM from endothelium wallNeeds TM from endothelium wall Heterozygous 50 of level of normal Heterozygous 50 of level of normal

individualsindividuals Homozygous babies are born with Homozygous babies are born with

undetected levels (thrombi in microvascular undetected levels (thrombi in microvascular of skin DIC necrosis purpura of skin DIC necrosis purpura fulminans)fulminans)

33 Protein S DeficiencyProtein S Deficiency

Non-enzymatic co-factor for PCNon-enzymatic co-factor for PC Binds to TM-PCBinds to TM-PC Same properties as PCSame properties as PC Two forms free in plasma and bound to C4b Two forms free in plasma and bound to C4b

binding protein (60) Only free fraction binding protein (60) Only free fraction functions as co-factor for APCfunctions as co-factor for APC

Sometimes difficult to get accurate measures of Sometimes difficult to get accurate measures of PS because of the latterPS because of the latter

Like PC can be acquired liver disease Warfarin Like PC can be acquired liver disease Warfarin pregnancy cancer DIC and chemopregnancy cancer DIC and chemo

44 Antithrombin III DeficiencyAntithrombin III Deficiency

Common cause (incidence 12000 ndash 15000 Common cause (incidence 12000 ndash 15000 heterozygotes 50 DVT) Quantitative vs heterozygotes 50 DVT) Quantitative vs Qualitative disorder (Acquired DIC cirrhosis Qualitative disorder (Acquired DIC cirrhosis NS)NS)

Bind to and inactivate thrombin Factors IXa Xa Bind to and inactivate thrombin Factors IXa Xa XIa and XIIa (ATheparin complex - rate of XIa and XIIa (ATheparin complex - rate of inhibition 1000-fold increased)inhibition 1000-fold increased)

Not necessarily a risk factor to be involved in Not necessarily a risk factor to be involved in heterozygotes to give TEheterozygotes to give TE

Increased incidence with ageing 80 at 55 yearsIncreased incidence with ageing 80 at 55 years

55 Abnormal ProthrombinAbnormal Prothrombin (PT 20210 A) (PT 20210 A)

CommonCommon Increased levels of prothrombin enhanced Increased levels of prothrombin enhanced

thrombin formationthrombin formation Only way for diagnosis DNA-PCR Only way for diagnosis DNA-PCR

techniquetechnique

66 Sticky Platelet SyndromeSticky Platelet Syndrome

Especially in arterial thrombosis (MI) and Especially in arterial thrombosis (MI) and development of recurrent TE while on Warfarindevelopment of recurrent TE while on Warfarin

3 Forms3 Forms If on aspirin it should be stopped 14 days prior to If on aspirin it should be stopped 14 days prior to

testingtesting

Also rememberAlso remember

PC PS and AT III are inhibitors of clottingPC PS and AT III are inhibitors of clotting

Non-familial (Acquired)Non-familial (Acquired)11 Antiphospholipid SyndromeAntiphospholipid Syndrome Antibodies directed against phospholipid cell membrane = Antibodies directed against phospholipid cell membrane =

APA (Antiphospholipid Ab)APA (Antiphospholipid Ab) APA ACA or LAAPA ACA or LA Primary (PAPS) or secondary (autoimmune disorders eg Primary (PAPS) or secondary (autoimmune disorders eg

SLE)SLE) ACA (Anticardiolipin Ab) IgM + IgGACA (Anticardiolipin Ab) IgM + IgG IgG the clinically important oneIgG the clinically important one IgM pregnancy infection (viral) trauma and post-opIgM pregnancy infection (viral) trauma and post-op LA (Lupus anticoagulant) Ab which affect clotting tests (LA-LA (Lupus anticoagulant) Ab which affect clotting tests (LA-

PTT RVV Kaolin)PTT RVV Kaolin) PAPS = TE miscarriage IUDPAPS = TE miscarriage IUD

Antiphospholipid Syndrome1048734 Antiphospholipid syndrome (APS) ndash Syndrome characterized by venous andor arterial thrombosis thrombocytopenia or recurrent fetal loss associated with antibodies to phospho-lipid- protein Complexes

1048734 Antiphospholipid antibodies (aPL)ndash IgG IgM or IgA antibodies that are directed to target proteins such as cardiolipin beta2-Glycoprotein I (β2GPI)or Prothrombin all of which bind to phospholipidsndash Lupus anticoagulant (LA) bull Antiphospholipid antibodies identified by in vitro phospholipid dependent clot-based assays antibodies are targeted against Prothrombin or β2GPI and prolong clotting times

Antiphospholipd Antibodies

Lupus Anticoagulant

Conditions where screening for APS Conditions where screening for APS is indicatedis indicated

The first thrombotic event below the age of 40The first thrombotic event below the age of 40 History of recurrent TEDHistory of recurrent TED Recurrent fetal loss in the 1Recurrent fetal loss in the 1stst or the 2 or the 2ndnd trimester trimester Patient with SLEPatient with SLE Pre-hormone replacement therapyPre-hormone replacement therapy

Non-familial (Acquired) continuedNon-familial (Acquired) continued

22 TPA (Tissue Plasminogen Activator) TPA (Tissue Plasminogen Activator) decreased levels impaired fibrinolysisdecreased levels impaired fibrinolysis

33 PAI (Plasminogen Activator Inhibitor) PAI (Plasminogen Activator Inhibitor) increased levels decreased TPAincreased levels decreased TPA

44 DysfibrinogenemiaDysfibrinogenemia55 F XII deficiency Hageman factorF XII deficiency Hageman factor66 Fibrinogen (increased)Fibrinogen (increased)77 F VIII (increased)F VIII (increased)88 PlasminogenPlasminogen99 Hyperhomocyteinemia ndash enzyme (folate)Hyperhomocyteinemia ndash enzyme (folate)

Investigation (Thrombotic Profile)Investigation (Thrombotic Profile)

NB Patients can be on Warfarin but not HeparinNB Patients can be on Warfarin but not Heparin FBC PLT amp ESRFBC PLT amp ESR PT aPTT TT amp FibrinogenPT aPTT TT amp Fibrinogen PC amp PSPC amp PS AT IIIAT III APCR (if + screening submit for PCR)APCR (if + screening submit for PCR) PT 20210A (PCR)PT 20210A (PCR) Lupus anticoagulant (RVVT KT LA-PTT) Lupus anticoagulant (RVVT KT LA-PTT) Cardiolipin antibodies (antiphospholipid syndrome)Cardiolipin antibodies (antiphospholipid syndrome) Sticky platelet syndrome (aspirin)Sticky platelet syndrome (aspirin) ANA screeningANA screening PNH screeningPNH screening

When to testWhen to test Younger lt 50 years recurrent TE unusual sites Younger lt 50 years recurrent TE unusual sites

TE on WarfarinTE on Warfarin Not ideal to test after acute episode (inhibitors of Not ideal to test after acute episode (inhibitors of

clotting may be low)clotting may be low) Ideal test after 6 weeks after settlement of Ideal test after 6 weeks after settlement of

hemostasishemostasis Most patients are on Warfarin then (PC amp PS are Most patients are on Warfarin then (PC amp PS are

Vit K dependent may be falsely low)Vit K dependent may be falsely low) My view if long-term Warfarin is planned do My view if long-term Warfarin is planned do

immediately according to duration of treatment it immediately according to duration of treatment it can be done after cessation of treatmentcan be done after cessation of treatment

When to test (continued)When to test (continued)

Practical (my experience) before treatment ndash if AT Practical (my experience) before treatment ndash if AT PS PC are low PS PC are low repeat after Rx has been stopped repeat after Rx has been stopped

SPS platelet aggregation studies (problem SPS platelet aggregation studies (problem sometimes aspirin cannot be stopped)sometimes aspirin cannot be stopped)

Remember the effect of the vessel wall on clotting Remember the effect of the vessel wall on clotting especially in arterial thrombosisespecially in arterial thrombosis

Every woman on contraception HRTEvery woman on contraception HRT

Arterial ThrombosisArterial Thrombosis

Arterial Thrombosis

Arterial ThrombosisArterial Thrombosis

Results as sever oResults as sever o2 2 starvation of the left starvation of the left ventricle of the heartventricle of the heart

This leads to myocardial ischemia amp may This leads to myocardial ischemia amp may progress to myocardial infarction or progress to myocardial infarction or ischemic left ventricular fibrillation amp ischemic left ventricular fibrillation amp sudden deathsudden death

Similar episodes involving the cerebral Similar episodes involving the cerebral circulation result in transient ischemic circulation result in transient ischemic attacks amp thrombotic stroke attacks amp thrombotic stroke

Myocardial Infarction SymptomMyocardial Infarction Symptom

Crushing tightness of the chest with Crushing tightness of the chest with sweating nausea breathlessness amp sweating nausea breathlessness amp collapsecollapse

Chest pain may radiates to the arm throat amp Chest pain may radiates to the arm throat amp jawjaw

Chest pain may confused with sever Chest pain may confused with sever indigestion in itrsquos early stagesindigestion in itrsquos early stages

Transient Ischemic attacksTransient Ischemic attacks

Itrsquos usually accompanied with neurological Itrsquos usually accompanied with neurological dysfunction or loss of visiondysfunction or loss of vision

Completed thrombotic strokeCompleted thrombotic stroke

Itrsquos accompanied by similar symptoms Itrsquos accompanied by similar symptoms which persist for more than 24 hours that which persist for more than 24 hours that may be severely amp permanently disablingmay be severely amp permanently disabling

Risk factors for arterial amp venous thrombosisRisk factors for arterial amp venous thrombosis

Venous thrombosisVenous thrombosisArterial thrombosisArterial thrombosisIncreasing ageIncreasing ageIncreasing ageIncreasing age

ObesityObesityObesityObesity

ImmobilityImmobilityLack of exerciseLack of exercise

Pregnancy rdquopost partomrdquoPregnancy rdquopost partomrdquoHigh fat low fiber dietHigh fat low fiber diet

MalignancyMalignancySmokingSmoking

Lupus anticoagulantLupus anticoagulantHyperlipidemiaHyperlipidemia

Nephrotic syndromeNephrotic syndromeHypertensionHypertension

PolycythemiaPolycythemiaElevated factor VII II concElevated factor VII II conc

goutgoutGenetic factorGenetic factor

Prophylaxis amp treatment of Prophylaxis amp treatment of thrombosisthrombosis

Prevent the risk factorsPrevent the risk factors SmokingSmoking ObesityObesity Lack of exerciseLack of exercise Poor dietPoor diet

Only when this proves to be impossibleOnly when this proves to be impossible

(Pharmacological intervention is required) (Pharmacological intervention is required)

THROMBOEMBOLIC DISORDERSTHROMBOEMBOLIC DISORDERS

Venous thromboembolismVenous thromboembolism

Arterial thromboembolismArterial thromboembolism

Risk Factors forRisk Factors forVenous ThrombosisVenous Thrombosis

AcquiredAcquired InheritedInherited MixedunknownMixedunknown

Venous Thrombosis Venous system low flow amp pressure Thrombi are fibrin rich Function of age biologic conditions genetic

ampenvironmental factors and their interactions Venous thromboembolism (VTE) ndash Deep vein thrombosis (DVT) ndash Pulmonary embolism (PE) ndash Superficial portal cerebral or retinal vein thrombosis Reasons for coagulation testing ndash Risk for recurrence of thrombosis ndash Treatment considerations (duration amp intensity) ndash Genetic counseling for affected family members ndash Prophylaxis for high risk situations

The most common is (DVT) deep venous The most common is (DVT) deep venous thrombosis of the lower limbs The main thrombosis of the lower limbs The main site where there is maximum stasis and low site where there is maximum stasis and low blood flow blood flow

Propagation of thrombus is associated with Propagation of thrombus is associated with red cell entrapmenthelliphellipred thrombusred cell entrapmenthelliphellipred thrombus

Venus thrombi may become dislodged or Venus thrombi may become dislodged or fragment resulting in the formation of fragment resulting in the formation of circulating thrombi This may result in circulating thrombi This may result in pulmonary embolismpulmonary embolism

Venous Thrombosis

Pulmonary embolismPulmonary embolism

Presents with acute chest painPresents with acute chest pain Breathlessness with shockBreathlessness with shock Cough amp hemopysisCough amp hemopysis May be fatalMay be fatal

Venous Thrombosis symptoms

Typically presents with pain swelling Typically presents with pain swelling discoloration amp warmth in the affected areadiscoloration amp warmth in the affected area

However However

(these symptoms may be absent amp non of (these symptoms may be absent amp non of them is specific)them is specific)

Hematologic manifestationsHematologic manifestations

Cutaneous manifestationsCutaneous manifestations

Genetic Risk Factors(Familial)

11 FV- Leiden (APCR activated prot C resistance)FV- Leiden (APCR activated prot C resistance)

22 Protein C (deficiency)Protein C (deficiency)

33 Protein S (deficiency)Protein S (deficiency)

44 Antithrombin III (deficiency)Antithrombin III (deficiency)

55 Abnormal Prothrombin (PT 20210 A)Abnormal Prothrombin (PT 20210 A)

66 Sticky platelet syndromeSticky platelet syndrome

Risk FactorsmdashAcquiredRisk FactorsmdashAcquired

Advancing ageAdvancing age Prior ThrombosisPrior Thrombosis ImmobilizationImmobilization Major surgeryMajor surgery MalignancyMalignancy EstrogensEstrogens

Antiphospholipid Antiphospholipid antibody syndromeantibody syndrome

Myeloproliferative Myeloproliferative DisordersDisorders

Heparin-induced Heparin-induced thrombocytopenia thrombocytopenia (HIT)(HIT)

ProlongedProlonged air travel air travel

Risk FactorsmdashMixedUnknownRisk FactorsmdashMixedUnknown

HyperhomocysteinemiaHyperhomocysteinemia High levels of factor VIIIHigh levels of factor VIII Acquired Protein C resistance in the absence of Acquired Protein C resistance in the absence of

Factor V LeidenFactor V Leiden High levels of Factor IX XIHigh levels of Factor IX XI

11 FV- LeidenFV- Leiden

One of the most common causes for thrombophilia One of the most common causes for thrombophilia ndash 20 of clinical disease (AT PC and PS ndash 5) + ndash 20 of clinical disease (AT PC and PS ndash 5) + risk factorrisk factor

Activated PC inhibits F Va and F VIIIaActivated PC inhibits F Va and F VIIIa Inability of APC to inhibit the above complex due Inability of APC to inhibit the above complex due

to mutated FVto mutated FV Heterozygous 5-10 times increased risk for TEHeterozygous 5-10 times increased risk for TE Homozygous 50-100 timesHomozygous 50-100 times

Factor Va

Arg 306 Arg 506 Arg 1765

Arginine CGA

Glutamine CAA

Factor Va resistant to APC cleavage

Factor V Leiden

Relative Risk forVenous Thrombosis

Factor V Leiden Heterozygote x 7

Factor V Leiden Homozygote x 80

Oral Contraceptives x 3

Oral Contraceptives + Factor V Leiden x 35

Leiden Study Group Data

22 Protein C DeficiencyProtein C Deficiency

Common cause (increasing TE with age)Common cause (increasing TE with age) Needs TM from endothelium wallNeeds TM from endothelium wall Heterozygous 50 of level of normal Heterozygous 50 of level of normal

individualsindividuals Homozygous babies are born with Homozygous babies are born with

undetected levels (thrombi in microvascular undetected levels (thrombi in microvascular of skin DIC necrosis purpura of skin DIC necrosis purpura fulminans)fulminans)

33 Protein S DeficiencyProtein S Deficiency

Non-enzymatic co-factor for PCNon-enzymatic co-factor for PC Binds to TM-PCBinds to TM-PC Same properties as PCSame properties as PC Two forms free in plasma and bound to C4b Two forms free in plasma and bound to C4b

binding protein (60) Only free fraction binding protein (60) Only free fraction functions as co-factor for APCfunctions as co-factor for APC

Sometimes difficult to get accurate measures of Sometimes difficult to get accurate measures of PS because of the latterPS because of the latter

Like PC can be acquired liver disease Warfarin Like PC can be acquired liver disease Warfarin pregnancy cancer DIC and chemopregnancy cancer DIC and chemo

44 Antithrombin III DeficiencyAntithrombin III Deficiency

Common cause (incidence 12000 ndash 15000 Common cause (incidence 12000 ndash 15000 heterozygotes 50 DVT) Quantitative vs heterozygotes 50 DVT) Quantitative vs Qualitative disorder (Acquired DIC cirrhosis Qualitative disorder (Acquired DIC cirrhosis NS)NS)

Bind to and inactivate thrombin Factors IXa Xa Bind to and inactivate thrombin Factors IXa Xa XIa and XIIa (ATheparin complex - rate of XIa and XIIa (ATheparin complex - rate of inhibition 1000-fold increased)inhibition 1000-fold increased)

Not necessarily a risk factor to be involved in Not necessarily a risk factor to be involved in heterozygotes to give TEheterozygotes to give TE

Increased incidence with ageing 80 at 55 yearsIncreased incidence with ageing 80 at 55 years

55 Abnormal ProthrombinAbnormal Prothrombin (PT 20210 A) (PT 20210 A)

CommonCommon Increased levels of prothrombin enhanced Increased levels of prothrombin enhanced

thrombin formationthrombin formation Only way for diagnosis DNA-PCR Only way for diagnosis DNA-PCR

techniquetechnique

66 Sticky Platelet SyndromeSticky Platelet Syndrome

Especially in arterial thrombosis (MI) and Especially in arterial thrombosis (MI) and development of recurrent TE while on Warfarindevelopment of recurrent TE while on Warfarin

3 Forms3 Forms If on aspirin it should be stopped 14 days prior to If on aspirin it should be stopped 14 days prior to

testingtesting

Also rememberAlso remember

PC PS and AT III are inhibitors of clottingPC PS and AT III are inhibitors of clotting

Non-familial (Acquired)Non-familial (Acquired)11 Antiphospholipid SyndromeAntiphospholipid Syndrome Antibodies directed against phospholipid cell membrane = Antibodies directed against phospholipid cell membrane =

APA (Antiphospholipid Ab)APA (Antiphospholipid Ab) APA ACA or LAAPA ACA or LA Primary (PAPS) or secondary (autoimmune disorders eg Primary (PAPS) or secondary (autoimmune disorders eg

SLE)SLE) ACA (Anticardiolipin Ab) IgM + IgGACA (Anticardiolipin Ab) IgM + IgG IgG the clinically important oneIgG the clinically important one IgM pregnancy infection (viral) trauma and post-opIgM pregnancy infection (viral) trauma and post-op LA (Lupus anticoagulant) Ab which affect clotting tests (LA-LA (Lupus anticoagulant) Ab which affect clotting tests (LA-

PTT RVV Kaolin)PTT RVV Kaolin) PAPS = TE miscarriage IUDPAPS = TE miscarriage IUD

Antiphospholipid Syndrome1048734 Antiphospholipid syndrome (APS) ndash Syndrome characterized by venous andor arterial thrombosis thrombocytopenia or recurrent fetal loss associated with antibodies to phospho-lipid- protein Complexes

1048734 Antiphospholipid antibodies (aPL)ndash IgG IgM or IgA antibodies that are directed to target proteins such as cardiolipin beta2-Glycoprotein I (β2GPI)or Prothrombin all of which bind to phospholipidsndash Lupus anticoagulant (LA) bull Antiphospholipid antibodies identified by in vitro phospholipid dependent clot-based assays antibodies are targeted against Prothrombin or β2GPI and prolong clotting times

Antiphospholipd Antibodies

Lupus Anticoagulant

Conditions where screening for APS Conditions where screening for APS is indicatedis indicated

The first thrombotic event below the age of 40The first thrombotic event below the age of 40 History of recurrent TEDHistory of recurrent TED Recurrent fetal loss in the 1Recurrent fetal loss in the 1stst or the 2 or the 2ndnd trimester trimester Patient with SLEPatient with SLE Pre-hormone replacement therapyPre-hormone replacement therapy

Non-familial (Acquired) continuedNon-familial (Acquired) continued

22 TPA (Tissue Plasminogen Activator) TPA (Tissue Plasminogen Activator) decreased levels impaired fibrinolysisdecreased levels impaired fibrinolysis

33 PAI (Plasminogen Activator Inhibitor) PAI (Plasminogen Activator Inhibitor) increased levels decreased TPAincreased levels decreased TPA

44 DysfibrinogenemiaDysfibrinogenemia55 F XII deficiency Hageman factorF XII deficiency Hageman factor66 Fibrinogen (increased)Fibrinogen (increased)77 F VIII (increased)F VIII (increased)88 PlasminogenPlasminogen99 Hyperhomocyteinemia ndash enzyme (folate)Hyperhomocyteinemia ndash enzyme (folate)

Investigation (Thrombotic Profile)Investigation (Thrombotic Profile)

NB Patients can be on Warfarin but not HeparinNB Patients can be on Warfarin but not Heparin FBC PLT amp ESRFBC PLT amp ESR PT aPTT TT amp FibrinogenPT aPTT TT amp Fibrinogen PC amp PSPC amp PS AT IIIAT III APCR (if + screening submit for PCR)APCR (if + screening submit for PCR) PT 20210A (PCR)PT 20210A (PCR) Lupus anticoagulant (RVVT KT LA-PTT) Lupus anticoagulant (RVVT KT LA-PTT) Cardiolipin antibodies (antiphospholipid syndrome)Cardiolipin antibodies (antiphospholipid syndrome) Sticky platelet syndrome (aspirin)Sticky platelet syndrome (aspirin) ANA screeningANA screening PNH screeningPNH screening

When to testWhen to test Younger lt 50 years recurrent TE unusual sites Younger lt 50 years recurrent TE unusual sites

TE on WarfarinTE on Warfarin Not ideal to test after acute episode (inhibitors of Not ideal to test after acute episode (inhibitors of

clotting may be low)clotting may be low) Ideal test after 6 weeks after settlement of Ideal test after 6 weeks after settlement of

hemostasishemostasis Most patients are on Warfarin then (PC amp PS are Most patients are on Warfarin then (PC amp PS are

Vit K dependent may be falsely low)Vit K dependent may be falsely low) My view if long-term Warfarin is planned do My view if long-term Warfarin is planned do

immediately according to duration of treatment it immediately according to duration of treatment it can be done after cessation of treatmentcan be done after cessation of treatment

When to test (continued)When to test (continued)

Practical (my experience) before treatment ndash if AT Practical (my experience) before treatment ndash if AT PS PC are low PS PC are low repeat after Rx has been stopped repeat after Rx has been stopped

SPS platelet aggregation studies (problem SPS platelet aggregation studies (problem sometimes aspirin cannot be stopped)sometimes aspirin cannot be stopped)

Remember the effect of the vessel wall on clotting Remember the effect of the vessel wall on clotting especially in arterial thrombosisespecially in arterial thrombosis

Every woman on contraception HRTEvery woman on contraception HRT

Arterial ThrombosisArterial Thrombosis

Arterial Thrombosis

Arterial ThrombosisArterial Thrombosis

Results as sever oResults as sever o2 2 starvation of the left starvation of the left ventricle of the heartventricle of the heart

This leads to myocardial ischemia amp may This leads to myocardial ischemia amp may progress to myocardial infarction or progress to myocardial infarction or ischemic left ventricular fibrillation amp ischemic left ventricular fibrillation amp sudden deathsudden death

Similar episodes involving the cerebral Similar episodes involving the cerebral circulation result in transient ischemic circulation result in transient ischemic attacks amp thrombotic stroke attacks amp thrombotic stroke

Myocardial Infarction SymptomMyocardial Infarction Symptom

Crushing tightness of the chest with Crushing tightness of the chest with sweating nausea breathlessness amp sweating nausea breathlessness amp collapsecollapse

Chest pain may radiates to the arm throat amp Chest pain may radiates to the arm throat amp jawjaw

Chest pain may confused with sever Chest pain may confused with sever indigestion in itrsquos early stagesindigestion in itrsquos early stages

Transient Ischemic attacksTransient Ischemic attacks

Itrsquos usually accompanied with neurological Itrsquos usually accompanied with neurological dysfunction or loss of visiondysfunction or loss of vision

Completed thrombotic strokeCompleted thrombotic stroke

Itrsquos accompanied by similar symptoms Itrsquos accompanied by similar symptoms which persist for more than 24 hours that which persist for more than 24 hours that may be severely amp permanently disablingmay be severely amp permanently disabling

Risk factors for arterial amp venous thrombosisRisk factors for arterial amp venous thrombosis

Venous thrombosisVenous thrombosisArterial thrombosisArterial thrombosisIncreasing ageIncreasing ageIncreasing ageIncreasing age

ObesityObesityObesityObesity

ImmobilityImmobilityLack of exerciseLack of exercise

Pregnancy rdquopost partomrdquoPregnancy rdquopost partomrdquoHigh fat low fiber dietHigh fat low fiber diet

MalignancyMalignancySmokingSmoking

Lupus anticoagulantLupus anticoagulantHyperlipidemiaHyperlipidemia

Nephrotic syndromeNephrotic syndromeHypertensionHypertension

PolycythemiaPolycythemiaElevated factor VII II concElevated factor VII II conc

goutgoutGenetic factorGenetic factor

Prophylaxis amp treatment of Prophylaxis amp treatment of thrombosisthrombosis

Prevent the risk factorsPrevent the risk factors SmokingSmoking ObesityObesity Lack of exerciseLack of exercise Poor dietPoor diet

Only when this proves to be impossibleOnly when this proves to be impossible

(Pharmacological intervention is required) (Pharmacological intervention is required)

Risk Factors forRisk Factors forVenous ThrombosisVenous Thrombosis

AcquiredAcquired InheritedInherited MixedunknownMixedunknown

Venous Thrombosis Venous system low flow amp pressure Thrombi are fibrin rich Function of age biologic conditions genetic

ampenvironmental factors and their interactions Venous thromboembolism (VTE) ndash Deep vein thrombosis (DVT) ndash Pulmonary embolism (PE) ndash Superficial portal cerebral or retinal vein thrombosis Reasons for coagulation testing ndash Risk for recurrence of thrombosis ndash Treatment considerations (duration amp intensity) ndash Genetic counseling for affected family members ndash Prophylaxis for high risk situations

The most common is (DVT) deep venous The most common is (DVT) deep venous thrombosis of the lower limbs The main thrombosis of the lower limbs The main site where there is maximum stasis and low site where there is maximum stasis and low blood flow blood flow

Propagation of thrombus is associated with Propagation of thrombus is associated with red cell entrapmenthelliphellipred thrombusred cell entrapmenthelliphellipred thrombus

Venus thrombi may become dislodged or Venus thrombi may become dislodged or fragment resulting in the formation of fragment resulting in the formation of circulating thrombi This may result in circulating thrombi This may result in pulmonary embolismpulmonary embolism

Venous Thrombosis

Pulmonary embolismPulmonary embolism

Presents with acute chest painPresents with acute chest pain Breathlessness with shockBreathlessness with shock Cough amp hemopysisCough amp hemopysis May be fatalMay be fatal

Venous Thrombosis symptoms

Typically presents with pain swelling Typically presents with pain swelling discoloration amp warmth in the affected areadiscoloration amp warmth in the affected area

However However

(these symptoms may be absent amp non of (these symptoms may be absent amp non of them is specific)them is specific)

Hematologic manifestationsHematologic manifestations

Cutaneous manifestationsCutaneous manifestations

Genetic Risk Factors(Familial)

11 FV- Leiden (APCR activated prot C resistance)FV- Leiden (APCR activated prot C resistance)

22 Protein C (deficiency)Protein C (deficiency)

33 Protein S (deficiency)Protein S (deficiency)

44 Antithrombin III (deficiency)Antithrombin III (deficiency)

55 Abnormal Prothrombin (PT 20210 A)Abnormal Prothrombin (PT 20210 A)

66 Sticky platelet syndromeSticky platelet syndrome

Risk FactorsmdashAcquiredRisk FactorsmdashAcquired

Advancing ageAdvancing age Prior ThrombosisPrior Thrombosis ImmobilizationImmobilization Major surgeryMajor surgery MalignancyMalignancy EstrogensEstrogens

Antiphospholipid Antiphospholipid antibody syndromeantibody syndrome

Myeloproliferative Myeloproliferative DisordersDisorders

Heparin-induced Heparin-induced thrombocytopenia thrombocytopenia (HIT)(HIT)

ProlongedProlonged air travel air travel

Risk FactorsmdashMixedUnknownRisk FactorsmdashMixedUnknown

HyperhomocysteinemiaHyperhomocysteinemia High levels of factor VIIIHigh levels of factor VIII Acquired Protein C resistance in the absence of Acquired Protein C resistance in the absence of

Factor V LeidenFactor V Leiden High levels of Factor IX XIHigh levels of Factor IX XI

11 FV- LeidenFV- Leiden

One of the most common causes for thrombophilia One of the most common causes for thrombophilia ndash 20 of clinical disease (AT PC and PS ndash 5) + ndash 20 of clinical disease (AT PC and PS ndash 5) + risk factorrisk factor

Activated PC inhibits F Va and F VIIIaActivated PC inhibits F Va and F VIIIa Inability of APC to inhibit the above complex due Inability of APC to inhibit the above complex due

to mutated FVto mutated FV Heterozygous 5-10 times increased risk for TEHeterozygous 5-10 times increased risk for TE Homozygous 50-100 timesHomozygous 50-100 times

Factor Va

Arg 306 Arg 506 Arg 1765

Arginine CGA

Glutamine CAA

Factor Va resistant to APC cleavage

Factor V Leiden

Relative Risk forVenous Thrombosis

Factor V Leiden Heterozygote x 7

Factor V Leiden Homozygote x 80

Oral Contraceptives x 3

Oral Contraceptives + Factor V Leiden x 35

Leiden Study Group Data

22 Protein C DeficiencyProtein C Deficiency

Common cause (increasing TE with age)Common cause (increasing TE with age) Needs TM from endothelium wallNeeds TM from endothelium wall Heterozygous 50 of level of normal Heterozygous 50 of level of normal

individualsindividuals Homozygous babies are born with Homozygous babies are born with

undetected levels (thrombi in microvascular undetected levels (thrombi in microvascular of skin DIC necrosis purpura of skin DIC necrosis purpura fulminans)fulminans)

33 Protein S DeficiencyProtein S Deficiency

Non-enzymatic co-factor for PCNon-enzymatic co-factor for PC Binds to TM-PCBinds to TM-PC Same properties as PCSame properties as PC Two forms free in plasma and bound to C4b Two forms free in plasma and bound to C4b

binding protein (60) Only free fraction binding protein (60) Only free fraction functions as co-factor for APCfunctions as co-factor for APC

Sometimes difficult to get accurate measures of Sometimes difficult to get accurate measures of PS because of the latterPS because of the latter

Like PC can be acquired liver disease Warfarin Like PC can be acquired liver disease Warfarin pregnancy cancer DIC and chemopregnancy cancer DIC and chemo

44 Antithrombin III DeficiencyAntithrombin III Deficiency

Common cause (incidence 12000 ndash 15000 Common cause (incidence 12000 ndash 15000 heterozygotes 50 DVT) Quantitative vs heterozygotes 50 DVT) Quantitative vs Qualitative disorder (Acquired DIC cirrhosis Qualitative disorder (Acquired DIC cirrhosis NS)NS)

Bind to and inactivate thrombin Factors IXa Xa Bind to and inactivate thrombin Factors IXa Xa XIa and XIIa (ATheparin complex - rate of XIa and XIIa (ATheparin complex - rate of inhibition 1000-fold increased)inhibition 1000-fold increased)

Not necessarily a risk factor to be involved in Not necessarily a risk factor to be involved in heterozygotes to give TEheterozygotes to give TE

Increased incidence with ageing 80 at 55 yearsIncreased incidence with ageing 80 at 55 years

55 Abnormal ProthrombinAbnormal Prothrombin (PT 20210 A) (PT 20210 A)

CommonCommon Increased levels of prothrombin enhanced Increased levels of prothrombin enhanced

thrombin formationthrombin formation Only way for diagnosis DNA-PCR Only way for diagnosis DNA-PCR

techniquetechnique

66 Sticky Platelet SyndromeSticky Platelet Syndrome

Especially in arterial thrombosis (MI) and Especially in arterial thrombosis (MI) and development of recurrent TE while on Warfarindevelopment of recurrent TE while on Warfarin

3 Forms3 Forms If on aspirin it should be stopped 14 days prior to If on aspirin it should be stopped 14 days prior to

testingtesting

Also rememberAlso remember

PC PS and AT III are inhibitors of clottingPC PS and AT III are inhibitors of clotting

Non-familial (Acquired)Non-familial (Acquired)11 Antiphospholipid SyndromeAntiphospholipid Syndrome Antibodies directed against phospholipid cell membrane = Antibodies directed against phospholipid cell membrane =

APA (Antiphospholipid Ab)APA (Antiphospholipid Ab) APA ACA or LAAPA ACA or LA Primary (PAPS) or secondary (autoimmune disorders eg Primary (PAPS) or secondary (autoimmune disorders eg

SLE)SLE) ACA (Anticardiolipin Ab) IgM + IgGACA (Anticardiolipin Ab) IgM + IgG IgG the clinically important oneIgG the clinically important one IgM pregnancy infection (viral) trauma and post-opIgM pregnancy infection (viral) trauma and post-op LA (Lupus anticoagulant) Ab which affect clotting tests (LA-LA (Lupus anticoagulant) Ab which affect clotting tests (LA-

PTT RVV Kaolin)PTT RVV Kaolin) PAPS = TE miscarriage IUDPAPS = TE miscarriage IUD

Antiphospholipid Syndrome1048734 Antiphospholipid syndrome (APS) ndash Syndrome characterized by venous andor arterial thrombosis thrombocytopenia or recurrent fetal loss associated with antibodies to phospho-lipid- protein Complexes

1048734 Antiphospholipid antibodies (aPL)ndash IgG IgM or IgA antibodies that are directed to target proteins such as cardiolipin beta2-Glycoprotein I (β2GPI)or Prothrombin all of which bind to phospholipidsndash Lupus anticoagulant (LA) bull Antiphospholipid antibodies identified by in vitro phospholipid dependent clot-based assays antibodies are targeted against Prothrombin or β2GPI and prolong clotting times

Antiphospholipd Antibodies

Lupus Anticoagulant

Conditions where screening for APS Conditions where screening for APS is indicatedis indicated

The first thrombotic event below the age of 40The first thrombotic event below the age of 40 History of recurrent TEDHistory of recurrent TED Recurrent fetal loss in the 1Recurrent fetal loss in the 1stst or the 2 or the 2ndnd trimester trimester Patient with SLEPatient with SLE Pre-hormone replacement therapyPre-hormone replacement therapy

Non-familial (Acquired) continuedNon-familial (Acquired) continued

22 TPA (Tissue Plasminogen Activator) TPA (Tissue Plasminogen Activator) decreased levels impaired fibrinolysisdecreased levels impaired fibrinolysis

33 PAI (Plasminogen Activator Inhibitor) PAI (Plasminogen Activator Inhibitor) increased levels decreased TPAincreased levels decreased TPA

44 DysfibrinogenemiaDysfibrinogenemia55 F XII deficiency Hageman factorF XII deficiency Hageman factor66 Fibrinogen (increased)Fibrinogen (increased)77 F VIII (increased)F VIII (increased)88 PlasminogenPlasminogen99 Hyperhomocyteinemia ndash enzyme (folate)Hyperhomocyteinemia ndash enzyme (folate)

Investigation (Thrombotic Profile)Investigation (Thrombotic Profile)

NB Patients can be on Warfarin but not HeparinNB Patients can be on Warfarin but not Heparin FBC PLT amp ESRFBC PLT amp ESR PT aPTT TT amp FibrinogenPT aPTT TT amp Fibrinogen PC amp PSPC amp PS AT IIIAT III APCR (if + screening submit for PCR)APCR (if + screening submit for PCR) PT 20210A (PCR)PT 20210A (PCR) Lupus anticoagulant (RVVT KT LA-PTT) Lupus anticoagulant (RVVT KT LA-PTT) Cardiolipin antibodies (antiphospholipid syndrome)Cardiolipin antibodies (antiphospholipid syndrome) Sticky platelet syndrome (aspirin)Sticky platelet syndrome (aspirin) ANA screeningANA screening PNH screeningPNH screening

When to testWhen to test Younger lt 50 years recurrent TE unusual sites Younger lt 50 years recurrent TE unusual sites

TE on WarfarinTE on Warfarin Not ideal to test after acute episode (inhibitors of Not ideal to test after acute episode (inhibitors of

clotting may be low)clotting may be low) Ideal test after 6 weeks after settlement of Ideal test after 6 weeks after settlement of

hemostasishemostasis Most patients are on Warfarin then (PC amp PS are Most patients are on Warfarin then (PC amp PS are

Vit K dependent may be falsely low)Vit K dependent may be falsely low) My view if long-term Warfarin is planned do My view if long-term Warfarin is planned do

immediately according to duration of treatment it immediately according to duration of treatment it can be done after cessation of treatmentcan be done after cessation of treatment

When to test (continued)When to test (continued)

Practical (my experience) before treatment ndash if AT Practical (my experience) before treatment ndash if AT PS PC are low PS PC are low repeat after Rx has been stopped repeat after Rx has been stopped

SPS platelet aggregation studies (problem SPS platelet aggregation studies (problem sometimes aspirin cannot be stopped)sometimes aspirin cannot be stopped)

Remember the effect of the vessel wall on clotting Remember the effect of the vessel wall on clotting especially in arterial thrombosisespecially in arterial thrombosis

Every woman on contraception HRTEvery woman on contraception HRT

Arterial ThrombosisArterial Thrombosis

Arterial Thrombosis

Arterial ThrombosisArterial Thrombosis

Results as sever oResults as sever o2 2 starvation of the left starvation of the left ventricle of the heartventricle of the heart

This leads to myocardial ischemia amp may This leads to myocardial ischemia amp may progress to myocardial infarction or progress to myocardial infarction or ischemic left ventricular fibrillation amp ischemic left ventricular fibrillation amp sudden deathsudden death

Similar episodes involving the cerebral Similar episodes involving the cerebral circulation result in transient ischemic circulation result in transient ischemic attacks amp thrombotic stroke attacks amp thrombotic stroke

Myocardial Infarction SymptomMyocardial Infarction Symptom

Crushing tightness of the chest with Crushing tightness of the chest with sweating nausea breathlessness amp sweating nausea breathlessness amp collapsecollapse

Chest pain may radiates to the arm throat amp Chest pain may radiates to the arm throat amp jawjaw

Chest pain may confused with sever Chest pain may confused with sever indigestion in itrsquos early stagesindigestion in itrsquos early stages

Transient Ischemic attacksTransient Ischemic attacks

Itrsquos usually accompanied with neurological Itrsquos usually accompanied with neurological dysfunction or loss of visiondysfunction or loss of vision

Completed thrombotic strokeCompleted thrombotic stroke

Itrsquos accompanied by similar symptoms Itrsquos accompanied by similar symptoms which persist for more than 24 hours that which persist for more than 24 hours that may be severely amp permanently disablingmay be severely amp permanently disabling

Risk factors for arterial amp venous thrombosisRisk factors for arterial amp venous thrombosis

Venous thrombosisVenous thrombosisArterial thrombosisArterial thrombosisIncreasing ageIncreasing ageIncreasing ageIncreasing age

ObesityObesityObesityObesity

ImmobilityImmobilityLack of exerciseLack of exercise

Pregnancy rdquopost partomrdquoPregnancy rdquopost partomrdquoHigh fat low fiber dietHigh fat low fiber diet

MalignancyMalignancySmokingSmoking

Lupus anticoagulantLupus anticoagulantHyperlipidemiaHyperlipidemia

Nephrotic syndromeNephrotic syndromeHypertensionHypertension

PolycythemiaPolycythemiaElevated factor VII II concElevated factor VII II conc

goutgoutGenetic factorGenetic factor

Prophylaxis amp treatment of Prophylaxis amp treatment of thrombosisthrombosis

Prevent the risk factorsPrevent the risk factors SmokingSmoking ObesityObesity Lack of exerciseLack of exercise Poor dietPoor diet

Only when this proves to be impossibleOnly when this proves to be impossible

(Pharmacological intervention is required) (Pharmacological intervention is required)

Venous Thrombosis Venous system low flow amp pressure Thrombi are fibrin rich Function of age biologic conditions genetic

ampenvironmental factors and their interactions Venous thromboembolism (VTE) ndash Deep vein thrombosis (DVT) ndash Pulmonary embolism (PE) ndash Superficial portal cerebral or retinal vein thrombosis Reasons for coagulation testing ndash Risk for recurrence of thrombosis ndash Treatment considerations (duration amp intensity) ndash Genetic counseling for affected family members ndash Prophylaxis for high risk situations

The most common is (DVT) deep venous The most common is (DVT) deep venous thrombosis of the lower limbs The main thrombosis of the lower limbs The main site where there is maximum stasis and low site where there is maximum stasis and low blood flow blood flow

Propagation of thrombus is associated with Propagation of thrombus is associated with red cell entrapmenthelliphellipred thrombusred cell entrapmenthelliphellipred thrombus

Venus thrombi may become dislodged or Venus thrombi may become dislodged or fragment resulting in the formation of fragment resulting in the formation of circulating thrombi This may result in circulating thrombi This may result in pulmonary embolismpulmonary embolism

Venous Thrombosis

Pulmonary embolismPulmonary embolism

Presents with acute chest painPresents with acute chest pain Breathlessness with shockBreathlessness with shock Cough amp hemopysisCough amp hemopysis May be fatalMay be fatal

Venous Thrombosis symptoms

Typically presents with pain swelling Typically presents with pain swelling discoloration amp warmth in the affected areadiscoloration amp warmth in the affected area

However However

(these symptoms may be absent amp non of (these symptoms may be absent amp non of them is specific)them is specific)

Hematologic manifestationsHematologic manifestations

Cutaneous manifestationsCutaneous manifestations

Genetic Risk Factors(Familial)

11 FV- Leiden (APCR activated prot C resistance)FV- Leiden (APCR activated prot C resistance)

22 Protein C (deficiency)Protein C (deficiency)

33 Protein S (deficiency)Protein S (deficiency)

44 Antithrombin III (deficiency)Antithrombin III (deficiency)

55 Abnormal Prothrombin (PT 20210 A)Abnormal Prothrombin (PT 20210 A)

66 Sticky platelet syndromeSticky platelet syndrome

Risk FactorsmdashAcquiredRisk FactorsmdashAcquired

Advancing ageAdvancing age Prior ThrombosisPrior Thrombosis ImmobilizationImmobilization Major surgeryMajor surgery MalignancyMalignancy EstrogensEstrogens

Antiphospholipid Antiphospholipid antibody syndromeantibody syndrome

Myeloproliferative Myeloproliferative DisordersDisorders

Heparin-induced Heparin-induced thrombocytopenia thrombocytopenia (HIT)(HIT)

ProlongedProlonged air travel air travel

Risk FactorsmdashMixedUnknownRisk FactorsmdashMixedUnknown

HyperhomocysteinemiaHyperhomocysteinemia High levels of factor VIIIHigh levels of factor VIII Acquired Protein C resistance in the absence of Acquired Protein C resistance in the absence of

Factor V LeidenFactor V Leiden High levels of Factor IX XIHigh levels of Factor IX XI

11 FV- LeidenFV- Leiden

One of the most common causes for thrombophilia One of the most common causes for thrombophilia ndash 20 of clinical disease (AT PC and PS ndash 5) + ndash 20 of clinical disease (AT PC and PS ndash 5) + risk factorrisk factor

Activated PC inhibits F Va and F VIIIaActivated PC inhibits F Va and F VIIIa Inability of APC to inhibit the above complex due Inability of APC to inhibit the above complex due

to mutated FVto mutated FV Heterozygous 5-10 times increased risk for TEHeterozygous 5-10 times increased risk for TE Homozygous 50-100 timesHomozygous 50-100 times

Factor Va

Arg 306 Arg 506 Arg 1765

Arginine CGA

Glutamine CAA

Factor Va resistant to APC cleavage

Factor V Leiden

Relative Risk forVenous Thrombosis

Factor V Leiden Heterozygote x 7

Factor V Leiden Homozygote x 80

Oral Contraceptives x 3

Oral Contraceptives + Factor V Leiden x 35

Leiden Study Group Data

22 Protein C DeficiencyProtein C Deficiency

Common cause (increasing TE with age)Common cause (increasing TE with age) Needs TM from endothelium wallNeeds TM from endothelium wall Heterozygous 50 of level of normal Heterozygous 50 of level of normal

individualsindividuals Homozygous babies are born with Homozygous babies are born with

undetected levels (thrombi in microvascular undetected levels (thrombi in microvascular of skin DIC necrosis purpura of skin DIC necrosis purpura fulminans)fulminans)

33 Protein S DeficiencyProtein S Deficiency

Non-enzymatic co-factor for PCNon-enzymatic co-factor for PC Binds to TM-PCBinds to TM-PC Same properties as PCSame properties as PC Two forms free in plasma and bound to C4b Two forms free in plasma and bound to C4b

binding protein (60) Only free fraction binding protein (60) Only free fraction functions as co-factor for APCfunctions as co-factor for APC

Sometimes difficult to get accurate measures of Sometimes difficult to get accurate measures of PS because of the latterPS because of the latter

Like PC can be acquired liver disease Warfarin Like PC can be acquired liver disease Warfarin pregnancy cancer DIC and chemopregnancy cancer DIC and chemo

44 Antithrombin III DeficiencyAntithrombin III Deficiency

Common cause (incidence 12000 ndash 15000 Common cause (incidence 12000 ndash 15000 heterozygotes 50 DVT) Quantitative vs heterozygotes 50 DVT) Quantitative vs Qualitative disorder (Acquired DIC cirrhosis Qualitative disorder (Acquired DIC cirrhosis NS)NS)

Bind to and inactivate thrombin Factors IXa Xa Bind to and inactivate thrombin Factors IXa Xa XIa and XIIa (ATheparin complex - rate of XIa and XIIa (ATheparin complex - rate of inhibition 1000-fold increased)inhibition 1000-fold increased)

Not necessarily a risk factor to be involved in Not necessarily a risk factor to be involved in heterozygotes to give TEheterozygotes to give TE

Increased incidence with ageing 80 at 55 yearsIncreased incidence with ageing 80 at 55 years

55 Abnormal ProthrombinAbnormal Prothrombin (PT 20210 A) (PT 20210 A)

CommonCommon Increased levels of prothrombin enhanced Increased levels of prothrombin enhanced

thrombin formationthrombin formation Only way for diagnosis DNA-PCR Only way for diagnosis DNA-PCR

techniquetechnique

66 Sticky Platelet SyndromeSticky Platelet Syndrome

Especially in arterial thrombosis (MI) and Especially in arterial thrombosis (MI) and development of recurrent TE while on Warfarindevelopment of recurrent TE while on Warfarin

3 Forms3 Forms If on aspirin it should be stopped 14 days prior to If on aspirin it should be stopped 14 days prior to

testingtesting

Also rememberAlso remember

PC PS and AT III are inhibitors of clottingPC PS and AT III are inhibitors of clotting

Non-familial (Acquired)Non-familial (Acquired)11 Antiphospholipid SyndromeAntiphospholipid Syndrome Antibodies directed against phospholipid cell membrane = Antibodies directed against phospholipid cell membrane =

APA (Antiphospholipid Ab)APA (Antiphospholipid Ab) APA ACA or LAAPA ACA or LA Primary (PAPS) or secondary (autoimmune disorders eg Primary (PAPS) or secondary (autoimmune disorders eg

SLE)SLE) ACA (Anticardiolipin Ab) IgM + IgGACA (Anticardiolipin Ab) IgM + IgG IgG the clinically important oneIgG the clinically important one IgM pregnancy infection (viral) trauma and post-opIgM pregnancy infection (viral) trauma and post-op LA (Lupus anticoagulant) Ab which affect clotting tests (LA-LA (Lupus anticoagulant) Ab which affect clotting tests (LA-

PTT RVV Kaolin)PTT RVV Kaolin) PAPS = TE miscarriage IUDPAPS = TE miscarriage IUD

Antiphospholipid Syndrome1048734 Antiphospholipid syndrome (APS) ndash Syndrome characterized by venous andor arterial thrombosis thrombocytopenia or recurrent fetal loss associated with antibodies to phospho-lipid- protein Complexes

1048734 Antiphospholipid antibodies (aPL)ndash IgG IgM or IgA antibodies that are directed to target proteins such as cardiolipin beta2-Glycoprotein I (β2GPI)or Prothrombin all of which bind to phospholipidsndash Lupus anticoagulant (LA) bull Antiphospholipid antibodies identified by in vitro phospholipid dependent clot-based assays antibodies are targeted against Prothrombin or β2GPI and prolong clotting times

Antiphospholipd Antibodies

Lupus Anticoagulant

Conditions where screening for APS Conditions where screening for APS is indicatedis indicated

The first thrombotic event below the age of 40The first thrombotic event below the age of 40 History of recurrent TEDHistory of recurrent TED Recurrent fetal loss in the 1Recurrent fetal loss in the 1stst or the 2 or the 2ndnd trimester trimester Patient with SLEPatient with SLE Pre-hormone replacement therapyPre-hormone replacement therapy

Non-familial (Acquired) continuedNon-familial (Acquired) continued

22 TPA (Tissue Plasminogen Activator) TPA (Tissue Plasminogen Activator) decreased levels impaired fibrinolysisdecreased levels impaired fibrinolysis

33 PAI (Plasminogen Activator Inhibitor) PAI (Plasminogen Activator Inhibitor) increased levels decreased TPAincreased levels decreased TPA

44 DysfibrinogenemiaDysfibrinogenemia55 F XII deficiency Hageman factorF XII deficiency Hageman factor66 Fibrinogen (increased)Fibrinogen (increased)77 F VIII (increased)F VIII (increased)88 PlasminogenPlasminogen99 Hyperhomocyteinemia ndash enzyme (folate)Hyperhomocyteinemia ndash enzyme (folate)

Investigation (Thrombotic Profile)Investigation (Thrombotic Profile)

NB Patients can be on Warfarin but not HeparinNB Patients can be on Warfarin but not Heparin FBC PLT amp ESRFBC PLT amp ESR PT aPTT TT amp FibrinogenPT aPTT TT amp Fibrinogen PC amp PSPC amp PS AT IIIAT III APCR (if + screening submit for PCR)APCR (if + screening submit for PCR) PT 20210A (PCR)PT 20210A (PCR) Lupus anticoagulant (RVVT KT LA-PTT) Lupus anticoagulant (RVVT KT LA-PTT) Cardiolipin antibodies (antiphospholipid syndrome)Cardiolipin antibodies (antiphospholipid syndrome) Sticky platelet syndrome (aspirin)Sticky platelet syndrome (aspirin) ANA screeningANA screening PNH screeningPNH screening

When to testWhen to test Younger lt 50 years recurrent TE unusual sites Younger lt 50 years recurrent TE unusual sites

TE on WarfarinTE on Warfarin Not ideal to test after acute episode (inhibitors of Not ideal to test after acute episode (inhibitors of

clotting may be low)clotting may be low) Ideal test after 6 weeks after settlement of Ideal test after 6 weeks after settlement of

hemostasishemostasis Most patients are on Warfarin then (PC amp PS are Most patients are on Warfarin then (PC amp PS are

Vit K dependent may be falsely low)Vit K dependent may be falsely low) My view if long-term Warfarin is planned do My view if long-term Warfarin is planned do

immediately according to duration of treatment it immediately according to duration of treatment it can be done after cessation of treatmentcan be done after cessation of treatment

When to test (continued)When to test (continued)

Practical (my experience) before treatment ndash if AT Practical (my experience) before treatment ndash if AT PS PC are low PS PC are low repeat after Rx has been stopped repeat after Rx has been stopped

SPS platelet aggregation studies (problem SPS platelet aggregation studies (problem sometimes aspirin cannot be stopped)sometimes aspirin cannot be stopped)

Remember the effect of the vessel wall on clotting Remember the effect of the vessel wall on clotting especially in arterial thrombosisespecially in arterial thrombosis

Every woman on contraception HRTEvery woman on contraception HRT

Arterial ThrombosisArterial Thrombosis

Arterial Thrombosis

Arterial ThrombosisArterial Thrombosis

Results as sever oResults as sever o2 2 starvation of the left starvation of the left ventricle of the heartventricle of the heart

This leads to myocardial ischemia amp may This leads to myocardial ischemia amp may progress to myocardial infarction or progress to myocardial infarction or ischemic left ventricular fibrillation amp ischemic left ventricular fibrillation amp sudden deathsudden death

Similar episodes involving the cerebral Similar episodes involving the cerebral circulation result in transient ischemic circulation result in transient ischemic attacks amp thrombotic stroke attacks amp thrombotic stroke

Myocardial Infarction SymptomMyocardial Infarction Symptom

Crushing tightness of the chest with Crushing tightness of the chest with sweating nausea breathlessness amp sweating nausea breathlessness amp collapsecollapse

Chest pain may radiates to the arm throat amp Chest pain may radiates to the arm throat amp jawjaw

Chest pain may confused with sever Chest pain may confused with sever indigestion in itrsquos early stagesindigestion in itrsquos early stages

Transient Ischemic attacksTransient Ischemic attacks

Itrsquos usually accompanied with neurological Itrsquos usually accompanied with neurological dysfunction or loss of visiondysfunction or loss of vision

Completed thrombotic strokeCompleted thrombotic stroke

Itrsquos accompanied by similar symptoms Itrsquos accompanied by similar symptoms which persist for more than 24 hours that which persist for more than 24 hours that may be severely amp permanently disablingmay be severely amp permanently disabling

Risk factors for arterial amp venous thrombosisRisk factors for arterial amp venous thrombosis

Venous thrombosisVenous thrombosisArterial thrombosisArterial thrombosisIncreasing ageIncreasing ageIncreasing ageIncreasing age

ObesityObesityObesityObesity

ImmobilityImmobilityLack of exerciseLack of exercise

Pregnancy rdquopost partomrdquoPregnancy rdquopost partomrdquoHigh fat low fiber dietHigh fat low fiber diet

MalignancyMalignancySmokingSmoking

Lupus anticoagulantLupus anticoagulantHyperlipidemiaHyperlipidemia

Nephrotic syndromeNephrotic syndromeHypertensionHypertension

PolycythemiaPolycythemiaElevated factor VII II concElevated factor VII II conc

goutgoutGenetic factorGenetic factor

Prophylaxis amp treatment of Prophylaxis amp treatment of thrombosisthrombosis

Prevent the risk factorsPrevent the risk factors SmokingSmoking ObesityObesity Lack of exerciseLack of exercise Poor dietPoor diet

Only when this proves to be impossibleOnly when this proves to be impossible

(Pharmacological intervention is required) (Pharmacological intervention is required)

The most common is (DVT) deep venous The most common is (DVT) deep venous thrombosis of the lower limbs The main thrombosis of the lower limbs The main site where there is maximum stasis and low site where there is maximum stasis and low blood flow blood flow

Propagation of thrombus is associated with Propagation of thrombus is associated with red cell entrapmenthelliphellipred thrombusred cell entrapmenthelliphellipred thrombus

Venus thrombi may become dislodged or Venus thrombi may become dislodged or fragment resulting in the formation of fragment resulting in the formation of circulating thrombi This may result in circulating thrombi This may result in pulmonary embolismpulmonary embolism

Venous Thrombosis

Pulmonary embolismPulmonary embolism

Presents with acute chest painPresents with acute chest pain Breathlessness with shockBreathlessness with shock Cough amp hemopysisCough amp hemopysis May be fatalMay be fatal

Venous Thrombosis symptoms

Typically presents with pain swelling Typically presents with pain swelling discoloration amp warmth in the affected areadiscoloration amp warmth in the affected area

However However

(these symptoms may be absent amp non of (these symptoms may be absent amp non of them is specific)them is specific)

Hematologic manifestationsHematologic manifestations

Cutaneous manifestationsCutaneous manifestations

Genetic Risk Factors(Familial)

11 FV- Leiden (APCR activated prot C resistance)FV- Leiden (APCR activated prot C resistance)

22 Protein C (deficiency)Protein C (deficiency)

33 Protein S (deficiency)Protein S (deficiency)

44 Antithrombin III (deficiency)Antithrombin III (deficiency)

55 Abnormal Prothrombin (PT 20210 A)Abnormal Prothrombin (PT 20210 A)

66 Sticky platelet syndromeSticky platelet syndrome

Risk FactorsmdashAcquiredRisk FactorsmdashAcquired

Advancing ageAdvancing age Prior ThrombosisPrior Thrombosis ImmobilizationImmobilization Major surgeryMajor surgery MalignancyMalignancy EstrogensEstrogens

Antiphospholipid Antiphospholipid antibody syndromeantibody syndrome

Myeloproliferative Myeloproliferative DisordersDisorders

Heparin-induced Heparin-induced thrombocytopenia thrombocytopenia (HIT)(HIT)

ProlongedProlonged air travel air travel

Risk FactorsmdashMixedUnknownRisk FactorsmdashMixedUnknown

HyperhomocysteinemiaHyperhomocysteinemia High levels of factor VIIIHigh levels of factor VIII Acquired Protein C resistance in the absence of Acquired Protein C resistance in the absence of

Factor V LeidenFactor V Leiden High levels of Factor IX XIHigh levels of Factor IX XI

11 FV- LeidenFV- Leiden

One of the most common causes for thrombophilia One of the most common causes for thrombophilia ndash 20 of clinical disease (AT PC and PS ndash 5) + ndash 20 of clinical disease (AT PC and PS ndash 5) + risk factorrisk factor

Activated PC inhibits F Va and F VIIIaActivated PC inhibits F Va and F VIIIa Inability of APC to inhibit the above complex due Inability of APC to inhibit the above complex due

to mutated FVto mutated FV Heterozygous 5-10 times increased risk for TEHeterozygous 5-10 times increased risk for TE Homozygous 50-100 timesHomozygous 50-100 times

Factor Va

Arg 306 Arg 506 Arg 1765

Arginine CGA

Glutamine CAA

Factor Va resistant to APC cleavage

Factor V Leiden

Relative Risk forVenous Thrombosis

Factor V Leiden Heterozygote x 7

Factor V Leiden Homozygote x 80

Oral Contraceptives x 3

Oral Contraceptives + Factor V Leiden x 35

Leiden Study Group Data

22 Protein C DeficiencyProtein C Deficiency

Common cause (increasing TE with age)Common cause (increasing TE with age) Needs TM from endothelium wallNeeds TM from endothelium wall Heterozygous 50 of level of normal Heterozygous 50 of level of normal

individualsindividuals Homozygous babies are born with Homozygous babies are born with

undetected levels (thrombi in microvascular undetected levels (thrombi in microvascular of skin DIC necrosis purpura of skin DIC necrosis purpura fulminans)fulminans)

33 Protein S DeficiencyProtein S Deficiency

Non-enzymatic co-factor for PCNon-enzymatic co-factor for PC Binds to TM-PCBinds to TM-PC Same properties as PCSame properties as PC Two forms free in plasma and bound to C4b Two forms free in plasma and bound to C4b

binding protein (60) Only free fraction binding protein (60) Only free fraction functions as co-factor for APCfunctions as co-factor for APC

Sometimes difficult to get accurate measures of Sometimes difficult to get accurate measures of PS because of the latterPS because of the latter

Like PC can be acquired liver disease Warfarin Like PC can be acquired liver disease Warfarin pregnancy cancer DIC and chemopregnancy cancer DIC and chemo

44 Antithrombin III DeficiencyAntithrombin III Deficiency

Common cause (incidence 12000 ndash 15000 Common cause (incidence 12000 ndash 15000 heterozygotes 50 DVT) Quantitative vs heterozygotes 50 DVT) Quantitative vs Qualitative disorder (Acquired DIC cirrhosis Qualitative disorder (Acquired DIC cirrhosis NS)NS)

Bind to and inactivate thrombin Factors IXa Xa Bind to and inactivate thrombin Factors IXa Xa XIa and XIIa (ATheparin complex - rate of XIa and XIIa (ATheparin complex - rate of inhibition 1000-fold increased)inhibition 1000-fold increased)

Not necessarily a risk factor to be involved in Not necessarily a risk factor to be involved in heterozygotes to give TEheterozygotes to give TE

Increased incidence with ageing 80 at 55 yearsIncreased incidence with ageing 80 at 55 years

55 Abnormal ProthrombinAbnormal Prothrombin (PT 20210 A) (PT 20210 A)

CommonCommon Increased levels of prothrombin enhanced Increased levels of prothrombin enhanced

thrombin formationthrombin formation Only way for diagnosis DNA-PCR Only way for diagnosis DNA-PCR

techniquetechnique

66 Sticky Platelet SyndromeSticky Platelet Syndrome

Especially in arterial thrombosis (MI) and Especially in arterial thrombosis (MI) and development of recurrent TE while on Warfarindevelopment of recurrent TE while on Warfarin

3 Forms3 Forms If on aspirin it should be stopped 14 days prior to If on aspirin it should be stopped 14 days prior to

testingtesting

Also rememberAlso remember

PC PS and AT III are inhibitors of clottingPC PS and AT III are inhibitors of clotting

Non-familial (Acquired)Non-familial (Acquired)11 Antiphospholipid SyndromeAntiphospholipid Syndrome Antibodies directed against phospholipid cell membrane = Antibodies directed against phospholipid cell membrane =

APA (Antiphospholipid Ab)APA (Antiphospholipid Ab) APA ACA or LAAPA ACA or LA Primary (PAPS) or secondary (autoimmune disorders eg Primary (PAPS) or secondary (autoimmune disorders eg

SLE)SLE) ACA (Anticardiolipin Ab) IgM + IgGACA (Anticardiolipin Ab) IgM + IgG IgG the clinically important oneIgG the clinically important one IgM pregnancy infection (viral) trauma and post-opIgM pregnancy infection (viral) trauma and post-op LA (Lupus anticoagulant) Ab which affect clotting tests (LA-LA (Lupus anticoagulant) Ab which affect clotting tests (LA-

PTT RVV Kaolin)PTT RVV Kaolin) PAPS = TE miscarriage IUDPAPS = TE miscarriage IUD

Antiphospholipid Syndrome1048734 Antiphospholipid syndrome (APS) ndash Syndrome characterized by venous andor arterial thrombosis thrombocytopenia or recurrent fetal loss associated with antibodies to phospho-lipid- protein Complexes

1048734 Antiphospholipid antibodies (aPL)ndash IgG IgM or IgA antibodies that are directed to target proteins such as cardiolipin beta2-Glycoprotein I (β2GPI)or Prothrombin all of which bind to phospholipidsndash Lupus anticoagulant (LA) bull Antiphospholipid antibodies identified by in vitro phospholipid dependent clot-based assays antibodies are targeted against Prothrombin or β2GPI and prolong clotting times

Antiphospholipd Antibodies

Lupus Anticoagulant

Conditions where screening for APS Conditions where screening for APS is indicatedis indicated

The first thrombotic event below the age of 40The first thrombotic event below the age of 40 History of recurrent TEDHistory of recurrent TED Recurrent fetal loss in the 1Recurrent fetal loss in the 1stst or the 2 or the 2ndnd trimester trimester Patient with SLEPatient with SLE Pre-hormone replacement therapyPre-hormone replacement therapy

Non-familial (Acquired) continuedNon-familial (Acquired) continued

22 TPA (Tissue Plasminogen Activator) TPA (Tissue Plasminogen Activator) decreased levels impaired fibrinolysisdecreased levels impaired fibrinolysis

33 PAI (Plasminogen Activator Inhibitor) PAI (Plasminogen Activator Inhibitor) increased levels decreased TPAincreased levels decreased TPA

44 DysfibrinogenemiaDysfibrinogenemia55 F XII deficiency Hageman factorF XII deficiency Hageman factor66 Fibrinogen (increased)Fibrinogen (increased)77 F VIII (increased)F VIII (increased)88 PlasminogenPlasminogen99 Hyperhomocyteinemia ndash enzyme (folate)Hyperhomocyteinemia ndash enzyme (folate)

Investigation (Thrombotic Profile)Investigation (Thrombotic Profile)

NB Patients can be on Warfarin but not HeparinNB Patients can be on Warfarin but not Heparin FBC PLT amp ESRFBC PLT amp ESR PT aPTT TT amp FibrinogenPT aPTT TT amp Fibrinogen PC amp PSPC amp PS AT IIIAT III APCR (if + screening submit for PCR)APCR (if + screening submit for PCR) PT 20210A (PCR)PT 20210A (PCR) Lupus anticoagulant (RVVT KT LA-PTT) Lupus anticoagulant (RVVT KT LA-PTT) Cardiolipin antibodies (antiphospholipid syndrome)Cardiolipin antibodies (antiphospholipid syndrome) Sticky platelet syndrome (aspirin)Sticky platelet syndrome (aspirin) ANA screeningANA screening PNH screeningPNH screening

When to testWhen to test Younger lt 50 years recurrent TE unusual sites Younger lt 50 years recurrent TE unusual sites

TE on WarfarinTE on Warfarin Not ideal to test after acute episode (inhibitors of Not ideal to test after acute episode (inhibitors of

clotting may be low)clotting may be low) Ideal test after 6 weeks after settlement of Ideal test after 6 weeks after settlement of

hemostasishemostasis Most patients are on Warfarin then (PC amp PS are Most patients are on Warfarin then (PC amp PS are

Vit K dependent may be falsely low)Vit K dependent may be falsely low) My view if long-term Warfarin is planned do My view if long-term Warfarin is planned do

immediately according to duration of treatment it immediately according to duration of treatment it can be done after cessation of treatmentcan be done after cessation of treatment

When to test (continued)When to test (continued)

Practical (my experience) before treatment ndash if AT Practical (my experience) before treatment ndash if AT PS PC are low PS PC are low repeat after Rx has been stopped repeat after Rx has been stopped

SPS platelet aggregation studies (problem SPS platelet aggregation studies (problem sometimes aspirin cannot be stopped)sometimes aspirin cannot be stopped)

Remember the effect of the vessel wall on clotting Remember the effect of the vessel wall on clotting especially in arterial thrombosisespecially in arterial thrombosis

Every woman on contraception HRTEvery woman on contraception HRT

Arterial ThrombosisArterial Thrombosis

Arterial Thrombosis

Arterial ThrombosisArterial Thrombosis

Results as sever oResults as sever o2 2 starvation of the left starvation of the left ventricle of the heartventricle of the heart

This leads to myocardial ischemia amp may This leads to myocardial ischemia amp may progress to myocardial infarction or progress to myocardial infarction or ischemic left ventricular fibrillation amp ischemic left ventricular fibrillation amp sudden deathsudden death

Similar episodes involving the cerebral Similar episodes involving the cerebral circulation result in transient ischemic circulation result in transient ischemic attacks amp thrombotic stroke attacks amp thrombotic stroke

Myocardial Infarction SymptomMyocardial Infarction Symptom

Crushing tightness of the chest with Crushing tightness of the chest with sweating nausea breathlessness amp sweating nausea breathlessness amp collapsecollapse

Chest pain may radiates to the arm throat amp Chest pain may radiates to the arm throat amp jawjaw

Chest pain may confused with sever Chest pain may confused with sever indigestion in itrsquos early stagesindigestion in itrsquos early stages

Transient Ischemic attacksTransient Ischemic attacks

Itrsquos usually accompanied with neurological Itrsquos usually accompanied with neurological dysfunction or loss of visiondysfunction or loss of vision

Completed thrombotic strokeCompleted thrombotic stroke

Itrsquos accompanied by similar symptoms Itrsquos accompanied by similar symptoms which persist for more than 24 hours that which persist for more than 24 hours that may be severely amp permanently disablingmay be severely amp permanently disabling

Risk factors for arterial amp venous thrombosisRisk factors for arterial amp venous thrombosis

Venous thrombosisVenous thrombosisArterial thrombosisArterial thrombosisIncreasing ageIncreasing ageIncreasing ageIncreasing age

ObesityObesityObesityObesity

ImmobilityImmobilityLack of exerciseLack of exercise

Pregnancy rdquopost partomrdquoPregnancy rdquopost partomrdquoHigh fat low fiber dietHigh fat low fiber diet

MalignancyMalignancySmokingSmoking

Lupus anticoagulantLupus anticoagulantHyperlipidemiaHyperlipidemia

Nephrotic syndromeNephrotic syndromeHypertensionHypertension

PolycythemiaPolycythemiaElevated factor VII II concElevated factor VII II conc

goutgoutGenetic factorGenetic factor

Prophylaxis amp treatment of Prophylaxis amp treatment of thrombosisthrombosis

Prevent the risk factorsPrevent the risk factors SmokingSmoking ObesityObesity Lack of exerciseLack of exercise Poor dietPoor diet

Only when this proves to be impossibleOnly when this proves to be impossible

(Pharmacological intervention is required) (Pharmacological intervention is required)

Pulmonary embolismPulmonary embolism

Presents with acute chest painPresents with acute chest pain Breathlessness with shockBreathlessness with shock Cough amp hemopysisCough amp hemopysis May be fatalMay be fatal

Venous Thrombosis symptoms

Typically presents with pain swelling Typically presents with pain swelling discoloration amp warmth in the affected areadiscoloration amp warmth in the affected area

However However

(these symptoms may be absent amp non of (these symptoms may be absent amp non of them is specific)them is specific)

Hematologic manifestationsHematologic manifestations

Cutaneous manifestationsCutaneous manifestations

Genetic Risk Factors(Familial)

11 FV- Leiden (APCR activated prot C resistance)FV- Leiden (APCR activated prot C resistance)

22 Protein C (deficiency)Protein C (deficiency)

33 Protein S (deficiency)Protein S (deficiency)

44 Antithrombin III (deficiency)Antithrombin III (deficiency)

55 Abnormal Prothrombin (PT 20210 A)Abnormal Prothrombin (PT 20210 A)

66 Sticky platelet syndromeSticky platelet syndrome

Risk FactorsmdashAcquiredRisk FactorsmdashAcquired

Advancing ageAdvancing age Prior ThrombosisPrior Thrombosis ImmobilizationImmobilization Major surgeryMajor surgery MalignancyMalignancy EstrogensEstrogens

Antiphospholipid Antiphospholipid antibody syndromeantibody syndrome

Myeloproliferative Myeloproliferative DisordersDisorders

Heparin-induced Heparin-induced thrombocytopenia thrombocytopenia (HIT)(HIT)

ProlongedProlonged air travel air travel

Risk FactorsmdashMixedUnknownRisk FactorsmdashMixedUnknown

HyperhomocysteinemiaHyperhomocysteinemia High levels of factor VIIIHigh levels of factor VIII Acquired Protein C resistance in the absence of Acquired Protein C resistance in the absence of

Factor V LeidenFactor V Leiden High levels of Factor IX XIHigh levels of Factor IX XI

11 FV- LeidenFV- Leiden

One of the most common causes for thrombophilia One of the most common causes for thrombophilia ndash 20 of clinical disease (AT PC and PS ndash 5) + ndash 20 of clinical disease (AT PC and PS ndash 5) + risk factorrisk factor

Activated PC inhibits F Va and F VIIIaActivated PC inhibits F Va and F VIIIa Inability of APC to inhibit the above complex due Inability of APC to inhibit the above complex due

to mutated FVto mutated FV Heterozygous 5-10 times increased risk for TEHeterozygous 5-10 times increased risk for TE Homozygous 50-100 timesHomozygous 50-100 times

Factor Va

Arg 306 Arg 506 Arg 1765

Arginine CGA

Glutamine CAA

Factor Va resistant to APC cleavage

Factor V Leiden

Relative Risk forVenous Thrombosis

Factor V Leiden Heterozygote x 7

Factor V Leiden Homozygote x 80

Oral Contraceptives x 3

Oral Contraceptives + Factor V Leiden x 35

Leiden Study Group Data

22 Protein C DeficiencyProtein C Deficiency

Common cause (increasing TE with age)Common cause (increasing TE with age) Needs TM from endothelium wallNeeds TM from endothelium wall Heterozygous 50 of level of normal Heterozygous 50 of level of normal

individualsindividuals Homozygous babies are born with Homozygous babies are born with

undetected levels (thrombi in microvascular undetected levels (thrombi in microvascular of skin DIC necrosis purpura of skin DIC necrosis purpura fulminans)fulminans)

33 Protein S DeficiencyProtein S Deficiency

Non-enzymatic co-factor for PCNon-enzymatic co-factor for PC Binds to TM-PCBinds to TM-PC Same properties as PCSame properties as PC Two forms free in plasma and bound to C4b Two forms free in plasma and bound to C4b

binding protein (60) Only free fraction binding protein (60) Only free fraction functions as co-factor for APCfunctions as co-factor for APC

Sometimes difficult to get accurate measures of Sometimes difficult to get accurate measures of PS because of the latterPS because of the latter

Like PC can be acquired liver disease Warfarin Like PC can be acquired liver disease Warfarin pregnancy cancer DIC and chemopregnancy cancer DIC and chemo

44 Antithrombin III DeficiencyAntithrombin III Deficiency

Common cause (incidence 12000 ndash 15000 Common cause (incidence 12000 ndash 15000 heterozygotes 50 DVT) Quantitative vs heterozygotes 50 DVT) Quantitative vs Qualitative disorder (Acquired DIC cirrhosis Qualitative disorder (Acquired DIC cirrhosis NS)NS)

Bind to and inactivate thrombin Factors IXa Xa Bind to and inactivate thrombin Factors IXa Xa XIa and XIIa (ATheparin complex - rate of XIa and XIIa (ATheparin complex - rate of inhibition 1000-fold increased)inhibition 1000-fold increased)

Not necessarily a risk factor to be involved in Not necessarily a risk factor to be involved in heterozygotes to give TEheterozygotes to give TE

Increased incidence with ageing 80 at 55 yearsIncreased incidence with ageing 80 at 55 years

55 Abnormal ProthrombinAbnormal Prothrombin (PT 20210 A) (PT 20210 A)

CommonCommon Increased levels of prothrombin enhanced Increased levels of prothrombin enhanced

thrombin formationthrombin formation Only way for diagnosis DNA-PCR Only way for diagnosis DNA-PCR

techniquetechnique

66 Sticky Platelet SyndromeSticky Platelet Syndrome

Especially in arterial thrombosis (MI) and Especially in arterial thrombosis (MI) and development of recurrent TE while on Warfarindevelopment of recurrent TE while on Warfarin

3 Forms3 Forms If on aspirin it should be stopped 14 days prior to If on aspirin it should be stopped 14 days prior to

testingtesting

Also rememberAlso remember

PC PS and AT III are inhibitors of clottingPC PS and AT III are inhibitors of clotting

Non-familial (Acquired)Non-familial (Acquired)11 Antiphospholipid SyndromeAntiphospholipid Syndrome Antibodies directed against phospholipid cell membrane = Antibodies directed against phospholipid cell membrane =

APA (Antiphospholipid Ab)APA (Antiphospholipid Ab) APA ACA or LAAPA ACA or LA Primary (PAPS) or secondary (autoimmune disorders eg Primary (PAPS) or secondary (autoimmune disorders eg

SLE)SLE) ACA (Anticardiolipin Ab) IgM + IgGACA (Anticardiolipin Ab) IgM + IgG IgG the clinically important oneIgG the clinically important one IgM pregnancy infection (viral) trauma and post-opIgM pregnancy infection (viral) trauma and post-op LA (Lupus anticoagulant) Ab which affect clotting tests (LA-LA (Lupus anticoagulant) Ab which affect clotting tests (LA-

PTT RVV Kaolin)PTT RVV Kaolin) PAPS = TE miscarriage IUDPAPS = TE miscarriage IUD

Antiphospholipid Syndrome1048734 Antiphospholipid syndrome (APS) ndash Syndrome characterized by venous andor arterial thrombosis thrombocytopenia or recurrent fetal loss associated with antibodies to phospho-lipid- protein Complexes

1048734 Antiphospholipid antibodies (aPL)ndash IgG IgM or IgA antibodies that are directed to target proteins such as cardiolipin beta2-Glycoprotein I (β2GPI)or Prothrombin all of which bind to phospholipidsndash Lupus anticoagulant (LA) bull Antiphospholipid antibodies identified by in vitro phospholipid dependent clot-based assays antibodies are targeted against Prothrombin or β2GPI and prolong clotting times

Antiphospholipd Antibodies

Lupus Anticoagulant

Conditions where screening for APS Conditions where screening for APS is indicatedis indicated

The first thrombotic event below the age of 40The first thrombotic event below the age of 40 History of recurrent TEDHistory of recurrent TED Recurrent fetal loss in the 1Recurrent fetal loss in the 1stst or the 2 or the 2ndnd trimester trimester Patient with SLEPatient with SLE Pre-hormone replacement therapyPre-hormone replacement therapy

Non-familial (Acquired) continuedNon-familial (Acquired) continued

22 TPA (Tissue Plasminogen Activator) TPA (Tissue Plasminogen Activator) decreased levels impaired fibrinolysisdecreased levels impaired fibrinolysis

33 PAI (Plasminogen Activator Inhibitor) PAI (Plasminogen Activator Inhibitor) increased levels decreased TPAincreased levels decreased TPA

44 DysfibrinogenemiaDysfibrinogenemia55 F XII deficiency Hageman factorF XII deficiency Hageman factor66 Fibrinogen (increased)Fibrinogen (increased)77 F VIII (increased)F VIII (increased)88 PlasminogenPlasminogen99 Hyperhomocyteinemia ndash enzyme (folate)Hyperhomocyteinemia ndash enzyme (folate)

Investigation (Thrombotic Profile)Investigation (Thrombotic Profile)

NB Patients can be on Warfarin but not HeparinNB Patients can be on Warfarin but not Heparin FBC PLT amp ESRFBC PLT amp ESR PT aPTT TT amp FibrinogenPT aPTT TT amp Fibrinogen PC amp PSPC amp PS AT IIIAT III APCR (if + screening submit for PCR)APCR (if + screening submit for PCR) PT 20210A (PCR)PT 20210A (PCR) Lupus anticoagulant (RVVT KT LA-PTT) Lupus anticoagulant (RVVT KT LA-PTT) Cardiolipin antibodies (antiphospholipid syndrome)Cardiolipin antibodies (antiphospholipid syndrome) Sticky platelet syndrome (aspirin)Sticky platelet syndrome (aspirin) ANA screeningANA screening PNH screeningPNH screening

When to testWhen to test Younger lt 50 years recurrent TE unusual sites Younger lt 50 years recurrent TE unusual sites

TE on WarfarinTE on Warfarin Not ideal to test after acute episode (inhibitors of Not ideal to test after acute episode (inhibitors of

clotting may be low)clotting may be low) Ideal test after 6 weeks after settlement of Ideal test after 6 weeks after settlement of

hemostasishemostasis Most patients are on Warfarin then (PC amp PS are Most patients are on Warfarin then (PC amp PS are

Vit K dependent may be falsely low)Vit K dependent may be falsely low) My view if long-term Warfarin is planned do My view if long-term Warfarin is planned do

immediately according to duration of treatment it immediately according to duration of treatment it can be done after cessation of treatmentcan be done after cessation of treatment

When to test (continued)When to test (continued)

Practical (my experience) before treatment ndash if AT Practical (my experience) before treatment ndash if AT PS PC are low PS PC are low repeat after Rx has been stopped repeat after Rx has been stopped

SPS platelet aggregation studies (problem SPS platelet aggregation studies (problem sometimes aspirin cannot be stopped)sometimes aspirin cannot be stopped)

Remember the effect of the vessel wall on clotting Remember the effect of the vessel wall on clotting especially in arterial thrombosisespecially in arterial thrombosis

Every woman on contraception HRTEvery woman on contraception HRT

Arterial ThrombosisArterial Thrombosis

Arterial Thrombosis

Arterial ThrombosisArterial Thrombosis

Results as sever oResults as sever o2 2 starvation of the left starvation of the left ventricle of the heartventricle of the heart

This leads to myocardial ischemia amp may This leads to myocardial ischemia amp may progress to myocardial infarction or progress to myocardial infarction or ischemic left ventricular fibrillation amp ischemic left ventricular fibrillation amp sudden deathsudden death

Similar episodes involving the cerebral Similar episodes involving the cerebral circulation result in transient ischemic circulation result in transient ischemic attacks amp thrombotic stroke attacks amp thrombotic stroke

Myocardial Infarction SymptomMyocardial Infarction Symptom

Crushing tightness of the chest with Crushing tightness of the chest with sweating nausea breathlessness amp sweating nausea breathlessness amp collapsecollapse

Chest pain may radiates to the arm throat amp Chest pain may radiates to the arm throat amp jawjaw

Chest pain may confused with sever Chest pain may confused with sever indigestion in itrsquos early stagesindigestion in itrsquos early stages

Transient Ischemic attacksTransient Ischemic attacks

Itrsquos usually accompanied with neurological Itrsquos usually accompanied with neurological dysfunction or loss of visiondysfunction or loss of vision

Completed thrombotic strokeCompleted thrombotic stroke

Itrsquos accompanied by similar symptoms Itrsquos accompanied by similar symptoms which persist for more than 24 hours that which persist for more than 24 hours that may be severely amp permanently disablingmay be severely amp permanently disabling

Risk factors for arterial amp venous thrombosisRisk factors for arterial amp venous thrombosis

Venous thrombosisVenous thrombosisArterial thrombosisArterial thrombosisIncreasing ageIncreasing ageIncreasing ageIncreasing age

ObesityObesityObesityObesity

ImmobilityImmobilityLack of exerciseLack of exercise

Pregnancy rdquopost partomrdquoPregnancy rdquopost partomrdquoHigh fat low fiber dietHigh fat low fiber diet

MalignancyMalignancySmokingSmoking

Lupus anticoagulantLupus anticoagulantHyperlipidemiaHyperlipidemia

Nephrotic syndromeNephrotic syndromeHypertensionHypertension

PolycythemiaPolycythemiaElevated factor VII II concElevated factor VII II conc

goutgoutGenetic factorGenetic factor

Prophylaxis amp treatment of Prophylaxis amp treatment of thrombosisthrombosis

Prevent the risk factorsPrevent the risk factors SmokingSmoking ObesityObesity Lack of exerciseLack of exercise Poor dietPoor diet

Only when this proves to be impossibleOnly when this proves to be impossible

(Pharmacological intervention is required) (Pharmacological intervention is required)

Venous Thrombosis symptoms

Typically presents with pain swelling Typically presents with pain swelling discoloration amp warmth in the affected areadiscoloration amp warmth in the affected area

However However

(these symptoms may be absent amp non of (these symptoms may be absent amp non of them is specific)them is specific)

Hematologic manifestationsHematologic manifestations

Cutaneous manifestationsCutaneous manifestations

Genetic Risk Factors(Familial)

11 FV- Leiden (APCR activated prot C resistance)FV- Leiden (APCR activated prot C resistance)

22 Protein C (deficiency)Protein C (deficiency)

33 Protein S (deficiency)Protein S (deficiency)

44 Antithrombin III (deficiency)Antithrombin III (deficiency)

55 Abnormal Prothrombin (PT 20210 A)Abnormal Prothrombin (PT 20210 A)

66 Sticky platelet syndromeSticky platelet syndrome

Risk FactorsmdashAcquiredRisk FactorsmdashAcquired

Advancing ageAdvancing age Prior ThrombosisPrior Thrombosis ImmobilizationImmobilization Major surgeryMajor surgery MalignancyMalignancy EstrogensEstrogens

Antiphospholipid Antiphospholipid antibody syndromeantibody syndrome

Myeloproliferative Myeloproliferative DisordersDisorders

Heparin-induced Heparin-induced thrombocytopenia thrombocytopenia (HIT)(HIT)

ProlongedProlonged air travel air travel

Risk FactorsmdashMixedUnknownRisk FactorsmdashMixedUnknown

HyperhomocysteinemiaHyperhomocysteinemia High levels of factor VIIIHigh levels of factor VIII Acquired Protein C resistance in the absence of Acquired Protein C resistance in the absence of

Factor V LeidenFactor V Leiden High levels of Factor IX XIHigh levels of Factor IX XI

11 FV- LeidenFV- Leiden

One of the most common causes for thrombophilia One of the most common causes for thrombophilia ndash 20 of clinical disease (AT PC and PS ndash 5) + ndash 20 of clinical disease (AT PC and PS ndash 5) + risk factorrisk factor

Activated PC inhibits F Va and F VIIIaActivated PC inhibits F Va and F VIIIa Inability of APC to inhibit the above complex due Inability of APC to inhibit the above complex due

to mutated FVto mutated FV Heterozygous 5-10 times increased risk for TEHeterozygous 5-10 times increased risk for TE Homozygous 50-100 timesHomozygous 50-100 times

Factor Va

Arg 306 Arg 506 Arg 1765

Arginine CGA

Glutamine CAA

Factor Va resistant to APC cleavage

Factor V Leiden

Relative Risk forVenous Thrombosis

Factor V Leiden Heterozygote x 7

Factor V Leiden Homozygote x 80

Oral Contraceptives x 3

Oral Contraceptives + Factor V Leiden x 35

Leiden Study Group Data

22 Protein C DeficiencyProtein C Deficiency

Common cause (increasing TE with age)Common cause (increasing TE with age) Needs TM from endothelium wallNeeds TM from endothelium wall Heterozygous 50 of level of normal Heterozygous 50 of level of normal

individualsindividuals Homozygous babies are born with Homozygous babies are born with

undetected levels (thrombi in microvascular undetected levels (thrombi in microvascular of skin DIC necrosis purpura of skin DIC necrosis purpura fulminans)fulminans)

33 Protein S DeficiencyProtein S Deficiency

Non-enzymatic co-factor for PCNon-enzymatic co-factor for PC Binds to TM-PCBinds to TM-PC Same properties as PCSame properties as PC Two forms free in plasma and bound to C4b Two forms free in plasma and bound to C4b

binding protein (60) Only free fraction binding protein (60) Only free fraction functions as co-factor for APCfunctions as co-factor for APC

Sometimes difficult to get accurate measures of Sometimes difficult to get accurate measures of PS because of the latterPS because of the latter

Like PC can be acquired liver disease Warfarin Like PC can be acquired liver disease Warfarin pregnancy cancer DIC and chemopregnancy cancer DIC and chemo

44 Antithrombin III DeficiencyAntithrombin III Deficiency

Common cause (incidence 12000 ndash 15000 Common cause (incidence 12000 ndash 15000 heterozygotes 50 DVT) Quantitative vs heterozygotes 50 DVT) Quantitative vs Qualitative disorder (Acquired DIC cirrhosis Qualitative disorder (Acquired DIC cirrhosis NS)NS)

Bind to and inactivate thrombin Factors IXa Xa Bind to and inactivate thrombin Factors IXa Xa XIa and XIIa (ATheparin complex - rate of XIa and XIIa (ATheparin complex - rate of inhibition 1000-fold increased)inhibition 1000-fold increased)

Not necessarily a risk factor to be involved in Not necessarily a risk factor to be involved in heterozygotes to give TEheterozygotes to give TE

Increased incidence with ageing 80 at 55 yearsIncreased incidence with ageing 80 at 55 years

55 Abnormal ProthrombinAbnormal Prothrombin (PT 20210 A) (PT 20210 A)

CommonCommon Increased levels of prothrombin enhanced Increased levels of prothrombin enhanced

thrombin formationthrombin formation Only way for diagnosis DNA-PCR Only way for diagnosis DNA-PCR

techniquetechnique

66 Sticky Platelet SyndromeSticky Platelet Syndrome

Especially in arterial thrombosis (MI) and Especially in arterial thrombosis (MI) and development of recurrent TE while on Warfarindevelopment of recurrent TE while on Warfarin

3 Forms3 Forms If on aspirin it should be stopped 14 days prior to If on aspirin it should be stopped 14 days prior to

testingtesting

Also rememberAlso remember

PC PS and AT III are inhibitors of clottingPC PS and AT III are inhibitors of clotting

Non-familial (Acquired)Non-familial (Acquired)11 Antiphospholipid SyndromeAntiphospholipid Syndrome Antibodies directed against phospholipid cell membrane = Antibodies directed against phospholipid cell membrane =

APA (Antiphospholipid Ab)APA (Antiphospholipid Ab) APA ACA or LAAPA ACA or LA Primary (PAPS) or secondary (autoimmune disorders eg Primary (PAPS) or secondary (autoimmune disorders eg

SLE)SLE) ACA (Anticardiolipin Ab) IgM + IgGACA (Anticardiolipin Ab) IgM + IgG IgG the clinically important oneIgG the clinically important one IgM pregnancy infection (viral) trauma and post-opIgM pregnancy infection (viral) trauma and post-op LA (Lupus anticoagulant) Ab which affect clotting tests (LA-LA (Lupus anticoagulant) Ab which affect clotting tests (LA-

PTT RVV Kaolin)PTT RVV Kaolin) PAPS = TE miscarriage IUDPAPS = TE miscarriage IUD

Antiphospholipid Syndrome1048734 Antiphospholipid syndrome (APS) ndash Syndrome characterized by venous andor arterial thrombosis thrombocytopenia or recurrent fetal loss associated with antibodies to phospho-lipid- protein Complexes

1048734 Antiphospholipid antibodies (aPL)ndash IgG IgM or IgA antibodies that are directed to target proteins such as cardiolipin beta2-Glycoprotein I (β2GPI)or Prothrombin all of which bind to phospholipidsndash Lupus anticoagulant (LA) bull Antiphospholipid antibodies identified by in vitro phospholipid dependent clot-based assays antibodies are targeted against Prothrombin or β2GPI and prolong clotting times

Antiphospholipd Antibodies

Lupus Anticoagulant

Conditions where screening for APS Conditions where screening for APS is indicatedis indicated

The first thrombotic event below the age of 40The first thrombotic event below the age of 40 History of recurrent TEDHistory of recurrent TED Recurrent fetal loss in the 1Recurrent fetal loss in the 1stst or the 2 or the 2ndnd trimester trimester Patient with SLEPatient with SLE Pre-hormone replacement therapyPre-hormone replacement therapy

Non-familial (Acquired) continuedNon-familial (Acquired) continued

22 TPA (Tissue Plasminogen Activator) TPA (Tissue Plasminogen Activator) decreased levels impaired fibrinolysisdecreased levels impaired fibrinolysis

33 PAI (Plasminogen Activator Inhibitor) PAI (Plasminogen Activator Inhibitor) increased levels decreased TPAincreased levels decreased TPA

44 DysfibrinogenemiaDysfibrinogenemia55 F XII deficiency Hageman factorF XII deficiency Hageman factor66 Fibrinogen (increased)Fibrinogen (increased)77 F VIII (increased)F VIII (increased)88 PlasminogenPlasminogen99 Hyperhomocyteinemia ndash enzyme (folate)Hyperhomocyteinemia ndash enzyme (folate)

Investigation (Thrombotic Profile)Investigation (Thrombotic Profile)

NB Patients can be on Warfarin but not HeparinNB Patients can be on Warfarin but not Heparin FBC PLT amp ESRFBC PLT amp ESR PT aPTT TT amp FibrinogenPT aPTT TT amp Fibrinogen PC amp PSPC amp PS AT IIIAT III APCR (if + screening submit for PCR)APCR (if + screening submit for PCR) PT 20210A (PCR)PT 20210A (PCR) Lupus anticoagulant (RVVT KT LA-PTT) Lupus anticoagulant (RVVT KT LA-PTT) Cardiolipin antibodies (antiphospholipid syndrome)Cardiolipin antibodies (antiphospholipid syndrome) Sticky platelet syndrome (aspirin)Sticky platelet syndrome (aspirin) ANA screeningANA screening PNH screeningPNH screening

When to testWhen to test Younger lt 50 years recurrent TE unusual sites Younger lt 50 years recurrent TE unusual sites

TE on WarfarinTE on Warfarin Not ideal to test after acute episode (inhibitors of Not ideal to test after acute episode (inhibitors of

clotting may be low)clotting may be low) Ideal test after 6 weeks after settlement of Ideal test after 6 weeks after settlement of

hemostasishemostasis Most patients are on Warfarin then (PC amp PS are Most patients are on Warfarin then (PC amp PS are

Vit K dependent may be falsely low)Vit K dependent may be falsely low) My view if long-term Warfarin is planned do My view if long-term Warfarin is planned do

immediately according to duration of treatment it immediately according to duration of treatment it can be done after cessation of treatmentcan be done after cessation of treatment

When to test (continued)When to test (continued)

Practical (my experience) before treatment ndash if AT Practical (my experience) before treatment ndash if AT PS PC are low PS PC are low repeat after Rx has been stopped repeat after Rx has been stopped

SPS platelet aggregation studies (problem SPS platelet aggregation studies (problem sometimes aspirin cannot be stopped)sometimes aspirin cannot be stopped)

Remember the effect of the vessel wall on clotting Remember the effect of the vessel wall on clotting especially in arterial thrombosisespecially in arterial thrombosis

Every woman on contraception HRTEvery woman on contraception HRT

Arterial ThrombosisArterial Thrombosis

Arterial Thrombosis

Arterial ThrombosisArterial Thrombosis

Results as sever oResults as sever o2 2 starvation of the left starvation of the left ventricle of the heartventricle of the heart

This leads to myocardial ischemia amp may This leads to myocardial ischemia amp may progress to myocardial infarction or progress to myocardial infarction or ischemic left ventricular fibrillation amp ischemic left ventricular fibrillation amp sudden deathsudden death

Similar episodes involving the cerebral Similar episodes involving the cerebral circulation result in transient ischemic circulation result in transient ischemic attacks amp thrombotic stroke attacks amp thrombotic stroke

Myocardial Infarction SymptomMyocardial Infarction Symptom

Crushing tightness of the chest with Crushing tightness of the chest with sweating nausea breathlessness amp sweating nausea breathlessness amp collapsecollapse

Chest pain may radiates to the arm throat amp Chest pain may radiates to the arm throat amp jawjaw

Chest pain may confused with sever Chest pain may confused with sever indigestion in itrsquos early stagesindigestion in itrsquos early stages

Transient Ischemic attacksTransient Ischemic attacks

Itrsquos usually accompanied with neurological Itrsquos usually accompanied with neurological dysfunction or loss of visiondysfunction or loss of vision

Completed thrombotic strokeCompleted thrombotic stroke

Itrsquos accompanied by similar symptoms Itrsquos accompanied by similar symptoms which persist for more than 24 hours that which persist for more than 24 hours that may be severely amp permanently disablingmay be severely amp permanently disabling

Risk factors for arterial amp venous thrombosisRisk factors for arterial amp venous thrombosis

Venous thrombosisVenous thrombosisArterial thrombosisArterial thrombosisIncreasing ageIncreasing ageIncreasing ageIncreasing age

ObesityObesityObesityObesity

ImmobilityImmobilityLack of exerciseLack of exercise

Pregnancy rdquopost partomrdquoPregnancy rdquopost partomrdquoHigh fat low fiber dietHigh fat low fiber diet

MalignancyMalignancySmokingSmoking

Lupus anticoagulantLupus anticoagulantHyperlipidemiaHyperlipidemia

Nephrotic syndromeNephrotic syndromeHypertensionHypertension

PolycythemiaPolycythemiaElevated factor VII II concElevated factor VII II conc

goutgoutGenetic factorGenetic factor

Prophylaxis amp treatment of Prophylaxis amp treatment of thrombosisthrombosis

Prevent the risk factorsPrevent the risk factors SmokingSmoking ObesityObesity Lack of exerciseLack of exercise Poor dietPoor diet

Only when this proves to be impossibleOnly when this proves to be impossible

(Pharmacological intervention is required) (Pharmacological intervention is required)

Hematologic manifestationsHematologic manifestations

Cutaneous manifestationsCutaneous manifestations

Genetic Risk Factors(Familial)

11 FV- Leiden (APCR activated prot C resistance)FV- Leiden (APCR activated prot C resistance)

22 Protein C (deficiency)Protein C (deficiency)

33 Protein S (deficiency)Protein S (deficiency)

44 Antithrombin III (deficiency)Antithrombin III (deficiency)

55 Abnormal Prothrombin (PT 20210 A)Abnormal Prothrombin (PT 20210 A)

66 Sticky platelet syndromeSticky platelet syndrome

Risk FactorsmdashAcquiredRisk FactorsmdashAcquired

Advancing ageAdvancing age Prior ThrombosisPrior Thrombosis ImmobilizationImmobilization Major surgeryMajor surgery MalignancyMalignancy EstrogensEstrogens

Antiphospholipid Antiphospholipid antibody syndromeantibody syndrome

Myeloproliferative Myeloproliferative DisordersDisorders

Heparin-induced Heparin-induced thrombocytopenia thrombocytopenia (HIT)(HIT)

ProlongedProlonged air travel air travel

Risk FactorsmdashMixedUnknownRisk FactorsmdashMixedUnknown

HyperhomocysteinemiaHyperhomocysteinemia High levels of factor VIIIHigh levels of factor VIII Acquired Protein C resistance in the absence of Acquired Protein C resistance in the absence of

Factor V LeidenFactor V Leiden High levels of Factor IX XIHigh levels of Factor IX XI

11 FV- LeidenFV- Leiden

One of the most common causes for thrombophilia One of the most common causes for thrombophilia ndash 20 of clinical disease (AT PC and PS ndash 5) + ndash 20 of clinical disease (AT PC and PS ndash 5) + risk factorrisk factor

Activated PC inhibits F Va and F VIIIaActivated PC inhibits F Va and F VIIIa Inability of APC to inhibit the above complex due Inability of APC to inhibit the above complex due

to mutated FVto mutated FV Heterozygous 5-10 times increased risk for TEHeterozygous 5-10 times increased risk for TE Homozygous 50-100 timesHomozygous 50-100 times

Factor Va

Arg 306 Arg 506 Arg 1765

Arginine CGA

Glutamine CAA

Factor Va resistant to APC cleavage

Factor V Leiden

Relative Risk forVenous Thrombosis

Factor V Leiden Heterozygote x 7

Factor V Leiden Homozygote x 80

Oral Contraceptives x 3

Oral Contraceptives + Factor V Leiden x 35

Leiden Study Group Data

22 Protein C DeficiencyProtein C Deficiency

Common cause (increasing TE with age)Common cause (increasing TE with age) Needs TM from endothelium wallNeeds TM from endothelium wall Heterozygous 50 of level of normal Heterozygous 50 of level of normal

individualsindividuals Homozygous babies are born with Homozygous babies are born with

undetected levels (thrombi in microvascular undetected levels (thrombi in microvascular of skin DIC necrosis purpura of skin DIC necrosis purpura fulminans)fulminans)

33 Protein S DeficiencyProtein S Deficiency

Non-enzymatic co-factor for PCNon-enzymatic co-factor for PC Binds to TM-PCBinds to TM-PC Same properties as PCSame properties as PC Two forms free in plasma and bound to C4b Two forms free in plasma and bound to C4b

binding protein (60) Only free fraction binding protein (60) Only free fraction functions as co-factor for APCfunctions as co-factor for APC

Sometimes difficult to get accurate measures of Sometimes difficult to get accurate measures of PS because of the latterPS because of the latter

Like PC can be acquired liver disease Warfarin Like PC can be acquired liver disease Warfarin pregnancy cancer DIC and chemopregnancy cancer DIC and chemo

44 Antithrombin III DeficiencyAntithrombin III Deficiency

Common cause (incidence 12000 ndash 15000 Common cause (incidence 12000 ndash 15000 heterozygotes 50 DVT) Quantitative vs heterozygotes 50 DVT) Quantitative vs Qualitative disorder (Acquired DIC cirrhosis Qualitative disorder (Acquired DIC cirrhosis NS)NS)

Bind to and inactivate thrombin Factors IXa Xa Bind to and inactivate thrombin Factors IXa Xa XIa and XIIa (ATheparin complex - rate of XIa and XIIa (ATheparin complex - rate of inhibition 1000-fold increased)inhibition 1000-fold increased)

Not necessarily a risk factor to be involved in Not necessarily a risk factor to be involved in heterozygotes to give TEheterozygotes to give TE

Increased incidence with ageing 80 at 55 yearsIncreased incidence with ageing 80 at 55 years

55 Abnormal ProthrombinAbnormal Prothrombin (PT 20210 A) (PT 20210 A)

CommonCommon Increased levels of prothrombin enhanced Increased levels of prothrombin enhanced

thrombin formationthrombin formation Only way for diagnosis DNA-PCR Only way for diagnosis DNA-PCR

techniquetechnique

66 Sticky Platelet SyndromeSticky Platelet Syndrome

Especially in arterial thrombosis (MI) and Especially in arterial thrombosis (MI) and development of recurrent TE while on Warfarindevelopment of recurrent TE while on Warfarin

3 Forms3 Forms If on aspirin it should be stopped 14 days prior to If on aspirin it should be stopped 14 days prior to

testingtesting

Also rememberAlso remember

PC PS and AT III are inhibitors of clottingPC PS and AT III are inhibitors of clotting

Non-familial (Acquired)Non-familial (Acquired)11 Antiphospholipid SyndromeAntiphospholipid Syndrome Antibodies directed against phospholipid cell membrane = Antibodies directed against phospholipid cell membrane =

APA (Antiphospholipid Ab)APA (Antiphospholipid Ab) APA ACA or LAAPA ACA or LA Primary (PAPS) or secondary (autoimmune disorders eg Primary (PAPS) or secondary (autoimmune disorders eg

SLE)SLE) ACA (Anticardiolipin Ab) IgM + IgGACA (Anticardiolipin Ab) IgM + IgG IgG the clinically important oneIgG the clinically important one IgM pregnancy infection (viral) trauma and post-opIgM pregnancy infection (viral) trauma and post-op LA (Lupus anticoagulant) Ab which affect clotting tests (LA-LA (Lupus anticoagulant) Ab which affect clotting tests (LA-

PTT RVV Kaolin)PTT RVV Kaolin) PAPS = TE miscarriage IUDPAPS = TE miscarriage IUD

Antiphospholipid Syndrome1048734 Antiphospholipid syndrome (APS) ndash Syndrome characterized by venous andor arterial thrombosis thrombocytopenia or recurrent fetal loss associated with antibodies to phospho-lipid- protein Complexes

1048734 Antiphospholipid antibodies (aPL)ndash IgG IgM or IgA antibodies that are directed to target proteins such as cardiolipin beta2-Glycoprotein I (β2GPI)or Prothrombin all of which bind to phospholipidsndash Lupus anticoagulant (LA) bull Antiphospholipid antibodies identified by in vitro phospholipid dependent clot-based assays antibodies are targeted against Prothrombin or β2GPI and prolong clotting times

Antiphospholipd Antibodies

Lupus Anticoagulant

Conditions where screening for APS Conditions where screening for APS is indicatedis indicated

The first thrombotic event below the age of 40The first thrombotic event below the age of 40 History of recurrent TEDHistory of recurrent TED Recurrent fetal loss in the 1Recurrent fetal loss in the 1stst or the 2 or the 2ndnd trimester trimester Patient with SLEPatient with SLE Pre-hormone replacement therapyPre-hormone replacement therapy

Non-familial (Acquired) continuedNon-familial (Acquired) continued

22 TPA (Tissue Plasminogen Activator) TPA (Tissue Plasminogen Activator) decreased levels impaired fibrinolysisdecreased levels impaired fibrinolysis

33 PAI (Plasminogen Activator Inhibitor) PAI (Plasminogen Activator Inhibitor) increased levels decreased TPAincreased levels decreased TPA

44 DysfibrinogenemiaDysfibrinogenemia55 F XII deficiency Hageman factorF XII deficiency Hageman factor66 Fibrinogen (increased)Fibrinogen (increased)77 F VIII (increased)F VIII (increased)88 PlasminogenPlasminogen99 Hyperhomocyteinemia ndash enzyme (folate)Hyperhomocyteinemia ndash enzyme (folate)

Investigation (Thrombotic Profile)Investigation (Thrombotic Profile)

NB Patients can be on Warfarin but not HeparinNB Patients can be on Warfarin but not Heparin FBC PLT amp ESRFBC PLT amp ESR PT aPTT TT amp FibrinogenPT aPTT TT amp Fibrinogen PC amp PSPC amp PS AT IIIAT III APCR (if + screening submit for PCR)APCR (if + screening submit for PCR) PT 20210A (PCR)PT 20210A (PCR) Lupus anticoagulant (RVVT KT LA-PTT) Lupus anticoagulant (RVVT KT LA-PTT) Cardiolipin antibodies (antiphospholipid syndrome)Cardiolipin antibodies (antiphospholipid syndrome) Sticky platelet syndrome (aspirin)Sticky platelet syndrome (aspirin) ANA screeningANA screening PNH screeningPNH screening

When to testWhen to test Younger lt 50 years recurrent TE unusual sites Younger lt 50 years recurrent TE unusual sites

TE on WarfarinTE on Warfarin Not ideal to test after acute episode (inhibitors of Not ideal to test after acute episode (inhibitors of

clotting may be low)clotting may be low) Ideal test after 6 weeks after settlement of Ideal test after 6 weeks after settlement of

hemostasishemostasis Most patients are on Warfarin then (PC amp PS are Most patients are on Warfarin then (PC amp PS are

Vit K dependent may be falsely low)Vit K dependent may be falsely low) My view if long-term Warfarin is planned do My view if long-term Warfarin is planned do

immediately according to duration of treatment it immediately according to duration of treatment it can be done after cessation of treatmentcan be done after cessation of treatment

When to test (continued)When to test (continued)

Practical (my experience) before treatment ndash if AT Practical (my experience) before treatment ndash if AT PS PC are low PS PC are low repeat after Rx has been stopped repeat after Rx has been stopped

SPS platelet aggregation studies (problem SPS platelet aggregation studies (problem sometimes aspirin cannot be stopped)sometimes aspirin cannot be stopped)

Remember the effect of the vessel wall on clotting Remember the effect of the vessel wall on clotting especially in arterial thrombosisespecially in arterial thrombosis

Every woman on contraception HRTEvery woman on contraception HRT

Arterial ThrombosisArterial Thrombosis

Arterial Thrombosis

Arterial ThrombosisArterial Thrombosis

Results as sever oResults as sever o2 2 starvation of the left starvation of the left ventricle of the heartventricle of the heart

This leads to myocardial ischemia amp may This leads to myocardial ischemia amp may progress to myocardial infarction or progress to myocardial infarction or ischemic left ventricular fibrillation amp ischemic left ventricular fibrillation amp sudden deathsudden death

Similar episodes involving the cerebral Similar episodes involving the cerebral circulation result in transient ischemic circulation result in transient ischemic attacks amp thrombotic stroke attacks amp thrombotic stroke

Myocardial Infarction SymptomMyocardial Infarction Symptom

Crushing tightness of the chest with Crushing tightness of the chest with sweating nausea breathlessness amp sweating nausea breathlessness amp collapsecollapse

Chest pain may radiates to the arm throat amp Chest pain may radiates to the arm throat amp jawjaw

Chest pain may confused with sever Chest pain may confused with sever indigestion in itrsquos early stagesindigestion in itrsquos early stages

Transient Ischemic attacksTransient Ischemic attacks

Itrsquos usually accompanied with neurological Itrsquos usually accompanied with neurological dysfunction or loss of visiondysfunction or loss of vision

Completed thrombotic strokeCompleted thrombotic stroke

Itrsquos accompanied by similar symptoms Itrsquos accompanied by similar symptoms which persist for more than 24 hours that which persist for more than 24 hours that may be severely amp permanently disablingmay be severely amp permanently disabling

Risk factors for arterial amp venous thrombosisRisk factors for arterial amp venous thrombosis

Venous thrombosisVenous thrombosisArterial thrombosisArterial thrombosisIncreasing ageIncreasing ageIncreasing ageIncreasing age

ObesityObesityObesityObesity

ImmobilityImmobilityLack of exerciseLack of exercise

Pregnancy rdquopost partomrdquoPregnancy rdquopost partomrdquoHigh fat low fiber dietHigh fat low fiber diet

MalignancyMalignancySmokingSmoking

Lupus anticoagulantLupus anticoagulantHyperlipidemiaHyperlipidemia

Nephrotic syndromeNephrotic syndromeHypertensionHypertension

PolycythemiaPolycythemiaElevated factor VII II concElevated factor VII II conc

goutgoutGenetic factorGenetic factor

Prophylaxis amp treatment of Prophylaxis amp treatment of thrombosisthrombosis

Prevent the risk factorsPrevent the risk factors SmokingSmoking ObesityObesity Lack of exerciseLack of exercise Poor dietPoor diet

Only when this proves to be impossibleOnly when this proves to be impossible

(Pharmacological intervention is required) (Pharmacological intervention is required)

Cutaneous manifestationsCutaneous manifestations

Genetic Risk Factors(Familial)

11 FV- Leiden (APCR activated prot C resistance)FV- Leiden (APCR activated prot C resistance)

22 Protein C (deficiency)Protein C (deficiency)

33 Protein S (deficiency)Protein S (deficiency)

44 Antithrombin III (deficiency)Antithrombin III (deficiency)

55 Abnormal Prothrombin (PT 20210 A)Abnormal Prothrombin (PT 20210 A)

66 Sticky platelet syndromeSticky platelet syndrome

Risk FactorsmdashAcquiredRisk FactorsmdashAcquired

Advancing ageAdvancing age Prior ThrombosisPrior Thrombosis ImmobilizationImmobilization Major surgeryMajor surgery MalignancyMalignancy EstrogensEstrogens

Antiphospholipid Antiphospholipid antibody syndromeantibody syndrome

Myeloproliferative Myeloproliferative DisordersDisorders

Heparin-induced Heparin-induced thrombocytopenia thrombocytopenia (HIT)(HIT)

ProlongedProlonged air travel air travel

Risk FactorsmdashMixedUnknownRisk FactorsmdashMixedUnknown

HyperhomocysteinemiaHyperhomocysteinemia High levels of factor VIIIHigh levels of factor VIII Acquired Protein C resistance in the absence of Acquired Protein C resistance in the absence of

Factor V LeidenFactor V Leiden High levels of Factor IX XIHigh levels of Factor IX XI

11 FV- LeidenFV- Leiden

One of the most common causes for thrombophilia One of the most common causes for thrombophilia ndash 20 of clinical disease (AT PC and PS ndash 5) + ndash 20 of clinical disease (AT PC and PS ndash 5) + risk factorrisk factor

Activated PC inhibits F Va and F VIIIaActivated PC inhibits F Va and F VIIIa Inability of APC to inhibit the above complex due Inability of APC to inhibit the above complex due

to mutated FVto mutated FV Heterozygous 5-10 times increased risk for TEHeterozygous 5-10 times increased risk for TE Homozygous 50-100 timesHomozygous 50-100 times

Factor Va

Arg 306 Arg 506 Arg 1765

Arginine CGA

Glutamine CAA

Factor Va resistant to APC cleavage

Factor V Leiden

Relative Risk forVenous Thrombosis

Factor V Leiden Heterozygote x 7

Factor V Leiden Homozygote x 80

Oral Contraceptives x 3

Oral Contraceptives + Factor V Leiden x 35

Leiden Study Group Data

22 Protein C DeficiencyProtein C Deficiency

Common cause (increasing TE with age)Common cause (increasing TE with age) Needs TM from endothelium wallNeeds TM from endothelium wall Heterozygous 50 of level of normal Heterozygous 50 of level of normal

individualsindividuals Homozygous babies are born with Homozygous babies are born with

undetected levels (thrombi in microvascular undetected levels (thrombi in microvascular of skin DIC necrosis purpura of skin DIC necrosis purpura fulminans)fulminans)

33 Protein S DeficiencyProtein S Deficiency

Non-enzymatic co-factor for PCNon-enzymatic co-factor for PC Binds to TM-PCBinds to TM-PC Same properties as PCSame properties as PC Two forms free in plasma and bound to C4b Two forms free in plasma and bound to C4b

binding protein (60) Only free fraction binding protein (60) Only free fraction functions as co-factor for APCfunctions as co-factor for APC

Sometimes difficult to get accurate measures of Sometimes difficult to get accurate measures of PS because of the latterPS because of the latter

Like PC can be acquired liver disease Warfarin Like PC can be acquired liver disease Warfarin pregnancy cancer DIC and chemopregnancy cancer DIC and chemo

44 Antithrombin III DeficiencyAntithrombin III Deficiency

Common cause (incidence 12000 ndash 15000 Common cause (incidence 12000 ndash 15000 heterozygotes 50 DVT) Quantitative vs heterozygotes 50 DVT) Quantitative vs Qualitative disorder (Acquired DIC cirrhosis Qualitative disorder (Acquired DIC cirrhosis NS)NS)

Bind to and inactivate thrombin Factors IXa Xa Bind to and inactivate thrombin Factors IXa Xa XIa and XIIa (ATheparin complex - rate of XIa and XIIa (ATheparin complex - rate of inhibition 1000-fold increased)inhibition 1000-fold increased)

Not necessarily a risk factor to be involved in Not necessarily a risk factor to be involved in heterozygotes to give TEheterozygotes to give TE

Increased incidence with ageing 80 at 55 yearsIncreased incidence with ageing 80 at 55 years

55 Abnormal ProthrombinAbnormal Prothrombin (PT 20210 A) (PT 20210 A)

CommonCommon Increased levels of prothrombin enhanced Increased levels of prothrombin enhanced

thrombin formationthrombin formation Only way for diagnosis DNA-PCR Only way for diagnosis DNA-PCR

techniquetechnique

66 Sticky Platelet SyndromeSticky Platelet Syndrome

Especially in arterial thrombosis (MI) and Especially in arterial thrombosis (MI) and development of recurrent TE while on Warfarindevelopment of recurrent TE while on Warfarin

3 Forms3 Forms If on aspirin it should be stopped 14 days prior to If on aspirin it should be stopped 14 days prior to

testingtesting

Also rememberAlso remember

PC PS and AT III are inhibitors of clottingPC PS and AT III are inhibitors of clotting

Non-familial (Acquired)Non-familial (Acquired)11 Antiphospholipid SyndromeAntiphospholipid Syndrome Antibodies directed against phospholipid cell membrane = Antibodies directed against phospholipid cell membrane =

APA (Antiphospholipid Ab)APA (Antiphospholipid Ab) APA ACA or LAAPA ACA or LA Primary (PAPS) or secondary (autoimmune disorders eg Primary (PAPS) or secondary (autoimmune disorders eg

SLE)SLE) ACA (Anticardiolipin Ab) IgM + IgGACA (Anticardiolipin Ab) IgM + IgG IgG the clinically important oneIgG the clinically important one IgM pregnancy infection (viral) trauma and post-opIgM pregnancy infection (viral) trauma and post-op LA (Lupus anticoagulant) Ab which affect clotting tests (LA-LA (Lupus anticoagulant) Ab which affect clotting tests (LA-

PTT RVV Kaolin)PTT RVV Kaolin) PAPS = TE miscarriage IUDPAPS = TE miscarriage IUD

Antiphospholipid Syndrome1048734 Antiphospholipid syndrome (APS) ndash Syndrome characterized by venous andor arterial thrombosis thrombocytopenia or recurrent fetal loss associated with antibodies to phospho-lipid- protein Complexes

1048734 Antiphospholipid antibodies (aPL)ndash IgG IgM or IgA antibodies that are directed to target proteins such as cardiolipin beta2-Glycoprotein I (β2GPI)or Prothrombin all of which bind to phospholipidsndash Lupus anticoagulant (LA) bull Antiphospholipid antibodies identified by in vitro phospholipid dependent clot-based assays antibodies are targeted against Prothrombin or β2GPI and prolong clotting times

Antiphospholipd Antibodies

Lupus Anticoagulant

Conditions where screening for APS Conditions where screening for APS is indicatedis indicated

The first thrombotic event below the age of 40The first thrombotic event below the age of 40 History of recurrent TEDHistory of recurrent TED Recurrent fetal loss in the 1Recurrent fetal loss in the 1stst or the 2 or the 2ndnd trimester trimester Patient with SLEPatient with SLE Pre-hormone replacement therapyPre-hormone replacement therapy

Non-familial (Acquired) continuedNon-familial (Acquired) continued

22 TPA (Tissue Plasminogen Activator) TPA (Tissue Plasminogen Activator) decreased levels impaired fibrinolysisdecreased levels impaired fibrinolysis

33 PAI (Plasminogen Activator Inhibitor) PAI (Plasminogen Activator Inhibitor) increased levels decreased TPAincreased levels decreased TPA

44 DysfibrinogenemiaDysfibrinogenemia55 F XII deficiency Hageman factorF XII deficiency Hageman factor66 Fibrinogen (increased)Fibrinogen (increased)77 F VIII (increased)F VIII (increased)88 PlasminogenPlasminogen99 Hyperhomocyteinemia ndash enzyme (folate)Hyperhomocyteinemia ndash enzyme (folate)

Investigation (Thrombotic Profile)Investigation (Thrombotic Profile)

NB Patients can be on Warfarin but not HeparinNB Patients can be on Warfarin but not Heparin FBC PLT amp ESRFBC PLT amp ESR PT aPTT TT amp FibrinogenPT aPTT TT amp Fibrinogen PC amp PSPC amp PS AT IIIAT III APCR (if + screening submit for PCR)APCR (if + screening submit for PCR) PT 20210A (PCR)PT 20210A (PCR) Lupus anticoagulant (RVVT KT LA-PTT) Lupus anticoagulant (RVVT KT LA-PTT) Cardiolipin antibodies (antiphospholipid syndrome)Cardiolipin antibodies (antiphospholipid syndrome) Sticky platelet syndrome (aspirin)Sticky platelet syndrome (aspirin) ANA screeningANA screening PNH screeningPNH screening

When to testWhen to test Younger lt 50 years recurrent TE unusual sites Younger lt 50 years recurrent TE unusual sites

TE on WarfarinTE on Warfarin Not ideal to test after acute episode (inhibitors of Not ideal to test after acute episode (inhibitors of

clotting may be low)clotting may be low) Ideal test after 6 weeks after settlement of Ideal test after 6 weeks after settlement of

hemostasishemostasis Most patients are on Warfarin then (PC amp PS are Most patients are on Warfarin then (PC amp PS are

Vit K dependent may be falsely low)Vit K dependent may be falsely low) My view if long-term Warfarin is planned do My view if long-term Warfarin is planned do

immediately according to duration of treatment it immediately according to duration of treatment it can be done after cessation of treatmentcan be done after cessation of treatment

When to test (continued)When to test (continued)

Practical (my experience) before treatment ndash if AT Practical (my experience) before treatment ndash if AT PS PC are low PS PC are low repeat after Rx has been stopped repeat after Rx has been stopped

SPS platelet aggregation studies (problem SPS platelet aggregation studies (problem sometimes aspirin cannot be stopped)sometimes aspirin cannot be stopped)

Remember the effect of the vessel wall on clotting Remember the effect of the vessel wall on clotting especially in arterial thrombosisespecially in arterial thrombosis

Every woman on contraception HRTEvery woman on contraception HRT

Arterial ThrombosisArterial Thrombosis

Arterial Thrombosis

Arterial ThrombosisArterial Thrombosis

Results as sever oResults as sever o2 2 starvation of the left starvation of the left ventricle of the heartventricle of the heart

This leads to myocardial ischemia amp may This leads to myocardial ischemia amp may progress to myocardial infarction or progress to myocardial infarction or ischemic left ventricular fibrillation amp ischemic left ventricular fibrillation amp sudden deathsudden death

Similar episodes involving the cerebral Similar episodes involving the cerebral circulation result in transient ischemic circulation result in transient ischemic attacks amp thrombotic stroke attacks amp thrombotic stroke

Myocardial Infarction SymptomMyocardial Infarction Symptom

Crushing tightness of the chest with Crushing tightness of the chest with sweating nausea breathlessness amp sweating nausea breathlessness amp collapsecollapse

Chest pain may radiates to the arm throat amp Chest pain may radiates to the arm throat amp jawjaw

Chest pain may confused with sever Chest pain may confused with sever indigestion in itrsquos early stagesindigestion in itrsquos early stages

Transient Ischemic attacksTransient Ischemic attacks

Itrsquos usually accompanied with neurological Itrsquos usually accompanied with neurological dysfunction or loss of visiondysfunction or loss of vision

Completed thrombotic strokeCompleted thrombotic stroke

Itrsquos accompanied by similar symptoms Itrsquos accompanied by similar symptoms which persist for more than 24 hours that which persist for more than 24 hours that may be severely amp permanently disablingmay be severely amp permanently disabling

Risk factors for arterial amp venous thrombosisRisk factors for arterial amp venous thrombosis

Venous thrombosisVenous thrombosisArterial thrombosisArterial thrombosisIncreasing ageIncreasing ageIncreasing ageIncreasing age

ObesityObesityObesityObesity

ImmobilityImmobilityLack of exerciseLack of exercise

Pregnancy rdquopost partomrdquoPregnancy rdquopost partomrdquoHigh fat low fiber dietHigh fat low fiber diet

MalignancyMalignancySmokingSmoking

Lupus anticoagulantLupus anticoagulantHyperlipidemiaHyperlipidemia

Nephrotic syndromeNephrotic syndromeHypertensionHypertension

PolycythemiaPolycythemiaElevated factor VII II concElevated factor VII II conc

goutgoutGenetic factorGenetic factor

Prophylaxis amp treatment of Prophylaxis amp treatment of thrombosisthrombosis

Prevent the risk factorsPrevent the risk factors SmokingSmoking ObesityObesity Lack of exerciseLack of exercise Poor dietPoor diet

Only when this proves to be impossibleOnly when this proves to be impossible

(Pharmacological intervention is required) (Pharmacological intervention is required)

Genetic Risk Factors(Familial)

11 FV- Leiden (APCR activated prot C resistance)FV- Leiden (APCR activated prot C resistance)

22 Protein C (deficiency)Protein C (deficiency)

33 Protein S (deficiency)Protein S (deficiency)

44 Antithrombin III (deficiency)Antithrombin III (deficiency)

55 Abnormal Prothrombin (PT 20210 A)Abnormal Prothrombin (PT 20210 A)

66 Sticky platelet syndromeSticky platelet syndrome

Risk FactorsmdashAcquiredRisk FactorsmdashAcquired

Advancing ageAdvancing age Prior ThrombosisPrior Thrombosis ImmobilizationImmobilization Major surgeryMajor surgery MalignancyMalignancy EstrogensEstrogens

Antiphospholipid Antiphospholipid antibody syndromeantibody syndrome

Myeloproliferative Myeloproliferative DisordersDisorders

Heparin-induced Heparin-induced thrombocytopenia thrombocytopenia (HIT)(HIT)

ProlongedProlonged air travel air travel

Risk FactorsmdashMixedUnknownRisk FactorsmdashMixedUnknown

HyperhomocysteinemiaHyperhomocysteinemia High levels of factor VIIIHigh levels of factor VIII Acquired Protein C resistance in the absence of Acquired Protein C resistance in the absence of

Factor V LeidenFactor V Leiden High levels of Factor IX XIHigh levels of Factor IX XI

11 FV- LeidenFV- Leiden

One of the most common causes for thrombophilia One of the most common causes for thrombophilia ndash 20 of clinical disease (AT PC and PS ndash 5) + ndash 20 of clinical disease (AT PC and PS ndash 5) + risk factorrisk factor

Activated PC inhibits F Va and F VIIIaActivated PC inhibits F Va and F VIIIa Inability of APC to inhibit the above complex due Inability of APC to inhibit the above complex due

to mutated FVto mutated FV Heterozygous 5-10 times increased risk for TEHeterozygous 5-10 times increased risk for TE Homozygous 50-100 timesHomozygous 50-100 times

Factor Va

Arg 306 Arg 506 Arg 1765

Arginine CGA

Glutamine CAA

Factor Va resistant to APC cleavage

Factor V Leiden

Relative Risk forVenous Thrombosis

Factor V Leiden Heterozygote x 7

Factor V Leiden Homozygote x 80

Oral Contraceptives x 3

Oral Contraceptives + Factor V Leiden x 35

Leiden Study Group Data

22 Protein C DeficiencyProtein C Deficiency

Common cause (increasing TE with age)Common cause (increasing TE with age) Needs TM from endothelium wallNeeds TM from endothelium wall Heterozygous 50 of level of normal Heterozygous 50 of level of normal

individualsindividuals Homozygous babies are born with Homozygous babies are born with

undetected levels (thrombi in microvascular undetected levels (thrombi in microvascular of skin DIC necrosis purpura of skin DIC necrosis purpura fulminans)fulminans)

33 Protein S DeficiencyProtein S Deficiency

Non-enzymatic co-factor for PCNon-enzymatic co-factor for PC Binds to TM-PCBinds to TM-PC Same properties as PCSame properties as PC Two forms free in plasma and bound to C4b Two forms free in plasma and bound to C4b

binding protein (60) Only free fraction binding protein (60) Only free fraction functions as co-factor for APCfunctions as co-factor for APC

Sometimes difficult to get accurate measures of Sometimes difficult to get accurate measures of PS because of the latterPS because of the latter

Like PC can be acquired liver disease Warfarin Like PC can be acquired liver disease Warfarin pregnancy cancer DIC and chemopregnancy cancer DIC and chemo

44 Antithrombin III DeficiencyAntithrombin III Deficiency

Common cause (incidence 12000 ndash 15000 Common cause (incidence 12000 ndash 15000 heterozygotes 50 DVT) Quantitative vs heterozygotes 50 DVT) Quantitative vs Qualitative disorder (Acquired DIC cirrhosis Qualitative disorder (Acquired DIC cirrhosis NS)NS)

Bind to and inactivate thrombin Factors IXa Xa Bind to and inactivate thrombin Factors IXa Xa XIa and XIIa (ATheparin complex - rate of XIa and XIIa (ATheparin complex - rate of inhibition 1000-fold increased)inhibition 1000-fold increased)

Not necessarily a risk factor to be involved in Not necessarily a risk factor to be involved in heterozygotes to give TEheterozygotes to give TE

Increased incidence with ageing 80 at 55 yearsIncreased incidence with ageing 80 at 55 years

55 Abnormal ProthrombinAbnormal Prothrombin (PT 20210 A) (PT 20210 A)

CommonCommon Increased levels of prothrombin enhanced Increased levels of prothrombin enhanced

thrombin formationthrombin formation Only way for diagnosis DNA-PCR Only way for diagnosis DNA-PCR

techniquetechnique

66 Sticky Platelet SyndromeSticky Platelet Syndrome

Especially in arterial thrombosis (MI) and Especially in arterial thrombosis (MI) and development of recurrent TE while on Warfarindevelopment of recurrent TE while on Warfarin

3 Forms3 Forms If on aspirin it should be stopped 14 days prior to If on aspirin it should be stopped 14 days prior to

testingtesting

Also rememberAlso remember

PC PS and AT III are inhibitors of clottingPC PS and AT III are inhibitors of clotting

Non-familial (Acquired)Non-familial (Acquired)11 Antiphospholipid SyndromeAntiphospholipid Syndrome Antibodies directed against phospholipid cell membrane = Antibodies directed against phospholipid cell membrane =

APA (Antiphospholipid Ab)APA (Antiphospholipid Ab) APA ACA or LAAPA ACA or LA Primary (PAPS) or secondary (autoimmune disorders eg Primary (PAPS) or secondary (autoimmune disorders eg

SLE)SLE) ACA (Anticardiolipin Ab) IgM + IgGACA (Anticardiolipin Ab) IgM + IgG IgG the clinically important oneIgG the clinically important one IgM pregnancy infection (viral) trauma and post-opIgM pregnancy infection (viral) trauma and post-op LA (Lupus anticoagulant) Ab which affect clotting tests (LA-LA (Lupus anticoagulant) Ab which affect clotting tests (LA-

PTT RVV Kaolin)PTT RVV Kaolin) PAPS = TE miscarriage IUDPAPS = TE miscarriage IUD

Antiphospholipid Syndrome1048734 Antiphospholipid syndrome (APS) ndash Syndrome characterized by venous andor arterial thrombosis thrombocytopenia or recurrent fetal loss associated with antibodies to phospho-lipid- protein Complexes

1048734 Antiphospholipid antibodies (aPL)ndash IgG IgM or IgA antibodies that are directed to target proteins such as cardiolipin beta2-Glycoprotein I (β2GPI)or Prothrombin all of which bind to phospholipidsndash Lupus anticoagulant (LA) bull Antiphospholipid antibodies identified by in vitro phospholipid dependent clot-based assays antibodies are targeted against Prothrombin or β2GPI and prolong clotting times

Antiphospholipd Antibodies

Lupus Anticoagulant

Conditions where screening for APS Conditions where screening for APS is indicatedis indicated

The first thrombotic event below the age of 40The first thrombotic event below the age of 40 History of recurrent TEDHistory of recurrent TED Recurrent fetal loss in the 1Recurrent fetal loss in the 1stst or the 2 or the 2ndnd trimester trimester Patient with SLEPatient with SLE Pre-hormone replacement therapyPre-hormone replacement therapy

Non-familial (Acquired) continuedNon-familial (Acquired) continued

22 TPA (Tissue Plasminogen Activator) TPA (Tissue Plasminogen Activator) decreased levels impaired fibrinolysisdecreased levels impaired fibrinolysis

33 PAI (Plasminogen Activator Inhibitor) PAI (Plasminogen Activator Inhibitor) increased levels decreased TPAincreased levels decreased TPA

44 DysfibrinogenemiaDysfibrinogenemia55 F XII deficiency Hageman factorF XII deficiency Hageman factor66 Fibrinogen (increased)Fibrinogen (increased)77 F VIII (increased)F VIII (increased)88 PlasminogenPlasminogen99 Hyperhomocyteinemia ndash enzyme (folate)Hyperhomocyteinemia ndash enzyme (folate)

Investigation (Thrombotic Profile)Investigation (Thrombotic Profile)

NB Patients can be on Warfarin but not HeparinNB Patients can be on Warfarin but not Heparin FBC PLT amp ESRFBC PLT amp ESR PT aPTT TT amp FibrinogenPT aPTT TT amp Fibrinogen PC amp PSPC amp PS AT IIIAT III APCR (if + screening submit for PCR)APCR (if + screening submit for PCR) PT 20210A (PCR)PT 20210A (PCR) Lupus anticoagulant (RVVT KT LA-PTT) Lupus anticoagulant (RVVT KT LA-PTT) Cardiolipin antibodies (antiphospholipid syndrome)Cardiolipin antibodies (antiphospholipid syndrome) Sticky platelet syndrome (aspirin)Sticky platelet syndrome (aspirin) ANA screeningANA screening PNH screeningPNH screening

When to testWhen to test Younger lt 50 years recurrent TE unusual sites Younger lt 50 years recurrent TE unusual sites

TE on WarfarinTE on Warfarin Not ideal to test after acute episode (inhibitors of Not ideal to test after acute episode (inhibitors of

clotting may be low)clotting may be low) Ideal test after 6 weeks after settlement of Ideal test after 6 weeks after settlement of

hemostasishemostasis Most patients are on Warfarin then (PC amp PS are Most patients are on Warfarin then (PC amp PS are

Vit K dependent may be falsely low)Vit K dependent may be falsely low) My view if long-term Warfarin is planned do My view if long-term Warfarin is planned do

immediately according to duration of treatment it immediately according to duration of treatment it can be done after cessation of treatmentcan be done after cessation of treatment

When to test (continued)When to test (continued)

Practical (my experience) before treatment ndash if AT Practical (my experience) before treatment ndash if AT PS PC are low PS PC are low repeat after Rx has been stopped repeat after Rx has been stopped

SPS platelet aggregation studies (problem SPS platelet aggregation studies (problem sometimes aspirin cannot be stopped)sometimes aspirin cannot be stopped)

Remember the effect of the vessel wall on clotting Remember the effect of the vessel wall on clotting especially in arterial thrombosisespecially in arterial thrombosis

Every woman on contraception HRTEvery woman on contraception HRT

Arterial ThrombosisArterial Thrombosis

Arterial Thrombosis

Arterial ThrombosisArterial Thrombosis

Results as sever oResults as sever o2 2 starvation of the left starvation of the left ventricle of the heartventricle of the heart

This leads to myocardial ischemia amp may This leads to myocardial ischemia amp may progress to myocardial infarction or progress to myocardial infarction or ischemic left ventricular fibrillation amp ischemic left ventricular fibrillation amp sudden deathsudden death

Similar episodes involving the cerebral Similar episodes involving the cerebral circulation result in transient ischemic circulation result in transient ischemic attacks amp thrombotic stroke attacks amp thrombotic stroke

Myocardial Infarction SymptomMyocardial Infarction Symptom

Crushing tightness of the chest with Crushing tightness of the chest with sweating nausea breathlessness amp sweating nausea breathlessness amp collapsecollapse

Chest pain may radiates to the arm throat amp Chest pain may radiates to the arm throat amp jawjaw

Chest pain may confused with sever Chest pain may confused with sever indigestion in itrsquos early stagesindigestion in itrsquos early stages

Transient Ischemic attacksTransient Ischemic attacks

Itrsquos usually accompanied with neurological Itrsquos usually accompanied with neurological dysfunction or loss of visiondysfunction or loss of vision

Completed thrombotic strokeCompleted thrombotic stroke

Itrsquos accompanied by similar symptoms Itrsquos accompanied by similar symptoms which persist for more than 24 hours that which persist for more than 24 hours that may be severely amp permanently disablingmay be severely amp permanently disabling

Risk factors for arterial amp venous thrombosisRisk factors for arterial amp venous thrombosis

Venous thrombosisVenous thrombosisArterial thrombosisArterial thrombosisIncreasing ageIncreasing ageIncreasing ageIncreasing age

ObesityObesityObesityObesity

ImmobilityImmobilityLack of exerciseLack of exercise

Pregnancy rdquopost partomrdquoPregnancy rdquopost partomrdquoHigh fat low fiber dietHigh fat low fiber diet

MalignancyMalignancySmokingSmoking

Lupus anticoagulantLupus anticoagulantHyperlipidemiaHyperlipidemia

Nephrotic syndromeNephrotic syndromeHypertensionHypertension

PolycythemiaPolycythemiaElevated factor VII II concElevated factor VII II conc

goutgoutGenetic factorGenetic factor

Prophylaxis amp treatment of Prophylaxis amp treatment of thrombosisthrombosis

Prevent the risk factorsPrevent the risk factors SmokingSmoking ObesityObesity Lack of exerciseLack of exercise Poor dietPoor diet

Only when this proves to be impossibleOnly when this proves to be impossible

(Pharmacological intervention is required) (Pharmacological intervention is required)

Risk FactorsmdashAcquiredRisk FactorsmdashAcquired

Advancing ageAdvancing age Prior ThrombosisPrior Thrombosis ImmobilizationImmobilization Major surgeryMajor surgery MalignancyMalignancy EstrogensEstrogens

Antiphospholipid Antiphospholipid antibody syndromeantibody syndrome

Myeloproliferative Myeloproliferative DisordersDisorders

Heparin-induced Heparin-induced thrombocytopenia thrombocytopenia (HIT)(HIT)

ProlongedProlonged air travel air travel

Risk FactorsmdashMixedUnknownRisk FactorsmdashMixedUnknown

HyperhomocysteinemiaHyperhomocysteinemia High levels of factor VIIIHigh levels of factor VIII Acquired Protein C resistance in the absence of Acquired Protein C resistance in the absence of

Factor V LeidenFactor V Leiden High levels of Factor IX XIHigh levels of Factor IX XI

11 FV- LeidenFV- Leiden

One of the most common causes for thrombophilia One of the most common causes for thrombophilia ndash 20 of clinical disease (AT PC and PS ndash 5) + ndash 20 of clinical disease (AT PC and PS ndash 5) + risk factorrisk factor

Activated PC inhibits F Va and F VIIIaActivated PC inhibits F Va and F VIIIa Inability of APC to inhibit the above complex due Inability of APC to inhibit the above complex due

to mutated FVto mutated FV Heterozygous 5-10 times increased risk for TEHeterozygous 5-10 times increased risk for TE Homozygous 50-100 timesHomozygous 50-100 times

Factor Va

Arg 306 Arg 506 Arg 1765

Arginine CGA

Glutamine CAA

Factor Va resistant to APC cleavage

Factor V Leiden

Relative Risk forVenous Thrombosis

Factor V Leiden Heterozygote x 7

Factor V Leiden Homozygote x 80

Oral Contraceptives x 3

Oral Contraceptives + Factor V Leiden x 35

Leiden Study Group Data

22 Protein C DeficiencyProtein C Deficiency

Common cause (increasing TE with age)Common cause (increasing TE with age) Needs TM from endothelium wallNeeds TM from endothelium wall Heterozygous 50 of level of normal Heterozygous 50 of level of normal

individualsindividuals Homozygous babies are born with Homozygous babies are born with

undetected levels (thrombi in microvascular undetected levels (thrombi in microvascular of skin DIC necrosis purpura of skin DIC necrosis purpura fulminans)fulminans)

33 Protein S DeficiencyProtein S Deficiency

Non-enzymatic co-factor for PCNon-enzymatic co-factor for PC Binds to TM-PCBinds to TM-PC Same properties as PCSame properties as PC Two forms free in plasma and bound to C4b Two forms free in plasma and bound to C4b

binding protein (60) Only free fraction binding protein (60) Only free fraction functions as co-factor for APCfunctions as co-factor for APC

Sometimes difficult to get accurate measures of Sometimes difficult to get accurate measures of PS because of the latterPS because of the latter

Like PC can be acquired liver disease Warfarin Like PC can be acquired liver disease Warfarin pregnancy cancer DIC and chemopregnancy cancer DIC and chemo

44 Antithrombin III DeficiencyAntithrombin III Deficiency

Common cause (incidence 12000 ndash 15000 Common cause (incidence 12000 ndash 15000 heterozygotes 50 DVT) Quantitative vs heterozygotes 50 DVT) Quantitative vs Qualitative disorder (Acquired DIC cirrhosis Qualitative disorder (Acquired DIC cirrhosis NS)NS)

Bind to and inactivate thrombin Factors IXa Xa Bind to and inactivate thrombin Factors IXa Xa XIa and XIIa (ATheparin complex - rate of XIa and XIIa (ATheparin complex - rate of inhibition 1000-fold increased)inhibition 1000-fold increased)

Not necessarily a risk factor to be involved in Not necessarily a risk factor to be involved in heterozygotes to give TEheterozygotes to give TE

Increased incidence with ageing 80 at 55 yearsIncreased incidence with ageing 80 at 55 years

55 Abnormal ProthrombinAbnormal Prothrombin (PT 20210 A) (PT 20210 A)

CommonCommon Increased levels of prothrombin enhanced Increased levels of prothrombin enhanced

thrombin formationthrombin formation Only way for diagnosis DNA-PCR Only way for diagnosis DNA-PCR

techniquetechnique

66 Sticky Platelet SyndromeSticky Platelet Syndrome

Especially in arterial thrombosis (MI) and Especially in arterial thrombosis (MI) and development of recurrent TE while on Warfarindevelopment of recurrent TE while on Warfarin

3 Forms3 Forms If on aspirin it should be stopped 14 days prior to If on aspirin it should be stopped 14 days prior to

testingtesting

Also rememberAlso remember

PC PS and AT III are inhibitors of clottingPC PS and AT III are inhibitors of clotting

Non-familial (Acquired)Non-familial (Acquired)11 Antiphospholipid SyndromeAntiphospholipid Syndrome Antibodies directed against phospholipid cell membrane = Antibodies directed against phospholipid cell membrane =

APA (Antiphospholipid Ab)APA (Antiphospholipid Ab) APA ACA or LAAPA ACA or LA Primary (PAPS) or secondary (autoimmune disorders eg Primary (PAPS) or secondary (autoimmune disorders eg

SLE)SLE) ACA (Anticardiolipin Ab) IgM + IgGACA (Anticardiolipin Ab) IgM + IgG IgG the clinically important oneIgG the clinically important one IgM pregnancy infection (viral) trauma and post-opIgM pregnancy infection (viral) trauma and post-op LA (Lupus anticoagulant) Ab which affect clotting tests (LA-LA (Lupus anticoagulant) Ab which affect clotting tests (LA-

PTT RVV Kaolin)PTT RVV Kaolin) PAPS = TE miscarriage IUDPAPS = TE miscarriage IUD

Antiphospholipid Syndrome1048734 Antiphospholipid syndrome (APS) ndash Syndrome characterized by venous andor arterial thrombosis thrombocytopenia or recurrent fetal loss associated with antibodies to phospho-lipid- protein Complexes

1048734 Antiphospholipid antibodies (aPL)ndash IgG IgM or IgA antibodies that are directed to target proteins such as cardiolipin beta2-Glycoprotein I (β2GPI)or Prothrombin all of which bind to phospholipidsndash Lupus anticoagulant (LA) bull Antiphospholipid antibodies identified by in vitro phospholipid dependent clot-based assays antibodies are targeted against Prothrombin or β2GPI and prolong clotting times

Antiphospholipd Antibodies

Lupus Anticoagulant

Conditions where screening for APS Conditions where screening for APS is indicatedis indicated

The first thrombotic event below the age of 40The first thrombotic event below the age of 40 History of recurrent TEDHistory of recurrent TED Recurrent fetal loss in the 1Recurrent fetal loss in the 1stst or the 2 or the 2ndnd trimester trimester Patient with SLEPatient with SLE Pre-hormone replacement therapyPre-hormone replacement therapy

Non-familial (Acquired) continuedNon-familial (Acquired) continued

22 TPA (Tissue Plasminogen Activator) TPA (Tissue Plasminogen Activator) decreased levels impaired fibrinolysisdecreased levels impaired fibrinolysis

33 PAI (Plasminogen Activator Inhibitor) PAI (Plasminogen Activator Inhibitor) increased levels decreased TPAincreased levels decreased TPA

44 DysfibrinogenemiaDysfibrinogenemia55 F XII deficiency Hageman factorF XII deficiency Hageman factor66 Fibrinogen (increased)Fibrinogen (increased)77 F VIII (increased)F VIII (increased)88 PlasminogenPlasminogen99 Hyperhomocyteinemia ndash enzyme (folate)Hyperhomocyteinemia ndash enzyme (folate)

Investigation (Thrombotic Profile)Investigation (Thrombotic Profile)

NB Patients can be on Warfarin but not HeparinNB Patients can be on Warfarin but not Heparin FBC PLT amp ESRFBC PLT amp ESR PT aPTT TT amp FibrinogenPT aPTT TT amp Fibrinogen PC amp PSPC amp PS AT IIIAT III APCR (if + screening submit for PCR)APCR (if + screening submit for PCR) PT 20210A (PCR)PT 20210A (PCR) Lupus anticoagulant (RVVT KT LA-PTT) Lupus anticoagulant (RVVT KT LA-PTT) Cardiolipin antibodies (antiphospholipid syndrome)Cardiolipin antibodies (antiphospholipid syndrome) Sticky platelet syndrome (aspirin)Sticky platelet syndrome (aspirin) ANA screeningANA screening PNH screeningPNH screening

When to testWhen to test Younger lt 50 years recurrent TE unusual sites Younger lt 50 years recurrent TE unusual sites

TE on WarfarinTE on Warfarin Not ideal to test after acute episode (inhibitors of Not ideal to test after acute episode (inhibitors of

clotting may be low)clotting may be low) Ideal test after 6 weeks after settlement of Ideal test after 6 weeks after settlement of

hemostasishemostasis Most patients are on Warfarin then (PC amp PS are Most patients are on Warfarin then (PC amp PS are

Vit K dependent may be falsely low)Vit K dependent may be falsely low) My view if long-term Warfarin is planned do My view if long-term Warfarin is planned do

immediately according to duration of treatment it immediately according to duration of treatment it can be done after cessation of treatmentcan be done after cessation of treatment

When to test (continued)When to test (continued)

Practical (my experience) before treatment ndash if AT Practical (my experience) before treatment ndash if AT PS PC are low PS PC are low repeat after Rx has been stopped repeat after Rx has been stopped

SPS platelet aggregation studies (problem SPS platelet aggregation studies (problem sometimes aspirin cannot be stopped)sometimes aspirin cannot be stopped)

Remember the effect of the vessel wall on clotting Remember the effect of the vessel wall on clotting especially in arterial thrombosisespecially in arterial thrombosis

Every woman on contraception HRTEvery woman on contraception HRT

Arterial ThrombosisArterial Thrombosis

Arterial Thrombosis

Arterial ThrombosisArterial Thrombosis

Results as sever oResults as sever o2 2 starvation of the left starvation of the left ventricle of the heartventricle of the heart

This leads to myocardial ischemia amp may This leads to myocardial ischemia amp may progress to myocardial infarction or progress to myocardial infarction or ischemic left ventricular fibrillation amp ischemic left ventricular fibrillation amp sudden deathsudden death

Similar episodes involving the cerebral Similar episodes involving the cerebral circulation result in transient ischemic circulation result in transient ischemic attacks amp thrombotic stroke attacks amp thrombotic stroke

Myocardial Infarction SymptomMyocardial Infarction Symptom

Crushing tightness of the chest with Crushing tightness of the chest with sweating nausea breathlessness amp sweating nausea breathlessness amp collapsecollapse

Chest pain may radiates to the arm throat amp Chest pain may radiates to the arm throat amp jawjaw

Chest pain may confused with sever Chest pain may confused with sever indigestion in itrsquos early stagesindigestion in itrsquos early stages

Transient Ischemic attacksTransient Ischemic attacks

Itrsquos usually accompanied with neurological Itrsquos usually accompanied with neurological dysfunction or loss of visiondysfunction or loss of vision

Completed thrombotic strokeCompleted thrombotic stroke

Itrsquos accompanied by similar symptoms Itrsquos accompanied by similar symptoms which persist for more than 24 hours that which persist for more than 24 hours that may be severely amp permanently disablingmay be severely amp permanently disabling

Risk factors for arterial amp venous thrombosisRisk factors for arterial amp venous thrombosis

Venous thrombosisVenous thrombosisArterial thrombosisArterial thrombosisIncreasing ageIncreasing ageIncreasing ageIncreasing age

ObesityObesityObesityObesity

ImmobilityImmobilityLack of exerciseLack of exercise

Pregnancy rdquopost partomrdquoPregnancy rdquopost partomrdquoHigh fat low fiber dietHigh fat low fiber diet

MalignancyMalignancySmokingSmoking

Lupus anticoagulantLupus anticoagulantHyperlipidemiaHyperlipidemia

Nephrotic syndromeNephrotic syndromeHypertensionHypertension

PolycythemiaPolycythemiaElevated factor VII II concElevated factor VII II conc

goutgoutGenetic factorGenetic factor

Prophylaxis amp treatment of Prophylaxis amp treatment of thrombosisthrombosis

Prevent the risk factorsPrevent the risk factors SmokingSmoking ObesityObesity Lack of exerciseLack of exercise Poor dietPoor diet

Only when this proves to be impossibleOnly when this proves to be impossible

(Pharmacological intervention is required) (Pharmacological intervention is required)

Risk FactorsmdashMixedUnknownRisk FactorsmdashMixedUnknown

HyperhomocysteinemiaHyperhomocysteinemia High levels of factor VIIIHigh levels of factor VIII Acquired Protein C resistance in the absence of Acquired Protein C resistance in the absence of

Factor V LeidenFactor V Leiden High levels of Factor IX XIHigh levels of Factor IX XI

11 FV- LeidenFV- Leiden

One of the most common causes for thrombophilia One of the most common causes for thrombophilia ndash 20 of clinical disease (AT PC and PS ndash 5) + ndash 20 of clinical disease (AT PC and PS ndash 5) + risk factorrisk factor

Activated PC inhibits F Va and F VIIIaActivated PC inhibits F Va and F VIIIa Inability of APC to inhibit the above complex due Inability of APC to inhibit the above complex due

to mutated FVto mutated FV Heterozygous 5-10 times increased risk for TEHeterozygous 5-10 times increased risk for TE Homozygous 50-100 timesHomozygous 50-100 times

Factor Va

Arg 306 Arg 506 Arg 1765

Arginine CGA

Glutamine CAA

Factor Va resistant to APC cleavage

Factor V Leiden

Relative Risk forVenous Thrombosis

Factor V Leiden Heterozygote x 7

Factor V Leiden Homozygote x 80

Oral Contraceptives x 3

Oral Contraceptives + Factor V Leiden x 35

Leiden Study Group Data

22 Protein C DeficiencyProtein C Deficiency

Common cause (increasing TE with age)Common cause (increasing TE with age) Needs TM from endothelium wallNeeds TM from endothelium wall Heterozygous 50 of level of normal Heterozygous 50 of level of normal

individualsindividuals Homozygous babies are born with Homozygous babies are born with

undetected levels (thrombi in microvascular undetected levels (thrombi in microvascular of skin DIC necrosis purpura of skin DIC necrosis purpura fulminans)fulminans)

33 Protein S DeficiencyProtein S Deficiency

Non-enzymatic co-factor for PCNon-enzymatic co-factor for PC Binds to TM-PCBinds to TM-PC Same properties as PCSame properties as PC Two forms free in plasma and bound to C4b Two forms free in plasma and bound to C4b

binding protein (60) Only free fraction binding protein (60) Only free fraction functions as co-factor for APCfunctions as co-factor for APC

Sometimes difficult to get accurate measures of Sometimes difficult to get accurate measures of PS because of the latterPS because of the latter

Like PC can be acquired liver disease Warfarin Like PC can be acquired liver disease Warfarin pregnancy cancer DIC and chemopregnancy cancer DIC and chemo

44 Antithrombin III DeficiencyAntithrombin III Deficiency

Common cause (incidence 12000 ndash 15000 Common cause (incidence 12000 ndash 15000 heterozygotes 50 DVT) Quantitative vs heterozygotes 50 DVT) Quantitative vs Qualitative disorder (Acquired DIC cirrhosis Qualitative disorder (Acquired DIC cirrhosis NS)NS)

Bind to and inactivate thrombin Factors IXa Xa Bind to and inactivate thrombin Factors IXa Xa XIa and XIIa (ATheparin complex - rate of XIa and XIIa (ATheparin complex - rate of inhibition 1000-fold increased)inhibition 1000-fold increased)

Not necessarily a risk factor to be involved in Not necessarily a risk factor to be involved in heterozygotes to give TEheterozygotes to give TE

Increased incidence with ageing 80 at 55 yearsIncreased incidence with ageing 80 at 55 years

55 Abnormal ProthrombinAbnormal Prothrombin (PT 20210 A) (PT 20210 A)

CommonCommon Increased levels of prothrombin enhanced Increased levels of prothrombin enhanced

thrombin formationthrombin formation Only way for diagnosis DNA-PCR Only way for diagnosis DNA-PCR

techniquetechnique

66 Sticky Platelet SyndromeSticky Platelet Syndrome

Especially in arterial thrombosis (MI) and Especially in arterial thrombosis (MI) and development of recurrent TE while on Warfarindevelopment of recurrent TE while on Warfarin

3 Forms3 Forms If on aspirin it should be stopped 14 days prior to If on aspirin it should be stopped 14 days prior to

testingtesting

Also rememberAlso remember

PC PS and AT III are inhibitors of clottingPC PS and AT III are inhibitors of clotting

Non-familial (Acquired)Non-familial (Acquired)11 Antiphospholipid SyndromeAntiphospholipid Syndrome Antibodies directed against phospholipid cell membrane = Antibodies directed against phospholipid cell membrane =

APA (Antiphospholipid Ab)APA (Antiphospholipid Ab) APA ACA or LAAPA ACA or LA Primary (PAPS) or secondary (autoimmune disorders eg Primary (PAPS) or secondary (autoimmune disorders eg

SLE)SLE) ACA (Anticardiolipin Ab) IgM + IgGACA (Anticardiolipin Ab) IgM + IgG IgG the clinically important oneIgG the clinically important one IgM pregnancy infection (viral) trauma and post-opIgM pregnancy infection (viral) trauma and post-op LA (Lupus anticoagulant) Ab which affect clotting tests (LA-LA (Lupus anticoagulant) Ab which affect clotting tests (LA-

PTT RVV Kaolin)PTT RVV Kaolin) PAPS = TE miscarriage IUDPAPS = TE miscarriage IUD

Antiphospholipid Syndrome1048734 Antiphospholipid syndrome (APS) ndash Syndrome characterized by venous andor arterial thrombosis thrombocytopenia or recurrent fetal loss associated with antibodies to phospho-lipid- protein Complexes

1048734 Antiphospholipid antibodies (aPL)ndash IgG IgM or IgA antibodies that are directed to target proteins such as cardiolipin beta2-Glycoprotein I (β2GPI)or Prothrombin all of which bind to phospholipidsndash Lupus anticoagulant (LA) bull Antiphospholipid antibodies identified by in vitro phospholipid dependent clot-based assays antibodies are targeted against Prothrombin or β2GPI and prolong clotting times

Antiphospholipd Antibodies

Lupus Anticoagulant

Conditions where screening for APS Conditions where screening for APS is indicatedis indicated

The first thrombotic event below the age of 40The first thrombotic event below the age of 40 History of recurrent TEDHistory of recurrent TED Recurrent fetal loss in the 1Recurrent fetal loss in the 1stst or the 2 or the 2ndnd trimester trimester Patient with SLEPatient with SLE Pre-hormone replacement therapyPre-hormone replacement therapy

Non-familial (Acquired) continuedNon-familial (Acquired) continued

22 TPA (Tissue Plasminogen Activator) TPA (Tissue Plasminogen Activator) decreased levels impaired fibrinolysisdecreased levels impaired fibrinolysis

33 PAI (Plasminogen Activator Inhibitor) PAI (Plasminogen Activator Inhibitor) increased levels decreased TPAincreased levels decreased TPA

44 DysfibrinogenemiaDysfibrinogenemia55 F XII deficiency Hageman factorF XII deficiency Hageman factor66 Fibrinogen (increased)Fibrinogen (increased)77 F VIII (increased)F VIII (increased)88 PlasminogenPlasminogen99 Hyperhomocyteinemia ndash enzyme (folate)Hyperhomocyteinemia ndash enzyme (folate)

Investigation (Thrombotic Profile)Investigation (Thrombotic Profile)

NB Patients can be on Warfarin but not HeparinNB Patients can be on Warfarin but not Heparin FBC PLT amp ESRFBC PLT amp ESR PT aPTT TT amp FibrinogenPT aPTT TT amp Fibrinogen PC amp PSPC amp PS AT IIIAT III APCR (if + screening submit for PCR)APCR (if + screening submit for PCR) PT 20210A (PCR)PT 20210A (PCR) Lupus anticoagulant (RVVT KT LA-PTT) Lupus anticoagulant (RVVT KT LA-PTT) Cardiolipin antibodies (antiphospholipid syndrome)Cardiolipin antibodies (antiphospholipid syndrome) Sticky platelet syndrome (aspirin)Sticky platelet syndrome (aspirin) ANA screeningANA screening PNH screeningPNH screening

When to testWhen to test Younger lt 50 years recurrent TE unusual sites Younger lt 50 years recurrent TE unusual sites

TE on WarfarinTE on Warfarin Not ideal to test after acute episode (inhibitors of Not ideal to test after acute episode (inhibitors of

clotting may be low)clotting may be low) Ideal test after 6 weeks after settlement of Ideal test after 6 weeks after settlement of

hemostasishemostasis Most patients are on Warfarin then (PC amp PS are Most patients are on Warfarin then (PC amp PS are

Vit K dependent may be falsely low)Vit K dependent may be falsely low) My view if long-term Warfarin is planned do My view if long-term Warfarin is planned do

immediately according to duration of treatment it immediately according to duration of treatment it can be done after cessation of treatmentcan be done after cessation of treatment

When to test (continued)When to test (continued)

Practical (my experience) before treatment ndash if AT Practical (my experience) before treatment ndash if AT PS PC are low PS PC are low repeat after Rx has been stopped repeat after Rx has been stopped

SPS platelet aggregation studies (problem SPS platelet aggregation studies (problem sometimes aspirin cannot be stopped)sometimes aspirin cannot be stopped)

Remember the effect of the vessel wall on clotting Remember the effect of the vessel wall on clotting especially in arterial thrombosisespecially in arterial thrombosis

Every woman on contraception HRTEvery woman on contraception HRT

Arterial ThrombosisArterial Thrombosis

Arterial Thrombosis

Arterial ThrombosisArterial Thrombosis

Results as sever oResults as sever o2 2 starvation of the left starvation of the left ventricle of the heartventricle of the heart

This leads to myocardial ischemia amp may This leads to myocardial ischemia amp may progress to myocardial infarction or progress to myocardial infarction or ischemic left ventricular fibrillation amp ischemic left ventricular fibrillation amp sudden deathsudden death

Similar episodes involving the cerebral Similar episodes involving the cerebral circulation result in transient ischemic circulation result in transient ischemic attacks amp thrombotic stroke attacks amp thrombotic stroke

Myocardial Infarction SymptomMyocardial Infarction Symptom

Crushing tightness of the chest with Crushing tightness of the chest with sweating nausea breathlessness amp sweating nausea breathlessness amp collapsecollapse

Chest pain may radiates to the arm throat amp Chest pain may radiates to the arm throat amp jawjaw

Chest pain may confused with sever Chest pain may confused with sever indigestion in itrsquos early stagesindigestion in itrsquos early stages

Transient Ischemic attacksTransient Ischemic attacks

Itrsquos usually accompanied with neurological Itrsquos usually accompanied with neurological dysfunction or loss of visiondysfunction or loss of vision

Completed thrombotic strokeCompleted thrombotic stroke

Itrsquos accompanied by similar symptoms Itrsquos accompanied by similar symptoms which persist for more than 24 hours that which persist for more than 24 hours that may be severely amp permanently disablingmay be severely amp permanently disabling

Risk factors for arterial amp venous thrombosisRisk factors for arterial amp venous thrombosis

Venous thrombosisVenous thrombosisArterial thrombosisArterial thrombosisIncreasing ageIncreasing ageIncreasing ageIncreasing age

ObesityObesityObesityObesity

ImmobilityImmobilityLack of exerciseLack of exercise

Pregnancy rdquopost partomrdquoPregnancy rdquopost partomrdquoHigh fat low fiber dietHigh fat low fiber diet

MalignancyMalignancySmokingSmoking

Lupus anticoagulantLupus anticoagulantHyperlipidemiaHyperlipidemia

Nephrotic syndromeNephrotic syndromeHypertensionHypertension

PolycythemiaPolycythemiaElevated factor VII II concElevated factor VII II conc

goutgoutGenetic factorGenetic factor

Prophylaxis amp treatment of Prophylaxis amp treatment of thrombosisthrombosis

Prevent the risk factorsPrevent the risk factors SmokingSmoking ObesityObesity Lack of exerciseLack of exercise Poor dietPoor diet

Only when this proves to be impossibleOnly when this proves to be impossible

(Pharmacological intervention is required) (Pharmacological intervention is required)

11 FV- LeidenFV- Leiden

One of the most common causes for thrombophilia One of the most common causes for thrombophilia ndash 20 of clinical disease (AT PC and PS ndash 5) + ndash 20 of clinical disease (AT PC and PS ndash 5) + risk factorrisk factor

Activated PC inhibits F Va and F VIIIaActivated PC inhibits F Va and F VIIIa Inability of APC to inhibit the above complex due Inability of APC to inhibit the above complex due

to mutated FVto mutated FV Heterozygous 5-10 times increased risk for TEHeterozygous 5-10 times increased risk for TE Homozygous 50-100 timesHomozygous 50-100 times

Factor Va

Arg 306 Arg 506 Arg 1765

Arginine CGA

Glutamine CAA

Factor Va resistant to APC cleavage

Factor V Leiden

Relative Risk forVenous Thrombosis

Factor V Leiden Heterozygote x 7

Factor V Leiden Homozygote x 80

Oral Contraceptives x 3

Oral Contraceptives + Factor V Leiden x 35

Leiden Study Group Data

22 Protein C DeficiencyProtein C Deficiency

Common cause (increasing TE with age)Common cause (increasing TE with age) Needs TM from endothelium wallNeeds TM from endothelium wall Heterozygous 50 of level of normal Heterozygous 50 of level of normal

individualsindividuals Homozygous babies are born with Homozygous babies are born with

undetected levels (thrombi in microvascular undetected levels (thrombi in microvascular of skin DIC necrosis purpura of skin DIC necrosis purpura fulminans)fulminans)

33 Protein S DeficiencyProtein S Deficiency

Non-enzymatic co-factor for PCNon-enzymatic co-factor for PC Binds to TM-PCBinds to TM-PC Same properties as PCSame properties as PC Two forms free in plasma and bound to C4b Two forms free in plasma and bound to C4b

binding protein (60) Only free fraction binding protein (60) Only free fraction functions as co-factor for APCfunctions as co-factor for APC

Sometimes difficult to get accurate measures of Sometimes difficult to get accurate measures of PS because of the latterPS because of the latter

Like PC can be acquired liver disease Warfarin Like PC can be acquired liver disease Warfarin pregnancy cancer DIC and chemopregnancy cancer DIC and chemo

44 Antithrombin III DeficiencyAntithrombin III Deficiency

Common cause (incidence 12000 ndash 15000 Common cause (incidence 12000 ndash 15000 heterozygotes 50 DVT) Quantitative vs heterozygotes 50 DVT) Quantitative vs Qualitative disorder (Acquired DIC cirrhosis Qualitative disorder (Acquired DIC cirrhosis NS)NS)

Bind to and inactivate thrombin Factors IXa Xa Bind to and inactivate thrombin Factors IXa Xa XIa and XIIa (ATheparin complex - rate of XIa and XIIa (ATheparin complex - rate of inhibition 1000-fold increased)inhibition 1000-fold increased)

Not necessarily a risk factor to be involved in Not necessarily a risk factor to be involved in heterozygotes to give TEheterozygotes to give TE

Increased incidence with ageing 80 at 55 yearsIncreased incidence with ageing 80 at 55 years

55 Abnormal ProthrombinAbnormal Prothrombin (PT 20210 A) (PT 20210 A)

CommonCommon Increased levels of prothrombin enhanced Increased levels of prothrombin enhanced

thrombin formationthrombin formation Only way for diagnosis DNA-PCR Only way for diagnosis DNA-PCR

techniquetechnique

66 Sticky Platelet SyndromeSticky Platelet Syndrome

Especially in arterial thrombosis (MI) and Especially in arterial thrombosis (MI) and development of recurrent TE while on Warfarindevelopment of recurrent TE while on Warfarin

3 Forms3 Forms If on aspirin it should be stopped 14 days prior to If on aspirin it should be stopped 14 days prior to

testingtesting

Also rememberAlso remember

PC PS and AT III are inhibitors of clottingPC PS and AT III are inhibitors of clotting

Non-familial (Acquired)Non-familial (Acquired)11 Antiphospholipid SyndromeAntiphospholipid Syndrome Antibodies directed against phospholipid cell membrane = Antibodies directed against phospholipid cell membrane =

APA (Antiphospholipid Ab)APA (Antiphospholipid Ab) APA ACA or LAAPA ACA or LA Primary (PAPS) or secondary (autoimmune disorders eg Primary (PAPS) or secondary (autoimmune disorders eg

SLE)SLE) ACA (Anticardiolipin Ab) IgM + IgGACA (Anticardiolipin Ab) IgM + IgG IgG the clinically important oneIgG the clinically important one IgM pregnancy infection (viral) trauma and post-opIgM pregnancy infection (viral) trauma and post-op LA (Lupus anticoagulant) Ab which affect clotting tests (LA-LA (Lupus anticoagulant) Ab which affect clotting tests (LA-

PTT RVV Kaolin)PTT RVV Kaolin) PAPS = TE miscarriage IUDPAPS = TE miscarriage IUD

Antiphospholipid Syndrome1048734 Antiphospholipid syndrome (APS) ndash Syndrome characterized by venous andor arterial thrombosis thrombocytopenia or recurrent fetal loss associated with antibodies to phospho-lipid- protein Complexes

1048734 Antiphospholipid antibodies (aPL)ndash IgG IgM or IgA antibodies that are directed to target proteins such as cardiolipin beta2-Glycoprotein I (β2GPI)or Prothrombin all of which bind to phospholipidsndash Lupus anticoagulant (LA) bull Antiphospholipid antibodies identified by in vitro phospholipid dependent clot-based assays antibodies are targeted against Prothrombin or β2GPI and prolong clotting times

Antiphospholipd Antibodies

Lupus Anticoagulant

Conditions where screening for APS Conditions where screening for APS is indicatedis indicated

The first thrombotic event below the age of 40The first thrombotic event below the age of 40 History of recurrent TEDHistory of recurrent TED Recurrent fetal loss in the 1Recurrent fetal loss in the 1stst or the 2 or the 2ndnd trimester trimester Patient with SLEPatient with SLE Pre-hormone replacement therapyPre-hormone replacement therapy

Non-familial (Acquired) continuedNon-familial (Acquired) continued

22 TPA (Tissue Plasminogen Activator) TPA (Tissue Plasminogen Activator) decreased levels impaired fibrinolysisdecreased levels impaired fibrinolysis

33 PAI (Plasminogen Activator Inhibitor) PAI (Plasminogen Activator Inhibitor) increased levels decreased TPAincreased levels decreased TPA

44 DysfibrinogenemiaDysfibrinogenemia55 F XII deficiency Hageman factorF XII deficiency Hageman factor66 Fibrinogen (increased)Fibrinogen (increased)77 F VIII (increased)F VIII (increased)88 PlasminogenPlasminogen99 Hyperhomocyteinemia ndash enzyme (folate)Hyperhomocyteinemia ndash enzyme (folate)

Investigation (Thrombotic Profile)Investigation (Thrombotic Profile)

NB Patients can be on Warfarin but not HeparinNB Patients can be on Warfarin but not Heparin FBC PLT amp ESRFBC PLT amp ESR PT aPTT TT amp FibrinogenPT aPTT TT amp Fibrinogen PC amp PSPC amp PS AT IIIAT III APCR (if + screening submit for PCR)APCR (if + screening submit for PCR) PT 20210A (PCR)PT 20210A (PCR) Lupus anticoagulant (RVVT KT LA-PTT) Lupus anticoagulant (RVVT KT LA-PTT) Cardiolipin antibodies (antiphospholipid syndrome)Cardiolipin antibodies (antiphospholipid syndrome) Sticky platelet syndrome (aspirin)Sticky platelet syndrome (aspirin) ANA screeningANA screening PNH screeningPNH screening

When to testWhen to test Younger lt 50 years recurrent TE unusual sites Younger lt 50 years recurrent TE unusual sites

TE on WarfarinTE on Warfarin Not ideal to test after acute episode (inhibitors of Not ideal to test after acute episode (inhibitors of

clotting may be low)clotting may be low) Ideal test after 6 weeks after settlement of Ideal test after 6 weeks after settlement of

hemostasishemostasis Most patients are on Warfarin then (PC amp PS are Most patients are on Warfarin then (PC amp PS are

Vit K dependent may be falsely low)Vit K dependent may be falsely low) My view if long-term Warfarin is planned do My view if long-term Warfarin is planned do

immediately according to duration of treatment it immediately according to duration of treatment it can be done after cessation of treatmentcan be done after cessation of treatment

When to test (continued)When to test (continued)

Practical (my experience) before treatment ndash if AT Practical (my experience) before treatment ndash if AT PS PC are low PS PC are low repeat after Rx has been stopped repeat after Rx has been stopped

SPS platelet aggregation studies (problem SPS platelet aggregation studies (problem sometimes aspirin cannot be stopped)sometimes aspirin cannot be stopped)

Remember the effect of the vessel wall on clotting Remember the effect of the vessel wall on clotting especially in arterial thrombosisespecially in arterial thrombosis

Every woman on contraception HRTEvery woman on contraception HRT

Arterial ThrombosisArterial Thrombosis

Arterial Thrombosis

Arterial ThrombosisArterial Thrombosis

Results as sever oResults as sever o2 2 starvation of the left starvation of the left ventricle of the heartventricle of the heart

This leads to myocardial ischemia amp may This leads to myocardial ischemia amp may progress to myocardial infarction or progress to myocardial infarction or ischemic left ventricular fibrillation amp ischemic left ventricular fibrillation amp sudden deathsudden death

Similar episodes involving the cerebral Similar episodes involving the cerebral circulation result in transient ischemic circulation result in transient ischemic attacks amp thrombotic stroke attacks amp thrombotic stroke

Myocardial Infarction SymptomMyocardial Infarction Symptom

Crushing tightness of the chest with Crushing tightness of the chest with sweating nausea breathlessness amp sweating nausea breathlessness amp collapsecollapse

Chest pain may radiates to the arm throat amp Chest pain may radiates to the arm throat amp jawjaw

Chest pain may confused with sever Chest pain may confused with sever indigestion in itrsquos early stagesindigestion in itrsquos early stages

Transient Ischemic attacksTransient Ischemic attacks

Itrsquos usually accompanied with neurological Itrsquos usually accompanied with neurological dysfunction or loss of visiondysfunction or loss of vision

Completed thrombotic strokeCompleted thrombotic stroke

Itrsquos accompanied by similar symptoms Itrsquos accompanied by similar symptoms which persist for more than 24 hours that which persist for more than 24 hours that may be severely amp permanently disablingmay be severely amp permanently disabling

Risk factors for arterial amp venous thrombosisRisk factors for arterial amp venous thrombosis

Venous thrombosisVenous thrombosisArterial thrombosisArterial thrombosisIncreasing ageIncreasing ageIncreasing ageIncreasing age

ObesityObesityObesityObesity

ImmobilityImmobilityLack of exerciseLack of exercise

Pregnancy rdquopost partomrdquoPregnancy rdquopost partomrdquoHigh fat low fiber dietHigh fat low fiber diet

MalignancyMalignancySmokingSmoking

Lupus anticoagulantLupus anticoagulantHyperlipidemiaHyperlipidemia

Nephrotic syndromeNephrotic syndromeHypertensionHypertension

PolycythemiaPolycythemiaElevated factor VII II concElevated factor VII II conc

goutgoutGenetic factorGenetic factor

Prophylaxis amp treatment of Prophylaxis amp treatment of thrombosisthrombosis

Prevent the risk factorsPrevent the risk factors SmokingSmoking ObesityObesity Lack of exerciseLack of exercise Poor dietPoor diet

Only when this proves to be impossibleOnly when this proves to be impossible

(Pharmacological intervention is required) (Pharmacological intervention is required)

Factor Va

Arg 306 Arg 506 Arg 1765

Arginine CGA

Glutamine CAA

Factor Va resistant to APC cleavage

Factor V Leiden

Relative Risk forVenous Thrombosis

Factor V Leiden Heterozygote x 7

Factor V Leiden Homozygote x 80

Oral Contraceptives x 3

Oral Contraceptives + Factor V Leiden x 35

Leiden Study Group Data

22 Protein C DeficiencyProtein C Deficiency

Common cause (increasing TE with age)Common cause (increasing TE with age) Needs TM from endothelium wallNeeds TM from endothelium wall Heterozygous 50 of level of normal Heterozygous 50 of level of normal

individualsindividuals Homozygous babies are born with Homozygous babies are born with

undetected levels (thrombi in microvascular undetected levels (thrombi in microvascular of skin DIC necrosis purpura of skin DIC necrosis purpura fulminans)fulminans)

33 Protein S DeficiencyProtein S Deficiency

Non-enzymatic co-factor for PCNon-enzymatic co-factor for PC Binds to TM-PCBinds to TM-PC Same properties as PCSame properties as PC Two forms free in plasma and bound to C4b Two forms free in plasma and bound to C4b

binding protein (60) Only free fraction binding protein (60) Only free fraction functions as co-factor for APCfunctions as co-factor for APC

Sometimes difficult to get accurate measures of Sometimes difficult to get accurate measures of PS because of the latterPS because of the latter

Like PC can be acquired liver disease Warfarin Like PC can be acquired liver disease Warfarin pregnancy cancer DIC and chemopregnancy cancer DIC and chemo

44 Antithrombin III DeficiencyAntithrombin III Deficiency

Common cause (incidence 12000 ndash 15000 Common cause (incidence 12000 ndash 15000 heterozygotes 50 DVT) Quantitative vs heterozygotes 50 DVT) Quantitative vs Qualitative disorder (Acquired DIC cirrhosis Qualitative disorder (Acquired DIC cirrhosis NS)NS)

Bind to and inactivate thrombin Factors IXa Xa Bind to and inactivate thrombin Factors IXa Xa XIa and XIIa (ATheparin complex - rate of XIa and XIIa (ATheparin complex - rate of inhibition 1000-fold increased)inhibition 1000-fold increased)

Not necessarily a risk factor to be involved in Not necessarily a risk factor to be involved in heterozygotes to give TEheterozygotes to give TE

Increased incidence with ageing 80 at 55 yearsIncreased incidence with ageing 80 at 55 years

55 Abnormal ProthrombinAbnormal Prothrombin (PT 20210 A) (PT 20210 A)

CommonCommon Increased levels of prothrombin enhanced Increased levels of prothrombin enhanced

thrombin formationthrombin formation Only way for diagnosis DNA-PCR Only way for diagnosis DNA-PCR

techniquetechnique

66 Sticky Platelet SyndromeSticky Platelet Syndrome

Especially in arterial thrombosis (MI) and Especially in arterial thrombosis (MI) and development of recurrent TE while on Warfarindevelopment of recurrent TE while on Warfarin

3 Forms3 Forms If on aspirin it should be stopped 14 days prior to If on aspirin it should be stopped 14 days prior to

testingtesting

Also rememberAlso remember

PC PS and AT III are inhibitors of clottingPC PS and AT III are inhibitors of clotting

Non-familial (Acquired)Non-familial (Acquired)11 Antiphospholipid SyndromeAntiphospholipid Syndrome Antibodies directed against phospholipid cell membrane = Antibodies directed against phospholipid cell membrane =

APA (Antiphospholipid Ab)APA (Antiphospholipid Ab) APA ACA or LAAPA ACA or LA Primary (PAPS) or secondary (autoimmune disorders eg Primary (PAPS) or secondary (autoimmune disorders eg

SLE)SLE) ACA (Anticardiolipin Ab) IgM + IgGACA (Anticardiolipin Ab) IgM + IgG IgG the clinically important oneIgG the clinically important one IgM pregnancy infection (viral) trauma and post-opIgM pregnancy infection (viral) trauma and post-op LA (Lupus anticoagulant) Ab which affect clotting tests (LA-LA (Lupus anticoagulant) Ab which affect clotting tests (LA-

PTT RVV Kaolin)PTT RVV Kaolin) PAPS = TE miscarriage IUDPAPS = TE miscarriage IUD

Antiphospholipid Syndrome1048734 Antiphospholipid syndrome (APS) ndash Syndrome characterized by venous andor arterial thrombosis thrombocytopenia or recurrent fetal loss associated with antibodies to phospho-lipid- protein Complexes

1048734 Antiphospholipid antibodies (aPL)ndash IgG IgM or IgA antibodies that are directed to target proteins such as cardiolipin beta2-Glycoprotein I (β2GPI)or Prothrombin all of which bind to phospholipidsndash Lupus anticoagulant (LA) bull Antiphospholipid antibodies identified by in vitro phospholipid dependent clot-based assays antibodies are targeted against Prothrombin or β2GPI and prolong clotting times

Antiphospholipd Antibodies

Lupus Anticoagulant

Conditions where screening for APS Conditions where screening for APS is indicatedis indicated

The first thrombotic event below the age of 40The first thrombotic event below the age of 40 History of recurrent TEDHistory of recurrent TED Recurrent fetal loss in the 1Recurrent fetal loss in the 1stst or the 2 or the 2ndnd trimester trimester Patient with SLEPatient with SLE Pre-hormone replacement therapyPre-hormone replacement therapy

Non-familial (Acquired) continuedNon-familial (Acquired) continued

22 TPA (Tissue Plasminogen Activator) TPA (Tissue Plasminogen Activator) decreased levels impaired fibrinolysisdecreased levels impaired fibrinolysis

33 PAI (Plasminogen Activator Inhibitor) PAI (Plasminogen Activator Inhibitor) increased levels decreased TPAincreased levels decreased TPA

44 DysfibrinogenemiaDysfibrinogenemia55 F XII deficiency Hageman factorF XII deficiency Hageman factor66 Fibrinogen (increased)Fibrinogen (increased)77 F VIII (increased)F VIII (increased)88 PlasminogenPlasminogen99 Hyperhomocyteinemia ndash enzyme (folate)Hyperhomocyteinemia ndash enzyme (folate)

Investigation (Thrombotic Profile)Investigation (Thrombotic Profile)

NB Patients can be on Warfarin but not HeparinNB Patients can be on Warfarin but not Heparin FBC PLT amp ESRFBC PLT amp ESR PT aPTT TT amp FibrinogenPT aPTT TT amp Fibrinogen PC amp PSPC amp PS AT IIIAT III APCR (if + screening submit for PCR)APCR (if + screening submit for PCR) PT 20210A (PCR)PT 20210A (PCR) Lupus anticoagulant (RVVT KT LA-PTT) Lupus anticoagulant (RVVT KT LA-PTT) Cardiolipin antibodies (antiphospholipid syndrome)Cardiolipin antibodies (antiphospholipid syndrome) Sticky platelet syndrome (aspirin)Sticky platelet syndrome (aspirin) ANA screeningANA screening PNH screeningPNH screening

When to testWhen to test Younger lt 50 years recurrent TE unusual sites Younger lt 50 years recurrent TE unusual sites

TE on WarfarinTE on Warfarin Not ideal to test after acute episode (inhibitors of Not ideal to test after acute episode (inhibitors of

clotting may be low)clotting may be low) Ideal test after 6 weeks after settlement of Ideal test after 6 weeks after settlement of

hemostasishemostasis Most patients are on Warfarin then (PC amp PS are Most patients are on Warfarin then (PC amp PS are

Vit K dependent may be falsely low)Vit K dependent may be falsely low) My view if long-term Warfarin is planned do My view if long-term Warfarin is planned do

immediately according to duration of treatment it immediately according to duration of treatment it can be done after cessation of treatmentcan be done after cessation of treatment

When to test (continued)When to test (continued)

Practical (my experience) before treatment ndash if AT Practical (my experience) before treatment ndash if AT PS PC are low PS PC are low repeat after Rx has been stopped repeat after Rx has been stopped

SPS platelet aggregation studies (problem SPS platelet aggregation studies (problem sometimes aspirin cannot be stopped)sometimes aspirin cannot be stopped)

Remember the effect of the vessel wall on clotting Remember the effect of the vessel wall on clotting especially in arterial thrombosisespecially in arterial thrombosis

Every woman on contraception HRTEvery woman on contraception HRT

Arterial ThrombosisArterial Thrombosis

Arterial Thrombosis

Arterial ThrombosisArterial Thrombosis

Results as sever oResults as sever o2 2 starvation of the left starvation of the left ventricle of the heartventricle of the heart

This leads to myocardial ischemia amp may This leads to myocardial ischemia amp may progress to myocardial infarction or progress to myocardial infarction or ischemic left ventricular fibrillation amp ischemic left ventricular fibrillation amp sudden deathsudden death

Similar episodes involving the cerebral Similar episodes involving the cerebral circulation result in transient ischemic circulation result in transient ischemic attacks amp thrombotic stroke attacks amp thrombotic stroke

Myocardial Infarction SymptomMyocardial Infarction Symptom

Crushing tightness of the chest with Crushing tightness of the chest with sweating nausea breathlessness amp sweating nausea breathlessness amp collapsecollapse

Chest pain may radiates to the arm throat amp Chest pain may radiates to the arm throat amp jawjaw

Chest pain may confused with sever Chest pain may confused with sever indigestion in itrsquos early stagesindigestion in itrsquos early stages

Transient Ischemic attacksTransient Ischemic attacks

Itrsquos usually accompanied with neurological Itrsquos usually accompanied with neurological dysfunction or loss of visiondysfunction or loss of vision

Completed thrombotic strokeCompleted thrombotic stroke

Itrsquos accompanied by similar symptoms Itrsquos accompanied by similar symptoms which persist for more than 24 hours that which persist for more than 24 hours that may be severely amp permanently disablingmay be severely amp permanently disabling

Risk factors for arterial amp venous thrombosisRisk factors for arterial amp venous thrombosis

Venous thrombosisVenous thrombosisArterial thrombosisArterial thrombosisIncreasing ageIncreasing ageIncreasing ageIncreasing age

ObesityObesityObesityObesity

ImmobilityImmobilityLack of exerciseLack of exercise

Pregnancy rdquopost partomrdquoPregnancy rdquopost partomrdquoHigh fat low fiber dietHigh fat low fiber diet

MalignancyMalignancySmokingSmoking

Lupus anticoagulantLupus anticoagulantHyperlipidemiaHyperlipidemia

Nephrotic syndromeNephrotic syndromeHypertensionHypertension

PolycythemiaPolycythemiaElevated factor VII II concElevated factor VII II conc

goutgoutGenetic factorGenetic factor

Prophylaxis amp treatment of Prophylaxis amp treatment of thrombosisthrombosis

Prevent the risk factorsPrevent the risk factors SmokingSmoking ObesityObesity Lack of exerciseLack of exercise Poor dietPoor diet

Only when this proves to be impossibleOnly when this proves to be impossible

(Pharmacological intervention is required) (Pharmacological intervention is required)

Relative Risk forVenous Thrombosis

Factor V Leiden Heterozygote x 7

Factor V Leiden Homozygote x 80

Oral Contraceptives x 3

Oral Contraceptives + Factor V Leiden x 35

Leiden Study Group Data

22 Protein C DeficiencyProtein C Deficiency

Common cause (increasing TE with age)Common cause (increasing TE with age) Needs TM from endothelium wallNeeds TM from endothelium wall Heterozygous 50 of level of normal Heterozygous 50 of level of normal

individualsindividuals Homozygous babies are born with Homozygous babies are born with

undetected levels (thrombi in microvascular undetected levels (thrombi in microvascular of skin DIC necrosis purpura of skin DIC necrosis purpura fulminans)fulminans)

33 Protein S DeficiencyProtein S Deficiency

Non-enzymatic co-factor for PCNon-enzymatic co-factor for PC Binds to TM-PCBinds to TM-PC Same properties as PCSame properties as PC Two forms free in plasma and bound to C4b Two forms free in plasma and bound to C4b

binding protein (60) Only free fraction binding protein (60) Only free fraction functions as co-factor for APCfunctions as co-factor for APC

Sometimes difficult to get accurate measures of Sometimes difficult to get accurate measures of PS because of the latterPS because of the latter

Like PC can be acquired liver disease Warfarin Like PC can be acquired liver disease Warfarin pregnancy cancer DIC and chemopregnancy cancer DIC and chemo

44 Antithrombin III DeficiencyAntithrombin III Deficiency

Common cause (incidence 12000 ndash 15000 Common cause (incidence 12000 ndash 15000 heterozygotes 50 DVT) Quantitative vs heterozygotes 50 DVT) Quantitative vs Qualitative disorder (Acquired DIC cirrhosis Qualitative disorder (Acquired DIC cirrhosis NS)NS)

Bind to and inactivate thrombin Factors IXa Xa Bind to and inactivate thrombin Factors IXa Xa XIa and XIIa (ATheparin complex - rate of XIa and XIIa (ATheparin complex - rate of inhibition 1000-fold increased)inhibition 1000-fold increased)

Not necessarily a risk factor to be involved in Not necessarily a risk factor to be involved in heterozygotes to give TEheterozygotes to give TE

Increased incidence with ageing 80 at 55 yearsIncreased incidence with ageing 80 at 55 years

55 Abnormal ProthrombinAbnormal Prothrombin (PT 20210 A) (PT 20210 A)

CommonCommon Increased levels of prothrombin enhanced Increased levels of prothrombin enhanced

thrombin formationthrombin formation Only way for diagnosis DNA-PCR Only way for diagnosis DNA-PCR

techniquetechnique

66 Sticky Platelet SyndromeSticky Platelet Syndrome

Especially in arterial thrombosis (MI) and Especially in arterial thrombosis (MI) and development of recurrent TE while on Warfarindevelopment of recurrent TE while on Warfarin

3 Forms3 Forms If on aspirin it should be stopped 14 days prior to If on aspirin it should be stopped 14 days prior to

testingtesting

Also rememberAlso remember

PC PS and AT III are inhibitors of clottingPC PS and AT III are inhibitors of clotting

Non-familial (Acquired)Non-familial (Acquired)11 Antiphospholipid SyndromeAntiphospholipid Syndrome Antibodies directed against phospholipid cell membrane = Antibodies directed against phospholipid cell membrane =

APA (Antiphospholipid Ab)APA (Antiphospholipid Ab) APA ACA or LAAPA ACA or LA Primary (PAPS) or secondary (autoimmune disorders eg Primary (PAPS) or secondary (autoimmune disorders eg

SLE)SLE) ACA (Anticardiolipin Ab) IgM + IgGACA (Anticardiolipin Ab) IgM + IgG IgG the clinically important oneIgG the clinically important one IgM pregnancy infection (viral) trauma and post-opIgM pregnancy infection (viral) trauma and post-op LA (Lupus anticoagulant) Ab which affect clotting tests (LA-LA (Lupus anticoagulant) Ab which affect clotting tests (LA-

PTT RVV Kaolin)PTT RVV Kaolin) PAPS = TE miscarriage IUDPAPS = TE miscarriage IUD

Antiphospholipid Syndrome1048734 Antiphospholipid syndrome (APS) ndash Syndrome characterized by venous andor arterial thrombosis thrombocytopenia or recurrent fetal loss associated with antibodies to phospho-lipid- protein Complexes

1048734 Antiphospholipid antibodies (aPL)ndash IgG IgM or IgA antibodies that are directed to target proteins such as cardiolipin beta2-Glycoprotein I (β2GPI)or Prothrombin all of which bind to phospholipidsndash Lupus anticoagulant (LA) bull Antiphospholipid antibodies identified by in vitro phospholipid dependent clot-based assays antibodies are targeted against Prothrombin or β2GPI and prolong clotting times

Antiphospholipd Antibodies

Lupus Anticoagulant

Conditions where screening for APS Conditions where screening for APS is indicatedis indicated

The first thrombotic event below the age of 40The first thrombotic event below the age of 40 History of recurrent TEDHistory of recurrent TED Recurrent fetal loss in the 1Recurrent fetal loss in the 1stst or the 2 or the 2ndnd trimester trimester Patient with SLEPatient with SLE Pre-hormone replacement therapyPre-hormone replacement therapy

Non-familial (Acquired) continuedNon-familial (Acquired) continued

22 TPA (Tissue Plasminogen Activator) TPA (Tissue Plasminogen Activator) decreased levels impaired fibrinolysisdecreased levels impaired fibrinolysis

33 PAI (Plasminogen Activator Inhibitor) PAI (Plasminogen Activator Inhibitor) increased levels decreased TPAincreased levels decreased TPA

44 DysfibrinogenemiaDysfibrinogenemia55 F XII deficiency Hageman factorF XII deficiency Hageman factor66 Fibrinogen (increased)Fibrinogen (increased)77 F VIII (increased)F VIII (increased)88 PlasminogenPlasminogen99 Hyperhomocyteinemia ndash enzyme (folate)Hyperhomocyteinemia ndash enzyme (folate)

Investigation (Thrombotic Profile)Investigation (Thrombotic Profile)

NB Patients can be on Warfarin but not HeparinNB Patients can be on Warfarin but not Heparin FBC PLT amp ESRFBC PLT amp ESR PT aPTT TT amp FibrinogenPT aPTT TT amp Fibrinogen PC amp PSPC amp PS AT IIIAT III APCR (if + screening submit for PCR)APCR (if + screening submit for PCR) PT 20210A (PCR)PT 20210A (PCR) Lupus anticoagulant (RVVT KT LA-PTT) Lupus anticoagulant (RVVT KT LA-PTT) Cardiolipin antibodies (antiphospholipid syndrome)Cardiolipin antibodies (antiphospholipid syndrome) Sticky platelet syndrome (aspirin)Sticky platelet syndrome (aspirin) ANA screeningANA screening PNH screeningPNH screening

When to testWhen to test Younger lt 50 years recurrent TE unusual sites Younger lt 50 years recurrent TE unusual sites

TE on WarfarinTE on Warfarin Not ideal to test after acute episode (inhibitors of Not ideal to test after acute episode (inhibitors of

clotting may be low)clotting may be low) Ideal test after 6 weeks after settlement of Ideal test after 6 weeks after settlement of

hemostasishemostasis Most patients are on Warfarin then (PC amp PS are Most patients are on Warfarin then (PC amp PS are

Vit K dependent may be falsely low)Vit K dependent may be falsely low) My view if long-term Warfarin is planned do My view if long-term Warfarin is planned do

immediately according to duration of treatment it immediately according to duration of treatment it can be done after cessation of treatmentcan be done after cessation of treatment

When to test (continued)When to test (continued)

Practical (my experience) before treatment ndash if AT Practical (my experience) before treatment ndash if AT PS PC are low PS PC are low repeat after Rx has been stopped repeat after Rx has been stopped

SPS platelet aggregation studies (problem SPS platelet aggregation studies (problem sometimes aspirin cannot be stopped)sometimes aspirin cannot be stopped)

Remember the effect of the vessel wall on clotting Remember the effect of the vessel wall on clotting especially in arterial thrombosisespecially in arterial thrombosis

Every woman on contraception HRTEvery woman on contraception HRT

Arterial ThrombosisArterial Thrombosis

Arterial Thrombosis

Arterial ThrombosisArterial Thrombosis

Results as sever oResults as sever o2 2 starvation of the left starvation of the left ventricle of the heartventricle of the heart

This leads to myocardial ischemia amp may This leads to myocardial ischemia amp may progress to myocardial infarction or progress to myocardial infarction or ischemic left ventricular fibrillation amp ischemic left ventricular fibrillation amp sudden deathsudden death

Similar episodes involving the cerebral Similar episodes involving the cerebral circulation result in transient ischemic circulation result in transient ischemic attacks amp thrombotic stroke attacks amp thrombotic stroke

Myocardial Infarction SymptomMyocardial Infarction Symptom

Crushing tightness of the chest with Crushing tightness of the chest with sweating nausea breathlessness amp sweating nausea breathlessness amp collapsecollapse

Chest pain may radiates to the arm throat amp Chest pain may radiates to the arm throat amp jawjaw

Chest pain may confused with sever Chest pain may confused with sever indigestion in itrsquos early stagesindigestion in itrsquos early stages

Transient Ischemic attacksTransient Ischemic attacks

Itrsquos usually accompanied with neurological Itrsquos usually accompanied with neurological dysfunction or loss of visiondysfunction or loss of vision

Completed thrombotic strokeCompleted thrombotic stroke

Itrsquos accompanied by similar symptoms Itrsquos accompanied by similar symptoms which persist for more than 24 hours that which persist for more than 24 hours that may be severely amp permanently disablingmay be severely amp permanently disabling

Risk factors for arterial amp venous thrombosisRisk factors for arterial amp venous thrombosis

Venous thrombosisVenous thrombosisArterial thrombosisArterial thrombosisIncreasing ageIncreasing ageIncreasing ageIncreasing age

ObesityObesityObesityObesity

ImmobilityImmobilityLack of exerciseLack of exercise

Pregnancy rdquopost partomrdquoPregnancy rdquopost partomrdquoHigh fat low fiber dietHigh fat low fiber diet

MalignancyMalignancySmokingSmoking

Lupus anticoagulantLupus anticoagulantHyperlipidemiaHyperlipidemia

Nephrotic syndromeNephrotic syndromeHypertensionHypertension

PolycythemiaPolycythemiaElevated factor VII II concElevated factor VII II conc

goutgoutGenetic factorGenetic factor

Prophylaxis amp treatment of Prophylaxis amp treatment of thrombosisthrombosis

Prevent the risk factorsPrevent the risk factors SmokingSmoking ObesityObesity Lack of exerciseLack of exercise Poor dietPoor diet

Only when this proves to be impossibleOnly when this proves to be impossible

(Pharmacological intervention is required) (Pharmacological intervention is required)

22 Protein C DeficiencyProtein C Deficiency

Common cause (increasing TE with age)Common cause (increasing TE with age) Needs TM from endothelium wallNeeds TM from endothelium wall Heterozygous 50 of level of normal Heterozygous 50 of level of normal

individualsindividuals Homozygous babies are born with Homozygous babies are born with

undetected levels (thrombi in microvascular undetected levels (thrombi in microvascular of skin DIC necrosis purpura of skin DIC necrosis purpura fulminans)fulminans)

33 Protein S DeficiencyProtein S Deficiency

Non-enzymatic co-factor for PCNon-enzymatic co-factor for PC Binds to TM-PCBinds to TM-PC Same properties as PCSame properties as PC Two forms free in plasma and bound to C4b Two forms free in plasma and bound to C4b

binding protein (60) Only free fraction binding protein (60) Only free fraction functions as co-factor for APCfunctions as co-factor for APC

Sometimes difficult to get accurate measures of Sometimes difficult to get accurate measures of PS because of the latterPS because of the latter

Like PC can be acquired liver disease Warfarin Like PC can be acquired liver disease Warfarin pregnancy cancer DIC and chemopregnancy cancer DIC and chemo

44 Antithrombin III DeficiencyAntithrombin III Deficiency

Common cause (incidence 12000 ndash 15000 Common cause (incidence 12000 ndash 15000 heterozygotes 50 DVT) Quantitative vs heterozygotes 50 DVT) Quantitative vs Qualitative disorder (Acquired DIC cirrhosis Qualitative disorder (Acquired DIC cirrhosis NS)NS)

Bind to and inactivate thrombin Factors IXa Xa Bind to and inactivate thrombin Factors IXa Xa XIa and XIIa (ATheparin complex - rate of XIa and XIIa (ATheparin complex - rate of inhibition 1000-fold increased)inhibition 1000-fold increased)

Not necessarily a risk factor to be involved in Not necessarily a risk factor to be involved in heterozygotes to give TEheterozygotes to give TE

Increased incidence with ageing 80 at 55 yearsIncreased incidence with ageing 80 at 55 years

55 Abnormal ProthrombinAbnormal Prothrombin (PT 20210 A) (PT 20210 A)

CommonCommon Increased levels of prothrombin enhanced Increased levels of prothrombin enhanced

thrombin formationthrombin formation Only way for diagnosis DNA-PCR Only way for diagnosis DNA-PCR

techniquetechnique

66 Sticky Platelet SyndromeSticky Platelet Syndrome

Especially in arterial thrombosis (MI) and Especially in arterial thrombosis (MI) and development of recurrent TE while on Warfarindevelopment of recurrent TE while on Warfarin

3 Forms3 Forms If on aspirin it should be stopped 14 days prior to If on aspirin it should be stopped 14 days prior to

testingtesting

Also rememberAlso remember

PC PS and AT III are inhibitors of clottingPC PS and AT III are inhibitors of clotting

Non-familial (Acquired)Non-familial (Acquired)11 Antiphospholipid SyndromeAntiphospholipid Syndrome Antibodies directed against phospholipid cell membrane = Antibodies directed against phospholipid cell membrane =

APA (Antiphospholipid Ab)APA (Antiphospholipid Ab) APA ACA or LAAPA ACA or LA Primary (PAPS) or secondary (autoimmune disorders eg Primary (PAPS) or secondary (autoimmune disorders eg

SLE)SLE) ACA (Anticardiolipin Ab) IgM + IgGACA (Anticardiolipin Ab) IgM + IgG IgG the clinically important oneIgG the clinically important one IgM pregnancy infection (viral) trauma and post-opIgM pregnancy infection (viral) trauma and post-op LA (Lupus anticoagulant) Ab which affect clotting tests (LA-LA (Lupus anticoagulant) Ab which affect clotting tests (LA-

PTT RVV Kaolin)PTT RVV Kaolin) PAPS = TE miscarriage IUDPAPS = TE miscarriage IUD

Antiphospholipid Syndrome1048734 Antiphospholipid syndrome (APS) ndash Syndrome characterized by venous andor arterial thrombosis thrombocytopenia or recurrent fetal loss associated with antibodies to phospho-lipid- protein Complexes

1048734 Antiphospholipid antibodies (aPL)ndash IgG IgM or IgA antibodies that are directed to target proteins such as cardiolipin beta2-Glycoprotein I (β2GPI)or Prothrombin all of which bind to phospholipidsndash Lupus anticoagulant (LA) bull Antiphospholipid antibodies identified by in vitro phospholipid dependent clot-based assays antibodies are targeted against Prothrombin or β2GPI and prolong clotting times

Antiphospholipd Antibodies

Lupus Anticoagulant

Conditions where screening for APS Conditions where screening for APS is indicatedis indicated

The first thrombotic event below the age of 40The first thrombotic event below the age of 40 History of recurrent TEDHistory of recurrent TED Recurrent fetal loss in the 1Recurrent fetal loss in the 1stst or the 2 or the 2ndnd trimester trimester Patient with SLEPatient with SLE Pre-hormone replacement therapyPre-hormone replacement therapy

Non-familial (Acquired) continuedNon-familial (Acquired) continued

22 TPA (Tissue Plasminogen Activator) TPA (Tissue Plasminogen Activator) decreased levels impaired fibrinolysisdecreased levels impaired fibrinolysis

33 PAI (Plasminogen Activator Inhibitor) PAI (Plasminogen Activator Inhibitor) increased levels decreased TPAincreased levels decreased TPA

44 DysfibrinogenemiaDysfibrinogenemia55 F XII deficiency Hageman factorF XII deficiency Hageman factor66 Fibrinogen (increased)Fibrinogen (increased)77 F VIII (increased)F VIII (increased)88 PlasminogenPlasminogen99 Hyperhomocyteinemia ndash enzyme (folate)Hyperhomocyteinemia ndash enzyme (folate)

Investigation (Thrombotic Profile)Investigation (Thrombotic Profile)

NB Patients can be on Warfarin but not HeparinNB Patients can be on Warfarin but not Heparin FBC PLT amp ESRFBC PLT amp ESR PT aPTT TT amp FibrinogenPT aPTT TT amp Fibrinogen PC amp PSPC amp PS AT IIIAT III APCR (if + screening submit for PCR)APCR (if + screening submit for PCR) PT 20210A (PCR)PT 20210A (PCR) Lupus anticoagulant (RVVT KT LA-PTT) Lupus anticoagulant (RVVT KT LA-PTT) Cardiolipin antibodies (antiphospholipid syndrome)Cardiolipin antibodies (antiphospholipid syndrome) Sticky platelet syndrome (aspirin)Sticky platelet syndrome (aspirin) ANA screeningANA screening PNH screeningPNH screening

When to testWhen to test Younger lt 50 years recurrent TE unusual sites Younger lt 50 years recurrent TE unusual sites

TE on WarfarinTE on Warfarin Not ideal to test after acute episode (inhibitors of Not ideal to test after acute episode (inhibitors of

clotting may be low)clotting may be low) Ideal test after 6 weeks after settlement of Ideal test after 6 weeks after settlement of

hemostasishemostasis Most patients are on Warfarin then (PC amp PS are Most patients are on Warfarin then (PC amp PS are

Vit K dependent may be falsely low)Vit K dependent may be falsely low) My view if long-term Warfarin is planned do My view if long-term Warfarin is planned do

immediately according to duration of treatment it immediately according to duration of treatment it can be done after cessation of treatmentcan be done after cessation of treatment

When to test (continued)When to test (continued)

Practical (my experience) before treatment ndash if AT Practical (my experience) before treatment ndash if AT PS PC are low PS PC are low repeat after Rx has been stopped repeat after Rx has been stopped

SPS platelet aggregation studies (problem SPS platelet aggregation studies (problem sometimes aspirin cannot be stopped)sometimes aspirin cannot be stopped)

Remember the effect of the vessel wall on clotting Remember the effect of the vessel wall on clotting especially in arterial thrombosisespecially in arterial thrombosis

Every woman on contraception HRTEvery woman on contraception HRT

Arterial ThrombosisArterial Thrombosis

Arterial Thrombosis

Arterial ThrombosisArterial Thrombosis

Results as sever oResults as sever o2 2 starvation of the left starvation of the left ventricle of the heartventricle of the heart

This leads to myocardial ischemia amp may This leads to myocardial ischemia amp may progress to myocardial infarction or progress to myocardial infarction or ischemic left ventricular fibrillation amp ischemic left ventricular fibrillation amp sudden deathsudden death

Similar episodes involving the cerebral Similar episodes involving the cerebral circulation result in transient ischemic circulation result in transient ischemic attacks amp thrombotic stroke attacks amp thrombotic stroke

Myocardial Infarction SymptomMyocardial Infarction Symptom

Crushing tightness of the chest with Crushing tightness of the chest with sweating nausea breathlessness amp sweating nausea breathlessness amp collapsecollapse

Chest pain may radiates to the arm throat amp Chest pain may radiates to the arm throat amp jawjaw

Chest pain may confused with sever Chest pain may confused with sever indigestion in itrsquos early stagesindigestion in itrsquos early stages

Transient Ischemic attacksTransient Ischemic attacks

Itrsquos usually accompanied with neurological Itrsquos usually accompanied with neurological dysfunction or loss of visiondysfunction or loss of vision

Completed thrombotic strokeCompleted thrombotic stroke

Itrsquos accompanied by similar symptoms Itrsquos accompanied by similar symptoms which persist for more than 24 hours that which persist for more than 24 hours that may be severely amp permanently disablingmay be severely amp permanently disabling

Risk factors for arterial amp venous thrombosisRisk factors for arterial amp venous thrombosis

Venous thrombosisVenous thrombosisArterial thrombosisArterial thrombosisIncreasing ageIncreasing ageIncreasing ageIncreasing age

ObesityObesityObesityObesity

ImmobilityImmobilityLack of exerciseLack of exercise

Pregnancy rdquopost partomrdquoPregnancy rdquopost partomrdquoHigh fat low fiber dietHigh fat low fiber diet

MalignancyMalignancySmokingSmoking

Lupus anticoagulantLupus anticoagulantHyperlipidemiaHyperlipidemia

Nephrotic syndromeNephrotic syndromeHypertensionHypertension

PolycythemiaPolycythemiaElevated factor VII II concElevated factor VII II conc

goutgoutGenetic factorGenetic factor

Prophylaxis amp treatment of Prophylaxis amp treatment of thrombosisthrombosis

Prevent the risk factorsPrevent the risk factors SmokingSmoking ObesityObesity Lack of exerciseLack of exercise Poor dietPoor diet

Only when this proves to be impossibleOnly when this proves to be impossible

(Pharmacological intervention is required) (Pharmacological intervention is required)

33 Protein S DeficiencyProtein S Deficiency

Non-enzymatic co-factor for PCNon-enzymatic co-factor for PC Binds to TM-PCBinds to TM-PC Same properties as PCSame properties as PC Two forms free in plasma and bound to C4b Two forms free in plasma and bound to C4b

binding protein (60) Only free fraction binding protein (60) Only free fraction functions as co-factor for APCfunctions as co-factor for APC

Sometimes difficult to get accurate measures of Sometimes difficult to get accurate measures of PS because of the latterPS because of the latter

Like PC can be acquired liver disease Warfarin Like PC can be acquired liver disease Warfarin pregnancy cancer DIC and chemopregnancy cancer DIC and chemo

44 Antithrombin III DeficiencyAntithrombin III Deficiency

Common cause (incidence 12000 ndash 15000 Common cause (incidence 12000 ndash 15000 heterozygotes 50 DVT) Quantitative vs heterozygotes 50 DVT) Quantitative vs Qualitative disorder (Acquired DIC cirrhosis Qualitative disorder (Acquired DIC cirrhosis NS)NS)

Bind to and inactivate thrombin Factors IXa Xa Bind to and inactivate thrombin Factors IXa Xa XIa and XIIa (ATheparin complex - rate of XIa and XIIa (ATheparin complex - rate of inhibition 1000-fold increased)inhibition 1000-fold increased)

Not necessarily a risk factor to be involved in Not necessarily a risk factor to be involved in heterozygotes to give TEheterozygotes to give TE

Increased incidence with ageing 80 at 55 yearsIncreased incidence with ageing 80 at 55 years

55 Abnormal ProthrombinAbnormal Prothrombin (PT 20210 A) (PT 20210 A)

CommonCommon Increased levels of prothrombin enhanced Increased levels of prothrombin enhanced

thrombin formationthrombin formation Only way for diagnosis DNA-PCR Only way for diagnosis DNA-PCR

techniquetechnique

66 Sticky Platelet SyndromeSticky Platelet Syndrome

Especially in arterial thrombosis (MI) and Especially in arterial thrombosis (MI) and development of recurrent TE while on Warfarindevelopment of recurrent TE while on Warfarin

3 Forms3 Forms If on aspirin it should be stopped 14 days prior to If on aspirin it should be stopped 14 days prior to

testingtesting

Also rememberAlso remember

PC PS and AT III are inhibitors of clottingPC PS and AT III are inhibitors of clotting

Non-familial (Acquired)Non-familial (Acquired)11 Antiphospholipid SyndromeAntiphospholipid Syndrome Antibodies directed against phospholipid cell membrane = Antibodies directed against phospholipid cell membrane =

APA (Antiphospholipid Ab)APA (Antiphospholipid Ab) APA ACA or LAAPA ACA or LA Primary (PAPS) or secondary (autoimmune disorders eg Primary (PAPS) or secondary (autoimmune disorders eg

SLE)SLE) ACA (Anticardiolipin Ab) IgM + IgGACA (Anticardiolipin Ab) IgM + IgG IgG the clinically important oneIgG the clinically important one IgM pregnancy infection (viral) trauma and post-opIgM pregnancy infection (viral) trauma and post-op LA (Lupus anticoagulant) Ab which affect clotting tests (LA-LA (Lupus anticoagulant) Ab which affect clotting tests (LA-

PTT RVV Kaolin)PTT RVV Kaolin) PAPS = TE miscarriage IUDPAPS = TE miscarriage IUD

Antiphospholipid Syndrome1048734 Antiphospholipid syndrome (APS) ndash Syndrome characterized by venous andor arterial thrombosis thrombocytopenia or recurrent fetal loss associated with antibodies to phospho-lipid- protein Complexes

1048734 Antiphospholipid antibodies (aPL)ndash IgG IgM or IgA antibodies that are directed to target proteins such as cardiolipin beta2-Glycoprotein I (β2GPI)or Prothrombin all of which bind to phospholipidsndash Lupus anticoagulant (LA) bull Antiphospholipid antibodies identified by in vitro phospholipid dependent clot-based assays antibodies are targeted against Prothrombin or β2GPI and prolong clotting times

Antiphospholipd Antibodies

Lupus Anticoagulant

Conditions where screening for APS Conditions where screening for APS is indicatedis indicated

The first thrombotic event below the age of 40The first thrombotic event below the age of 40 History of recurrent TEDHistory of recurrent TED Recurrent fetal loss in the 1Recurrent fetal loss in the 1stst or the 2 or the 2ndnd trimester trimester Patient with SLEPatient with SLE Pre-hormone replacement therapyPre-hormone replacement therapy

Non-familial (Acquired) continuedNon-familial (Acquired) continued

22 TPA (Tissue Plasminogen Activator) TPA (Tissue Plasminogen Activator) decreased levels impaired fibrinolysisdecreased levels impaired fibrinolysis

33 PAI (Plasminogen Activator Inhibitor) PAI (Plasminogen Activator Inhibitor) increased levels decreased TPAincreased levels decreased TPA

44 DysfibrinogenemiaDysfibrinogenemia55 F XII deficiency Hageman factorF XII deficiency Hageman factor66 Fibrinogen (increased)Fibrinogen (increased)77 F VIII (increased)F VIII (increased)88 PlasminogenPlasminogen99 Hyperhomocyteinemia ndash enzyme (folate)Hyperhomocyteinemia ndash enzyme (folate)

Investigation (Thrombotic Profile)Investigation (Thrombotic Profile)

NB Patients can be on Warfarin but not HeparinNB Patients can be on Warfarin but not Heparin FBC PLT amp ESRFBC PLT amp ESR PT aPTT TT amp FibrinogenPT aPTT TT amp Fibrinogen PC amp PSPC amp PS AT IIIAT III APCR (if + screening submit for PCR)APCR (if + screening submit for PCR) PT 20210A (PCR)PT 20210A (PCR) Lupus anticoagulant (RVVT KT LA-PTT) Lupus anticoagulant (RVVT KT LA-PTT) Cardiolipin antibodies (antiphospholipid syndrome)Cardiolipin antibodies (antiphospholipid syndrome) Sticky platelet syndrome (aspirin)Sticky platelet syndrome (aspirin) ANA screeningANA screening PNH screeningPNH screening

When to testWhen to test Younger lt 50 years recurrent TE unusual sites Younger lt 50 years recurrent TE unusual sites

TE on WarfarinTE on Warfarin Not ideal to test after acute episode (inhibitors of Not ideal to test after acute episode (inhibitors of

clotting may be low)clotting may be low) Ideal test after 6 weeks after settlement of Ideal test after 6 weeks after settlement of

hemostasishemostasis Most patients are on Warfarin then (PC amp PS are Most patients are on Warfarin then (PC amp PS are

Vit K dependent may be falsely low)Vit K dependent may be falsely low) My view if long-term Warfarin is planned do My view if long-term Warfarin is planned do

immediately according to duration of treatment it immediately according to duration of treatment it can be done after cessation of treatmentcan be done after cessation of treatment

When to test (continued)When to test (continued)

Practical (my experience) before treatment ndash if AT Practical (my experience) before treatment ndash if AT PS PC are low PS PC are low repeat after Rx has been stopped repeat after Rx has been stopped

SPS platelet aggregation studies (problem SPS platelet aggregation studies (problem sometimes aspirin cannot be stopped)sometimes aspirin cannot be stopped)

Remember the effect of the vessel wall on clotting Remember the effect of the vessel wall on clotting especially in arterial thrombosisespecially in arterial thrombosis

Every woman on contraception HRTEvery woman on contraception HRT

Arterial ThrombosisArterial Thrombosis

Arterial Thrombosis

Arterial ThrombosisArterial Thrombosis

Results as sever oResults as sever o2 2 starvation of the left starvation of the left ventricle of the heartventricle of the heart

This leads to myocardial ischemia amp may This leads to myocardial ischemia amp may progress to myocardial infarction or progress to myocardial infarction or ischemic left ventricular fibrillation amp ischemic left ventricular fibrillation amp sudden deathsudden death

Similar episodes involving the cerebral Similar episodes involving the cerebral circulation result in transient ischemic circulation result in transient ischemic attacks amp thrombotic stroke attacks amp thrombotic stroke

Myocardial Infarction SymptomMyocardial Infarction Symptom

Crushing tightness of the chest with Crushing tightness of the chest with sweating nausea breathlessness amp sweating nausea breathlessness amp collapsecollapse

Chest pain may radiates to the arm throat amp Chest pain may radiates to the arm throat amp jawjaw

Chest pain may confused with sever Chest pain may confused with sever indigestion in itrsquos early stagesindigestion in itrsquos early stages

Transient Ischemic attacksTransient Ischemic attacks

Itrsquos usually accompanied with neurological Itrsquos usually accompanied with neurological dysfunction or loss of visiondysfunction or loss of vision

Completed thrombotic strokeCompleted thrombotic stroke

Itrsquos accompanied by similar symptoms Itrsquos accompanied by similar symptoms which persist for more than 24 hours that which persist for more than 24 hours that may be severely amp permanently disablingmay be severely amp permanently disabling

Risk factors for arterial amp venous thrombosisRisk factors for arterial amp venous thrombosis

Venous thrombosisVenous thrombosisArterial thrombosisArterial thrombosisIncreasing ageIncreasing ageIncreasing ageIncreasing age

ObesityObesityObesityObesity

ImmobilityImmobilityLack of exerciseLack of exercise

Pregnancy rdquopost partomrdquoPregnancy rdquopost partomrdquoHigh fat low fiber dietHigh fat low fiber diet

MalignancyMalignancySmokingSmoking

Lupus anticoagulantLupus anticoagulantHyperlipidemiaHyperlipidemia

Nephrotic syndromeNephrotic syndromeHypertensionHypertension

PolycythemiaPolycythemiaElevated factor VII II concElevated factor VII II conc

goutgoutGenetic factorGenetic factor

Prophylaxis amp treatment of Prophylaxis amp treatment of thrombosisthrombosis

Prevent the risk factorsPrevent the risk factors SmokingSmoking ObesityObesity Lack of exerciseLack of exercise Poor dietPoor diet

Only when this proves to be impossibleOnly when this proves to be impossible

(Pharmacological intervention is required) (Pharmacological intervention is required)

44 Antithrombin III DeficiencyAntithrombin III Deficiency

Common cause (incidence 12000 ndash 15000 Common cause (incidence 12000 ndash 15000 heterozygotes 50 DVT) Quantitative vs heterozygotes 50 DVT) Quantitative vs Qualitative disorder (Acquired DIC cirrhosis Qualitative disorder (Acquired DIC cirrhosis NS)NS)

Bind to and inactivate thrombin Factors IXa Xa Bind to and inactivate thrombin Factors IXa Xa XIa and XIIa (ATheparin complex - rate of XIa and XIIa (ATheparin complex - rate of inhibition 1000-fold increased)inhibition 1000-fold increased)

Not necessarily a risk factor to be involved in Not necessarily a risk factor to be involved in heterozygotes to give TEheterozygotes to give TE

Increased incidence with ageing 80 at 55 yearsIncreased incidence with ageing 80 at 55 years

55 Abnormal ProthrombinAbnormal Prothrombin (PT 20210 A) (PT 20210 A)

CommonCommon Increased levels of prothrombin enhanced Increased levels of prothrombin enhanced

thrombin formationthrombin formation Only way for diagnosis DNA-PCR Only way for diagnosis DNA-PCR

techniquetechnique

66 Sticky Platelet SyndromeSticky Platelet Syndrome

Especially in arterial thrombosis (MI) and Especially in arterial thrombosis (MI) and development of recurrent TE while on Warfarindevelopment of recurrent TE while on Warfarin

3 Forms3 Forms If on aspirin it should be stopped 14 days prior to If on aspirin it should be stopped 14 days prior to

testingtesting

Also rememberAlso remember

PC PS and AT III are inhibitors of clottingPC PS and AT III are inhibitors of clotting

Non-familial (Acquired)Non-familial (Acquired)11 Antiphospholipid SyndromeAntiphospholipid Syndrome Antibodies directed against phospholipid cell membrane = Antibodies directed against phospholipid cell membrane =

APA (Antiphospholipid Ab)APA (Antiphospholipid Ab) APA ACA or LAAPA ACA or LA Primary (PAPS) or secondary (autoimmune disorders eg Primary (PAPS) or secondary (autoimmune disorders eg

SLE)SLE) ACA (Anticardiolipin Ab) IgM + IgGACA (Anticardiolipin Ab) IgM + IgG IgG the clinically important oneIgG the clinically important one IgM pregnancy infection (viral) trauma and post-opIgM pregnancy infection (viral) trauma and post-op LA (Lupus anticoagulant) Ab which affect clotting tests (LA-LA (Lupus anticoagulant) Ab which affect clotting tests (LA-

PTT RVV Kaolin)PTT RVV Kaolin) PAPS = TE miscarriage IUDPAPS = TE miscarriage IUD

Antiphospholipid Syndrome1048734 Antiphospholipid syndrome (APS) ndash Syndrome characterized by venous andor arterial thrombosis thrombocytopenia or recurrent fetal loss associated with antibodies to phospho-lipid- protein Complexes

1048734 Antiphospholipid antibodies (aPL)ndash IgG IgM or IgA antibodies that are directed to target proteins such as cardiolipin beta2-Glycoprotein I (β2GPI)or Prothrombin all of which bind to phospholipidsndash Lupus anticoagulant (LA) bull Antiphospholipid antibodies identified by in vitro phospholipid dependent clot-based assays antibodies are targeted against Prothrombin or β2GPI and prolong clotting times

Antiphospholipd Antibodies

Lupus Anticoagulant

Conditions where screening for APS Conditions where screening for APS is indicatedis indicated

The first thrombotic event below the age of 40The first thrombotic event below the age of 40 History of recurrent TEDHistory of recurrent TED Recurrent fetal loss in the 1Recurrent fetal loss in the 1stst or the 2 or the 2ndnd trimester trimester Patient with SLEPatient with SLE Pre-hormone replacement therapyPre-hormone replacement therapy

Non-familial (Acquired) continuedNon-familial (Acquired) continued

22 TPA (Tissue Plasminogen Activator) TPA (Tissue Plasminogen Activator) decreased levels impaired fibrinolysisdecreased levels impaired fibrinolysis

33 PAI (Plasminogen Activator Inhibitor) PAI (Plasminogen Activator Inhibitor) increased levels decreased TPAincreased levels decreased TPA

44 DysfibrinogenemiaDysfibrinogenemia55 F XII deficiency Hageman factorF XII deficiency Hageman factor66 Fibrinogen (increased)Fibrinogen (increased)77 F VIII (increased)F VIII (increased)88 PlasminogenPlasminogen99 Hyperhomocyteinemia ndash enzyme (folate)Hyperhomocyteinemia ndash enzyme (folate)

Investigation (Thrombotic Profile)Investigation (Thrombotic Profile)

NB Patients can be on Warfarin but not HeparinNB Patients can be on Warfarin but not Heparin FBC PLT amp ESRFBC PLT amp ESR PT aPTT TT amp FibrinogenPT aPTT TT amp Fibrinogen PC amp PSPC amp PS AT IIIAT III APCR (if + screening submit for PCR)APCR (if + screening submit for PCR) PT 20210A (PCR)PT 20210A (PCR) Lupus anticoagulant (RVVT KT LA-PTT) Lupus anticoagulant (RVVT KT LA-PTT) Cardiolipin antibodies (antiphospholipid syndrome)Cardiolipin antibodies (antiphospholipid syndrome) Sticky platelet syndrome (aspirin)Sticky platelet syndrome (aspirin) ANA screeningANA screening PNH screeningPNH screening

When to testWhen to test Younger lt 50 years recurrent TE unusual sites Younger lt 50 years recurrent TE unusual sites

TE on WarfarinTE on Warfarin Not ideal to test after acute episode (inhibitors of Not ideal to test after acute episode (inhibitors of

clotting may be low)clotting may be low) Ideal test after 6 weeks after settlement of Ideal test after 6 weeks after settlement of

hemostasishemostasis Most patients are on Warfarin then (PC amp PS are Most patients are on Warfarin then (PC amp PS are

Vit K dependent may be falsely low)Vit K dependent may be falsely low) My view if long-term Warfarin is planned do My view if long-term Warfarin is planned do

immediately according to duration of treatment it immediately according to duration of treatment it can be done after cessation of treatmentcan be done after cessation of treatment

When to test (continued)When to test (continued)

Practical (my experience) before treatment ndash if AT Practical (my experience) before treatment ndash if AT PS PC are low PS PC are low repeat after Rx has been stopped repeat after Rx has been stopped

SPS platelet aggregation studies (problem SPS platelet aggregation studies (problem sometimes aspirin cannot be stopped)sometimes aspirin cannot be stopped)

Remember the effect of the vessel wall on clotting Remember the effect of the vessel wall on clotting especially in arterial thrombosisespecially in arterial thrombosis

Every woman on contraception HRTEvery woman on contraception HRT

Arterial ThrombosisArterial Thrombosis

Arterial Thrombosis

Arterial ThrombosisArterial Thrombosis

Results as sever oResults as sever o2 2 starvation of the left starvation of the left ventricle of the heartventricle of the heart

This leads to myocardial ischemia amp may This leads to myocardial ischemia amp may progress to myocardial infarction or progress to myocardial infarction or ischemic left ventricular fibrillation amp ischemic left ventricular fibrillation amp sudden deathsudden death

Similar episodes involving the cerebral Similar episodes involving the cerebral circulation result in transient ischemic circulation result in transient ischemic attacks amp thrombotic stroke attacks amp thrombotic stroke

Myocardial Infarction SymptomMyocardial Infarction Symptom

Crushing tightness of the chest with Crushing tightness of the chest with sweating nausea breathlessness amp sweating nausea breathlessness amp collapsecollapse

Chest pain may radiates to the arm throat amp Chest pain may radiates to the arm throat amp jawjaw

Chest pain may confused with sever Chest pain may confused with sever indigestion in itrsquos early stagesindigestion in itrsquos early stages

Transient Ischemic attacksTransient Ischemic attacks

Itrsquos usually accompanied with neurological Itrsquos usually accompanied with neurological dysfunction or loss of visiondysfunction or loss of vision

Completed thrombotic strokeCompleted thrombotic stroke

Itrsquos accompanied by similar symptoms Itrsquos accompanied by similar symptoms which persist for more than 24 hours that which persist for more than 24 hours that may be severely amp permanently disablingmay be severely amp permanently disabling

Risk factors for arterial amp venous thrombosisRisk factors for arterial amp venous thrombosis

Venous thrombosisVenous thrombosisArterial thrombosisArterial thrombosisIncreasing ageIncreasing ageIncreasing ageIncreasing age

ObesityObesityObesityObesity

ImmobilityImmobilityLack of exerciseLack of exercise

Pregnancy rdquopost partomrdquoPregnancy rdquopost partomrdquoHigh fat low fiber dietHigh fat low fiber diet

MalignancyMalignancySmokingSmoking

Lupus anticoagulantLupus anticoagulantHyperlipidemiaHyperlipidemia

Nephrotic syndromeNephrotic syndromeHypertensionHypertension

PolycythemiaPolycythemiaElevated factor VII II concElevated factor VII II conc

goutgoutGenetic factorGenetic factor

Prophylaxis amp treatment of Prophylaxis amp treatment of thrombosisthrombosis

Prevent the risk factorsPrevent the risk factors SmokingSmoking ObesityObesity Lack of exerciseLack of exercise Poor dietPoor diet

Only when this proves to be impossibleOnly when this proves to be impossible

(Pharmacological intervention is required) (Pharmacological intervention is required)

55 Abnormal ProthrombinAbnormal Prothrombin (PT 20210 A) (PT 20210 A)

CommonCommon Increased levels of prothrombin enhanced Increased levels of prothrombin enhanced

thrombin formationthrombin formation Only way for diagnosis DNA-PCR Only way for diagnosis DNA-PCR

techniquetechnique

66 Sticky Platelet SyndromeSticky Platelet Syndrome

Especially in arterial thrombosis (MI) and Especially in arterial thrombosis (MI) and development of recurrent TE while on Warfarindevelopment of recurrent TE while on Warfarin

3 Forms3 Forms If on aspirin it should be stopped 14 days prior to If on aspirin it should be stopped 14 days prior to

testingtesting

Also rememberAlso remember

PC PS and AT III are inhibitors of clottingPC PS and AT III are inhibitors of clotting

Non-familial (Acquired)Non-familial (Acquired)11 Antiphospholipid SyndromeAntiphospholipid Syndrome Antibodies directed against phospholipid cell membrane = Antibodies directed against phospholipid cell membrane =

APA (Antiphospholipid Ab)APA (Antiphospholipid Ab) APA ACA or LAAPA ACA or LA Primary (PAPS) or secondary (autoimmune disorders eg Primary (PAPS) or secondary (autoimmune disorders eg

SLE)SLE) ACA (Anticardiolipin Ab) IgM + IgGACA (Anticardiolipin Ab) IgM + IgG IgG the clinically important oneIgG the clinically important one IgM pregnancy infection (viral) trauma and post-opIgM pregnancy infection (viral) trauma and post-op LA (Lupus anticoagulant) Ab which affect clotting tests (LA-LA (Lupus anticoagulant) Ab which affect clotting tests (LA-

PTT RVV Kaolin)PTT RVV Kaolin) PAPS = TE miscarriage IUDPAPS = TE miscarriage IUD

Antiphospholipid Syndrome1048734 Antiphospholipid syndrome (APS) ndash Syndrome characterized by venous andor arterial thrombosis thrombocytopenia or recurrent fetal loss associated with antibodies to phospho-lipid- protein Complexes

1048734 Antiphospholipid antibodies (aPL)ndash IgG IgM or IgA antibodies that are directed to target proteins such as cardiolipin beta2-Glycoprotein I (β2GPI)or Prothrombin all of which bind to phospholipidsndash Lupus anticoagulant (LA) bull Antiphospholipid antibodies identified by in vitro phospholipid dependent clot-based assays antibodies are targeted against Prothrombin or β2GPI and prolong clotting times

Antiphospholipd Antibodies

Lupus Anticoagulant

Conditions where screening for APS Conditions where screening for APS is indicatedis indicated

The first thrombotic event below the age of 40The first thrombotic event below the age of 40 History of recurrent TEDHistory of recurrent TED Recurrent fetal loss in the 1Recurrent fetal loss in the 1stst or the 2 or the 2ndnd trimester trimester Patient with SLEPatient with SLE Pre-hormone replacement therapyPre-hormone replacement therapy

Non-familial (Acquired) continuedNon-familial (Acquired) continued

22 TPA (Tissue Plasminogen Activator) TPA (Tissue Plasminogen Activator) decreased levels impaired fibrinolysisdecreased levels impaired fibrinolysis

33 PAI (Plasminogen Activator Inhibitor) PAI (Plasminogen Activator Inhibitor) increased levels decreased TPAincreased levels decreased TPA

44 DysfibrinogenemiaDysfibrinogenemia55 F XII deficiency Hageman factorF XII deficiency Hageman factor66 Fibrinogen (increased)Fibrinogen (increased)77 F VIII (increased)F VIII (increased)88 PlasminogenPlasminogen99 Hyperhomocyteinemia ndash enzyme (folate)Hyperhomocyteinemia ndash enzyme (folate)

Investigation (Thrombotic Profile)Investigation (Thrombotic Profile)

NB Patients can be on Warfarin but not HeparinNB Patients can be on Warfarin but not Heparin FBC PLT amp ESRFBC PLT amp ESR PT aPTT TT amp FibrinogenPT aPTT TT amp Fibrinogen PC amp PSPC amp PS AT IIIAT III APCR (if + screening submit for PCR)APCR (if + screening submit for PCR) PT 20210A (PCR)PT 20210A (PCR) Lupus anticoagulant (RVVT KT LA-PTT) Lupus anticoagulant (RVVT KT LA-PTT) Cardiolipin antibodies (antiphospholipid syndrome)Cardiolipin antibodies (antiphospholipid syndrome) Sticky platelet syndrome (aspirin)Sticky platelet syndrome (aspirin) ANA screeningANA screening PNH screeningPNH screening

When to testWhen to test Younger lt 50 years recurrent TE unusual sites Younger lt 50 years recurrent TE unusual sites

TE on WarfarinTE on Warfarin Not ideal to test after acute episode (inhibitors of Not ideal to test after acute episode (inhibitors of

clotting may be low)clotting may be low) Ideal test after 6 weeks after settlement of Ideal test after 6 weeks after settlement of

hemostasishemostasis Most patients are on Warfarin then (PC amp PS are Most patients are on Warfarin then (PC amp PS are

Vit K dependent may be falsely low)Vit K dependent may be falsely low) My view if long-term Warfarin is planned do My view if long-term Warfarin is planned do

immediately according to duration of treatment it immediately according to duration of treatment it can be done after cessation of treatmentcan be done after cessation of treatment

When to test (continued)When to test (continued)

Practical (my experience) before treatment ndash if AT Practical (my experience) before treatment ndash if AT PS PC are low PS PC are low repeat after Rx has been stopped repeat after Rx has been stopped

SPS platelet aggregation studies (problem SPS platelet aggregation studies (problem sometimes aspirin cannot be stopped)sometimes aspirin cannot be stopped)

Remember the effect of the vessel wall on clotting Remember the effect of the vessel wall on clotting especially in arterial thrombosisespecially in arterial thrombosis

Every woman on contraception HRTEvery woman on contraception HRT

Arterial ThrombosisArterial Thrombosis

Arterial Thrombosis

Arterial ThrombosisArterial Thrombosis

Results as sever oResults as sever o2 2 starvation of the left starvation of the left ventricle of the heartventricle of the heart

This leads to myocardial ischemia amp may This leads to myocardial ischemia amp may progress to myocardial infarction or progress to myocardial infarction or ischemic left ventricular fibrillation amp ischemic left ventricular fibrillation amp sudden deathsudden death

Similar episodes involving the cerebral Similar episodes involving the cerebral circulation result in transient ischemic circulation result in transient ischemic attacks amp thrombotic stroke attacks amp thrombotic stroke

Myocardial Infarction SymptomMyocardial Infarction Symptom

Crushing tightness of the chest with Crushing tightness of the chest with sweating nausea breathlessness amp sweating nausea breathlessness amp collapsecollapse

Chest pain may radiates to the arm throat amp Chest pain may radiates to the arm throat amp jawjaw

Chest pain may confused with sever Chest pain may confused with sever indigestion in itrsquos early stagesindigestion in itrsquos early stages

Transient Ischemic attacksTransient Ischemic attacks

Itrsquos usually accompanied with neurological Itrsquos usually accompanied with neurological dysfunction or loss of visiondysfunction or loss of vision

Completed thrombotic strokeCompleted thrombotic stroke

Itrsquos accompanied by similar symptoms Itrsquos accompanied by similar symptoms which persist for more than 24 hours that which persist for more than 24 hours that may be severely amp permanently disablingmay be severely amp permanently disabling

Risk factors for arterial amp venous thrombosisRisk factors for arterial amp venous thrombosis

Venous thrombosisVenous thrombosisArterial thrombosisArterial thrombosisIncreasing ageIncreasing ageIncreasing ageIncreasing age

ObesityObesityObesityObesity

ImmobilityImmobilityLack of exerciseLack of exercise

Pregnancy rdquopost partomrdquoPregnancy rdquopost partomrdquoHigh fat low fiber dietHigh fat low fiber diet

MalignancyMalignancySmokingSmoking

Lupus anticoagulantLupus anticoagulantHyperlipidemiaHyperlipidemia

Nephrotic syndromeNephrotic syndromeHypertensionHypertension

PolycythemiaPolycythemiaElevated factor VII II concElevated factor VII II conc

goutgoutGenetic factorGenetic factor

Prophylaxis amp treatment of Prophylaxis amp treatment of thrombosisthrombosis

Prevent the risk factorsPrevent the risk factors SmokingSmoking ObesityObesity Lack of exerciseLack of exercise Poor dietPoor diet

Only when this proves to be impossibleOnly when this proves to be impossible

(Pharmacological intervention is required) (Pharmacological intervention is required)

66 Sticky Platelet SyndromeSticky Platelet Syndrome

Especially in arterial thrombosis (MI) and Especially in arterial thrombosis (MI) and development of recurrent TE while on Warfarindevelopment of recurrent TE while on Warfarin

3 Forms3 Forms If on aspirin it should be stopped 14 days prior to If on aspirin it should be stopped 14 days prior to

testingtesting

Also rememberAlso remember

PC PS and AT III are inhibitors of clottingPC PS and AT III are inhibitors of clotting

Non-familial (Acquired)Non-familial (Acquired)11 Antiphospholipid SyndromeAntiphospholipid Syndrome Antibodies directed against phospholipid cell membrane = Antibodies directed against phospholipid cell membrane =

APA (Antiphospholipid Ab)APA (Antiphospholipid Ab) APA ACA or LAAPA ACA or LA Primary (PAPS) or secondary (autoimmune disorders eg Primary (PAPS) or secondary (autoimmune disorders eg

SLE)SLE) ACA (Anticardiolipin Ab) IgM + IgGACA (Anticardiolipin Ab) IgM + IgG IgG the clinically important oneIgG the clinically important one IgM pregnancy infection (viral) trauma and post-opIgM pregnancy infection (viral) trauma and post-op LA (Lupus anticoagulant) Ab which affect clotting tests (LA-LA (Lupus anticoagulant) Ab which affect clotting tests (LA-

PTT RVV Kaolin)PTT RVV Kaolin) PAPS = TE miscarriage IUDPAPS = TE miscarriage IUD

Antiphospholipid Syndrome1048734 Antiphospholipid syndrome (APS) ndash Syndrome characterized by venous andor arterial thrombosis thrombocytopenia or recurrent fetal loss associated with antibodies to phospho-lipid- protein Complexes

1048734 Antiphospholipid antibodies (aPL)ndash IgG IgM or IgA antibodies that are directed to target proteins such as cardiolipin beta2-Glycoprotein I (β2GPI)or Prothrombin all of which bind to phospholipidsndash Lupus anticoagulant (LA) bull Antiphospholipid antibodies identified by in vitro phospholipid dependent clot-based assays antibodies are targeted against Prothrombin or β2GPI and prolong clotting times

Antiphospholipd Antibodies

Lupus Anticoagulant

Conditions where screening for APS Conditions where screening for APS is indicatedis indicated

The first thrombotic event below the age of 40The first thrombotic event below the age of 40 History of recurrent TEDHistory of recurrent TED Recurrent fetal loss in the 1Recurrent fetal loss in the 1stst or the 2 or the 2ndnd trimester trimester Patient with SLEPatient with SLE Pre-hormone replacement therapyPre-hormone replacement therapy

Non-familial (Acquired) continuedNon-familial (Acquired) continued

22 TPA (Tissue Plasminogen Activator) TPA (Tissue Plasminogen Activator) decreased levels impaired fibrinolysisdecreased levels impaired fibrinolysis

33 PAI (Plasminogen Activator Inhibitor) PAI (Plasminogen Activator Inhibitor) increased levels decreased TPAincreased levels decreased TPA

44 DysfibrinogenemiaDysfibrinogenemia55 F XII deficiency Hageman factorF XII deficiency Hageman factor66 Fibrinogen (increased)Fibrinogen (increased)77 F VIII (increased)F VIII (increased)88 PlasminogenPlasminogen99 Hyperhomocyteinemia ndash enzyme (folate)Hyperhomocyteinemia ndash enzyme (folate)

Investigation (Thrombotic Profile)Investigation (Thrombotic Profile)

NB Patients can be on Warfarin but not HeparinNB Patients can be on Warfarin but not Heparin FBC PLT amp ESRFBC PLT amp ESR PT aPTT TT amp FibrinogenPT aPTT TT amp Fibrinogen PC amp PSPC amp PS AT IIIAT III APCR (if + screening submit for PCR)APCR (if + screening submit for PCR) PT 20210A (PCR)PT 20210A (PCR) Lupus anticoagulant (RVVT KT LA-PTT) Lupus anticoagulant (RVVT KT LA-PTT) Cardiolipin antibodies (antiphospholipid syndrome)Cardiolipin antibodies (antiphospholipid syndrome) Sticky platelet syndrome (aspirin)Sticky platelet syndrome (aspirin) ANA screeningANA screening PNH screeningPNH screening

When to testWhen to test Younger lt 50 years recurrent TE unusual sites Younger lt 50 years recurrent TE unusual sites

TE on WarfarinTE on Warfarin Not ideal to test after acute episode (inhibitors of Not ideal to test after acute episode (inhibitors of

clotting may be low)clotting may be low) Ideal test after 6 weeks after settlement of Ideal test after 6 weeks after settlement of

hemostasishemostasis Most patients are on Warfarin then (PC amp PS are Most patients are on Warfarin then (PC amp PS are

Vit K dependent may be falsely low)Vit K dependent may be falsely low) My view if long-term Warfarin is planned do My view if long-term Warfarin is planned do

immediately according to duration of treatment it immediately according to duration of treatment it can be done after cessation of treatmentcan be done after cessation of treatment

When to test (continued)When to test (continued)

Practical (my experience) before treatment ndash if AT Practical (my experience) before treatment ndash if AT PS PC are low PS PC are low repeat after Rx has been stopped repeat after Rx has been stopped

SPS platelet aggregation studies (problem SPS platelet aggregation studies (problem sometimes aspirin cannot be stopped)sometimes aspirin cannot be stopped)

Remember the effect of the vessel wall on clotting Remember the effect of the vessel wall on clotting especially in arterial thrombosisespecially in arterial thrombosis

Every woman on contraception HRTEvery woman on contraception HRT

Arterial ThrombosisArterial Thrombosis

Arterial Thrombosis

Arterial ThrombosisArterial Thrombosis

Results as sever oResults as sever o2 2 starvation of the left starvation of the left ventricle of the heartventricle of the heart

This leads to myocardial ischemia amp may This leads to myocardial ischemia amp may progress to myocardial infarction or progress to myocardial infarction or ischemic left ventricular fibrillation amp ischemic left ventricular fibrillation amp sudden deathsudden death

Similar episodes involving the cerebral Similar episodes involving the cerebral circulation result in transient ischemic circulation result in transient ischemic attacks amp thrombotic stroke attacks amp thrombotic stroke

Myocardial Infarction SymptomMyocardial Infarction Symptom

Crushing tightness of the chest with Crushing tightness of the chest with sweating nausea breathlessness amp sweating nausea breathlessness amp collapsecollapse

Chest pain may radiates to the arm throat amp Chest pain may radiates to the arm throat amp jawjaw

Chest pain may confused with sever Chest pain may confused with sever indigestion in itrsquos early stagesindigestion in itrsquos early stages

Transient Ischemic attacksTransient Ischemic attacks

Itrsquos usually accompanied with neurological Itrsquos usually accompanied with neurological dysfunction or loss of visiondysfunction or loss of vision

Completed thrombotic strokeCompleted thrombotic stroke

Itrsquos accompanied by similar symptoms Itrsquos accompanied by similar symptoms which persist for more than 24 hours that which persist for more than 24 hours that may be severely amp permanently disablingmay be severely amp permanently disabling

Risk factors for arterial amp venous thrombosisRisk factors for arterial amp venous thrombosis

Venous thrombosisVenous thrombosisArterial thrombosisArterial thrombosisIncreasing ageIncreasing ageIncreasing ageIncreasing age

ObesityObesityObesityObesity

ImmobilityImmobilityLack of exerciseLack of exercise

Pregnancy rdquopost partomrdquoPregnancy rdquopost partomrdquoHigh fat low fiber dietHigh fat low fiber diet

MalignancyMalignancySmokingSmoking

Lupus anticoagulantLupus anticoagulantHyperlipidemiaHyperlipidemia

Nephrotic syndromeNephrotic syndromeHypertensionHypertension

PolycythemiaPolycythemiaElevated factor VII II concElevated factor VII II conc

goutgoutGenetic factorGenetic factor

Prophylaxis amp treatment of Prophylaxis amp treatment of thrombosisthrombosis

Prevent the risk factorsPrevent the risk factors SmokingSmoking ObesityObesity Lack of exerciseLack of exercise Poor dietPoor diet

Only when this proves to be impossibleOnly when this proves to be impossible

(Pharmacological intervention is required) (Pharmacological intervention is required)

Non-familial (Acquired)Non-familial (Acquired)11 Antiphospholipid SyndromeAntiphospholipid Syndrome Antibodies directed against phospholipid cell membrane = Antibodies directed against phospholipid cell membrane =

APA (Antiphospholipid Ab)APA (Antiphospholipid Ab) APA ACA or LAAPA ACA or LA Primary (PAPS) or secondary (autoimmune disorders eg Primary (PAPS) or secondary (autoimmune disorders eg

SLE)SLE) ACA (Anticardiolipin Ab) IgM + IgGACA (Anticardiolipin Ab) IgM + IgG IgG the clinically important oneIgG the clinically important one IgM pregnancy infection (viral) trauma and post-opIgM pregnancy infection (viral) trauma and post-op LA (Lupus anticoagulant) Ab which affect clotting tests (LA-LA (Lupus anticoagulant) Ab which affect clotting tests (LA-

PTT RVV Kaolin)PTT RVV Kaolin) PAPS = TE miscarriage IUDPAPS = TE miscarriage IUD

Antiphospholipid Syndrome1048734 Antiphospholipid syndrome (APS) ndash Syndrome characterized by venous andor arterial thrombosis thrombocytopenia or recurrent fetal loss associated with antibodies to phospho-lipid- protein Complexes

1048734 Antiphospholipid antibodies (aPL)ndash IgG IgM or IgA antibodies that are directed to target proteins such as cardiolipin beta2-Glycoprotein I (β2GPI)or Prothrombin all of which bind to phospholipidsndash Lupus anticoagulant (LA) bull Antiphospholipid antibodies identified by in vitro phospholipid dependent clot-based assays antibodies are targeted against Prothrombin or β2GPI and prolong clotting times

Antiphospholipd Antibodies

Lupus Anticoagulant

Conditions where screening for APS Conditions where screening for APS is indicatedis indicated

The first thrombotic event below the age of 40The first thrombotic event below the age of 40 History of recurrent TEDHistory of recurrent TED Recurrent fetal loss in the 1Recurrent fetal loss in the 1stst or the 2 or the 2ndnd trimester trimester Patient with SLEPatient with SLE Pre-hormone replacement therapyPre-hormone replacement therapy

Non-familial (Acquired) continuedNon-familial (Acquired) continued

22 TPA (Tissue Plasminogen Activator) TPA (Tissue Plasminogen Activator) decreased levels impaired fibrinolysisdecreased levels impaired fibrinolysis

33 PAI (Plasminogen Activator Inhibitor) PAI (Plasminogen Activator Inhibitor) increased levels decreased TPAincreased levels decreased TPA

44 DysfibrinogenemiaDysfibrinogenemia55 F XII deficiency Hageman factorF XII deficiency Hageman factor66 Fibrinogen (increased)Fibrinogen (increased)77 F VIII (increased)F VIII (increased)88 PlasminogenPlasminogen99 Hyperhomocyteinemia ndash enzyme (folate)Hyperhomocyteinemia ndash enzyme (folate)

Investigation (Thrombotic Profile)Investigation (Thrombotic Profile)

NB Patients can be on Warfarin but not HeparinNB Patients can be on Warfarin but not Heparin FBC PLT amp ESRFBC PLT amp ESR PT aPTT TT amp FibrinogenPT aPTT TT amp Fibrinogen PC amp PSPC amp PS AT IIIAT III APCR (if + screening submit for PCR)APCR (if + screening submit for PCR) PT 20210A (PCR)PT 20210A (PCR) Lupus anticoagulant (RVVT KT LA-PTT) Lupus anticoagulant (RVVT KT LA-PTT) Cardiolipin antibodies (antiphospholipid syndrome)Cardiolipin antibodies (antiphospholipid syndrome) Sticky platelet syndrome (aspirin)Sticky platelet syndrome (aspirin) ANA screeningANA screening PNH screeningPNH screening

When to testWhen to test Younger lt 50 years recurrent TE unusual sites Younger lt 50 years recurrent TE unusual sites

TE on WarfarinTE on Warfarin Not ideal to test after acute episode (inhibitors of Not ideal to test after acute episode (inhibitors of

clotting may be low)clotting may be low) Ideal test after 6 weeks after settlement of Ideal test after 6 weeks after settlement of

hemostasishemostasis Most patients are on Warfarin then (PC amp PS are Most patients are on Warfarin then (PC amp PS are

Vit K dependent may be falsely low)Vit K dependent may be falsely low) My view if long-term Warfarin is planned do My view if long-term Warfarin is planned do

immediately according to duration of treatment it immediately according to duration of treatment it can be done after cessation of treatmentcan be done after cessation of treatment

When to test (continued)When to test (continued)

Practical (my experience) before treatment ndash if AT Practical (my experience) before treatment ndash if AT PS PC are low PS PC are low repeat after Rx has been stopped repeat after Rx has been stopped

SPS platelet aggregation studies (problem SPS platelet aggregation studies (problem sometimes aspirin cannot be stopped)sometimes aspirin cannot be stopped)

Remember the effect of the vessel wall on clotting Remember the effect of the vessel wall on clotting especially in arterial thrombosisespecially in arterial thrombosis

Every woman on contraception HRTEvery woman on contraception HRT

Arterial ThrombosisArterial Thrombosis

Arterial Thrombosis

Arterial ThrombosisArterial Thrombosis

Results as sever oResults as sever o2 2 starvation of the left starvation of the left ventricle of the heartventricle of the heart

This leads to myocardial ischemia amp may This leads to myocardial ischemia amp may progress to myocardial infarction or progress to myocardial infarction or ischemic left ventricular fibrillation amp ischemic left ventricular fibrillation amp sudden deathsudden death

Similar episodes involving the cerebral Similar episodes involving the cerebral circulation result in transient ischemic circulation result in transient ischemic attacks amp thrombotic stroke attacks amp thrombotic stroke

Myocardial Infarction SymptomMyocardial Infarction Symptom

Crushing tightness of the chest with Crushing tightness of the chest with sweating nausea breathlessness amp sweating nausea breathlessness amp collapsecollapse

Chest pain may radiates to the arm throat amp Chest pain may radiates to the arm throat amp jawjaw

Chest pain may confused with sever Chest pain may confused with sever indigestion in itrsquos early stagesindigestion in itrsquos early stages

Transient Ischemic attacksTransient Ischemic attacks

Itrsquos usually accompanied with neurological Itrsquos usually accompanied with neurological dysfunction or loss of visiondysfunction or loss of vision

Completed thrombotic strokeCompleted thrombotic stroke

Itrsquos accompanied by similar symptoms Itrsquos accompanied by similar symptoms which persist for more than 24 hours that which persist for more than 24 hours that may be severely amp permanently disablingmay be severely amp permanently disabling

Risk factors for arterial amp venous thrombosisRisk factors for arterial amp venous thrombosis

Venous thrombosisVenous thrombosisArterial thrombosisArterial thrombosisIncreasing ageIncreasing ageIncreasing ageIncreasing age

ObesityObesityObesityObesity

ImmobilityImmobilityLack of exerciseLack of exercise

Pregnancy rdquopost partomrdquoPregnancy rdquopost partomrdquoHigh fat low fiber dietHigh fat low fiber diet

MalignancyMalignancySmokingSmoking

Lupus anticoagulantLupus anticoagulantHyperlipidemiaHyperlipidemia

Nephrotic syndromeNephrotic syndromeHypertensionHypertension

PolycythemiaPolycythemiaElevated factor VII II concElevated factor VII II conc

goutgoutGenetic factorGenetic factor

Prophylaxis amp treatment of Prophylaxis amp treatment of thrombosisthrombosis

Prevent the risk factorsPrevent the risk factors SmokingSmoking ObesityObesity Lack of exerciseLack of exercise Poor dietPoor diet

Only when this proves to be impossibleOnly when this proves to be impossible

(Pharmacological intervention is required) (Pharmacological intervention is required)

Antiphospholipid Syndrome1048734 Antiphospholipid syndrome (APS) ndash Syndrome characterized by venous andor arterial thrombosis thrombocytopenia or recurrent fetal loss associated with antibodies to phospho-lipid- protein Complexes

1048734 Antiphospholipid antibodies (aPL)ndash IgG IgM or IgA antibodies that are directed to target proteins such as cardiolipin beta2-Glycoprotein I (β2GPI)or Prothrombin all of which bind to phospholipidsndash Lupus anticoagulant (LA) bull Antiphospholipid antibodies identified by in vitro phospholipid dependent clot-based assays antibodies are targeted against Prothrombin or β2GPI and prolong clotting times

Antiphospholipd Antibodies

Lupus Anticoagulant

Conditions where screening for APS Conditions where screening for APS is indicatedis indicated

The first thrombotic event below the age of 40The first thrombotic event below the age of 40 History of recurrent TEDHistory of recurrent TED Recurrent fetal loss in the 1Recurrent fetal loss in the 1stst or the 2 or the 2ndnd trimester trimester Patient with SLEPatient with SLE Pre-hormone replacement therapyPre-hormone replacement therapy

Non-familial (Acquired) continuedNon-familial (Acquired) continued

22 TPA (Tissue Plasminogen Activator) TPA (Tissue Plasminogen Activator) decreased levels impaired fibrinolysisdecreased levels impaired fibrinolysis

33 PAI (Plasminogen Activator Inhibitor) PAI (Plasminogen Activator Inhibitor) increased levels decreased TPAincreased levels decreased TPA

44 DysfibrinogenemiaDysfibrinogenemia55 F XII deficiency Hageman factorF XII deficiency Hageman factor66 Fibrinogen (increased)Fibrinogen (increased)77 F VIII (increased)F VIII (increased)88 PlasminogenPlasminogen99 Hyperhomocyteinemia ndash enzyme (folate)Hyperhomocyteinemia ndash enzyme (folate)

Investigation (Thrombotic Profile)Investigation (Thrombotic Profile)

NB Patients can be on Warfarin but not HeparinNB Patients can be on Warfarin but not Heparin FBC PLT amp ESRFBC PLT amp ESR PT aPTT TT amp FibrinogenPT aPTT TT amp Fibrinogen PC amp PSPC amp PS AT IIIAT III APCR (if + screening submit for PCR)APCR (if + screening submit for PCR) PT 20210A (PCR)PT 20210A (PCR) Lupus anticoagulant (RVVT KT LA-PTT) Lupus anticoagulant (RVVT KT LA-PTT) Cardiolipin antibodies (antiphospholipid syndrome)Cardiolipin antibodies (antiphospholipid syndrome) Sticky platelet syndrome (aspirin)Sticky platelet syndrome (aspirin) ANA screeningANA screening PNH screeningPNH screening

When to testWhen to test Younger lt 50 years recurrent TE unusual sites Younger lt 50 years recurrent TE unusual sites

TE on WarfarinTE on Warfarin Not ideal to test after acute episode (inhibitors of Not ideal to test after acute episode (inhibitors of

clotting may be low)clotting may be low) Ideal test after 6 weeks after settlement of Ideal test after 6 weeks after settlement of

hemostasishemostasis Most patients are on Warfarin then (PC amp PS are Most patients are on Warfarin then (PC amp PS are

Vit K dependent may be falsely low)Vit K dependent may be falsely low) My view if long-term Warfarin is planned do My view if long-term Warfarin is planned do

immediately according to duration of treatment it immediately according to duration of treatment it can be done after cessation of treatmentcan be done after cessation of treatment

When to test (continued)When to test (continued)

Practical (my experience) before treatment ndash if AT Practical (my experience) before treatment ndash if AT PS PC are low PS PC are low repeat after Rx has been stopped repeat after Rx has been stopped

SPS platelet aggregation studies (problem SPS platelet aggregation studies (problem sometimes aspirin cannot be stopped)sometimes aspirin cannot be stopped)

Remember the effect of the vessel wall on clotting Remember the effect of the vessel wall on clotting especially in arterial thrombosisespecially in arterial thrombosis

Every woman on contraception HRTEvery woman on contraception HRT

Arterial ThrombosisArterial Thrombosis

Arterial Thrombosis

Arterial ThrombosisArterial Thrombosis

Results as sever oResults as sever o2 2 starvation of the left starvation of the left ventricle of the heartventricle of the heart

This leads to myocardial ischemia amp may This leads to myocardial ischemia amp may progress to myocardial infarction or progress to myocardial infarction or ischemic left ventricular fibrillation amp ischemic left ventricular fibrillation amp sudden deathsudden death

Similar episodes involving the cerebral Similar episodes involving the cerebral circulation result in transient ischemic circulation result in transient ischemic attacks amp thrombotic stroke attacks amp thrombotic stroke

Myocardial Infarction SymptomMyocardial Infarction Symptom

Crushing tightness of the chest with Crushing tightness of the chest with sweating nausea breathlessness amp sweating nausea breathlessness amp collapsecollapse

Chest pain may radiates to the arm throat amp Chest pain may radiates to the arm throat amp jawjaw

Chest pain may confused with sever Chest pain may confused with sever indigestion in itrsquos early stagesindigestion in itrsquos early stages

Transient Ischemic attacksTransient Ischemic attacks

Itrsquos usually accompanied with neurological Itrsquos usually accompanied with neurological dysfunction or loss of visiondysfunction or loss of vision

Completed thrombotic strokeCompleted thrombotic stroke

Itrsquos accompanied by similar symptoms Itrsquos accompanied by similar symptoms which persist for more than 24 hours that which persist for more than 24 hours that may be severely amp permanently disablingmay be severely amp permanently disabling

Risk factors for arterial amp venous thrombosisRisk factors for arterial amp venous thrombosis

Venous thrombosisVenous thrombosisArterial thrombosisArterial thrombosisIncreasing ageIncreasing ageIncreasing ageIncreasing age

ObesityObesityObesityObesity

ImmobilityImmobilityLack of exerciseLack of exercise

Pregnancy rdquopost partomrdquoPregnancy rdquopost partomrdquoHigh fat low fiber dietHigh fat low fiber diet

MalignancyMalignancySmokingSmoking

Lupus anticoagulantLupus anticoagulantHyperlipidemiaHyperlipidemia

Nephrotic syndromeNephrotic syndromeHypertensionHypertension

PolycythemiaPolycythemiaElevated factor VII II concElevated factor VII II conc

goutgoutGenetic factorGenetic factor

Prophylaxis amp treatment of Prophylaxis amp treatment of thrombosisthrombosis

Prevent the risk factorsPrevent the risk factors SmokingSmoking ObesityObesity Lack of exerciseLack of exercise Poor dietPoor diet

Only when this proves to be impossibleOnly when this proves to be impossible

(Pharmacological intervention is required) (Pharmacological intervention is required)

Antiphospholipd Antibodies

Lupus Anticoagulant

Conditions where screening for APS Conditions where screening for APS is indicatedis indicated

The first thrombotic event below the age of 40The first thrombotic event below the age of 40 History of recurrent TEDHistory of recurrent TED Recurrent fetal loss in the 1Recurrent fetal loss in the 1stst or the 2 or the 2ndnd trimester trimester Patient with SLEPatient with SLE Pre-hormone replacement therapyPre-hormone replacement therapy

Non-familial (Acquired) continuedNon-familial (Acquired) continued

22 TPA (Tissue Plasminogen Activator) TPA (Tissue Plasminogen Activator) decreased levels impaired fibrinolysisdecreased levels impaired fibrinolysis

33 PAI (Plasminogen Activator Inhibitor) PAI (Plasminogen Activator Inhibitor) increased levels decreased TPAincreased levels decreased TPA

44 DysfibrinogenemiaDysfibrinogenemia55 F XII deficiency Hageman factorF XII deficiency Hageman factor66 Fibrinogen (increased)Fibrinogen (increased)77 F VIII (increased)F VIII (increased)88 PlasminogenPlasminogen99 Hyperhomocyteinemia ndash enzyme (folate)Hyperhomocyteinemia ndash enzyme (folate)

Investigation (Thrombotic Profile)Investigation (Thrombotic Profile)

NB Patients can be on Warfarin but not HeparinNB Patients can be on Warfarin but not Heparin FBC PLT amp ESRFBC PLT amp ESR PT aPTT TT amp FibrinogenPT aPTT TT amp Fibrinogen PC amp PSPC amp PS AT IIIAT III APCR (if + screening submit for PCR)APCR (if + screening submit for PCR) PT 20210A (PCR)PT 20210A (PCR) Lupus anticoagulant (RVVT KT LA-PTT) Lupus anticoagulant (RVVT KT LA-PTT) Cardiolipin antibodies (antiphospholipid syndrome)Cardiolipin antibodies (antiphospholipid syndrome) Sticky platelet syndrome (aspirin)Sticky platelet syndrome (aspirin) ANA screeningANA screening PNH screeningPNH screening

When to testWhen to test Younger lt 50 years recurrent TE unusual sites Younger lt 50 years recurrent TE unusual sites

TE on WarfarinTE on Warfarin Not ideal to test after acute episode (inhibitors of Not ideal to test after acute episode (inhibitors of

clotting may be low)clotting may be low) Ideal test after 6 weeks after settlement of Ideal test after 6 weeks after settlement of

hemostasishemostasis Most patients are on Warfarin then (PC amp PS are Most patients are on Warfarin then (PC amp PS are

Vit K dependent may be falsely low)Vit K dependent may be falsely low) My view if long-term Warfarin is planned do My view if long-term Warfarin is planned do

immediately according to duration of treatment it immediately according to duration of treatment it can be done after cessation of treatmentcan be done after cessation of treatment

When to test (continued)When to test (continued)

Practical (my experience) before treatment ndash if AT Practical (my experience) before treatment ndash if AT PS PC are low PS PC are low repeat after Rx has been stopped repeat after Rx has been stopped

SPS platelet aggregation studies (problem SPS platelet aggregation studies (problem sometimes aspirin cannot be stopped)sometimes aspirin cannot be stopped)

Remember the effect of the vessel wall on clotting Remember the effect of the vessel wall on clotting especially in arterial thrombosisespecially in arterial thrombosis

Every woman on contraception HRTEvery woman on contraception HRT

Arterial ThrombosisArterial Thrombosis

Arterial Thrombosis

Arterial ThrombosisArterial Thrombosis

Results as sever oResults as sever o2 2 starvation of the left starvation of the left ventricle of the heartventricle of the heart

This leads to myocardial ischemia amp may This leads to myocardial ischemia amp may progress to myocardial infarction or progress to myocardial infarction or ischemic left ventricular fibrillation amp ischemic left ventricular fibrillation amp sudden deathsudden death

Similar episodes involving the cerebral Similar episodes involving the cerebral circulation result in transient ischemic circulation result in transient ischemic attacks amp thrombotic stroke attacks amp thrombotic stroke

Myocardial Infarction SymptomMyocardial Infarction Symptom

Crushing tightness of the chest with Crushing tightness of the chest with sweating nausea breathlessness amp sweating nausea breathlessness amp collapsecollapse

Chest pain may radiates to the arm throat amp Chest pain may radiates to the arm throat amp jawjaw

Chest pain may confused with sever Chest pain may confused with sever indigestion in itrsquos early stagesindigestion in itrsquos early stages

Transient Ischemic attacksTransient Ischemic attacks

Itrsquos usually accompanied with neurological Itrsquos usually accompanied with neurological dysfunction or loss of visiondysfunction or loss of vision

Completed thrombotic strokeCompleted thrombotic stroke

Itrsquos accompanied by similar symptoms Itrsquos accompanied by similar symptoms which persist for more than 24 hours that which persist for more than 24 hours that may be severely amp permanently disablingmay be severely amp permanently disabling

Risk factors for arterial amp venous thrombosisRisk factors for arterial amp venous thrombosis

Venous thrombosisVenous thrombosisArterial thrombosisArterial thrombosisIncreasing ageIncreasing ageIncreasing ageIncreasing age

ObesityObesityObesityObesity

ImmobilityImmobilityLack of exerciseLack of exercise

Pregnancy rdquopost partomrdquoPregnancy rdquopost partomrdquoHigh fat low fiber dietHigh fat low fiber diet

MalignancyMalignancySmokingSmoking

Lupus anticoagulantLupus anticoagulantHyperlipidemiaHyperlipidemia

Nephrotic syndromeNephrotic syndromeHypertensionHypertension

PolycythemiaPolycythemiaElevated factor VII II concElevated factor VII II conc

goutgoutGenetic factorGenetic factor

Prophylaxis amp treatment of Prophylaxis amp treatment of thrombosisthrombosis

Prevent the risk factorsPrevent the risk factors SmokingSmoking ObesityObesity Lack of exerciseLack of exercise Poor dietPoor diet

Only when this proves to be impossibleOnly when this proves to be impossible

(Pharmacological intervention is required) (Pharmacological intervention is required)

Lupus Anticoagulant

Conditions where screening for APS Conditions where screening for APS is indicatedis indicated

The first thrombotic event below the age of 40The first thrombotic event below the age of 40 History of recurrent TEDHistory of recurrent TED Recurrent fetal loss in the 1Recurrent fetal loss in the 1stst or the 2 or the 2ndnd trimester trimester Patient with SLEPatient with SLE Pre-hormone replacement therapyPre-hormone replacement therapy

Non-familial (Acquired) continuedNon-familial (Acquired) continued

22 TPA (Tissue Plasminogen Activator) TPA (Tissue Plasminogen Activator) decreased levels impaired fibrinolysisdecreased levels impaired fibrinolysis

33 PAI (Plasminogen Activator Inhibitor) PAI (Plasminogen Activator Inhibitor) increased levels decreased TPAincreased levels decreased TPA

44 DysfibrinogenemiaDysfibrinogenemia55 F XII deficiency Hageman factorF XII deficiency Hageman factor66 Fibrinogen (increased)Fibrinogen (increased)77 F VIII (increased)F VIII (increased)88 PlasminogenPlasminogen99 Hyperhomocyteinemia ndash enzyme (folate)Hyperhomocyteinemia ndash enzyme (folate)

Investigation (Thrombotic Profile)Investigation (Thrombotic Profile)

NB Patients can be on Warfarin but not HeparinNB Patients can be on Warfarin but not Heparin FBC PLT amp ESRFBC PLT amp ESR PT aPTT TT amp FibrinogenPT aPTT TT amp Fibrinogen PC amp PSPC amp PS AT IIIAT III APCR (if + screening submit for PCR)APCR (if + screening submit for PCR) PT 20210A (PCR)PT 20210A (PCR) Lupus anticoagulant (RVVT KT LA-PTT) Lupus anticoagulant (RVVT KT LA-PTT) Cardiolipin antibodies (antiphospholipid syndrome)Cardiolipin antibodies (antiphospholipid syndrome) Sticky platelet syndrome (aspirin)Sticky platelet syndrome (aspirin) ANA screeningANA screening PNH screeningPNH screening

When to testWhen to test Younger lt 50 years recurrent TE unusual sites Younger lt 50 years recurrent TE unusual sites

TE on WarfarinTE on Warfarin Not ideal to test after acute episode (inhibitors of Not ideal to test after acute episode (inhibitors of

clotting may be low)clotting may be low) Ideal test after 6 weeks after settlement of Ideal test after 6 weeks after settlement of

hemostasishemostasis Most patients are on Warfarin then (PC amp PS are Most patients are on Warfarin then (PC amp PS are

Vit K dependent may be falsely low)Vit K dependent may be falsely low) My view if long-term Warfarin is planned do My view if long-term Warfarin is planned do

immediately according to duration of treatment it immediately according to duration of treatment it can be done after cessation of treatmentcan be done after cessation of treatment

When to test (continued)When to test (continued)

Practical (my experience) before treatment ndash if AT Practical (my experience) before treatment ndash if AT PS PC are low PS PC are low repeat after Rx has been stopped repeat after Rx has been stopped

SPS platelet aggregation studies (problem SPS platelet aggregation studies (problem sometimes aspirin cannot be stopped)sometimes aspirin cannot be stopped)

Remember the effect of the vessel wall on clotting Remember the effect of the vessel wall on clotting especially in arterial thrombosisespecially in arterial thrombosis

Every woman on contraception HRTEvery woman on contraception HRT

Arterial ThrombosisArterial Thrombosis

Arterial Thrombosis

Arterial ThrombosisArterial Thrombosis

Results as sever oResults as sever o2 2 starvation of the left starvation of the left ventricle of the heartventricle of the heart

This leads to myocardial ischemia amp may This leads to myocardial ischemia amp may progress to myocardial infarction or progress to myocardial infarction or ischemic left ventricular fibrillation amp ischemic left ventricular fibrillation amp sudden deathsudden death

Similar episodes involving the cerebral Similar episodes involving the cerebral circulation result in transient ischemic circulation result in transient ischemic attacks amp thrombotic stroke attacks amp thrombotic stroke

Myocardial Infarction SymptomMyocardial Infarction Symptom

Crushing tightness of the chest with Crushing tightness of the chest with sweating nausea breathlessness amp sweating nausea breathlessness amp collapsecollapse

Chest pain may radiates to the arm throat amp Chest pain may radiates to the arm throat amp jawjaw

Chest pain may confused with sever Chest pain may confused with sever indigestion in itrsquos early stagesindigestion in itrsquos early stages

Transient Ischemic attacksTransient Ischemic attacks

Itrsquos usually accompanied with neurological Itrsquos usually accompanied with neurological dysfunction or loss of visiondysfunction or loss of vision

Completed thrombotic strokeCompleted thrombotic stroke

Itrsquos accompanied by similar symptoms Itrsquos accompanied by similar symptoms which persist for more than 24 hours that which persist for more than 24 hours that may be severely amp permanently disablingmay be severely amp permanently disabling

Risk factors for arterial amp venous thrombosisRisk factors for arterial amp venous thrombosis

Venous thrombosisVenous thrombosisArterial thrombosisArterial thrombosisIncreasing ageIncreasing ageIncreasing ageIncreasing age

ObesityObesityObesityObesity

ImmobilityImmobilityLack of exerciseLack of exercise

Pregnancy rdquopost partomrdquoPregnancy rdquopost partomrdquoHigh fat low fiber dietHigh fat low fiber diet

MalignancyMalignancySmokingSmoking

Lupus anticoagulantLupus anticoagulantHyperlipidemiaHyperlipidemia

Nephrotic syndromeNephrotic syndromeHypertensionHypertension

PolycythemiaPolycythemiaElevated factor VII II concElevated factor VII II conc

goutgoutGenetic factorGenetic factor

Prophylaxis amp treatment of Prophylaxis amp treatment of thrombosisthrombosis

Prevent the risk factorsPrevent the risk factors SmokingSmoking ObesityObesity Lack of exerciseLack of exercise Poor dietPoor diet

Only when this proves to be impossibleOnly when this proves to be impossible

(Pharmacological intervention is required) (Pharmacological intervention is required)

Conditions where screening for APS Conditions where screening for APS is indicatedis indicated

The first thrombotic event below the age of 40The first thrombotic event below the age of 40 History of recurrent TEDHistory of recurrent TED Recurrent fetal loss in the 1Recurrent fetal loss in the 1stst or the 2 or the 2ndnd trimester trimester Patient with SLEPatient with SLE Pre-hormone replacement therapyPre-hormone replacement therapy

Non-familial (Acquired) continuedNon-familial (Acquired) continued

22 TPA (Tissue Plasminogen Activator) TPA (Tissue Plasminogen Activator) decreased levels impaired fibrinolysisdecreased levels impaired fibrinolysis

33 PAI (Plasminogen Activator Inhibitor) PAI (Plasminogen Activator Inhibitor) increased levels decreased TPAincreased levels decreased TPA

44 DysfibrinogenemiaDysfibrinogenemia55 F XII deficiency Hageman factorF XII deficiency Hageman factor66 Fibrinogen (increased)Fibrinogen (increased)77 F VIII (increased)F VIII (increased)88 PlasminogenPlasminogen99 Hyperhomocyteinemia ndash enzyme (folate)Hyperhomocyteinemia ndash enzyme (folate)

Investigation (Thrombotic Profile)Investigation (Thrombotic Profile)

NB Patients can be on Warfarin but not HeparinNB Patients can be on Warfarin but not Heparin FBC PLT amp ESRFBC PLT amp ESR PT aPTT TT amp FibrinogenPT aPTT TT amp Fibrinogen PC amp PSPC amp PS AT IIIAT III APCR (if + screening submit for PCR)APCR (if + screening submit for PCR) PT 20210A (PCR)PT 20210A (PCR) Lupus anticoagulant (RVVT KT LA-PTT) Lupus anticoagulant (RVVT KT LA-PTT) Cardiolipin antibodies (antiphospholipid syndrome)Cardiolipin antibodies (antiphospholipid syndrome) Sticky platelet syndrome (aspirin)Sticky platelet syndrome (aspirin) ANA screeningANA screening PNH screeningPNH screening

When to testWhen to test Younger lt 50 years recurrent TE unusual sites Younger lt 50 years recurrent TE unusual sites

TE on WarfarinTE on Warfarin Not ideal to test after acute episode (inhibitors of Not ideal to test after acute episode (inhibitors of

clotting may be low)clotting may be low) Ideal test after 6 weeks after settlement of Ideal test after 6 weeks after settlement of

hemostasishemostasis Most patients are on Warfarin then (PC amp PS are Most patients are on Warfarin then (PC amp PS are

Vit K dependent may be falsely low)Vit K dependent may be falsely low) My view if long-term Warfarin is planned do My view if long-term Warfarin is planned do

immediately according to duration of treatment it immediately according to duration of treatment it can be done after cessation of treatmentcan be done after cessation of treatment

When to test (continued)When to test (continued)

Practical (my experience) before treatment ndash if AT Practical (my experience) before treatment ndash if AT PS PC are low PS PC are low repeat after Rx has been stopped repeat after Rx has been stopped

SPS platelet aggregation studies (problem SPS platelet aggregation studies (problem sometimes aspirin cannot be stopped)sometimes aspirin cannot be stopped)

Remember the effect of the vessel wall on clotting Remember the effect of the vessel wall on clotting especially in arterial thrombosisespecially in arterial thrombosis

Every woman on contraception HRTEvery woman on contraception HRT

Arterial ThrombosisArterial Thrombosis

Arterial Thrombosis

Arterial ThrombosisArterial Thrombosis

Results as sever oResults as sever o2 2 starvation of the left starvation of the left ventricle of the heartventricle of the heart

This leads to myocardial ischemia amp may This leads to myocardial ischemia amp may progress to myocardial infarction or progress to myocardial infarction or ischemic left ventricular fibrillation amp ischemic left ventricular fibrillation amp sudden deathsudden death

Similar episodes involving the cerebral Similar episodes involving the cerebral circulation result in transient ischemic circulation result in transient ischemic attacks amp thrombotic stroke attacks amp thrombotic stroke

Myocardial Infarction SymptomMyocardial Infarction Symptom

Crushing tightness of the chest with Crushing tightness of the chest with sweating nausea breathlessness amp sweating nausea breathlessness amp collapsecollapse

Chest pain may radiates to the arm throat amp Chest pain may radiates to the arm throat amp jawjaw

Chest pain may confused with sever Chest pain may confused with sever indigestion in itrsquos early stagesindigestion in itrsquos early stages

Transient Ischemic attacksTransient Ischemic attacks

Itrsquos usually accompanied with neurological Itrsquos usually accompanied with neurological dysfunction or loss of visiondysfunction or loss of vision

Completed thrombotic strokeCompleted thrombotic stroke

Itrsquos accompanied by similar symptoms Itrsquos accompanied by similar symptoms which persist for more than 24 hours that which persist for more than 24 hours that may be severely amp permanently disablingmay be severely amp permanently disabling

Risk factors for arterial amp venous thrombosisRisk factors for arterial amp venous thrombosis

Venous thrombosisVenous thrombosisArterial thrombosisArterial thrombosisIncreasing ageIncreasing ageIncreasing ageIncreasing age

ObesityObesityObesityObesity

ImmobilityImmobilityLack of exerciseLack of exercise

Pregnancy rdquopost partomrdquoPregnancy rdquopost partomrdquoHigh fat low fiber dietHigh fat low fiber diet

MalignancyMalignancySmokingSmoking

Lupus anticoagulantLupus anticoagulantHyperlipidemiaHyperlipidemia

Nephrotic syndromeNephrotic syndromeHypertensionHypertension

PolycythemiaPolycythemiaElevated factor VII II concElevated factor VII II conc

goutgoutGenetic factorGenetic factor

Prophylaxis amp treatment of Prophylaxis amp treatment of thrombosisthrombosis

Prevent the risk factorsPrevent the risk factors SmokingSmoking ObesityObesity Lack of exerciseLack of exercise Poor dietPoor diet

Only when this proves to be impossibleOnly when this proves to be impossible

(Pharmacological intervention is required) (Pharmacological intervention is required)

Non-familial (Acquired) continuedNon-familial (Acquired) continued

22 TPA (Tissue Plasminogen Activator) TPA (Tissue Plasminogen Activator) decreased levels impaired fibrinolysisdecreased levels impaired fibrinolysis

33 PAI (Plasminogen Activator Inhibitor) PAI (Plasminogen Activator Inhibitor) increased levels decreased TPAincreased levels decreased TPA

44 DysfibrinogenemiaDysfibrinogenemia55 F XII deficiency Hageman factorF XII deficiency Hageman factor66 Fibrinogen (increased)Fibrinogen (increased)77 F VIII (increased)F VIII (increased)88 PlasminogenPlasminogen99 Hyperhomocyteinemia ndash enzyme (folate)Hyperhomocyteinemia ndash enzyme (folate)

Investigation (Thrombotic Profile)Investigation (Thrombotic Profile)

NB Patients can be on Warfarin but not HeparinNB Patients can be on Warfarin but not Heparin FBC PLT amp ESRFBC PLT amp ESR PT aPTT TT amp FibrinogenPT aPTT TT amp Fibrinogen PC amp PSPC amp PS AT IIIAT III APCR (if + screening submit for PCR)APCR (if + screening submit for PCR) PT 20210A (PCR)PT 20210A (PCR) Lupus anticoagulant (RVVT KT LA-PTT) Lupus anticoagulant (RVVT KT LA-PTT) Cardiolipin antibodies (antiphospholipid syndrome)Cardiolipin antibodies (antiphospholipid syndrome) Sticky platelet syndrome (aspirin)Sticky platelet syndrome (aspirin) ANA screeningANA screening PNH screeningPNH screening

When to testWhen to test Younger lt 50 years recurrent TE unusual sites Younger lt 50 years recurrent TE unusual sites

TE on WarfarinTE on Warfarin Not ideal to test after acute episode (inhibitors of Not ideal to test after acute episode (inhibitors of

clotting may be low)clotting may be low) Ideal test after 6 weeks after settlement of Ideal test after 6 weeks after settlement of

hemostasishemostasis Most patients are on Warfarin then (PC amp PS are Most patients are on Warfarin then (PC amp PS are

Vit K dependent may be falsely low)Vit K dependent may be falsely low) My view if long-term Warfarin is planned do My view if long-term Warfarin is planned do

immediately according to duration of treatment it immediately according to duration of treatment it can be done after cessation of treatmentcan be done after cessation of treatment

When to test (continued)When to test (continued)

Practical (my experience) before treatment ndash if AT Practical (my experience) before treatment ndash if AT PS PC are low PS PC are low repeat after Rx has been stopped repeat after Rx has been stopped

SPS platelet aggregation studies (problem SPS platelet aggregation studies (problem sometimes aspirin cannot be stopped)sometimes aspirin cannot be stopped)

Remember the effect of the vessel wall on clotting Remember the effect of the vessel wall on clotting especially in arterial thrombosisespecially in arterial thrombosis

Every woman on contraception HRTEvery woman on contraception HRT

Arterial ThrombosisArterial Thrombosis

Arterial Thrombosis

Arterial ThrombosisArterial Thrombosis

Results as sever oResults as sever o2 2 starvation of the left starvation of the left ventricle of the heartventricle of the heart

This leads to myocardial ischemia amp may This leads to myocardial ischemia amp may progress to myocardial infarction or progress to myocardial infarction or ischemic left ventricular fibrillation amp ischemic left ventricular fibrillation amp sudden deathsudden death

Similar episodes involving the cerebral Similar episodes involving the cerebral circulation result in transient ischemic circulation result in transient ischemic attacks amp thrombotic stroke attacks amp thrombotic stroke

Myocardial Infarction SymptomMyocardial Infarction Symptom

Crushing tightness of the chest with Crushing tightness of the chest with sweating nausea breathlessness amp sweating nausea breathlessness amp collapsecollapse

Chest pain may radiates to the arm throat amp Chest pain may radiates to the arm throat amp jawjaw

Chest pain may confused with sever Chest pain may confused with sever indigestion in itrsquos early stagesindigestion in itrsquos early stages

Transient Ischemic attacksTransient Ischemic attacks

Itrsquos usually accompanied with neurological Itrsquos usually accompanied with neurological dysfunction or loss of visiondysfunction or loss of vision

Completed thrombotic strokeCompleted thrombotic stroke

Itrsquos accompanied by similar symptoms Itrsquos accompanied by similar symptoms which persist for more than 24 hours that which persist for more than 24 hours that may be severely amp permanently disablingmay be severely amp permanently disabling

Risk factors for arterial amp venous thrombosisRisk factors for arterial amp venous thrombosis

Venous thrombosisVenous thrombosisArterial thrombosisArterial thrombosisIncreasing ageIncreasing ageIncreasing ageIncreasing age

ObesityObesityObesityObesity

ImmobilityImmobilityLack of exerciseLack of exercise

Pregnancy rdquopost partomrdquoPregnancy rdquopost partomrdquoHigh fat low fiber dietHigh fat low fiber diet

MalignancyMalignancySmokingSmoking

Lupus anticoagulantLupus anticoagulantHyperlipidemiaHyperlipidemia

Nephrotic syndromeNephrotic syndromeHypertensionHypertension

PolycythemiaPolycythemiaElevated factor VII II concElevated factor VII II conc

goutgoutGenetic factorGenetic factor

Prophylaxis amp treatment of Prophylaxis amp treatment of thrombosisthrombosis

Prevent the risk factorsPrevent the risk factors SmokingSmoking ObesityObesity Lack of exerciseLack of exercise Poor dietPoor diet

Only when this proves to be impossibleOnly when this proves to be impossible

(Pharmacological intervention is required) (Pharmacological intervention is required)

Investigation (Thrombotic Profile)Investigation (Thrombotic Profile)

NB Patients can be on Warfarin but not HeparinNB Patients can be on Warfarin but not Heparin FBC PLT amp ESRFBC PLT amp ESR PT aPTT TT amp FibrinogenPT aPTT TT amp Fibrinogen PC amp PSPC amp PS AT IIIAT III APCR (if + screening submit for PCR)APCR (if + screening submit for PCR) PT 20210A (PCR)PT 20210A (PCR) Lupus anticoagulant (RVVT KT LA-PTT) Lupus anticoagulant (RVVT KT LA-PTT) Cardiolipin antibodies (antiphospholipid syndrome)Cardiolipin antibodies (antiphospholipid syndrome) Sticky platelet syndrome (aspirin)Sticky platelet syndrome (aspirin) ANA screeningANA screening PNH screeningPNH screening

When to testWhen to test Younger lt 50 years recurrent TE unusual sites Younger lt 50 years recurrent TE unusual sites

TE on WarfarinTE on Warfarin Not ideal to test after acute episode (inhibitors of Not ideal to test after acute episode (inhibitors of

clotting may be low)clotting may be low) Ideal test after 6 weeks after settlement of Ideal test after 6 weeks after settlement of

hemostasishemostasis Most patients are on Warfarin then (PC amp PS are Most patients are on Warfarin then (PC amp PS are

Vit K dependent may be falsely low)Vit K dependent may be falsely low) My view if long-term Warfarin is planned do My view if long-term Warfarin is planned do

immediately according to duration of treatment it immediately according to duration of treatment it can be done after cessation of treatmentcan be done after cessation of treatment

When to test (continued)When to test (continued)

Practical (my experience) before treatment ndash if AT Practical (my experience) before treatment ndash if AT PS PC are low PS PC are low repeat after Rx has been stopped repeat after Rx has been stopped

SPS platelet aggregation studies (problem SPS platelet aggregation studies (problem sometimes aspirin cannot be stopped)sometimes aspirin cannot be stopped)

Remember the effect of the vessel wall on clotting Remember the effect of the vessel wall on clotting especially in arterial thrombosisespecially in arterial thrombosis

Every woman on contraception HRTEvery woman on contraception HRT

Arterial ThrombosisArterial Thrombosis

Arterial Thrombosis

Arterial ThrombosisArterial Thrombosis

Results as sever oResults as sever o2 2 starvation of the left starvation of the left ventricle of the heartventricle of the heart

This leads to myocardial ischemia amp may This leads to myocardial ischemia amp may progress to myocardial infarction or progress to myocardial infarction or ischemic left ventricular fibrillation amp ischemic left ventricular fibrillation amp sudden deathsudden death

Similar episodes involving the cerebral Similar episodes involving the cerebral circulation result in transient ischemic circulation result in transient ischemic attacks amp thrombotic stroke attacks amp thrombotic stroke

Myocardial Infarction SymptomMyocardial Infarction Symptom

Crushing tightness of the chest with Crushing tightness of the chest with sweating nausea breathlessness amp sweating nausea breathlessness amp collapsecollapse

Chest pain may radiates to the arm throat amp Chest pain may radiates to the arm throat amp jawjaw

Chest pain may confused with sever Chest pain may confused with sever indigestion in itrsquos early stagesindigestion in itrsquos early stages

Transient Ischemic attacksTransient Ischemic attacks

Itrsquos usually accompanied with neurological Itrsquos usually accompanied with neurological dysfunction or loss of visiondysfunction or loss of vision

Completed thrombotic strokeCompleted thrombotic stroke

Itrsquos accompanied by similar symptoms Itrsquos accompanied by similar symptoms which persist for more than 24 hours that which persist for more than 24 hours that may be severely amp permanently disablingmay be severely amp permanently disabling

Risk factors for arterial amp venous thrombosisRisk factors for arterial amp venous thrombosis

Venous thrombosisVenous thrombosisArterial thrombosisArterial thrombosisIncreasing ageIncreasing ageIncreasing ageIncreasing age

ObesityObesityObesityObesity

ImmobilityImmobilityLack of exerciseLack of exercise

Pregnancy rdquopost partomrdquoPregnancy rdquopost partomrdquoHigh fat low fiber dietHigh fat low fiber diet

MalignancyMalignancySmokingSmoking

Lupus anticoagulantLupus anticoagulantHyperlipidemiaHyperlipidemia

Nephrotic syndromeNephrotic syndromeHypertensionHypertension

PolycythemiaPolycythemiaElevated factor VII II concElevated factor VII II conc

goutgoutGenetic factorGenetic factor

Prophylaxis amp treatment of Prophylaxis amp treatment of thrombosisthrombosis

Prevent the risk factorsPrevent the risk factors SmokingSmoking ObesityObesity Lack of exerciseLack of exercise Poor dietPoor diet

Only when this proves to be impossibleOnly when this proves to be impossible

(Pharmacological intervention is required) (Pharmacological intervention is required)

When to testWhen to test Younger lt 50 years recurrent TE unusual sites Younger lt 50 years recurrent TE unusual sites

TE on WarfarinTE on Warfarin Not ideal to test after acute episode (inhibitors of Not ideal to test after acute episode (inhibitors of

clotting may be low)clotting may be low) Ideal test after 6 weeks after settlement of Ideal test after 6 weeks after settlement of

hemostasishemostasis Most patients are on Warfarin then (PC amp PS are Most patients are on Warfarin then (PC amp PS are

Vit K dependent may be falsely low)Vit K dependent may be falsely low) My view if long-term Warfarin is planned do My view if long-term Warfarin is planned do

immediately according to duration of treatment it immediately according to duration of treatment it can be done after cessation of treatmentcan be done after cessation of treatment

When to test (continued)When to test (continued)

Practical (my experience) before treatment ndash if AT Practical (my experience) before treatment ndash if AT PS PC are low PS PC are low repeat after Rx has been stopped repeat after Rx has been stopped

SPS platelet aggregation studies (problem SPS platelet aggregation studies (problem sometimes aspirin cannot be stopped)sometimes aspirin cannot be stopped)

Remember the effect of the vessel wall on clotting Remember the effect of the vessel wall on clotting especially in arterial thrombosisespecially in arterial thrombosis

Every woman on contraception HRTEvery woman on contraception HRT

Arterial ThrombosisArterial Thrombosis

Arterial Thrombosis

Arterial ThrombosisArterial Thrombosis

Results as sever oResults as sever o2 2 starvation of the left starvation of the left ventricle of the heartventricle of the heart

This leads to myocardial ischemia amp may This leads to myocardial ischemia amp may progress to myocardial infarction or progress to myocardial infarction or ischemic left ventricular fibrillation amp ischemic left ventricular fibrillation amp sudden deathsudden death

Similar episodes involving the cerebral Similar episodes involving the cerebral circulation result in transient ischemic circulation result in transient ischemic attacks amp thrombotic stroke attacks amp thrombotic stroke

Myocardial Infarction SymptomMyocardial Infarction Symptom

Crushing tightness of the chest with Crushing tightness of the chest with sweating nausea breathlessness amp sweating nausea breathlessness amp collapsecollapse

Chest pain may radiates to the arm throat amp Chest pain may radiates to the arm throat amp jawjaw

Chest pain may confused with sever Chest pain may confused with sever indigestion in itrsquos early stagesindigestion in itrsquos early stages

Transient Ischemic attacksTransient Ischemic attacks

Itrsquos usually accompanied with neurological Itrsquos usually accompanied with neurological dysfunction or loss of visiondysfunction or loss of vision

Completed thrombotic strokeCompleted thrombotic stroke

Itrsquos accompanied by similar symptoms Itrsquos accompanied by similar symptoms which persist for more than 24 hours that which persist for more than 24 hours that may be severely amp permanently disablingmay be severely amp permanently disabling

Risk factors for arterial amp venous thrombosisRisk factors for arterial amp venous thrombosis

Venous thrombosisVenous thrombosisArterial thrombosisArterial thrombosisIncreasing ageIncreasing ageIncreasing ageIncreasing age

ObesityObesityObesityObesity

ImmobilityImmobilityLack of exerciseLack of exercise

Pregnancy rdquopost partomrdquoPregnancy rdquopost partomrdquoHigh fat low fiber dietHigh fat low fiber diet

MalignancyMalignancySmokingSmoking

Lupus anticoagulantLupus anticoagulantHyperlipidemiaHyperlipidemia

Nephrotic syndromeNephrotic syndromeHypertensionHypertension

PolycythemiaPolycythemiaElevated factor VII II concElevated factor VII II conc

goutgoutGenetic factorGenetic factor

Prophylaxis amp treatment of Prophylaxis amp treatment of thrombosisthrombosis

Prevent the risk factorsPrevent the risk factors SmokingSmoking ObesityObesity Lack of exerciseLack of exercise Poor dietPoor diet

Only when this proves to be impossibleOnly when this proves to be impossible

(Pharmacological intervention is required) (Pharmacological intervention is required)

When to test (continued)When to test (continued)

Practical (my experience) before treatment ndash if AT Practical (my experience) before treatment ndash if AT PS PC are low PS PC are low repeat after Rx has been stopped repeat after Rx has been stopped

SPS platelet aggregation studies (problem SPS platelet aggregation studies (problem sometimes aspirin cannot be stopped)sometimes aspirin cannot be stopped)

Remember the effect of the vessel wall on clotting Remember the effect of the vessel wall on clotting especially in arterial thrombosisespecially in arterial thrombosis

Every woman on contraception HRTEvery woman on contraception HRT

Arterial ThrombosisArterial Thrombosis

Arterial Thrombosis

Arterial ThrombosisArterial Thrombosis

Results as sever oResults as sever o2 2 starvation of the left starvation of the left ventricle of the heartventricle of the heart

This leads to myocardial ischemia amp may This leads to myocardial ischemia amp may progress to myocardial infarction or progress to myocardial infarction or ischemic left ventricular fibrillation amp ischemic left ventricular fibrillation amp sudden deathsudden death

Similar episodes involving the cerebral Similar episodes involving the cerebral circulation result in transient ischemic circulation result in transient ischemic attacks amp thrombotic stroke attacks amp thrombotic stroke

Myocardial Infarction SymptomMyocardial Infarction Symptom

Crushing tightness of the chest with Crushing tightness of the chest with sweating nausea breathlessness amp sweating nausea breathlessness amp collapsecollapse

Chest pain may radiates to the arm throat amp Chest pain may radiates to the arm throat amp jawjaw

Chest pain may confused with sever Chest pain may confused with sever indigestion in itrsquos early stagesindigestion in itrsquos early stages

Transient Ischemic attacksTransient Ischemic attacks

Itrsquos usually accompanied with neurological Itrsquos usually accompanied with neurological dysfunction or loss of visiondysfunction or loss of vision

Completed thrombotic strokeCompleted thrombotic stroke

Itrsquos accompanied by similar symptoms Itrsquos accompanied by similar symptoms which persist for more than 24 hours that which persist for more than 24 hours that may be severely amp permanently disablingmay be severely amp permanently disabling

Risk factors for arterial amp venous thrombosisRisk factors for arterial amp venous thrombosis

Venous thrombosisVenous thrombosisArterial thrombosisArterial thrombosisIncreasing ageIncreasing ageIncreasing ageIncreasing age

ObesityObesityObesityObesity

ImmobilityImmobilityLack of exerciseLack of exercise

Pregnancy rdquopost partomrdquoPregnancy rdquopost partomrdquoHigh fat low fiber dietHigh fat low fiber diet

MalignancyMalignancySmokingSmoking

Lupus anticoagulantLupus anticoagulantHyperlipidemiaHyperlipidemia

Nephrotic syndromeNephrotic syndromeHypertensionHypertension

PolycythemiaPolycythemiaElevated factor VII II concElevated factor VII II conc

goutgoutGenetic factorGenetic factor

Prophylaxis amp treatment of Prophylaxis amp treatment of thrombosisthrombosis

Prevent the risk factorsPrevent the risk factors SmokingSmoking ObesityObesity Lack of exerciseLack of exercise Poor dietPoor diet

Only when this proves to be impossibleOnly when this proves to be impossible

(Pharmacological intervention is required) (Pharmacological intervention is required)

Arterial ThrombosisArterial Thrombosis

Arterial Thrombosis

Arterial ThrombosisArterial Thrombosis

Results as sever oResults as sever o2 2 starvation of the left starvation of the left ventricle of the heartventricle of the heart

This leads to myocardial ischemia amp may This leads to myocardial ischemia amp may progress to myocardial infarction or progress to myocardial infarction or ischemic left ventricular fibrillation amp ischemic left ventricular fibrillation amp sudden deathsudden death

Similar episodes involving the cerebral Similar episodes involving the cerebral circulation result in transient ischemic circulation result in transient ischemic attacks amp thrombotic stroke attacks amp thrombotic stroke

Myocardial Infarction SymptomMyocardial Infarction Symptom

Crushing tightness of the chest with Crushing tightness of the chest with sweating nausea breathlessness amp sweating nausea breathlessness amp collapsecollapse

Chest pain may radiates to the arm throat amp Chest pain may radiates to the arm throat amp jawjaw

Chest pain may confused with sever Chest pain may confused with sever indigestion in itrsquos early stagesindigestion in itrsquos early stages

Transient Ischemic attacksTransient Ischemic attacks

Itrsquos usually accompanied with neurological Itrsquos usually accompanied with neurological dysfunction or loss of visiondysfunction or loss of vision

Completed thrombotic strokeCompleted thrombotic stroke

Itrsquos accompanied by similar symptoms Itrsquos accompanied by similar symptoms which persist for more than 24 hours that which persist for more than 24 hours that may be severely amp permanently disablingmay be severely amp permanently disabling

Risk factors for arterial amp venous thrombosisRisk factors for arterial amp venous thrombosis

Venous thrombosisVenous thrombosisArterial thrombosisArterial thrombosisIncreasing ageIncreasing ageIncreasing ageIncreasing age

ObesityObesityObesityObesity

ImmobilityImmobilityLack of exerciseLack of exercise

Pregnancy rdquopost partomrdquoPregnancy rdquopost partomrdquoHigh fat low fiber dietHigh fat low fiber diet

MalignancyMalignancySmokingSmoking

Lupus anticoagulantLupus anticoagulantHyperlipidemiaHyperlipidemia

Nephrotic syndromeNephrotic syndromeHypertensionHypertension

PolycythemiaPolycythemiaElevated factor VII II concElevated factor VII II conc

goutgoutGenetic factorGenetic factor

Prophylaxis amp treatment of Prophylaxis amp treatment of thrombosisthrombosis

Prevent the risk factorsPrevent the risk factors SmokingSmoking ObesityObesity Lack of exerciseLack of exercise Poor dietPoor diet

Only when this proves to be impossibleOnly when this proves to be impossible

(Pharmacological intervention is required) (Pharmacological intervention is required)

Arterial Thrombosis

Arterial ThrombosisArterial Thrombosis

Results as sever oResults as sever o2 2 starvation of the left starvation of the left ventricle of the heartventricle of the heart

This leads to myocardial ischemia amp may This leads to myocardial ischemia amp may progress to myocardial infarction or progress to myocardial infarction or ischemic left ventricular fibrillation amp ischemic left ventricular fibrillation amp sudden deathsudden death

Similar episodes involving the cerebral Similar episodes involving the cerebral circulation result in transient ischemic circulation result in transient ischemic attacks amp thrombotic stroke attacks amp thrombotic stroke

Myocardial Infarction SymptomMyocardial Infarction Symptom

Crushing tightness of the chest with Crushing tightness of the chest with sweating nausea breathlessness amp sweating nausea breathlessness amp collapsecollapse

Chest pain may radiates to the arm throat amp Chest pain may radiates to the arm throat amp jawjaw

Chest pain may confused with sever Chest pain may confused with sever indigestion in itrsquos early stagesindigestion in itrsquos early stages

Transient Ischemic attacksTransient Ischemic attacks

Itrsquos usually accompanied with neurological Itrsquos usually accompanied with neurological dysfunction or loss of visiondysfunction or loss of vision

Completed thrombotic strokeCompleted thrombotic stroke

Itrsquos accompanied by similar symptoms Itrsquos accompanied by similar symptoms which persist for more than 24 hours that which persist for more than 24 hours that may be severely amp permanently disablingmay be severely amp permanently disabling

Risk factors for arterial amp venous thrombosisRisk factors for arterial amp venous thrombosis

Venous thrombosisVenous thrombosisArterial thrombosisArterial thrombosisIncreasing ageIncreasing ageIncreasing ageIncreasing age

ObesityObesityObesityObesity

ImmobilityImmobilityLack of exerciseLack of exercise

Pregnancy rdquopost partomrdquoPregnancy rdquopost partomrdquoHigh fat low fiber dietHigh fat low fiber diet

MalignancyMalignancySmokingSmoking

Lupus anticoagulantLupus anticoagulantHyperlipidemiaHyperlipidemia

Nephrotic syndromeNephrotic syndromeHypertensionHypertension

PolycythemiaPolycythemiaElevated factor VII II concElevated factor VII II conc

goutgoutGenetic factorGenetic factor

Prophylaxis amp treatment of Prophylaxis amp treatment of thrombosisthrombosis

Prevent the risk factorsPrevent the risk factors SmokingSmoking ObesityObesity Lack of exerciseLack of exercise Poor dietPoor diet

Only when this proves to be impossibleOnly when this proves to be impossible

(Pharmacological intervention is required) (Pharmacological intervention is required)

Arterial ThrombosisArterial Thrombosis

Results as sever oResults as sever o2 2 starvation of the left starvation of the left ventricle of the heartventricle of the heart

This leads to myocardial ischemia amp may This leads to myocardial ischemia amp may progress to myocardial infarction or progress to myocardial infarction or ischemic left ventricular fibrillation amp ischemic left ventricular fibrillation amp sudden deathsudden death

Similar episodes involving the cerebral Similar episodes involving the cerebral circulation result in transient ischemic circulation result in transient ischemic attacks amp thrombotic stroke attacks amp thrombotic stroke

Myocardial Infarction SymptomMyocardial Infarction Symptom

Crushing tightness of the chest with Crushing tightness of the chest with sweating nausea breathlessness amp sweating nausea breathlessness amp collapsecollapse

Chest pain may radiates to the arm throat amp Chest pain may radiates to the arm throat amp jawjaw

Chest pain may confused with sever Chest pain may confused with sever indigestion in itrsquos early stagesindigestion in itrsquos early stages

Transient Ischemic attacksTransient Ischemic attacks

Itrsquos usually accompanied with neurological Itrsquos usually accompanied with neurological dysfunction or loss of visiondysfunction or loss of vision

Completed thrombotic strokeCompleted thrombotic stroke

Itrsquos accompanied by similar symptoms Itrsquos accompanied by similar symptoms which persist for more than 24 hours that which persist for more than 24 hours that may be severely amp permanently disablingmay be severely amp permanently disabling

Risk factors for arterial amp venous thrombosisRisk factors for arterial amp venous thrombosis

Venous thrombosisVenous thrombosisArterial thrombosisArterial thrombosisIncreasing ageIncreasing ageIncreasing ageIncreasing age

ObesityObesityObesityObesity

ImmobilityImmobilityLack of exerciseLack of exercise

Pregnancy rdquopost partomrdquoPregnancy rdquopost partomrdquoHigh fat low fiber dietHigh fat low fiber diet

MalignancyMalignancySmokingSmoking

Lupus anticoagulantLupus anticoagulantHyperlipidemiaHyperlipidemia

Nephrotic syndromeNephrotic syndromeHypertensionHypertension

PolycythemiaPolycythemiaElevated factor VII II concElevated factor VII II conc

goutgoutGenetic factorGenetic factor

Prophylaxis amp treatment of Prophylaxis amp treatment of thrombosisthrombosis

Prevent the risk factorsPrevent the risk factors SmokingSmoking ObesityObesity Lack of exerciseLack of exercise Poor dietPoor diet

Only when this proves to be impossibleOnly when this proves to be impossible

(Pharmacological intervention is required) (Pharmacological intervention is required)

Myocardial Infarction SymptomMyocardial Infarction Symptom

Crushing tightness of the chest with Crushing tightness of the chest with sweating nausea breathlessness amp sweating nausea breathlessness amp collapsecollapse

Chest pain may radiates to the arm throat amp Chest pain may radiates to the arm throat amp jawjaw

Chest pain may confused with sever Chest pain may confused with sever indigestion in itrsquos early stagesindigestion in itrsquos early stages

Transient Ischemic attacksTransient Ischemic attacks

Itrsquos usually accompanied with neurological Itrsquos usually accompanied with neurological dysfunction or loss of visiondysfunction or loss of vision

Completed thrombotic strokeCompleted thrombotic stroke

Itrsquos accompanied by similar symptoms Itrsquos accompanied by similar symptoms which persist for more than 24 hours that which persist for more than 24 hours that may be severely amp permanently disablingmay be severely amp permanently disabling

Risk factors for arterial amp venous thrombosisRisk factors for arterial amp venous thrombosis

Venous thrombosisVenous thrombosisArterial thrombosisArterial thrombosisIncreasing ageIncreasing ageIncreasing ageIncreasing age

ObesityObesityObesityObesity

ImmobilityImmobilityLack of exerciseLack of exercise

Pregnancy rdquopost partomrdquoPregnancy rdquopost partomrdquoHigh fat low fiber dietHigh fat low fiber diet

MalignancyMalignancySmokingSmoking

Lupus anticoagulantLupus anticoagulantHyperlipidemiaHyperlipidemia

Nephrotic syndromeNephrotic syndromeHypertensionHypertension

PolycythemiaPolycythemiaElevated factor VII II concElevated factor VII II conc

goutgoutGenetic factorGenetic factor

Prophylaxis amp treatment of Prophylaxis amp treatment of thrombosisthrombosis

Prevent the risk factorsPrevent the risk factors SmokingSmoking ObesityObesity Lack of exerciseLack of exercise Poor dietPoor diet

Only when this proves to be impossibleOnly when this proves to be impossible

(Pharmacological intervention is required) (Pharmacological intervention is required)

Transient Ischemic attacksTransient Ischemic attacks

Itrsquos usually accompanied with neurological Itrsquos usually accompanied with neurological dysfunction or loss of visiondysfunction or loss of vision

Completed thrombotic strokeCompleted thrombotic stroke

Itrsquos accompanied by similar symptoms Itrsquos accompanied by similar symptoms which persist for more than 24 hours that which persist for more than 24 hours that may be severely amp permanently disablingmay be severely amp permanently disabling

Risk factors for arterial amp venous thrombosisRisk factors for arterial amp venous thrombosis

Venous thrombosisVenous thrombosisArterial thrombosisArterial thrombosisIncreasing ageIncreasing ageIncreasing ageIncreasing age

ObesityObesityObesityObesity

ImmobilityImmobilityLack of exerciseLack of exercise

Pregnancy rdquopost partomrdquoPregnancy rdquopost partomrdquoHigh fat low fiber dietHigh fat low fiber diet

MalignancyMalignancySmokingSmoking

Lupus anticoagulantLupus anticoagulantHyperlipidemiaHyperlipidemia

Nephrotic syndromeNephrotic syndromeHypertensionHypertension

PolycythemiaPolycythemiaElevated factor VII II concElevated factor VII II conc

goutgoutGenetic factorGenetic factor

Prophylaxis amp treatment of Prophylaxis amp treatment of thrombosisthrombosis

Prevent the risk factorsPrevent the risk factors SmokingSmoking ObesityObesity Lack of exerciseLack of exercise Poor dietPoor diet

Only when this proves to be impossibleOnly when this proves to be impossible

(Pharmacological intervention is required) (Pharmacological intervention is required)

Completed thrombotic strokeCompleted thrombotic stroke

Itrsquos accompanied by similar symptoms Itrsquos accompanied by similar symptoms which persist for more than 24 hours that which persist for more than 24 hours that may be severely amp permanently disablingmay be severely amp permanently disabling

Risk factors for arterial amp venous thrombosisRisk factors for arterial amp venous thrombosis

Venous thrombosisVenous thrombosisArterial thrombosisArterial thrombosisIncreasing ageIncreasing ageIncreasing ageIncreasing age

ObesityObesityObesityObesity

ImmobilityImmobilityLack of exerciseLack of exercise

Pregnancy rdquopost partomrdquoPregnancy rdquopost partomrdquoHigh fat low fiber dietHigh fat low fiber diet

MalignancyMalignancySmokingSmoking

Lupus anticoagulantLupus anticoagulantHyperlipidemiaHyperlipidemia

Nephrotic syndromeNephrotic syndromeHypertensionHypertension

PolycythemiaPolycythemiaElevated factor VII II concElevated factor VII II conc

goutgoutGenetic factorGenetic factor

Prophylaxis amp treatment of Prophylaxis amp treatment of thrombosisthrombosis

Prevent the risk factorsPrevent the risk factors SmokingSmoking ObesityObesity Lack of exerciseLack of exercise Poor dietPoor diet

Only when this proves to be impossibleOnly when this proves to be impossible

(Pharmacological intervention is required) (Pharmacological intervention is required)

Risk factors for arterial amp venous thrombosisRisk factors for arterial amp venous thrombosis

Venous thrombosisVenous thrombosisArterial thrombosisArterial thrombosisIncreasing ageIncreasing ageIncreasing ageIncreasing age

ObesityObesityObesityObesity

ImmobilityImmobilityLack of exerciseLack of exercise

Pregnancy rdquopost partomrdquoPregnancy rdquopost partomrdquoHigh fat low fiber dietHigh fat low fiber diet

MalignancyMalignancySmokingSmoking

Lupus anticoagulantLupus anticoagulantHyperlipidemiaHyperlipidemia

Nephrotic syndromeNephrotic syndromeHypertensionHypertension

PolycythemiaPolycythemiaElevated factor VII II concElevated factor VII II conc

goutgoutGenetic factorGenetic factor

Prophylaxis amp treatment of Prophylaxis amp treatment of thrombosisthrombosis

Prevent the risk factorsPrevent the risk factors SmokingSmoking ObesityObesity Lack of exerciseLack of exercise Poor dietPoor diet

Only when this proves to be impossibleOnly when this proves to be impossible

(Pharmacological intervention is required) (Pharmacological intervention is required)

Prophylaxis amp treatment of Prophylaxis amp treatment of thrombosisthrombosis

Prevent the risk factorsPrevent the risk factors SmokingSmoking ObesityObesity Lack of exerciseLack of exercise Poor dietPoor diet

Only when this proves to be impossibleOnly when this proves to be impossible

(Pharmacological intervention is required) (Pharmacological intervention is required)