thrombotic diseases
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Thrombotic Diseases. Ahmad Shihada Silmi Faculty of Sciences IUG MED TECH DEP Room # B326. Thrombotic disorders. - PowerPoint PPT PresentationTRANSCRIPT
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)