Thrombosis: Thrombosis Coagulation in the wrong place and at the wrong time


Pathophysiology of Thrombosis: Pathophysiology of Thrombosis 1. Abnormalities of blood flow 2. Abnormalities of the vessel wall 3. Abnormalities of blood composition 1821-1902 Rudolf Virchow’s Triad


Pathophysiology of Venous Thrombosis: Pathophysiology of Venous Thrombosis 1. Abnormalities of blood flow: Stasis: low – grade activation of coagulation factors and platelets - red clots composed of fibrin and RBC 2. Abnormalities of the vessel wall: normal 3. Abnormalities of blood composition 1821-1902 Rudolf Virchow’s Triad


Pathophysiology of Arterial Thrombosis: Pathophysiology of Arterial Thrombosis 1. Abnormalities of blood flow: turbulence (high shear) 2. Abnormalities of the vessel wall: Atherosclerosis (chronic vessel disease); rupture of atheroma: platelets deposition; TF exposure activation of coagulation factors: white clot composed mostly of platelets and some fibrin 3. Abnormalities of blood composition 1821-1902 Rudolf Virchow’s Triad


Pathophysiology of Thrombosis: Pathophysiology of Thrombosis 1. Abnormalities of blood flow 2. Abnormalities of the vessel wall 3. Abnormalities of blood composition: Heteditary and Acquired Thrombophilias 1821-1902 Rudolf Virchow’s Triad


Slide6: Thrombophilia=Tendency to Thrombosis HEREDITARY ACQUIRED


Hereditary Thrombophilia: Hereditary Thrombophilia Egeberg – 1965: Norwegian family with absence ATIII


Natural Anticoagulants: Natural Anticoagulants Antithrombin: synthesized by liver Function: neutralization of thrombin (FIIa), FXIa, FIXa, FXa by formation heparan sulphate complex Protein C: synthesized by liver; Vit K-depend Function: decrease in generation of thrombin Protein S: synthesized by liver; Vit K-depend Function: decrease in generation of thrombin


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Slide10: Poor response of aPTT to APC in 30% of patients with VTE (Dahlback, PANSC 1993) Mutation in Factor V (Bertina, Nature 1994) that causes decrease in inactivation of FVa and FVIIIa – increase in thrombin generation Activated Protein C Resistance


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Slide12: Antithrombin, Protein C, Protein S deficeincy (5-15% of patients) decrease in inhibition of coagulation Factor V Leiden mutation (Arg506Gln) APCR Prothrombin mutation (G20210A) increase in FII level MTHFR mutation (C677T) elevated Hey Hereditary Thrombophilia Syndromes


FREQUENCY OF INHERITED THROMBOPHILIAS AMONG HEALTHY SUBJECTS ANDUNSELECTED AND SELECTED PATIENTS WITH VENOUS THROMBOSIS: FREQUENCY OF INHERITED THROMBOPHILIAS AMONG HEALTHY SUBJECTS AND UNSELECTED AND SELECTED PATIENTS WITH VENOUS THROMBOSIS


Slide14: Age (1 in 10,000andlt;40 1 in 100andgt;75 year) Major surgery Active malignancy Myeloproliferative disorder Prolonged immobilization OC, Pregnancy, HRT APLA syndrome Hyperhomocysteinemia Acquired Hypercoagulability


Slide15: VTE GENETIC CAUSES ACQUIRED CAUSES


Slide16: Family History of venous thrombosis Thrombosis of young age Recurrent venous thrombosis Idiopathic venous thrombosis Venous thrombosis following mininal provocation Heparin resistance (ATIII- deficiency) Coumarin necrosis (protein C and protein S deficiency) Neonatal purpura fulminans (protein C deficeincy) Clinical Manifestations of Thrombophilia


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Clinical Manifestations of Thrombophilia: Thrombosis in an unusual site Inferior vena cava Mesenteric vein thrombosis Cerebral vein thrombosis Renal vein thrombosis Axillary vein thrombosis Clinical Manifestations of Thrombophilia


Slide19: Arg to Gln substitution at 506 of factor V 5-8 fold risk of venous thrombosis in heterozygotes 50-100 fold risk of venous thrombosis in homozygotes Risk factor for MI (controversial) Asymptomatic carriers – 5% Factor V Leiden- Arg506Gln


Slide20: G to A transition at 3’, 20210 (Poort, Blood 1996) Causes increase in Factor II 2-5 increase in the risk of venous thrombosis Risk factor for MI (controversial) Risk factor for ischemic stroke (controversial) Prevalence in normal population: 3% Prothrombin Mutation (G20210A)


Slide21: C to T at nt.677: Ala to Val; Thermolabile Homozygotes: increased homocysteine levels Heterozygotes: normal homocysteine levels 12%- asymptomatic 2-fold increased risk of venous thrombosis (controversial) Risk factor for MI (controversial) Methylenetetrahydropholate reductase (MTHFR)


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Slide23: Prolonged exposure of endothelial cells to homocysteine impairs EDRF Homocysteine stimulated the proliferation of smooth muscle cells – atherogenesis Homocysteine decreases thrombomodulin expression and activity – decreased activation of protein C Homocysteine inhibits the ATIII binding activity of endothelial heparan sulfate proteoglycan Homocysteine inhibits ADP-ase activity of HUVEC Homocysteine inhibits binding of tPA – decreased fibrinolysis Homocysteine induces TF activity Procoagulant effect of homocyteine on vascular endothelium


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Slide25: High levels of Factor VIII High levels of Factor IX High levels of Factor XI High levels of Fibrinogen Increase in risk for VTE 3-6-fold (Lancet 1995, 345:152; NEJM 2000, 342:696) Mechanism?: acute phase reactants, pregnancy, older age, smoking Other abnormalities associated with the risk of VT


Slide26: Screen for resistance to activated protein C (APC) by clotting assay or genetic test for factor V-Arg506Gln (Factor V Leiden) Confirm positive APC resistance assay with genetic test Genetic test for prothrombin or MTHFR mutations Functional assay of ATIII Functional assay of Protein C Immunological assays of total and free Protein S Clotting assay for Lupus Anticoagulant and ELISA for APLA Measurement of fasting total plasma homocysteine levels Screening/laboratory evaluation for thrombophilic patients


Management: Management Acute VTE: Heparin/LMWH and Coumadin Continue Coumadin for 3 months if DVT was provoked by surgery, trauma, immobilization Continue Coumadin for 6 months if DVT was unprovoked; for 12 months in protein C or S deficiency, FVL, FII mutation


Management: Management Continue Coumadin indefnitely if: 2 or more VTEs; 1 life-threatening event (massive PE, CVT, VC, MVT); APLs, ATIII deficiency; more than 1 genetic defect (homozygous FVL or FVL and homozygous FII)


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Slide30: Following the cessation of therapy 24.8% to 27% recurrence at 5 years and 30.3% recurrence at 8 years (Ann Intern Med 1996, 125:1; NEJM 1999, 340:901) 50% of recurrent DVT – in contralateral leg Warfarin causes 95% reduction in recurrency but 0.25% /year incidence of fatal bleeding DVT is a Chronic Disease


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Slide33: Second generation OC and hetero for FVL increase the risk for VTE 20 to 35- fold (Lancet 1994, 344:1453) Third generation OC and VTE increase the risk 50-fold (Lancet 1995, 345:1593) OC and hetero for FII mutation increase the risk for VTE 16-fold (ATVB 1999, 19:700). The risk for CVT – 150-fold (NEJM 1998, 338:1793) OC and risk of VTE in Thrombophilic patients


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Pregnancy = Hypercoagulable state: Pregnancy = Hypercoagulable state Venous stasis Increase in coagulation factorsa: VWF, FVIII, FV, Fng, APCR Decrease in Protein S Decrease in fibrinolysis (increase in PAI-1 and PAI-2)


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VTE and PREGNANCY: VTE and PREGNANCY Risk of VTE in pregnancy and puerperium is 1 in 1500 Risk of VTE in pregnancy and FVL is 2 in 1000 Risk of VTE in pregnancy and FII is 5 in 1000 Risk of VTE in pregnancy and FVL + FII is 5 in 100


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Slide39: Anti-Phospholipid Syndrome APLs


Slide40: Mechanism of APL-induced thrombosis ApoER2’ EC Platelet A2 R ApoER2’ Platelet activation EC activation A2 R


Slide41: Frequency of APL Ab in the general population: 3-10% (Thromb Haemost 1997, 77:444) Clinical manifestations: Venous (DVT + PE – 55%) and arterial thrombosis (CVA + TIA – 50%; MI – 25%) Recurrent pregnancy loss Laboratory findings: Ab against phospholipids (PL)-binding proteins: β2GP1, (FII, annexin 5) APL Ab increase the risk for VTE 9-fold (Blood 1995 85:3685) Antiphospholipid Syndrome (APL)


Slide42: Coagulation-based tests: prolongation of PL-depended coagulation test: DRVVT, aPTT, Kaolin clotting time Immunoassays: anticardiolipin Ab, anti 2GPI Ab, anti prothrombin Ab Laboratory tests for APL Ab


Slide43: For VTE: Warfarin aiming INR 2-3 (Am J Med, 1998, 104:332) For arterial thrombosis: Warfarin aiming INR 3 (Hematology, Education Program 2001) Anticoagulated patients do not benefit from addition of Aspirin (NEJM 1995, 126:2136) Long-term anticoagulation: Recurrence rate 50% at 2 years; 78% at 8 years (Ann Rheum Dis 1993; 52:689) Treatment of APL syndrome


Cancer and Clotting: Cancer and Clotting Armand Trousseau was the first to recognize the link. Trousseau A. Plegmasia Alba Dolens. In: Bailliere JB, editor. Clinique Medicale de I’Hotel-Dieu de Paris, 2nd ed. 1865; 3:654-712


TROUSSEAU’S SYNDROM(Dr. Armand Trousseau, 1865): TROUSSEAU’S SYNDROM (Dr. Armand Trousseau, 1865) 1. Recurrent sup. and deep thrombosis. 2. Phlebitis that relapses after the cessation of heparin and the initiation of Warfarin ('Warfarin Failure'). 3. Thrombosis around catheters. 4. Nonbacterial (Marantic) endocarditis with systemic embolization.


Multifactorial Pathophysiology of Thrombosis in Cancer Patients: Multifactorial Pathophysiology of Thrombosis in Cancer Patients 1. Abnormalities of blood flow: a) Immobilization and bed rest b) Vascular compression from bulky tumor d) Hyperviscosity 2. Abnormalities of the vessel wall: a) Direct vascular invasion by tumor b) Reduction in PA within vascular endothelium 3. Abnormalities of blood composition: a) Elevated I, V, VII, VIII factors b) Decreased clearance of the activated factors c) Activation of coagulation system by the tumor cells 1821-1902 Rudolf Virchow’s Triad


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