1. Thrombophilia=Tendency to Thrombosis HEREDITARYACQUIRED

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

3. Natural Anticoagulants Antithrombin : synthesized by liver 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 Protein C : synthesized by liver; Vit K-depend Function: decrease in generation of thrombin Protein S : synthesized by liver; Vit K-depend Protein S : synthesized by liver; Vit K-depend Function: decrease in generation of thrombin

4. Antithrombin, Protein C, Protein S deficiency (5-15% of VTE patients) Antithrombin, Protein C, Protein S deficiency (5-15% of VTE patients) decrease in inhibition of coagulation decrease in inhibition of coagulation Factor V Leiden mutation (Arg506Gln) increase in thrombin generation Factor V Leiden mutation (Arg506Gln) increase in thrombin generation Prothrombin mutation (G20210A) Prothrombin mutation (G20210A) increase in prothrombin (FII) level increase in prothrombin (FII) level MTHFR mutation (C677T) elevated Hey MTHFR mutation (C677T) elevated Hey Hereditary Thrombophilia Syndromes

5. antithrombin FII mutation ↑↑ Factor V Leiden

6. Age (1 in 10,000 75 year) Age (1 in 10,000 75 year) Major surgery Major surgery Active malignancy Active malignancy Myeloproliferative disorder Myeloproliferative disorder Prolonged immobilization Prolonged immobilization OC, Pregnancy, HRT OC, Pregnancy, HRT APLA syndrome APLA syndrome Hyperhomocysteinemia Hyperhomocysteinemia Acquired Hypercoagulability

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

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

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

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

11. Family History of venous thrombosis Family History of venous thrombosis Thrombosis of young age Thrombosis of young age Recurrent venous thrombosis Recurrent venous thrombosis Idiopathic venous thrombosis Idiopathic venous thrombosis Thrombosis in an unusual site Thrombosis in an unusual site Inferior vena cava Inferior vena cava Mesenteric vein thrombosis Mesenteric vein thrombosis Cerebral vein thrombosis Cerebral vein thrombosis Renal vein thrombosis Renal vein thrombosis Axillary vein thrombosis Axillary vein thrombosis Clinical Manifestations of Thrombophilia

12. Screen for resistance to activated protein C (APC) by clotting assay or genetic test for factor V-Arg506Gln (Factor V Leiden) 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 Genetic test for prothrombin or MTHFR mutations Functional assay of ATIII Functional assay of ATIII Functional assay of Protein C Functional assay of Protein C Immunological assays of total and free Protein S Immunological assays of total and free Protein S Measurement of fasting total plasma homocysteine levels Measurement of fasting total plasma homocysteine levels Screening/laboratory evaluation for hereditary thrombophilia

13. Management Acute VTE: Heparin/LMWH and Coumadin Acute VTE: Heparin/LMWH and Coumadin Continue Coumadin for 3 months if DVT was provoked by surgery, trauma, immobilization Continue Coumadin for 3 months if DVT was provoked by surgery, trauma, immobilization Continue Coumadin for 6-12 months if DVT was unprovoked Continue Coumadin for 6-12 months if DVT was unprovoked Continue Coumadin indefnitely if: 2 or more VTEs, 1 life-threatening event (massive PE, CVT, IVC, MVT) Continue Coumadin indefnitely if: 2 or more VTEs, 1 life-threatening event (massive PE, CVT, IVC, MVT) APLs, ATIII deficiency, more than 1 genetic defect (homozygous FVL or FVL and homozygous FII) APLs, ATIII deficiency, more than 1 genetic defect (homozygous FVL or FVL and homozygous FII)

14. I had a DVT after the flight to Australia. Should I be evaluated? Question

15. 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

16. I am on Warfarin for 3 months now. How long should I take it? Question

17. 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) 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 50% of recurrent DVT – in contralateral leg Warfarin causes 95% reduction in recurrency but 0.25% /year incidence of fatal bleeding Warfarin causes 95% reduction in recurrency but 0.25% /year incidence of fatal bleeding DVT is a Chronic Disease

18. בת 34, מעברה א. מ. ל., ללא גורמי סיכון בת 34, מעברה א. מ. ל., ללא גורמי סיכון עברה Acute Inferoposterior MI עברה Acute Inferoposterior MI בברור קרישיות יתר נמצא : בברור קרישיות יתר נמצא : FV תקין FV תקין FII תקין FII תקין MTHFR הומוזיגוטי MTHFR הומוזיגוטי Anticardiolipin שלילי Anticardiolipin שלילי Circulating anticoagulant חיובי Circulating anticoagulant חיובי הומוציסטאין - 20.8; הומוציסטאין - 20.8; מה האבחנה ? APL syndrome APL syndrome תיאור מקרה

19. Mechanism of APL-induced thrombosis ApoER2’ EC Platelet A2 R ApoER2’ Platelet activation EC activation A2 R

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

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

22. For VTE: Warfarin aiming INR 2-3 (Am J Med, 1998, 104:332) For VTE: Warfarin aiming INR 2-3 (Am J Med, 1998, 104:332) For arterial thrombosis: Warfarin aiming INR 3 (Hematology, Education Program 2001, 2005) For arterial thrombosis: Warfarin aiming INR 3 (Hematology, Education Program 2001, 2005) Anticoagulated patients do not benefit from addition of Aspirin (NEJM 1995, 126:2136) 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) Long-term anticoagulation: Recurrence rate 50% at 2 years; 78% at 8 years (Ann Rheum Dis 1993; 52:689) Treatment of APL syndrome

23. Oral contraceptives Oral contraceptives Normal pregnancy Normal pregnancy Pregnancy complications Pregnancy complications Hormone replacement therapy Hormone replacement therapy Women issues in Thrombophilia

24. My sister has Factor V Leiden and had a DVT on birth control pills. Can I take birth control pills ? Question

25. Second generation OC and hetero for FVL increase the risk for VTE 20 to 35- fold (Lancet 1994, 344:1453) 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) 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). 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) The risk for CVT – 150-fold (NEJM 1998, 338:1793) OC and risk of VTE in Thrombophilic patients

26. I have Factor V Leiden. Will I have problems with pregnancy? Question

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

28. בת 50, על טיפול הורמונלי תחליפי, עברה אירוע של cerebral vein thrombosis. בירור קרישיות יתר יכלול בין היתר גם : 1. רמת פיברינוגן בפלזמה 2. Lupus Anticoagulant 3. שומנים בדם 4. Factor V Leiden, מוטציה ב - FII 5. 2+4

29. החולה הנ " ל מטופלת בקומדין. המלצותיך להמשך הטיפול בקומדין : 1. 3 חודשים בלבד 2. 6 חודשים 3. 12 חודשים 4. כל החיים

30. בת 28 עם חסר אנטיתרומבין ואירוע של Rt DVT. המלצותיך לטיפול: 1. קומדין לכל החיים 2. Low Mol Weight Heparin 3. קומדין ל - 6 חודשים 4. אספירין