Thrombophilia. Steven R. Lentz, M.D. Ph.D. Carver College of Medicine The University of Iowa May 2003

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1 Thrombophilia Steven R. Lentz, M.D. Ph.D. Carver College of Medicine The University of Iowa May 2003

2 Thrombophilia Hereditary and acquired risk factors for thrombosis Venous thromboembolism Arterial thromboembolism Pregnancy complications

3 Virchow s Triad 1850 Vessel Wall Damage Factors Contributing to Thrombosis Altered Blood Flow (Stasis) Blood Coagulability

4 One or more Inherited Prothrombotic Mutation(s) Factor V Leiden Prothrombin 20210A Protein C deficiency Protein S deficiency Antithrombin deficiency Thrombosis After Schafer Acquired Prothrombotic Stimulus Antiphospholipid antibodies Malignancy Immobilization Surgery Pregnancy Estrogen Hyperhomocysteinemia Heparin-induced thrombocytopenia

5 Prevalence of Hereditary Risk Factors in Venous Thromboembolism (VTE) Asymptomatic Unselected Familial Mutation (N) Controls VTE VTE Factor V Leiden (1) 4% 20% 45% Prothrombin 20210A (1) 2% 6% 18% Protein C (>160) 0.8% 3% 6% Protein S (>13) 0.5% 1% 6% Antithrombin (>80) 0.2% 1% 4% (All Autosomal Dominant)

6 Factor V Leiden Most common hereditary risk factor for venous thrombosis Present in 4% of Caucasian population Caused by a point mutation in Factor V (R506Q) Poor anticoagulant response to activated protein C (APC Resistance)

7 The Protein C Anticoagulant Pathway Blood Flow Protein C Thrombin Thrombin Thrombomodulin APC Thrombus Thrombus at site of injury Anticoagulation downstream

8 The Protein C Anticoagulant Pathway Blood Flow Factor V Leiden Vai VIIIai APC PS Va VIIIa APC PS Thrombus

9 Activated Protein C Resistance 3 APTT Ratio 2 Control 1 Factor V Leiden APC (μg/ml)

10 Prothrombin Gene Mutation Second most common hereditary risk factor for venous thrombosis Present in 2% of Caucasian population Caused by a point mutation (G20210A) in the 3 UTR of prothrombin gene Elevated levels of prothrombin in plasma

11 Antithrombin Deficiency Antithrombin (also called AT III) inhibits thrombin, factor Xa and other clotting factors Activity enhanced by heparin Risk factor for venous thrombosis, especially during pregnancy

12 Influence of Hereditary Risk Factors on Probability of First DVT or PE Risk Factor Relative Risk General population 1 Heterozygous factor V Leiden 5 Heterozygous prothrombin 20210A 5 Protein C deficiency 10 Protein S deficiency 10 Antithrombin deficiency 20 Homozygous factor V Leiden 80

13 Influence of Hereditary Risk Factors on Probability of First DVT or PE Thrombosis-free Survival (%) 100 general population (RR=1) Age (years) heterozygous FVL (RR=5) protein C def (RR=10) antithrombin def (RR=20) homozygous FVL (RR=80) After Miletich (1998) Semin Thromb Hemost

14 Influence of Acquired Risk Factors on Probability of First DVT or PE Risk Factor Relative Risk General population 1 Hyperhomocysteinemia 2 Estrogen therapy 4 Active cancer ~7 Lupus anticoagulant or antiphospholipid antibody ~10

15 Hyperhomocysteinemia Elevated level of homocysteine in plasma Multiple causes Genetic factors uncommon Nutritional factors (folate, B12, B6) common Renal dysfunction common Cardiovascular disease, stroke, peripheral vascular disease Neural tube defects Dementia

16 Treatment of Hyperhomocysteinemia Folic acid Other B vitamins (B12, B6) Methionine restriction

17 Antiphospholipid Antibodies Lupus Anticoagulants Anticardiolipin Antibodies Clinically-Important APLA

18 Clinically Important Antiphospholipid Antibodies High titer (>30 GPL or MPL) anticardiolipin antibodies (IgG or IgM) Lupus anticoagulant Systemic lupus erythematosus or lupus-like syndrome

19 Management of Patients with Antiphospholipid Antibodies Chronic anticoagulation not necessary if no history of thrombosis Long-term anticoagulation with warfarin after first thrombotic event Target INR 2-3 (hematologists) Target INR 3-4 (rheumatologists) Some antiphospholipid antibodies interfere with INR (may need higher target INR or alternative method to monitor anticoagulation)

20 Influence of Combinations of Risk Factors on Probability of First DVT/PE Risk Factor Relative Risk General population 1 Hyperhomocysteinemia 2 Heterozygous factor V Leiden 5 Hyperhomocysteinemia and heterozygous factor V Leiden 20

21 Influence of Combinations of Risk Factors on Probability of First DVT or PE Risk Factor Relative Risk General population 1 Oral contraceptives 4 Heterozygous factor V Leiden 5 Oral contraceptives and heterozygous factor V Leiden 35

22 Influence of Oral Contraceptives and Factor V Leiden on Probability of First DVT or PE Thrombosis-free Survival (%) 100 general population (RR=1) oral contraceptives (RR=4) pregnancy (RR=10) Age (years) oral contraceptives and heterozygous FVL (RR=35)

23 Hereditary Risk Factors and Arterial Thrombosis (Stroke or MI) Risk Factor Relative Risk Heterozygous Factor V Leiden 1 Heterozygous Prothrombin 20210A 1 Protein S deficiency 1 Protein C deficiency 1 Antithrombin deficiency 1 Possible exception: young patients, especially in association with smoking or hypertension

24 Other Putative Risk Factors (Not Ready for Prime Time) Fibrinogen Lipoprotein (a) Factor VIII Von Willebrand factor Thrombomodulin Heparin Cofactor II Factor XII GPIa C807T GPIIIa PLA2 PAI-1 4G/5G D-dimer TFPI MTHFR Protein Z

25 Laboratory Testing for Thrombophilia Factor V Leiden Prothrombin 20210A gene mutation Anticardiolipin antibodies Lupus anticoagulant workup Plasma total homocysteine Antithrombin (not reliable in patients receiving heparin)

26 Other Tests to Consider in Convalescent Period Protein C Protein S These tests are not reliable in acute setting or in patients receiving warfarin

27 Rationale for Thrombophilia Testing Prophylactic anticoagulation during high risk situations (surgery, pregnancy, immobilization) Extended duration of anticoagulation after a thrombotic event Antiphospholipid antibody Antithrombin deficiency Two or more thrombophilic alleles (Factor V Leiden, Prothrombin 20210A, Protein C deficiency, Protein S deficiency) Family genetic counseling

28 Probability of Recurrence After First DVT or PE Relative Risk Temporary risk factor 1 Heterozygous factor V Leiden 2 Homozygous factor V Leiden 4 Antiphospholipid antibody 4 Unprovoked DVT or PE 8 Recurrent DVT or PE 8 Active Cancer 8

29 Recurrence after First DVT or PE 30 Recurrent DVT/PE (%) warfarin unprovoked temporary risk factor Days Levine et al. Thromb Haemost 1995; 74:606

30 Duration of Anticoagulation for First Unprovoked DVT Recurrence (%) months (INR 2-3) 12 months (INR 2-3) Indefinite (INR 1.5-2) Indefinite (INR 2-3) Years

31 My Approach to Prevention of Recurrent Venous Thromboembolism Low Risk (anticoagulate for 6 weeks to 3 months) Superficial venous thrombosis Secondary DVT or PE Intermediate Risk (anticoagulate for at least 3 to 6 months; consider indefinite anticoagulation at INR or 2-3) Unprovoked DVT or PE Unprovoked DVT or PE with one genetic risk factor High Risk (anticoagulate indefinitely at target INR 2-3) Recurrent unprovoked DVT or PE Life-threatening venous thrombosis Unprovoked DVT or PE with antiphospholipid antibody, two or more genetic risk factors, or active cancer

32 References Kearon et al. Management of patients with hereditary hypercoagulable disorders. Annu Rev Med 51: , 2000 Kupferminc, et al. Increased frequency of genetic thrombophilia in women with complications of pregnancy. New Eng J Med 340:9-13, 1999 Gerhardt, et al. Prothrombin and factor V mutations in women with a history of thrombosis during pregnancy and the peurperium. New Eng J Med 342: , 2000 Gordy et al. American College of Medical Genetics Consensus Statement on Factor V Leiden mutation testing. Genetics in Medicine 3: , 2001 Ridker at al. Long-term low-intensity warfarin therapy for the prevention of recurrent venous thromboembolism. New Eng J Med 348: , 2003

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