Factor V Leiden Inherited Prothrombin 20210A Protein C Deficiency Prothrombotic Protein S Deficiency Mutation(S) Antithrombin Deficiency

ThrombophiliaThrombophilia DiagnosisDiagnosis andand ManagementManagement

Kevin P. Hubbard, DO, FACOI

Clinical Professor of Medicine Kansas City University of Medicine and Biosciences-College of Osteopathic Medicine Kansas City, Missouri Thrombophilia

• Hereditary and acquired risk factors for thrombosis • Venous thromboembolism • Arterial thromboembolism • Pregnancy complications Virchow’s Triad 1850

Vessel Wall Altered Blood Flow Damage Factors (Stasis) Contributing to Thrombosis

Blood Coagulability One or more Factor V Leiden Inherited Prothrombin 20210A Protein C deficiency Prothrombotic Protein S deficiency Mutation(s) Antithrombin deficiency

Thrombosis

Acquired Antiphospholipid antibodies Malignancy Prothrombotic Immobilization Stimulus Surgery Pregnancy Estrogen Hyperhomocysteinemia After Schafer Heparin-induced thrombocytopenia 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) 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) The Protein C Anticoagulant Pathway

Blood Flow Protein C

Thrombin Thrombin APC Thrombomodulin

Thrombus Anticoagulation Thrombus downstream at site of injury The Protein C Anticoagulant Pathway

Blood Flow Vai Factor V Leiden VIIIai

VIIIa Va APC APC PS PS Thrombus Activated Protein C Resistance

Control APTT 2 Ratio

1 Factor V Leiden

0 12345 APC (µg/ml) 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 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 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 Influence of Hereditary Risk Factors on Probability of First DVT or PE

100 general population (RR=1)

80 heterozygous FVL (RR=5)

60 protein C def (RR=10)

40 antithrombin def (RR=20) 20 homozygous FVL (RR=80) 0 Thrombosis-free Survival (%) Survival Thrombosis-free 0 20406080 Age (years) After Miletich (1998) Semin Thromb Hemost 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 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 Treatment of Hyperhomocysteinemia

•Folic acid Foltx® •Other B vitamins (B12, B6) •Methionine restriction Antiphospholipid Antibodies

Lupus Anticardiolipin Anticoagulants Antibodies

Clinically-Important APLA Clinically Important Antiphospholipid Antibodies

•High titer (>30 GPL or MPL) anticardiolipin antibodies (IgG or IgM) •Lupus anticoagulant •Systemic lupus erythematosus or lupus-like syndrome 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) 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 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 Influence of Oral Contraceptives and Factor V Leiden on Probability of First DVT or PE

100 general population (RR=1) oral contraceptives (RR=4) pregnancy (RR=10)

90 oral contraceptives and heterozygous FVL (RR=35)

80 Thrombosis-free Survival (%) Thrombosis-free 15 20 25 30 35 40 Age (years) 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 Other Putative Risk Factors (Not Ready for Prime Time)

• Fibrinogen • GPIa C807T • Lipoprotein (a) • GPIIIa PLA2 • Factor VIII • PAI-1 4G/5G • Von Willebrand factor • D-dimer • Thrombomodulin • TFPI • Heparin Cofactor II • MTHFR • Factor XII • Protein Z 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) OtherOther TestsTests toto ConsiderConsider inin ConvalescentConvalescent PeriodPeriod

• Protein C • Protein S • These tests are not reliable in acute setting or in patients receiving warfarin 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 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 Recurrence after First DVT or PE

Recurrent 20 DVT/PE unprovoked (%) 10 warfarin

temporary risk factor

100 200 300 Days

Levine et al. Thromb Haemost 1995; 74:606 Duration of Anticoagulation for First Unprovoked DVT

30 3 months (INR 2-3) 12 months (INR 2-3) 20

Indefinite (INR 1.5-2) 10 Recurrence (%)

Indefinite (INR 2-3)

123 Years MyMy ApproachApproach toto PreventionPrevention ofof RecurrentRecurrent VenousVenous ThromboembolismThromboembolism • 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 1.5-2 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 References

Kearon et al. Management of patients with hereditary hypercoagulable disorders. Annu Rev Med 51:169-185, 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 342:374-380, 2000 Gordy et al. American College of Medical Genetics Consensus Statement on Factor V Leiden mutation testing. Genetics in Medicine 3:139-148, 2001 Ridker et al. Long-term low-intensity warfarin therapy for the prevention of recurrent venous thromboembolism. New Eng J Med 348:1425-1434, 2003 Lopez et al. Deep venous thrombosis. American Society of Hematology Education Book, 2004