1. Indications for a thrombophilia workup in Obstetrics Helen H. Kay, MD February, 2005

2. Definition of thrombophilia A disorder associated with an increased tendency to thrombosis.

3. Coagulation pathway

4. History of Inherited Thrombophilias l 1956 Dysfibrinogen- emia described l 1965 Antithrombin III deficiency discovered l 1981 Protein C deficiency l 1984 Protein S deficiency l 1993 APCR/Factor V Leiden mutation l 1996 Prothrombin G20210A mutation l 1990’s MTHFR mutation –Mild to moderate hyperhomocysteinemia –A more severe form described in 1985

5. Pregnancy as a hypercoagulable state l Virchow’s Triad –Increase in coagulation factors (fibrinogen, VII, VIII, X, von Willebrand) Also a decrease in coagulation inhibitor Protein S Increased resistance to activated protein C (APC) Increased levels of plasminogen activator inhibitor 1 and 2 (PAI- 1, PAI-2) Increased levels of thrombin activatable fibrinolysis inhibitor (TAFI) –Venous stasis Due to venocaval obstruction by gravid uterus Left greater than right (85%,15%) –Endothelial damage From delivery, infection

6. Incidence of VTE: Antepartum l 0.13-0.85/1000 pregnancies, 0.17-1.0/1000 pregnant-women-years l This is modestly higher than age-matched nonpregnant controls (0.2-0.4/1000 person- years) l Leiden Thrombophilia Study (1995) found 4x increase risk due to pregnancy

7. Incidence of VTE: Postpartum l Risk is greater than during pregnancy l 1.0-6.1/1000 deliveries l Rates cover only the 4-6 weeks of the puerperium (compared to 40 wks) l Rate of VTE is estimated to be 3-8x greater postpartum than antepartum

8. Risk Factors for Venous Thrombosis Acquired Pregnancy Advancing age Prior thrombosis Immobilization Major surgery Malignancy Estrogens (OCP, HRT< SERMs) Antiphospholipid antibody syndrome Myeloproliferative disorders, IBD Heparin-induced thrombocytopenia Prolonged air travel Inherited Antithrombin Deficiency Protein C deficiency Protein S deficiency Factor V Leiden (FVL) Prothrombin G20210A Dysfibrinogenemias (rare) Mixed/Unknown Homocysteine Factor VIII APC resistance in the absence of FVL Factor IX Factor XI TAFI Free TFPI PAI-I, PAI-II

9. Factor V Leiden mutation l Substitution of adenine for guanine at the 1691 position l Factor V resistant to cleavage by APC l Mutation present in 5.2% of Europeans, rare in Asians and Africans l Autosomal dominant l Heterozygosity present in 20-40% nonpregnant patients with thromboembolic disease l Homozygosity rare, risk >100 fold

10. Prothrombin gene mutation G20210A l Autosomal dominant l Heterozygosity for mutation in the promoter of prothrombin gene (G20210) l Present in 2-3% of Europeans, 150-200% increased levels of prothrombin l Accounts for 17% of thromboembolism in pregnancy l In asymptomatic patients, risk of clotting is 0.5%, 1 in 200 l Homozygosity is rare, very high risk of thromboembolism, >100 fold

11. Antithrombin III deficiency l Autosomal dominant, point mutations, deletions, insertions l Most thrombogenic of inherited thrombophilias l Type I and II l 70-90% lifetime risk of thromboembolism l Antithrombin inactivates factors Xa, Ixa, VIIa, plasmin l Anticoagulant activity increased 5000 to 40,000 fold by heparin l Prevalence low, 1% of patients with thromboembolism

12. Protein C deficiency l Autosomal dominant l Numerous mutations lead to types I and II l Protein C is a vitamin K-dependent glycoprotein substrate l Activated to APC by thrombin, half-life of 6-8 hours l Inactivates factor Va and VIIIa with protein S and factor V, decreases thrombin l Prevalence of deficiency is 0.2-0.5% l Risks of thromboembolism in pregnancy is 5-20%

13. Protein S deficiency l Autosomal dominant l Vitamin K-dependent glycoprotein l Inactivates factors Va, VIIIa, Xa l Plasma half-life of 42 hours l Multiple mutations, types I, II,III, highly variable procoagulant sequelae l Prevalence is 0.03-1.3% l 16% of maternal thromboembolism l Normal pregnancy is associated with decreased levels of PS activity, in the 30 range

14. Protein Z deficiency l Autosomal dominant l Vitamin K-dependent plasma protein l Cofactor for a PZ-dependent protease inhibitor of factor Xa.

15. Thrombophilias of questionable significance l MTHFRm 667/C-T l 11% among Europeans l Results in mild to moderate hyperhomocysteinemia l Homozygosity for the 4G/4G mutation in the PAI-1 gene l Results in a 3-5 fold increased level of circulating PAI-1 l Polymorphisms of the thrombomodulin gene associated with increased risk of thrombosis

16. Oral Contraceptives and Thrombophilias l OCP users have 4x risk of VTE compared with non- users l Carriers of FVL or PT mutation have 3-10x risk of VTE over those without mutation l If both OCP use and thrombophilia risk of VTE is 30x l Most data find 3 rd generation OCP’s double risk of VTE over other OCP’s

17. Prevalence of thrombophilias PrevalenceThrombotic effect Antithrombin III deficiency Autosomal dominant Factor V Leiden Autosomal dominant Prothrombin mutation Autosomal dominant Protein C deficiency Autosomal dominant Protein S deficiency Autosomal dominant Antiphospholipid antibody syndrome Mild hyperhomocysteinemia Due primarily to MTHFR mutation, Autosomal recessive Hereditary Acquired Mixed/Unknown ++++0.02% ++ 5-15% in Caucasians ++ approximately 3% in Caucasians ++ 0.5% + 0.5% Varied<15% Dependant on level 11% of homocysteine

18. Increase in risk of VTE to thrombophilias (nonpregnant) l Coagulation inhibitor deficiencies10x –Protein S, C or Antithrombin –Rare, so risk estimates difficult to assess and vary widely; ATIII is most severe l Factor V Leiden5-8x l PT G20210A2-3x l MTHFR mutation1-2x l Increased F VIII (>20 umol/L)3-4x

19. Increase in risk of VTE due to thrombophilias (pregnant) Type Antithrombin Protein C Protein S Factor VL PT G20210A MTHFR mutation RR (95% CI) 6.2 (2.2-17.3) 2.3 (0.8-6.6) 3.2 (1.3-8.0) 9.0 (4.7-17.4) 10.8 (2.9-40.3) 2.1 (1.0-4.5) Grandone, AJOG 1998 and Gerhardt, NEJM 2000

20. Pregnancy complications due to inherited thrombophilias l Spontaneous abortion/fetal loss/IUFD l Severe preeclampsia l Placental abruption l Intrauterine growth restriction

21. Fetal loss in thrombophilias Type Antithrombin Protein C Protein S Factor V PT G20210A MTHFR Combined (2) RR (95% CI) for 1 st trim sab 1.7 (1.0-2.8) 1.4 (0.9-2.2) 1.2 (0.7-1.9) 0.9 (0.5-1.5) -- 0.8 (0.2-3.6) RR (95% CI) for IUFD 5.2 (1.5-18.1) 2.3 (0.6-8.3) 3.3 (1.0-11.3) 3.2 (1.0-10.9) 3.3 (1.1-10.3) 0.8 (0.5-1.2) 14.3 (2.4-86.0) Preston, Lancet, 1996 and Martinelli, NEJM 2000

22. Increased risk of preeclampsia in thrombophilias Type Factor VL MTHFR mutation PT G20210A RR 4.9-5.3 1.8-2.9 2.2 Kupferminc, NEJM 1999 and Grandone, Thromb Haemost 1997

23. Severe preeclampsia and high frequency of thrombophilia Thrombophilia Factor V MTHFR Prothrombin All mutations Protein S Protein C Antithrombin III Anticardiolipin antibodies All thrombophilias Odds ratio 4.6 (1.8, 11.6) 3.0 (1.3, 6.8) 2.6 (0.7, 10.2) 5.3 (2.7, 10.3) 10.7 (1.2, 94.3) NA 8.0 (4.1, 15.9) Kupferminc, Obstet Gynecol, 2000

24. Increased risk of placental abruption in thrombophilias Type Factor VL MTHFR mutation PT G20210A RR (95% CI) 4.9 (1.4-17.4) 2.0 (0.5-8.1) 8.9 (1.8-43.6) Kupferminc, NEJM 1999

25. Increased risk of IUGR in thrombophilias Type Factor VL MTHFR mutation PT G20210A RR (95% CI) 1.9 (0.6-6.3) 4.2 (1.6-10.9) 4.6 (1.0-20.0) Kupferminc, 2000 RR (95% CI) 1.18 (0.54-2.55) 1.55 (0.83-2.90) 0.92 (0.36-2.35) Infante-Rivard, 2002

26. Thrombophilia among women with obstetric complications Type Factor VL MTHFR mutation PT G20210A Deficiency of Protein S, Protein C, Antithrombin Anticardiolipin ab’s RR (95% CI) 3.7 (1.5-9.0) 3.1 (1.4-7.1) 3.9 (1.1-14.6) 9.7 (1.2-78.0) 2.0 (1.7-2.3) Kupferminc, NEJM 1999

27. Historical screen for thrombophilia l Personal history of a thrombosis l Family history of DVT or pulmonary embolism l Family history of strokes <60 years of age or MI <60 years in women l Personal history of abruption, severe IUGR, severe or early preeclampsia <32 weeks l Family history of –Three pregnancy losses <10 weeks –Two losses >10 weeks, <20 weeks –Any unexplained loss >20 weeks

28. Screening for thrombophilia in patients with adverse pregnancy outcomes l Protein C (functional assay) l Protein S (functional or free level) l Antithrombin III (functional assay) l Factor V Leiden mutation (PCR) l Prothrombin 20210A mutation (PCR) l Anticardiolipin antibodies, IgG, IgM, l Lupus anticoagulant (APTT, DRVVT) l Platelet count

29. Supplemental screening for thrombophilia in patients with adverse pregnancy outcomes l Homocysteine l APC resistance l Other Factor V mutations l Thrombomodulin gene variants l Protein Z levels l PAI-1 activity levels l PAI-1 4G/4G polymorphisms l MTHFR C677T mutation l Factor evaluation for VII, VIII, IX, XI

30. Prophylactic heparin to prevent recurrent adverse pregnancy outcomes l Kupferminc, 2001 - women with history of severe preeclampsia, abruption, IUGR or fetal demise, and known thrombophilia l Started at 8-12 weeks until 6 weeks postpartum l Treated patients had higher birth weight and gestational age at delivery l No fetal losses or severe preeclampsia

31. Prophylactic heparin to prevent recurrence of adverse pregnancy outcomes l Paidas et al, 2004 l Cohort of patients carrying either FVL or prothrombin gene mutation with at least one prior adverse pregnancy outcome l 41 heparin-treated pregnancies compared with remaining 158 pregnancies l Antenatal heparin administration associated with 80% reduction in adverse pregnancy outcome

32. Low risk l Pregnancy with transient risk factors: prolonged bedrest, surgery, obesity l Family history of thromboembolism l History of adverse pregnancy outcome without thrombophilia

33. Moderate risk l History of adverse pregnancy outcome with one thrombophilic condition l History of thromboembolism with transient risk factors l Thrombophilia with family history of thromboembolism

34. High risk l History of idiopathic thromboembolism outside of pregnancy l History of thromboembolism with thrombophilia l History of antiphospholipid antibody syndrome l Two or more thrombophilic disorders but no personal thromboembolism

35. Highest risk l History of antiphospholipid antibody syndrome l Active arterial or venous thromboembolism l Two or more thrombophilic disorders and adverse pregnancy outcome l Antithrombin III deficiency l Homozygous for Factor V Leiden, prothrombin mutation

36. Treatment strategy for thrombophilia: no personal history of thromboembolism but a family history and positive work-up Katz, 2002

37. Treatment strategy for thrombophilia: history of thromboembolic disease with risk factors Katz, 2002

38. Treatment strategy for thrombophilia: pregnant with a personal history of adverse pregnancy outcomes, and a positive thrombophilia workup Katz, 2002

39. Treatment regimens l Full therapeutic regimens –Unfractionated heparin Standard dosing, to attain PTT 1.5-2.5 –LMWH Dalteparin 200 U/kg qd or 100 U/kg q12 hours Enoxaparin 1 mg/kg q12 hours Anti-Xa level 4 hrs after dosing =0.8-1.0 U/ml, and repeat qmonth –Warfarin Postpartum Adjust dosage to attain INR 2.0-3.0

40. Treatment regimens l Prophylactic regimens –Unfractionated heparin 5000 U sc bid; increase to 7500-10000 U bid in latter half of pregnancy –LMWH Dalteparin 2500 U bid or 5000-7500 U qd Enoxaparin 30 mg bid (0.5 mg/kg/q12 h) or 40 mg qd –For obese patients may check anti-Xa level and target 0.4- 0.6 3-4 hours after morning dose, repeat qtrimester

41. Adverse reactions to heparin l Hemorrhage l Osteoporosis with risk of fracture l Heparin-induced thrombocytopenia, 5% –thromboembolism

42. Treatment for MTHFR mutation l Heterozygous –No treatment l Homozygous –Folic acid 1 mg/d –B 6 25 mg –B 12 250  cg

43. Anticoagulant management at delivery l Vaginal delivery –Unfractionated heparin – stop in labor –LMWH – change to unfractionated heparin at 36-38 weeks –Warfarin – change to unfractionated heparin at 36-38 weeks –Resume 6-8 hours after delivery, give warfarin with heparin until appropriate anticoagulation –Treat for a minimum of 6 weeks

44. Anticoagulant management at delivery l Elective cesarean delivery –Unfractionated heparin – stop after last evening dose –LMWH – stop at least 24 hours before surgery –Warfarin – change to unfractionated heparin at 36-38 weeks –Resume anticoagulation 6-8 hours after surgery, give warfarin with heparin until appropriate anticoagulation –Treat for a minimum of 6 weeks

45. Conclusions l Presence of thrombophilia adds to hypercoagulability of pregnancy –Postpartum period is highest risk time l Major “vascular” obstetric complications are increased in thrombophilias l Women with prior hx VTE, strong FHx, or hx obstetric complications should be screened

46. Screening for history of adverse pregnancy outcome l 3 or more first trimester losses l 2 or more second trimester losses l IUFD l Early and severe preeclampsia l Severe IUGR l Abruption

47. Conclusions l Screening should include, possibly in stepwise fashion… –Deficiencies for Protein S, C or antithrombin activity; FVL, PT G20210A; anticardiolipin ab’s, lupus anticoagulant; platelets l Treatment depends on type of defect, prior history l Routine screening for all pregnant women or those seeking OCP’s is not recommended at this time