1. Charles J. Lockwood, M.D. The Anita O’Keefe Young Professor and Chair Department of Obstetrics, Gynecology and Reproductive Sciences Yale University School of Medicine What is the evidence for the relation of thrombophilia to adverse pregnancy outcome?

2. Inherited Thrombophilia Factor V Leiden Prothrombin G20210A mutation 667C-T MTHFR thermolabile mutant antithrombin (aka ATIII) deficiency protein C (PC) deficiency protein S (PS) deficiency

3. Venous Thromboembolism (VTE) in Pregnancy Pregnancy presents major challenges to a women’s hemostatic system including: 1) avoidance of hemorrhage during implantation, placentation and remodeling of spiral arteries; and 2) avoidance of catastrophic hemorrhage after separation of the placenta from the uterine wall following delivery.

4. Venous Thromboembolism (VTE) in Pregnancy To meet these hemostatic challenges pregnancy is accompanied by changes in both clotting and anti-clotting factors that maximize hemostasis. However, a high price is paid to prevent such hemorrhage as pregnancy and the puerperium are associated with a 10-fold increase in VTE, a leading cause of maternal mortality

5. Hemostatic Pathway Platelet Aggregation X IX XIa /platelets IXa VIIIa Xa TF/ VII X TFPI - Va II IIa Fibrinogen Fibrin

6. Anticoagulant Pathway X IX XIa /platelets IXa VIIIa Xa TF/ VII - (APC/S) X TFPI - Va II IIa - (APC/S)

7. Anticoagulant Pathway (cont) Platelet Aggregation X IX XIa /platelets IXa VIIIa Xa TF/ VII X TFPI - Va II IIa Fibrinogen Fibrin +/- heparin Antithrombin -  2 macroglobulin - Hep.Cofactor II -

8. Anticoagulant and Fibrinolytic Pathways IX XI / platelets IXa VIIIa Xa X TF/ VII - (APC/S) X TFPI - Va II IIa - (APC/S) FDP FXIII - Fibrin Fibrinogen + tPA Plasmin +/- heparin heparin CoF II -  2 macroglobulin - Antithrombin - PAI-1 TAFI Antiplasmin - - - -

9. Pregnancy-Associated Changes in Hemostatic and Fibrinolytic Proteins Increase in Clotting Factors: 20 to 200% increase in levels of fibrinogen and factors II, VII, X, VIII and XII Decrease in Anticoagulant and Fibrinolytic Activity: Protein S levels (free and total) decrease by 40% PAI-1 levels increase two to three-fold in pregnancy

10. Risk of Maternal VTE in Patients with the Major Thrombophilias

11. APCR/Factor V Leiden mutation A) APCR/Factor V Leiden mutation 30% life-time risk of VTE prevalence 5-15% in European population accounts for 40% VTE in pregnancy 10-fold increase risk of VTE in pregnancy Risk of VTE in asympt. heterozygotes= 0.2% Risk of VTE in homozygotes= 16 to 17% Gerhardt A et al. N Engl J Med 2000; 342:374-380. Haematologica. 2001;86(12):1305-9. Br J Haematol. 2001;113(2):553-5.

12. B) Prothrombin G20210A mutation 30% life-time risk of VTE prevalence 2-3% in European population accounts for 17% VTE in pregnancy 15-fold increase risk of VTE in pregnancy Risk of VTE in heterozygotes = 0.5% Risk of VTE in homozygotes = 15% Risk with compound heterozygotes = 4-10% Gerhardt A et al. N Engl J Med 2000; 342:374-380. Thromb Haemost. 2001;86(3):800-3.

13. C) Hyperhomocysteinemia 1.5 RR of VTE with hyperhomocysteinemia AD deficiencies in CBS (0.3-1.4% of population) AR 667C-T MTHFR thermolabile mutant (11% of Europeans)

14. D) Antithrombin deficiency 70-90% life-time risk of VTE prevalence 1/3000 accounts for 2-20% of VTE in pregnancy > 50 fold increase risk of VTE in pregnancy 50% risk of VTE per pregnant patient Thromb Haemost 1990; 63:319-20

15. E) Protein C Deficiency: Life-time risk of VTE > 30% Prevalence is 0.2-0.5% Accounts for 10% of VTE in pregnancy > 20-fold increased risk of VTE Risk of VTE in pregnancy is 4% Thromb Haemost 1990; 63:319-20

16. F) Protein S Deficiency Life-time risk of VTE > 30% Prevalence of primary deficiency is 0.08%; of acquired deficiency is 7% Accounts for 10% of VTE in pregnancy > 20-fold increase risk of VTE Risk of VTE in pregnancy is 4% Thromb Haemost 1990; 63:319-20

17. Risk of Maternal VTE in Patients with the Major Thrombophilias Among 125 pregnant women with prior VTE: 1) 0/44 recurrences among those with no thrombophilia and whose previous VTE was associated with a temporary risk 2) 3/51 recurrences (5.9%) (95% CI: 1.2- 16.2) if they had thrombophilia or unexplained previous VTE. Brill-Edwards N Eng J Med 343; 1439-44.

19. Maternal Risks: Conclusions Patients with prior VTE associated with known risk factors without thrombophilia do not need antenatal heparin, but should receive postpartum therapy. Patients with prior VTE which is unexplained or who have a thrombophilia should be offered prophylactic heparin therapy during pregnancy.

20. Managment cont’d Patients with AT deficiency, or homozygotes for FVL or prothrombin mutations should receive full therapeutic heparin regardless of history throughout pregnancy and postpartum anticoagulation. Patients with a low thrombogenic thrombophilias but no history of VTE should only receive postpartum anticoagulation if they undergo C-sections or have other risk factors.

21. Management cont’d We have no evidence that patients with recurrent euploid fetal losses after 10 weeks, recurrent abruptions, severe, early onset preeclampsia or recurrent severe IUGR who are found to have an inherited low-thrombogenic thrombophilias will benefit from prophylactic heparin during pregnancy.

22. What is the Risk of Adverse Obstetrical Outcomes with Maternal Thrombophilias?

26. RFL and Other thrombophilias Prothrombin mutation associated with: 1)early recurrent (2.6, 1.0-0.3); and 2)late non-recurrent (2.3, 1.1-4.9) fetal loss; Protein S deficiency associated with: 1)recurrent fetal loss (14.7, 1.0-218); and 2)late non-recurrent fetal loss (7.4, 1.3-43). Lancet. 2003;361(9361):901-8.

27. EPCOT Study: RFL and Other thrombophilias Of 1384 women enrolled in EPCOT risk of fetal loss was modestly increased in women with thrombophilia vs. controls: OR 1.35 (1.01-1.82). The odds ratio was higher for stillbirth than for miscarriage: 3.6(1.4-9.4) vs 1.27 (0.94-1.71). Lancet. 1996;348(9032):913-6.

28. EPCOT Study: Cont. OR for stillbirth was : 14.3 (2.4-86.0) with combined defects 5.2 (1.5-18.1) in AT 2.3 (0.6-8.3) in PC deficiency, 3.3 (1.0-11.3) in PS deficiency, 2.0 (0.5-7.7) for FVL Lancet. 2003;361(9361):901-8.

29. EPCOT Study: Cont. OR for SAB in these subgroups were 0.8 (0.2-3.6) for combined defects 1.7 (1.0-2.8) for AT deficiency 1.4 (0.9-2.2) for PC deficiency 1.2 (0.7-1.9) for PS deficiency 0.9 (0.5-1.5) for FVL Lancet. 2003;361(9361):901-8.

33. Thrombophilias and Latter Adverse Pregnancy Outcomes OutcomeOR (95% CI) Abruption7.2 (2.6-20) Severe PE5.4 (2.3-12.4) IUGR4.8 (2.2-10.3) N Engl J Med 1999;341:5

35. Management of Inherited Thrombophilias in Patients with Adverse Pregnancy Outcomes Treat patients with: history of recurrent (> 2) fetal loss > 10 weeks, recurrent severe IUGR, severe early-onset preeclampsia or massive abruptions with documented thrombophilias and characteristic placental pathology

36. Charles J. Lockwood, M.D. The Anita O’Keefe Young Professor and Chair Department of Obstetrics, Gynecology and Reproductive Sciences Yale University School of Medicine What is the evidence for the relation of thrombophilia to adverse pregnancy outcome?