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Thrombophilias in Obstetrics: Impact on Pregnancy Complications and Thromboembolism Risk

Thrombophilias are a complex group of conditions that significantly increase the risk of venous thromboembolism (VTE) during pregnancy, the leading cause of maternal mortality. Understanding their implications is essential as they may contribute to severe obstetric complications such as stillbirth, intrauterine growth restriction (IUGR), severe preeclampsia, and placental abruption. This discussion covers the various hereditary thrombophilias, including Factor V Leiden and Prothrombin G20210A mutations, and details their impact on hemostasis, risk assessment, and clinical management during pregnancy.

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Thrombophilias in Obstetrics: Impact on Pregnancy Complications and Thromboembolism Risk

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  1. Thrombophilias in Obstetrics Modified from a presentation to the Society of Maternal Fetal Medicine by Bob Silver, MD University of Utah Health Sciences

  2. Thrombophilias A heterogeneous group of conditions that predispose individuals to (venous) thromboembolism

  3. Why we care • Thromboembolism • #1 killer in pregnancy • Common obstetric problems • Stillbirth • Severe IUGR • Severe preeclampsia • Abruption

  4. Initiation of Hemostasis

  5. Limitation of Hemostasis

  6. Procoagulant Anticoagulant

  7. Procoagulant Anticoagulant

  8. Factor IX Factor VIII Factor X Factor V Factor II Factor XIII Factor VII Protein C Protein S Antithrombin III Fibrinolysis PAI-1 Components of Hemostasis

  9. Pregnancy enhances clotting • Increase 20-200% • Factor II • Factor VII • Factor VIII • Factor X • Factor XII • Decrease in Protein S • Increase in PAI-1 300% • Resistance to APC • Impaired fibrinolysis

  10. Hereditary Thrombophilias • Protein C pathway • Factor V Leiden • Protein C deficiency • Protein S deficiency • Prothrombin G20210A mutation • Antithrombin III deficiency • Hyperhomocystinemia • C677T MTHFR mutation

  11. Factor V Leiden Mutation • Mutation in Factor V • Protein C/S complex • Impaired anticoagulation • 5-11% of white Europeans • Heterozygous • Autosomal dominant • Homozygous rare

  12. Prothrombin G20210A mutation • Mutation in promotor • 150-200%  in prothrombin levels • 2-3% of Europeans • Heterozygous • autosomal dominant • Homozygous similar to Factor V

  13. Protein C / Protein S Deficiencies • Protein C deficiency • Type I –  number and activity • Type II –  activity • Protein S deficiency • Type I –  total and free forms • Type II –  cofactor activity • Type III -  free only • Autosomal dominant • 0.2-0.5, 0.8 prevalence

  14. AT III Deficiency • Multiple mutations • Most thrombogenic disorder • Type I • Levels and activity • Type II • Activity

  15. Hyperhomocysteinemia • Atherosclerosis, NTD, thromboembolism • Severe – homozygous • 1 in 200,000-355,000 • Cystathionine  -synthase • Mild to moderate – • Heterozygotes for CS mutation • Homozygous for 667C-T MTHFR (11%)

  16. Factor V Leiden 5-9% 20-40%* Prothrombin G20210A 3% 6-15% Protein C deficiency 0.3% 1-2% Protein S deficiency 0.2% 1-2% AT III deficiency 0.07% <1% Hyperhomocystinemia 5% 5-10% Prevalence in Populations Gen Pop Thrombosis * Prevalence lower in African, Latin, and Asian Americans

  17. Factor V Leiden 5-10 RR 100 PT G20210 3-5 90 PC deficiency 5-50 80 PS deficiency 5-50 70 ATIII deficiency 50-100 60 % 50 C677T MTHFR +/+ 2.5 40 30 20 10 Lifetime Prevalence of Thromboembolism

  18. Thromboembolism in Pregnancy • 0.70 – 1.0 per 1,000 pregnancies • Presence of Thrombophilias • 8 fold increase in risk (overall) • Dramatic increase in risk if> 1 thrombophilia

  19. Thrombophilias and VTE in Pregnancy • Case-control study • 119 with prior VTE in pregnancy • 233 age-matched controls • Tested • inherited thrombophilias • APS Gerhardt et al, N Engl J Med 2000; 342:374

  20. Factor V Leiden 44% 8% Prothrombin G20210A 17% 3% Protein C deficiency 14% 4% Protein S deficiency 12% 5% Antithrombin III deficiency 7% 1.5% C677T MTHFR +/+ 10% 9% Prothrombin and Factor V Mutations in Women with VTE in Pregnancy Cases (119) Controls (233) Thrombophilia Gerhardt, NEJM 2000; 342:374

  21. Risk of VTE Associated with Hereditary Thrombophilias RR Factor V 6.9 PT G20210 9.5 PC def. 2.2 AT III def. 10.4 0 5 10 20 50 66 1

  22. No thrombophilia 0.03% Factor V Leiden 0.25% PT G20210A 0.5% AT III deficiency 0.4% PC deficiency 0.1% PT G20210A & Factor V 4.6% Estimated Probability of Thromboembolism Gerhardt, NEJM 2000; 342:374

  23. Thrombophilias and Pregnancy Complications • Preeclampsia • Pregnancy loss • Fetal growth restriction • Placental abruption

  24. Pathophysiology of Thrombophilia in Pregnancy • Thrombosis in uteroplacental circulation causes infarction • Abnormal placentation • Insufficiency • Abruption • Pregnancy loss • preeclampsia

  25. Villous Infarction Normal Villi

  26. Factor V Leiden Mutation 50 N = 24 40 30 Percent 20 10 N = 372 0 < 10% Infarction > 10% Infarction Dizon-Townson, AJOG 1997;177:402

  27. Thrombophilias and Pregnancy Complications • Case control study • 110 women with severe preeclampsia, IUGR, stillbirth, or abruption • Inherited thrombophilias and APS • 65% cases positive (18% controls) • 52% mutation • 13% acquired/inherited • OR for thrombophilia= 8.2, 4.4-15.3 Kupferminc, NEJM 1999;340:9

  28. Factor V PTG20210 MTHFR (+/+) 5 (2-16) 2 (0.4-14) 3 (1-85) 5 (1-7) 9 (2-44) 2 (0.5-8) 2 (0.6-6) 5 (1-20) 4 (2-11) 5 (1-22) 0 2 (0.4-12) Thrombophilias and Pregnancy Complications Preeclampsia Abruption IUGR Stillbirth Kupferminc, NEJM 1999;340:9

  29. Thrombophilias and Pregnancy Loss • Case control study • 67 women • 1st fetal death  20 wks • no prior thrombosis • 232 fertile controls • Postpartum tests for 3 mutations Martinelli, NEJM 2000;343:1015

  30. Factor V 5 (7%) 6 (3%) 3.2 (1.1-11) PT G20210A 7 (3%) 6 (9%) 3.3 (1.2-10) Either FV or PT 13 (6%) 11 (16%) 3.3 (1.1-7) C677T MTHFR 46 (20%) 9 (13%) 0.8 (.5-1) Thrombophilias and Pregnancy Loss Fetal Death (N=67) Fertile Controls (N=20) OR (95%CI) Martinelli, N Engl J Med 2000;343:1015

  31. Thrombophilias and Recurrent Miscarriage • Case-Control study • 50 women with 3 or more 1st trimester SAB • 50 healthy women • Tested for three mutations plus IgG anticardiolipin Kutteh, FertilSteril 2000;71:1048-53

  32. Thrombophilias and Recurrent Miscarriage RR Factor V 0.5 PT G20210 1.0 MTHFR +/+ 2.1 APS 6 0 2 5 30 1 Kutteh, FertilSteril 2000;71:1048-53

  33. Thrombophilias and Pregnancy Loss: Meta-analysis • Medline 1975 – 2002 • 31 studies • Mostly retrospective • Moderate-high quality Rey et al., Lancet 2003;361:901

  34. Thrombophilias and Pregnancy Loss: Meta-analysis: (RR: 95% CI) • Factor V Leiden: • Early recurrent loss: 2.0 (1.1 – 3.6) • Late recurrent loss: 7.8 (2.8 – 21.7) • Late sporadic loss: 3.3 (1.8 – 5.8) • Increased effect if other pathologies excluded Rey et al., Lancet 2003;361:901

  35. Thrombophilias and Pregnancy Loss: Meta-analysis: (RR: 95% CI) • Prothrombin gene mutation: • Early recurrent loss: 2.6 (1.0 – 6.3) • Late sporadic loss: 2.3 (1.1 – 4.9) • Protein S deficiency: • Recurrent loss: 14.7 (1.0 – 218.0) • Late sporadic loss: 7.4 (1.3 – 42.6) Rey et al., Lancet 2003;361:901

  36. Thrombophilias and Pregnancy Loss: Meta-analysis: (RR: 95% CI) • Protein C deficiency • ATIII deficiency • MTHFR homozygosity • No association with fetal loss Rey et al., Lancet 2003;361:901

  37. Thrombophilias and IUGR • Case-control study • 493 IUGR pregnancies (<10%) • 472 normal pregnancies • Tested newborns and mothers • Three mutations • Infante-Rivard, NEJM 2002;347:57-9

  38. Thrombophilias and IUGR RR Factor V 1.2 PT G20210 0.92 MTHFR +/- 0.98 MTHFR +/+ 1.6 0 2 3 1 • Infante-Rivard, NEJM 2002;347:57-9

  39. Thrombophilias and Preeclampsia RR Preeclampsia 1.2 HELLP 1.7 IUGR 2.4 0 2 3 20 1 • Livingston, AJOG 2001;185:153-7

  40. Thrombophilias andAdverse Pregnancy Outcomes • Fetal death • Consistent (not uniform) association (Not MTHFR) • Spontaneous abortion • Some association with APS • Others? Mostly No • Other complications: Mixed results • Preeclampsia? • IUGR? • Abruption?

  41. Factor V LeidenProspective Obstetric Outcome • Prospective cohort • 2,480 women in early pregnancy • Factor V Leiden – 270 (11%) • 8 fold increase in VTE • Less intrapartum blood loss Lindqvist, Thromb Haemost 1999;81:532-7

  42. Obstetric Outcome Controls Factor V Leiden Percent Abruptio Sab FD PIH IUGR Lindqvist, Thromb Haemost 1999;81:532-7

  43. Factor V LeidenProspective Obstetric Outcome • Prospective cohort - MFMU • 5,188 women in early pregnancy • Factor V Leiden – 134 (2.7%) • No increase in VTE! • 4 VTE – all testing negative Dizon-Townson, AJOG 2002;187:S159 (SFMFM)

  44. Factor V LeidenProspective Obstetric Outcome Dizon-Townson, AJOG 2002;187:S159 (SMFM)

  45. Thrombophilias andAdverse Pregnancy Outcomes • Apparently conflicting results • Retrospective vs. prospective • Most women with thrombophilias: • Normal pregnancy outcome • “Two-hit” hypothesis • Thrombophilia and fetal death (or thrombosis) is different than thrombophilia alone

  46. Thrombophilias: Who Should we Test?

  47. Venous thrombosis or embolism Factor V Leiden Factor V Leiden + Prothrombin G20210A Prothrombin G20210A Antiphospholipid Antibodies (LA and aCL) Consider other (PC def, PS def, AT-III def)

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