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Bob Silver, MD University of Utah Health Sciences

Thrombophilias in Obstetrics. Modified from a presentation to the Society of Maternal Fetal Medicine by. Bob Silver, MD University of Utah Health Sciences. Thrombophilias. A heterogeneous group of conditions that predispose individuals to (venous) thromboembolism. Why we care.

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Bob Silver, MD University of Utah Health Sciences

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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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