Seminars in Hematology
Volume 44, Issue 2 , Pages 93-97 , April 2007

Pregnancy Failure and Heritable Thrombophilia

  • Saskia Middeldorp

      Affiliations

    • Corresponding Author InformationAddress correspondence to Saskia Middeldorp, MD, PhD, Department of Clinical Epidemiology, C9-P, Leiden University Medical Center, PO Box 9600, 3500 RC Leiden, The Netherlands.

References 

  1. Egeberg O. Inherited antithrombin III deficiency causing thrombophilia. Thromb Diath Haemorrh. 1965;13:516–530
  2. Griffin JH, Evatt B, Zimmerman TS, Kleiss AJ, Wideman C. Deficiency of protein C in congenital thrombotic disease. J Clin Invest. 1981;68:1370–1373
  3. Comp PC, Esmon CT. Recurrent venous thromboembolism in patients with a partial deficiency of protein S. N Engl J Med. 1984;311:1525–1528
  4. Bertina RM, Koeleman BP, Koster T, Rosendaal FR, Dirven RJ, de Rond , et al. Mutation in blood coagulation factor V associated with resistance to activated protein C. Nature. 1994;369:64–67
  5. Dahlback B, Carlsson M, Svensson PJ. Familial thrombophilia due to a previously unrecognized mechanism characterized by poor anticoagulant response to activated protein C: prediction of a cofactor to activated protein C. Proc Natl Acad Sci U S A. 1993;90:1004–1008
  6. Poort SR, Rosendaal FR, Reitsma PH, Bertina RM. A common genetic variation in the 3′-untranslated region of the prothrombin gene is associated with elevated plasma prothrombin levels and an increase in venous thrombosis. Blood. 1996;88:3698–3703
  7. Falcon CR, Cattaneo M, Panzeri D, Martinelli I, Mannucci PM. High prevalence of hyperhomocyst(e)inemia in patients with juvenile venous thrombosis. Arterioscler Thromb. 1994;14:1080–1083
  8. den Heijer M, Rosendaal FR, Blom HJ, Gerrits WB, Bos GM. Hyperhomocysteinemia and venous thrombosis: A meta-analysis. Thromb Haemost. 1998;80:874–877
  9. Rosenberg IH, Mulrow CD. Trials that matter: Should we routinely measure homocysteine levels and “treat” mild hyperhomocysteinemia?. Ann Intern Med. 2006;145:226–227
  10. den Heijer RM, Willems HP, Blom HJ, Gerrits WB, Cattaneo M, Eichinger S, et al. Homocysteine lowering by B vitamins and the secondary prevention of deep-vein thrombosis and pulmonary embolism (A randomized, placebo-controlled, double blind trial). Blood. 2007;109:139–144
  11. Van de Poel MH, Coppens M, Middeldorp S, Hamulyak K, Veeger NJ, Prins MH, et al. Absolute risk of venous and arterial thromboembolism associated with mild hyperhomocysteinemia (Results from a retrospective family cohort study). J Thromb Haemost. 2005;3(suppl 1):P0481
  12. Ray JG, Shmorgun D, Chan WS. Common C677T polymorphism of the methylenetetrahydrofolate reductase gene and the risk of venous thromboembolism: Meta-analysis of 31 studies. Pathophysiol Haemost Thromb. 2002;32:51–58
  13. Koster T, Blann AD, Briet E, Vandenbroucke JP, Rosendaal FR. Role of clotting factor VIII in effect of von Willebrand factor on occurrence of deep-vein thrombosis. Lancet. 1995;345:152–155
  14. Kamphuisen PW, Houwing-Duistermaat J, Van Houwelingen HC, Eikenboom JCJ, Bertina RM, Rosendaal FR. Familial clustering of factor VIII and von Willebrand factor levels. Thromb Haemost. 1998;79:323–327
  15. Bank I, Libourel EJ, Middeldorp S, Hamulyak K, van Pampus ECM, Koopman MMW, et al. Elevated levels of FVIII:c within families are associated with an increased risk for venous and arterial thrombosis. J Thromb Haemost. 2005;3:79–84
  16. Kamphuisen PW, Lensen R, Houwing-Duistermaat JJ, Eikenboom JC, Harvey M, Bertina RM, et al. Heritability of elevated factor VIII antigen levels in factor V Leiden families with thrombophilia. Br J Haematol. 2000;109:519–522
  17. Farquharson RG, Jauniaux E, Exalto N. Updated and revised nomenclature for description of early pregnancy events. Hum Reprod. 2005;20:3008–3011
  18. Rai R, Regan L. Recurrent miscarriage. Lancet. 2006;368:601–611
  19. Goddijn M, Leschot NJ. Genetic aspects of miscarriage. Baillieres Best Pract Res Clin Obstet Gynaecol. 2000;14:855–865
  20. Miyakis S, Lockshin MD, Atsumi T, Branch DW, Brey RL, Cervera R, et al. International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). J Thromb Haemost. 2006;4:295–306
  21. Sanson BJ, Friederich PW, Simioni P, Zanardi S, Huisman MV, Girolami , et al. The risk of abortion and stillbirth in antithrombin-, protein C-, and protein S-deficient women. Thromb Haemost. 1996;75:387–388
  22. Preston FE, Rosendaal FR, Walker ID, Briet E, Berntorp E, Conard J, et al. Increased fetal loss in women with heritable thrombophilia. Lancet. 1996;348:913–916
  23. Meinardi JR, Middeldorp S, de Kam PJ, Koopman MMW, van Pampus ECM, Hamulyak K, et al. Increased risk for fetal loss in carriers of the factor V Leiden mutation. Ann Intern Med. 1999;130:736–739
  24. Rey E, Kahn SR, David M, Shrier I. Thrombophilic disorders and fetal loss: A meta-analysis. Lancet. 2003;361:901–908
  25. Robertson L, Wu O, Langhorne P, Twaddle S, Clark P, Lowe GDO, et al. Thrombophilia in pregnancy: A systematic review. Br J Haematol. 2006;132:171–196
  26. Morrison ER, Miedzybrodzka ZH, Campbell DM, Haites NE, Wilson BJ, Watson MS, et al. Prothrombotic genotypes are not associated with pre-eclampsia and gestational hypertension: Results from a large population-based study and systematic review. Thromb Haemost. 2002;87:779–785
  27. Sebire NJ, Regan L, Rai R. Biology and pathology of the placenta in relation to antiphospholipid antibody-associated pregnancy failure. Lupus. 2002;11:641–643
  28. Quenby S, Mountfield S, Cartwright JE, Whitley GS, Chamley L, Vince G. Antiphospholipid antibodies prevent extravillous trophoblast differentiation. Fertil Steril. 2005;83:691–698
  29. Bose P, Black S, Kadyrov M, Weissenborn U, Neulen J, Regan L, et al. Heparin and aspirin attenuate placental apoptosis in vitro: Implications for early pregnancy failure. Am J Obstet Gynecol. 2005;192:23–30
  30. Isermann B, Sood R, Pawlinski R, Zogg M, Kalloway S, Degen JL, et al. The thrombomodulin-protein C system is essential for the maintenance of pregnancy. Nat Med. 2003;9:331–337
  31. Rai R, Cohen H, Dave M, Regan L. Randomised controlled trial of aspirin and aspirin plus heparin in pregnant women with recurrent miscarriage associated with phospholipid antibodies (or antiphospholipid antibodies). BMJ. 1997;314:253–257
  32. Farquharson RG, Quenby S, Greaves M. Antiphospholipid syndrome in pregnancy: A randomized, controlled trial of treatment. Obstet Gynecol. 2002;100:408–413
  33. Noble LS, Kutteh WH, Lashey N, Franklin RD, Herrada J. Antiphospholipid antibodies associated with recurrent pregnancy loss: Prospective, multicenter, controlled pilot study comparing treatment with low-molecular-weight heparin versus unfractionated heparin. Fertil Steril. 2005;83:684–690
  34. Empson M, Lassere M, Craig JC, Scott JR. Prevention of recurrent miscarriage for women with antiphospholipid antibody or lupus anticoagulant. The Cochrane Database of Systematic Reviews. 2005;(2):
  35. Pattison NS. Does aspirin have a role in improving pregnancy outcome for women with the antiphospholipid antibody syndrome? (A randomized controlled trial). Am J Obstet Gynecol. 2000;183:1008–1101
  36. Bates S, Greer IA, Hirsh J, Ginsberg JS. Use of antithrombotic agents during pregnancy (The seventh ACCP conference on antithrombotic and thrombolytic therapy). Chest. 2004;126(suppl):627S–644S
  37. Pabinger I, Vormittag R. Thrombophilia and pregnancy outcomes. J Thromb Haemost. 2005;3:1603-1010
  38. Brenner B. Antithrombotic prophylaxis for women with thrombophilia and pregnancy complications—Yes. J Thromb Haemost. 2003;1:2070–2072
  39. Middeldorp S. Antithrombotic prophylaxis for women with thrombophilia and pregnancy complications—No. J Thromb Haemost. 2003;1:2073–2074
  40. Rai R, Backos M, Elgaddal S, Shlebak A, Regan L. Factor V Leiden and recurrent miscarriage—Prospective outcome of untreated pregnancies. Hum Reprod. 2002;17:442–445
  41. Lindqvist PG, Merlo J. The natural course of women with recurrent fetal loss. J Thromb Haemost. 2006;4:896–897
  42. Coppens M, Folkeringa N, Teune M, Hamulyak K, van der Meer J, Prins MH, et al. Natural course of the subsequent pregnancy after a single loss in women with and without the factor V Leiden or prothrombin 20210A mutations. Blood. 2006;(suppl):
  43. Gris JC, Mercier E, Quere I, Lavigne-Lissalde G, Cochery-Nouvellon E, Hoffet M, et al. Low-molecular-weight heparin versus low-dose aspirin in women with one fetal loss and a constitutional thrombophilic disorder. Blood. 2004;103:3695–3699
  44. Rodger M. Important publication missing key information. Blood. 2004;104:3413
  45. Gris JC, Quere I, Dauzat M, Mares P. Response: Thromboprophylaxis for first fetal loss. Blood. 2004;104:3413–3414
  46. DiNisio M, Peters LW, Middeldorp S. Anticoagulants for the treatment of recurrent pregnancy loss in women without antiphospholipid syndrome. The Cochrane Database of Systematic Reviews. 2005;(2):
  47. Brenner B, Hoffman R, Carp H, Dulitzky M, Younis J LIVE-ENOX Investigators. Efficacy and safety of two doses of enoxaparin in women with thrombophilia and recurrent pregnancy loss: The LIVE-ENOX study. J Thromb Haemost. 2005;3:227–229
  48. Lindqvist PG, Merlo J. Low molecular weight heparin for repeated pregnancy loss—Is it based on solid evidence?. J Thromb Haemost. 2005;3:221–223
  49. Middeldorp S. The use of LMWH in pregnancies at risk: New evidence or perception?. J Thromb Haemost. 2005;3:788–789
  50. Dolitzky M, Inbal A, Segal Y, Weiss A, Brenner B, Carp H. A randomized study of thromboprophylaxis in women with unexplained consecutive recurrent miscarriages. Fertil Steril. 2006;86:362–366
  51. Bank I, Libourel EJ, Middeldorp S, van Pampus ECM, Koopman MMW, Hamulyak K, et al. Prothrombin 20210A mutation: A mild risk factor for venous thromboembolism but not for arterial thrombotic disease and pregnancy-related complications in a family study. Arch Intern Med. 2004;164:1932–1937
  52. Middeldorp S, van der Poel MH, Bank I, Hamulyak K, Libourel EJ, Koopman MMW, et al. Unselected women with elevated levels of factor VIII:c or homocysteine are not at increased risk for obstetric complications. Thromb Haemost. 2004;92:787–790
  53. Nelen WL, Blom HJ, Steegers EA, den Heijer M, Eskes TK. Hyperhomocysteinemia and recurrent early pregnancy loss: A meta-analysis. Fertil Steril. 2000;74:1196–1199

PII: S0037-1963(07)00006-6

doi: 10.1053/j.seminhematol.2007.01.005

Seminars in Hematology
Volume 44, Issue 2 , Pages 93-97 , April 2007

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