Skip to main content
SpringerLink
Log in

Inherited and Acquired Thrombophilias

  • Review
  • Published:
Reproductive Sciences Aims and scope Submit manuscript

Abstract

Thrombophilias represent an evolving story that continues to stir controversy for care providers and obstetrical patients. The predominant thrombophilic mutations include the factor V Leiden mutation, prothrombin gene mutation G20210A, methylene tetrahydrafolate reductase C667T, and deficiencies of the natural anticoagulants proteins C and S, and antithrombin. Prospective cohort studies have provided an accurate assessment of the risk of placenta-mediated complications posed by common inherited thrombophilic conditions. Acquired thrombophilic conditions consist of the antiphospholipid antibody syndrome (APAS) and hyperhomocysteinemia. Well-conducted, placebo-controlled, randomized trials have demonstrated no benefit of anticoagulation in women with recurrent pregnancy loss and inherited thrombophilia. The routine use of anticoagulation to prevent other placenta-mediated complications in the setting of inherited thrombophilia should be considered experimental until the results of adequate clinical trials are available. Heparin anticoagulation and antiplatelet therapies are the cornerstone of treatment of APAS in pregnancy.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Bremme KA. Haemostatic changes in pregnancy. Best Pract Res Clin Haematol. 2003;16(2):153–168.

    Article  PubMed  Google Scholar 

  2. Bremme K, Ostlund E, Almqvist I, Heinonen K, Blombäck M. Enhanced thrombin generation and fibrinolytic activity in normal pregnancy and the puerperium. Obstet Gynecol. 1992;80(1): 132–137.

    CAS  PubMed  Google Scholar 

  3. Paidas MJ, Ku DH, Lee MJ, et al. Protein Z, protein S levels are lower in patients with thrombophilia and subsequent pregnancy complications. J Thromb Haemost. 2005;3(3):497–501.

    Article  CAS  PubMed  Google Scholar 

  4. Schatz F, Lockwood CJ. Progestin regulation of plasminogen activator inhibitor type 1 in primary cultures of endometrial stromal and decidual cells. J Clin Endocrinol Metab. 1993;77(3):621–625.

    CAS  PubMed  Google Scholar 

  5. Lockwood CJ, Krikun G, Schatz F. The decidua regulates hemostasis in human endometrium. Semin Reprod Endocrinol. 1999; 17(1):45–51.

    Article  CAS  PubMed  Google Scholar 

  6. Erlich J, Parry GC, Fearns C, et al. Tissue factor is required for uterine hemostasis and maintenance of the placental labyrinth during gestation. Proc Natl Acad Sci USA. 1999;96(14):8138–8143.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Greer IA, Nelson-Piercy C. Low-molecular-weight heparins for thromboprophylaxis and treatment of venous thromboembolism in pregnancy: a systematic review of safety and efficacy. Blood. 2005;106(2):401–407.

    Article  CAS  PubMed  Google Scholar 

  8. Egeberg O. Inherited antithrombin deficiency causing thrombophilia. Thromb Diath Haemorrh. 1965;13:516–530.

    CAS  PubMed  Google Scholar 

  9. Griffin JH, Evatt B, Zimmerman TS, Kleiss AJ, Wideman C. Deficiency of protein C in congenital thrombotic disease. J Clin Invest. 1981;68(5):1370–1373.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Comp PC, Nixon RR, Cooper MR, Esmon CT. Familial protein S deficiency is associated with recurrent thrombosis. J Clin Invest. 1984;74(6):2082–2088.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. ACOG. Clinical updates in women’s health: thrombosis, thrombophilia and thomboembolism in women. ACOG. 2010;6(4):179–198.

    Google Scholar 

  12. Dahlback B, Hildebrand B. Inherited resistance to activated protein C is corrected by anticoagulant cofactor activity found to be a property of factor V. Proc Natl Acad Sci USA. 1994;91(4): 1396–1400.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Ridker PM, Miletich JP, Hennekens CH, Buring JE. Ethnic distribution of factor V Leiden in 4047 men and women. Implications for venous thromboembolism screening. JAMA. 1997;277(16): 1305–1307.

    Article  CAS  PubMed  Google Scholar 

  14. Lockwood CJ. Inherited thrombophilias in pregnant patients. Prenat Neonat Med. 2001;6(1):12.

    Google Scholar 

  15. Voorberg J, Roelse J, Koopman R, et al. Association of idiopathic venous thromboembolism with single point-mutation at Arg506 of factor V. Lancet. 1994;343(8912):1535–1536.

    Article  CAS  PubMed  Google Scholar 

  16. Grandone E, Margaglione M, Colaizzo D, et al. Genetic susceptibility to pregnancy-related venous thromboembolism: roles of factor V Leiden, prothrombin G20210A, and methylenetetrahy-drofolate reductase C677T mutations. Am J Obstet Gynecol. 1998;179(5):1324–1328.

    Article  CAS  PubMed  Google Scholar 

  17. ZotzRB, Gerhardt A, ScharfRE. Inherited thrombophilia and gestational venous thromboembolism. Best Pract Res Clin Haematol. 2003;16(2):243–259.

    Article  PubMed  Google Scholar 

  18. Dizon-Townson D, Miller C, Sibai B, et al. The relationship of the factor V Leiden mutation and pregnancy outcomes for mother and fetus. Obstet Gynecol. 2005;106(3):517–524.

    Article  CAS  PubMed  Google Scholar 

  19. 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(10):3698–3703.

    Article  CAS  PubMed  Google Scholar 

  20. Franco RF, Reitsma PH. Genetic risk factors of venous thrombosis. Hum Genet. 2001;109(4):369–384.

    Article  CAS  PubMed  Google Scholar 

  21. Gerhardt A, Scharf RE, Beckmann MW, et al. Prothrombin and factor V mutations in women with a history of thrombosis during pregnancy and the puerperium. N Engl J Med. 2000;342(6):374–380.

    Article  CAS  PubMed  Google Scholar 

  22. Practice bulletin no. 113: inherited thrombophilias in pregnancy. Obstet Gynecol. 2010;116(1):212–222.

  23. Tormene D, Simioni P, Prandoni P, et al. Factor V Leiden mutation and the risk of venous thromboembolism in pregnant women. Haematologica. 2001;86(12):1305–1309.

    CAS  PubMed  Google Scholar 

  24. Martinelli I, Battaglioli T, De Stefano V, et al. The risk of first venous thromboembolism during pregnancy and puerperium in double heterozygotes for factor V Leiden and prothrombin G20210A. J Thromb Haemost. 2008;6(3):494–498.

    Article  CAS  PubMed  Google Scholar 

  25. Dahlback B. Protein S and C4b-binding protein: components involved in the regulation of the protein C anticoagulant system. Thromb Haemost. 1991;66(1):49–61.

    Article  CAS  PubMed  Google Scholar 

  26. Mosnier LO, Meijers JC, Bouma BN. The role of protein S in the activation of thrombin activatable fibrinolysis inhibitor (TAFI) and regulation of fibrinolysis. Thromb Haemost. 2001;86(4): 1040–1046.

    Article  CAS  PubMed  Google Scholar 

  27. Mosnier LO, Meijers JC, Bouma BN. A study of Protein S antigen levels in 3788 healthy volunteers: influence of age, sex and hormone use, and estimate for prevalence of deficiency state. Br J Haematol. 2001;113(3):636–641.

    Article  Google Scholar 

  28. Comp PC, Thurnau GR, Welsh J, Esmon CT. Functional and immunologic protein S levels are decreased during pregnancy. Blood. 1986;68(4):881–885.

    Article  CAS  PubMed  Google Scholar 

  29. dimming AM, Tait RC, Fildes S, Yoong A, Keeney S, Hay CR. Development of resistance to activated protein C during pregnancy. Br J Haematol. 1995;90(3):725–727.

    Article  CAS  PubMed  Google Scholar 

  30. Sugimura M, Kobayashi T, Kanayama N, Terao T. Detection of decreased response to activated protein C during pregnancy by an endogenous thrombin potential-based assay. Semin Thromb Hemost. 1999;25(5):497–502.

    Article  CAS  PubMed  Google Scholar 

  31. Colman RW, Marder VJ, Clowes AW, George JN, Goldhaber SZ. Blood coagulation factors. In: Greenberg DL, Davie EW, eds. Hemostasis and Thrombosis, Basic, Principles and Clinical Practice. Philadelphia, PA: Lippincott Williams & Wilkins; 2006:249–269.

    Google Scholar 

  32. Lockwood CJ. Inherited thrombophilias in pregnant patients: detection and treatment paradigm. Obstet Gynecol. 2002;99(2): 333–341.

    PubMed  Google Scholar 

  33. Preston FE, Rosendaal FR, Walker ID, et al. Increased fetal loss in women with heritable thrombophilia. Lancet. 1996;348(9032): 913–916.

    Article  CAS  PubMed  Google Scholar 

  34. Rey E, Kahn SR, David M, Shrier I. Thrombophilic disorders and fetal loss: a meta-analysis. Lancet. 2003;361(9361):901–908.

    Article  PubMed  Google Scholar 

  35. Patnaik MM, Moll S. Inherited antithrombin deficiency: a review. Haemophilia. 2008;14(6):1229–1239.

    Article  CAS  PubMed  Google Scholar 

  36. Alfirevic Z, Roberts D, Martlew V. How strong is the association between maternal thrombophilia and adverse pregnancy outcome? A systematic review. Eur J Obstet Gynecol Reprod Biol. 2002;101(1):6–14.

    Article  PubMed  Google Scholar 

  37. Han X, Fiehler R, Broze GJ Jr. Characterization of the protein Z-dependent protease inhibitor. Blood. 2000;96(9):3049–3055.

    Article  CAS  PubMed  Google Scholar 

  38. Kemkes-Matthes B, Matthes KJ. Protein Z. Semin Thromb Hemost. 2001;27(5):551–556.

    Article  CAS  PubMed  Google Scholar 

  39. Broze GJ Jr. Protein Z-dependent regulation of coagulation. Thromb Haemost. 2001;86(1):8–13.

    CAS  PubMed  Google Scholar 

  40. Broze GJ Jr. Protein-Z and thrombosis. Lancet. 2001 ;357(9260): 900–901.

    Article  PubMed  Google Scholar 

  41. Han X, Huang ZF, Fiehler R, Broze GJ Jr. The protein Z-dependent protease inhibitor is a serpin. Biochemistry. 1999; 38(34): 11073–11078.

    Article  CAS  PubMed  Google Scholar 

  42. Yurdakök M, Gürakan B, Ozbag E, Viğit S, Dündar S, Kirazli S. Plasma protein Z levels in healthy newborn infants. Am J Hematol. 1995;48(3):206–207.

    Article  PubMed  Google Scholar 

  43. Miletich JP,Broze GJ Jr. Human plasma protein Z antigen: range in normal subjects and effect of warfarin therapy. Blood. 1987; 69(6):1580–1586.

    Article  CAS  PubMed  Google Scholar 

  44. Kemkes-Matthes B, Nees M, Kühnel G, Matzdorff A, Matthes KJ. Protein Z influences the prothrombotic phenotype in Factor V Leiden patients. Thromb Res. 2002;106(4–5):183–185.

    Article  CAS  PubMed  Google Scholar 

  45. McColl MD, Deans A, Maclean P, Tait RC, Greer IA, Walker ID. Plasma protein Z deficiency is common in women with antipho-spholipid antibodies. Br J Haematol. 2003;120(5):913–914.

    Article  Google Scholar 

  46. Gris JC, Balducchi JP, Quéré I, Hoffet M, Marès P. Enoxaparin sodium improves pregnancy outcome in aspirin-resistant antipho-spholipid/antiprotein antibody syndromes. Thromb Haemost. 2002;87(3):536–537.

    Article  CAS  PubMed  Google Scholar 

  47. Gris JC, Mercier E, Quéré I, et al. Low-molecular-weight heparin versus low-dose aspirin in women with one fetal loss and a constitutional thrombophilic disorder. Blood. 2004;103(10):3695–3699.

    Article  CAS  PubMed  Google Scholar 

  48. Hunt LT, Dayhoff MO. A surprising new protein superfamily containing ovalbumin, antithrombin-III, and alpha 1-proteinase inhibitor. Biochem Biophys Res Commun. 1980;95(2):864–871.

    Article  CAS  PubMed  Google Scholar 

  49. Gettins P, Patston PA, Schapira M. Structure and mechanism of action of serpins. Hematol Oncol Clin North Am. 1992;6(6): 1393–1408.

    Article  CAS  PubMed  Google Scholar 

  50. Andreasen PA, Georg B, Lund LR, Riccio A, Stacey SN. Plasminogen activator inhibitors: hormonally regulated serpins. Mol Cell Endocrinol. 1990;68(1):1–19.

    Article  CAS  PubMed  Google Scholar 

  51. Kruithof EK, Tran-Thang C, Gudinchet A, et al. Fibrinolysis in pregnancy: a study of plasminogen activator inhibitors. Blood. 1987;69(2):460–466.

    Article  CAS  PubMed  Google Scholar 

  52. Gilabert J, Estellés A, Aznar J, et al. Contribution of platelets to increased plasminogen activator inhibitor type 1 in severe preeclampsia. Thromb Haemost. 1990;63(3):361–366.

    Article  CAS  PubMed  Google Scholar 

  53. Astedt B, Lecander I, Ny T. The placental type plasminogen activator inhibitor, PAI-2. Fibrinolysis. 1987;1(4):203–208.

    Article  Google Scholar 

  54. Francis CW. Plasminogen activator inhibitor-1 levels and polymorphisms. Arch Pathol Lab Med. 2002;126(11):1401–1404.

    CAS  PubMed  Google Scholar 

  55. Hefler L, Jirecek S, Heim K, et al. Genetic polymorphisms associated with thrombophilia and vascular disease in women with unexplained late intrauterine fetal death: a multicenter study. J Soc Gynecol Investig. 2004;11(1):42–44.

    Article  CAS  PubMed  Google Scholar 

  56. Weiler H, Isermann BH. Thrombomodulin. J Thromb Haemost. 2003;1(7):1515–1524.

    Article  CAS  PubMed  Google Scholar 

  57. Paidas MJ, Ku DH, Lee MJ, Lockwood CJ, Arkel YS. Pregnant patients with thrombophilia and subsequent adverse pregnancy outcomes have a decreased first trimester response to thrombomodulin in an activated partial thromboplastin time (APTT) system. J Thromb Haemost. 2004;2(5):840–841.

    Article  CAS  PubMed  Google Scholar 

  58. Foka ZJ., et al., Factor V Leiden and prothrombin G20210A mutations, but not methylenetetrahydrofolate reductase C677T, are associated with recurrent miscarriages. Hum Reprod. 2000; 15(2):458–462.

    Article  CAS  PubMed  Google Scholar 

  59. Foka ZJ, Lambropoulos AF, Saravelos H, et al. Maternal thrombophilias are not associated with early pregnancy loss. Thromb Haemost. 2004;91(2):290–295.

    Article  CAS  Google Scholar 

  60. Murphy RP, Donoghue C, Nallen RJ, et al. Prospective evaluation of the risk conferred by factor V Leiden and thermolabile methy-lenetetrahydrofolate reductase polymorphisms in pregnancy. Arterioscler Thromb Vasc Biol. 2000;20(1):266–270.

    Article  CAS  PubMed  Google Scholar 

  61. Nelen WL, Blom HJ, Steegers EA, den Heijer M, Eskes TK. Hyperhomocysteinemia and recurrent early pregnancy loss: a meta-analysis. Fertil Steril. 2000;74(6):1196–1169.

    Article  CAS  PubMed  Google Scholar 

  62. Langhoff-Roos J, Paidas MJ, Ku DH, Arkel YS, Lockwood CJ. Inherited thrombophilias and early pregnancy loss. In: Mor G, ed. Immunology of Pregnancy. New York, NY: Eurekah UR; 2006:229–243.

    Chapter  Google Scholar 

  63. Wilson WA, Gharavi AE, Koike T, et al. International consensus statement on preliminary classification criteria for definite anti-phospholipid syndrome: report of an international workshop. Arthritis Rheum. 1999;42(7): 1309–1311.

    Article  CAS  PubMed  Google Scholar 

  64. Miyakis S, Lockshin MD, Atsumi T, et al. International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). J Thromb Haemost. 2006; 4(2):295–306.

    Article  CAS  PubMed  Google Scholar 

  65. Galli M, Barbui T. Antiphospholipid antibodies and thrombosis: strength of association. Hematol J. 2003;4(3):180–186.

    Article  CAS  PubMed  Google Scholar 

  66. Galli M, Luciani D, Bertolini G, Barbui T. Anti-beta 2-glycoprotein I, antiprothrombin antibodies, and the risk of thrombosis in the antiphospholipid syndrome. Blood. 2003;102(8):2717–2723.

    Article  CAS  PubMed  Google Scholar 

  67. Wahl DG, Guillemin F, de Maistre E, Perret C, Lecompte T, Thibaut G. Risk for venous thrombosis related to antiphospholipid antibodies in systemic lupus erythematosus—a meta-analysis. Lupus. 1997;6(5):467–473.

    Article  CAS  PubMed  Google Scholar 

  68. García-Fuster MJ, Fernández C, Forner MJ, Vayá A. Risk factors and clinical characteristics of thromboembolic venous disease in young patients: aprospective study [in Spanish]. Med Clin (Bare). 2004;123(6):217–219.

    Article  Google Scholar 

  69. Yamada H, Atsumi T, Kato EH, Shimada S, Morikawa M, Minakami H. Prevalence of diverse antiphospholipid antibodies in women with recurrent spontaneous abortion. Fertil Steril. 2003; 80(5):1276–1278.

    Article  PubMed  Google Scholar 

  70. Yamada H, Atsumi T, Kobashi G, et al. Antiphospholipid antibodies increase the risk of pregnancy-induced hypertension and adverse pregnancy outcomes. J Reprod Immunol. 2009;79(2): 188–195.

    Article  CAS  PubMed  Google Scholar 

  71. Branch DW, Silver RM, Blackwell JL, Reading JC, Scott JR. Outcome of treated pregnancies in women with antiphospholipid syndrome: an update of the Utah experience. Obstet Gynecol. 1992;80(4):614–620.

    CAS  PubMed  Google Scholar 

  72. Cervera R, Piette JC, Font J, et al. Antiphospholipid syndrome: clinical and immunologic manifestations and patterns of disease expression in a cohort of 1,000 patients. Arthritis Rheum. 2002; 46(4):1019–1027.

    Article  PubMed  Google Scholar 

  73. Branch DW, Silver RM. Criteria for antiphospholipid syndrome: early pregnancy loss, fetal loss, or recurrent pregnancy loss? Lupus. 1996;5(5):409–413.

    Article  CAS  PubMed  Google Scholar 

  74. Rai RS, Clifford K, Cohen H, Regan L. High prospective fetal loss rate in untreated pregnancies of women with recurrent miscarriage and antiphospholipid antibodies. Hum Reprod. 1995;10(12): 3301–3304.

    Article  CAS  PubMed  Google Scholar 

  75. Lockwood CJ, Romero R, Feinberg RF, Clyne LP, Coster B, Hobbins JC. The prevalence and biologic significance of lupus anticoagulant and anticardiolipin antibodies in a general obstetric population. Am J Obstet Gynecol. 1989;161(2):369–373.

    Article  CAS  PubMed  Google Scholar 

  76. Rand JH, Wu XX, Andree HA, et al. Pregnancy loss in the antiphospholipid-antibody syndrome—a possible thrombogenic mechanism. N Engl J Med. 1997;337(3):154–160.

    Article  CAS  PubMed  Google Scholar 

  77. Field SL, Brighton TA, McNeil HP, Chesterman CN. Recent insights into antiphospholipid antibody-mediated thrombosis. Baillieres Best Pract Res Clin Haematol. 1999;12(3):407–422.

    Article  CAS  PubMed  Google Scholar 

  78. Redecha P, Tilley R, Tencati M, et al. Tissue factor: a link between C5a and neutrophil activation in antiphospholipid antibody induced fetal injury. Blood. 2007;110(7):2423–2431.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Pierangeli SS, Girardi G, Vega-Ostertag M, Liu X, Espinola RG, Salmon J. Requirement of activation of complement C3 and C5 for antiphospholipid antibody-mediated thrombophilia. Arthritis Rheum. 2005;52(7):2120–2124.

    Article  CAS  PubMed  Google Scholar 

  80. Girardi G, Redecha P, Salmon JE. Heparin prevents antiphospholipid antibody-induced fetal loss by inhibiting complement activation. Nat Med. 2004;10(11):1222–1226.

    Article  CAS  PubMed  Google Scholar 

  81. Mecacci F, Bianchi B, Pieralli A, et al. Pregnancy outcome in systemic lupus erythematosus complicated by anti-phospholipid antibodies. Rheumatology (Oxford). 2009;48(3):246–249.

    Article  CAS  Google Scholar 

  82. Mulla MJ, Myrtolli K, Brosens JJ, et al. Antiphospholipid antibodies limit trophoblast migration by reducing IL-6 production and STAT3 activity. Am J Reprod Immunol. 2010;63(5):339–348.

    Article  CAS  PubMed  Google Scholar 

  83. Dekker GA, de Vries JI, Doelitzsch PM, et al. Underlying disorders associated with severe early-onset preeclampsia. Am J Obstet Gynecol. 1995;173(4):1042–1048.

    Article  CAS  PubMed  Google Scholar 

  84. Dizon-Townson DS, Nelson LM, Easton K, Ward K. The factor V Leiden mutation may predispose women to severe preeclampsia. Am J Obstet Gynecol. 1996;175(4 pt 1):902–905.

    Article  CAS  PubMed  Google Scholar 

  85. Kupferminc MJ, Eldor A, Steinman N, et al. Increased frequency of genetic thrombophilia in women with complications of pregnancy. N Engl J Med. 1999;340(1):9–13.

    Article  CAS  PubMed  Google Scholar 

  86. Kupferminc MJ, Fait G, Many A, Gordon D, Eldor A, Lessing JB. Severe preeclampsia and high frequency of genetic thrombophilic mutations. Obstet Gynecol. 2000;96(1):45–49.

    CAS  PubMed  Google Scholar 

  87. Livingston JC, Barton JR, Park V, Haddad B, Phillips O, Sibai BM. Maternal and fetal inherited thrombophilias are not related to the development of severe preeclampsia. Am J Obstet Gynecol. 2001;185(1):153–157.

    Article  CAS  PubMed  Google Scholar 

  88. Kahn SR, Platt R, McNamara H, et al. Inherited thrombophilia and preeclampsia within a multicenter cohort: the Montreal Preeclampsia Study. Am J Obstet Gynecol. 2009;200(2):151. e1–151.e9.

    Article  Google Scholar 

  89. Rodger MA, Betancourt MT, Clark P, et al. The association of factor V Leiden and prothrombin gene mutation and placenta-mediated pregnancy complications: a systematic review and meta-analysis of prospective cohort studies. PLoS Med. 2010; 7(6):e1000292.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  90. Lykke JA, Bare LA, Olsen J, et al. Thrombophilias and adverse pregnancy outcomes: results from the Danish National Birth Cohort. J Thromb Haemost. 2012;10(7):1320–1325.

    Article  CAS  PubMed  Google Scholar 

  91. Infante-Rivard C, Rivard GE, Yotov WV, et al. Absence of association of thrombophilia polymorphisms with intrauterine growth restriction. N Engl J Med. 2002;347(1): 19–25.

    Article  CAS  PubMed  Google Scholar 

  92. Howley HE, Walker M, Rodger MA. A systematic review of the association between factor V Leiden or prothrombin gene variant and intrauterine growth restriction. Am J Obstet Gynecol. 2005; 192(3):694–708.

    Article  CAS  PubMed  Google Scholar 

  93. Dudding T, Heron J, Thakkinstian A, et al. Factor V Leiden is associated with pre-eclampsia but not with fetal growth restriction: a genetic association study and meta-analysis. J Thromb Haemost. 2008;6(11): 1869–1875.

    Article  CAS  PubMed  Google Scholar 

  94. Kupferminc MJ, Many A, Bar-Am A, Lessing JB, Ascher-Landsberg J. Mid-trimester severe intrauterine growth restriction is associated with a high prevalence of thrombophilia. BJOG. 2002;109(12):1373–1376.

    Article  PubMed  Google Scholar 

  95. de Vries JI, Dekker GA, Huijgens PC, Jakobs C, Blomberg BM, van Geijn HP. Hyperhomocysteinaemia and protein S deficiency in complicated pregnancies. Br J Obstet Gynaecol. 1997;104(11): 1248–1254.

    Article  PubMed  Google Scholar 

  96. Martinelli P, Grandone E, Colaizzo D, et al. Familial thrombophilia and the occurrence of fetal growth restriction. Haematologica. 2001;86(4):428–431.

    CAS  PubMed  Google Scholar 

  97. Ananth CV, Smulian JC, Vintzileos AM. Incidence of placental abruption in relation to cigarette smoking and hypertensive disorders during pregnancy: a meta-analysis of observational studies. Obstet Gynecol. 1999;93(4):622–628.

    CAS  PubMed  Google Scholar 

  98. Addis A, Moretti ME, Ahmed Syed F, Einarson TR, Koren G. Fetal effects of cocaine: an updated meta-analysis. Reprod Toxicol. 2001;15(4):341–369.

    Article  CAS  PubMed  Google Scholar 

  99. Wiener-Megnagi Z, Ben-Shlomo I, Goldberg Y, Shalev E. Resistance to activated protein C and the Leiden mutation: high prevalence in patients with abruptio placentae. Am J Obstet Gynecol. 1998;179(6 pt 1): 1565–1567.

    Article  CAS  PubMed  Google Scholar 

  100. Procházka M, Happach C, Marsál K, Dahlbäck B, Lindqvist PG. Factor V Leiden in pregnancies complicated by placental abruption. BJOG. 2003;110(5):462–466.

    Article  PubMed  Google Scholar 

  101. Procházka M, Happach C, Marsál K, Dahlbäck B, Lindqvist PG. Frequency of selected thrombophilias in women with placental abruption. Aust N Z J Obstet Gynaecol. 2007;47(4):297–301.

    Article  PubMed  Google Scholar 

  102. Ananth CV, Peltier MR, De Marco C, et al., Associations between 2 polymorphisms in the methylenetetrahydrofolate reductase gene and placental abruption. Am J Obstet Gynecol. 2007;197(4):385 e1–385 e7.

    Article  CAS  Google Scholar 

  103. Ray JG, Laskin CA. Folic acid and homocyst(e)ine metabolic defects and the risk of placental abruption, pre-eclampsia and spontaneous pregnancy loss: a systematic review. Placenta. 1999;20(7):519–529.

    Article  CAS  PubMed  Google Scholar 

  104. Rodesch F, Simon P, Donner C, Jauniaux E. Oxygen measurements in endometrial and trophoblastic tissues during early pregnancy. Obstet Gynecol. 1992;80(2):283–285.

    CAS  PubMed  Google Scholar 

  105. Jaffe R. Investigation of abnormal first-trimester gestations by color Doppler imaging. J Clin Ultrasound. 1993;21(8):521–526.

    Article  CAS  PubMed  Google Scholar 

  106. Watson AL, Skepper JN, Jauniaux E, Burton GJ. Susceptibility of human placental syncytiotrophoblastic mitochondria to oxygen-mediated damage in relation to gestational age. J Clin Endocrinol Metab. 1998;83(5):1697–1705.

    CAS  PubMed  Google Scholar 

  107. Göpel W, Ludwig M, Junge AK, Kohlmann T, Diedrich K, Möller J. Selection pressure for the factor-V-Leiden mutation and embryo implantation. Lancet. 2001;358(9289):1238–1239.

    Article  PubMed  Google Scholar 

  108. Dudding TE, Attia J. The association between adverse pregnancy outcomes and maternal factor V Leiden genotype: a meta-analysis. Thromb Haemost. 2004;91(4):700–711.

    Article  CAS  PubMed  Google Scholar 

  109. Gris JC, Quéré I, Monpeyroux F, et al. Case–control study of the frequency of thrombophilic disorders in couples with late foetal loss and no thrombotic antecedent—the Nimes Obstetricians and Haematologists Study 5 (NOHA5). Thromb Haemost. 1999; 81(6):891–899.

    Article  CAS  PubMed  Google Scholar 

  110. Kocher O, Cirovic C, Malynn E, et al. Obstetric complications in patients with hereditary thrombophilia identified using the LCx microparticle enzyme immunoassay: a controlled study of 5,000 patients. Am J Clin Pathol. 2007;127(1):68–75.

    Article  CAS  PubMed  Google Scholar 

  111. Robertson L, Wu O, Langhorne P, et al. Thrombophilia in pregnancy: a systematic review. Br J Haematol. 2006;132(2):171–196.

    Article  CAS  PubMed  Google Scholar 

  112. Saade GR, McLintock C. Inherited thrombophilia and stillbirth. Semin Perinatol. 2002;26(1):51–69.

    Article  PubMed  Google Scholar 

  113. Kujovich JL. Thrombophilia and pregnancy complications. Am J Obstet Gynecol. 2004;191(2):412–424.

    Article  PubMed  Google Scholar 

  114. Jivraj S, Rai R, Underwood J, Regan L. Genetic thrombophilic mutations among couples with recurrent miscarriage. Hum Reprod. 2006;21(5):1161–1165.

    Article  CAS  PubMed  Google Scholar 

  115. Martinelli I, Taioli E, Cetin I, Mannucci PM. Recurrent late fetal death in women with and without thrombophilia. Thromb Haemost. 2002;87(2):358–359.

    Article  CAS  PubMed  Google Scholar 

  116. Kupferminc MJ, Peri H, Zwang E, Yaron Y, Wolman I, Eldor A. High prevalence of the prothrombin gene mutation in women with intrauterine growth retardation, abruptio placentae and second trimester loss. Acta Obstet Gynecol Scand. 2000;79(11): 963–967.

    CAS  PubMed  Google Scholar 

  117. Greer IA. Thrombophilia: implications for pregnancy outcome. Thromb Res. 2003;109(2–3):73–81.

    Article  CAS  PubMed  Google Scholar 

  118. Stanley-Christian H, Ghidini A, Sacher R, Shemirani M. Fetal genotype for specific inherited thrombophilias is not associated with severe preeclampsia. J Soc Gynecol Investig. 2005;12(3):198–201.

    Article  CAS  PubMed  Google Scholar 

  119. Vefring H, Lie RT, ØDegård R, Mansoor MA, Nilsen ST. Maternal and fetal variants of genetic thrombophilias and the risk of preeclampsia. Epidemiology. 2004;15(3):317–322.

    Article  PubMed  Google Scholar 

  120. Lykke JA, Paidas MJ, Langhoff-Roos J. Recurring complications in second pregnancy. Obstet Gynecol. 2009;113(6):1217–1224.

    Article  PubMed  Google Scholar 

  121. Coppens M, Folkeringa N, Teune MJ, et al. Outcome of the subsequent pregnancy after a first loss in women with the factor V Leiden or prothrombin 20210A mutations. J Thromb Haemost. 2007;5(7):1444–1448.

    Article  CAS  PubMed  Google Scholar 

  122. Lindqvist PG, Merlo J. The natural course of women with recurrent fetal loss. J Thromb Haemost. 2006;4(4):896–897.

    Article  CAS  PubMed  Google Scholar 

  123. Said JM, Higgins JR, Moses EK, et al. Inherited thrombophilia polymorphisms and pregnancy outcomes in nulliparous women. Obstet Gynecol. 2010;115(1):5–13.

    Article  CAS  PubMed  Google Scholar 

  124. Empson M, Lassere M, Craig JC, Scott JR. Recurrent pregnancy loss with antiphospholipid antibody: a systematic review of therapeutic trials. Obstet Gynecol. 2002;99(1): 135–144.

    PubMed  Google Scholar 

  125. Ziakas PD, Pavlou M, Voulgarelis M. Heparin treatment in antiphospholipid syndrome with recurrent pregnancy loss: a systematic review and meta-analysis. Obstet Gynecol. 2010; 115(6):1256–1262.

    Article  PubMed  Google Scholar 

  126. Kupferminc MJ, Fait G, Many A, et al. Low-molecular-weight heparin for the prevention of obstetric complications in women with thrombophilias. Hypertens Pregnancy. 2001;20(1):35–44.

    Article  CAS  PubMed  Google Scholar 

  127. Riyazi N, Leeda M, de Vries JI, Huijgens PC, van Geijn HP, Dekker GA. Low-molecular-weight heparin combined with aspirin in pregnant women with thrombophilia and a history of preeclampsia or fetal growth restriction: a preliminary study. Eur J Obstet Gynecol Reprod Biol. 1998;80(1):49–54.

    Article  CAS  PubMed  Google Scholar 

  128. Paidas M, Ku DH, Triche E, Lockwood C, Arkel Y. Does heparin therapy improve pregnancy outcome in patients with thrombophilias? J Thromb Haemost. 2004;2(7):1194–1195.

    Article  CAS  PubMed  Google Scholar 

  129. Brenner B, Hoffman R, Carp H, Dulitsky M, Younis J, Investigators LIVE-ENOX. 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(2):227–229.

    Article  CAS  PubMed  Google Scholar 

  130. Rodger M. Important publication missing key information. Blood. 2004;104(10):3413.

    Article  CAS  PubMed  Google Scholar 

  131. Urban G, Vergani P, Tironi R, et al. Antithrombotic prophylaxis in multiparous women with preeclampsia or intrauterine growth retardation in an antecedent pregnancy. Int J Fertil Womens Med. 2007;52(2–3):59–67.

    PubMed  Google Scholar 

  132. Walker MC, Ferguson SE, Allen VM. Heparin for pregnant women with acquired or inherited thrombophilias. Cochrane Database Syst Rev. 2003;(2):CD003580.

    Google Scholar 

  133. Di Nisio M, Peters L, Middeldorp S. Anticoagulants for the treatment of recurrent pregnancy loss in women without antiphospholipid syndrome. Cochrane Database Syst Rev. 2005;(2):CD004734.

    Google Scholar 

  134. Tulppala M, Marttunen M, Söderstrom-Anttila V, et al. Low-dose aspirin in prevention of miscarriage in women with unexplained or autoimmune related recurrent miscarriage: effect on prostacyclin and thromboxane A2 production. Hum Reprod. 1997;12(7):1567–1572.

    Article  CAS  PubMed  Google Scholar 

  135. Kaandorp SP, Goddijn M, van der Post JA, et al. Aspirin plus heparin or aspirin alone in women with recurrent miscarriage. N Engl J Med. 2010;362(17):1586–1596.

    Article  CAS  PubMed  Google Scholar 

  136. Clark P, Walker ID, Langhorne P, et al. SPIN (Scottish Pregnancy Intervention) study: a multicenter, randomized controlled trial of low-molecular-weight heparin and low-dose aspirin in women with recurrent miscarriage. Blood. 2010;115(21):4162–4167.

    Article  CAS  PubMed  Google Scholar 

  137. de Vries JI, van Pampus MG, Hague WM, Bezemer PD, Joosten JH, Investigators FRUIT. Low-molecular-weight heparin added to aspirin in the prevention of recurrent early-onset preeclampsia in women with inheritable thrombophilia: the FRUITRCT. J Thromb Haemost. 2012;10(1):64–72.

    Article  PubMed  CAS  Google Scholar 

  138. Scifres CM, Macones GA. The utility of thrombophilia testing in pregnant women with thrombosis: fact or fiction? Am J Obstet Gynecol. 2008;199(4):344 e1–344 e7.

    Article  Google Scholar 

  139. Rodger MA, Paidas M, McLintock C, et al. Inherited thrombophilia and pregnancy complications revisited. Obstet Gynecol. 2008;112(2 pt 1):320–324.

    Article  PubMed  Google Scholar 

  140. Bates SM, Greer IA, Middeldorp S, Veenstra DL, Prabulos AM, Vandvik PO. VTE, thrombophilia, antithrombotic therapy, and pregnancy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(suppl 2): e691S–e736S.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. High Risk Pregnancy Unit, University Hospital of Careggi, Largo Brambilla 3, 50124, Florence, Italy

    Marianna Pina Rambaldi MD, Federico Mecacci MD & Secondo Guaschino MD

  2. Gynecology Unit, University Hospital Burlo Garofolo, Trieste, Italy

    Secondo Guaschino MD

  3. Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, CT, New Haven, USA

    Michael J. Paidas MD

Authors
  1. Marianna Pina Rambaldi MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Federico Mecacci MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Secondo Guaschino MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Michael J. Paidas MD
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Marianna Pina Rambaldi MD.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Rambaldi, M.P., Mecacci, F., Guaschino, S. et al. Inherited and Acquired Thrombophilias. Reprod. Sci. 21, 167–182 (2014). https://doi.org/10.1177/1933719113497282

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1177/1933719113497282

Keywords

Search

Navigation