Inherited Thrombophilia and Pregnancy Loss

Introduction

A successful pregnancy is dependent on the development of adequate placental circulation. Abnormalities of placental vasculature may result in a number of gestational pathologies, including first and second trimester miscarriages, intrauterine growth retardation (IUGR), intrauterine fetal death (IUFD), placental abruption, and preeclampsia.¹

Approximately 5% of women experience two or more consecutive abortions. Habitual abortions, defined as three or more spontaneous recurrent pregnancy losses, may affect as many as 1% to 2% of women of reproductive age. The discovery of an association between recurrent pregnancy loss, and antiphospholipid antibodies, specifically lupus anticoagulant, and anticardiolipin antibodies increased interest in a possible acquired thrombotic autoimmune cause.

The inherited thrombophilias are a group of genetic disorders of blood coagulation resulting in an increased risk of thrombosis. Today, a full understanding of the inherited thrombophilias is becoming increasingly important in the management of high-risk gestations. Several reports over the last three years have suggested that not only are these disorders associated with an increased risk of thromboembolic disease during pregnancy and puerperium, but they are also associated with an increased incidence of vascular pathologies, resulting in poor gestational outcome.²

This review will cover recent data concerning thrombophilia and vascular placental pathology, potential pathophysiologic mechanisms for this association, and available therapeutic modalities for prevention of placental vascular thrombosis in order to maximize successful gestational outcome.

• References

• 1 Salafia CM, Minior VK, Pezzullo JC, Popek EJ, Rosenkrantz TS, Vintzileos AM. Intrauterine growth restriction in infants of less than thirty-two weeks’ gestation: Associated placental pathologic features. Am J Obstet Gynecol 1995; 173: 1049-1057.
• 2 Brenner B, Blumenfeld Z. Thrombophilia and fetal loss. Blood Rev 1997; 11 (02) 72-79.
• 3 Cook CL, Pridham DD. Recurrent pregnancy loss. Curr Opin Obstet Gynecol 1995; 7: 357-366.
• 4 Clifford K, Rai R, Watson H, Regan L. An informative protocol for the investigation of recurrent miscarriage: Preliminary experience of 500 consecutive cases. Hum Reprod 1994; 9: 1328-1332.
• 5 Hatasaka HH. Recurrent miscarriage: Epidemiologic factors, definitions, and incidence. Clin Obstet Gynecol 1994; 37: 625-634.
• 6 Raziel A, Arieli S, Bukovsky I, Caspi E, Golan A. Investigation of the uterine cavity in recurrent aborters. Fertil Steril 1994; 62: 1080-1082.
• 7 Triplett DA, Harris EN. Antiphospholipid antibodies and reproduction. Am J Reprod Immunol 1989; 21: 123-131.
• 8 Beressi AH, Tefferi A, Silverstein MN, Petitt RM, Hoagland WC. Outcome analysis of 34 pregnancies in women with essential thrombocythemia. Arch Intern Med 1995; 155: 1217-1222.
• 9 Hellgren M, Tengborn L, Abildgaard U. Pregnancy in women with congenital antithrombin III deficiency: Experience of treatment with heparin and antithrombin. Gynecol Obstet Invest 1982; 14: 127-141.
• 10 Conard J, Horellou MH, Van Dreden P, Lecompte T, Samama M. Thrombosis and pregnancy in congenital deficiencies in ATIII, protein C or protein S. Thromb Haemost 1990; 63: 319-320.
• 11 Sanson BJ, Friederich PW, Simioni P, Zanardi S, Hilsman MV, Girolami A, ten Cate JW, Prins MH. The risk of abortion and stillbirth in antithrombin-, protein C-, and protein S-deficient women. Thromb Haemost 1996; 75: 387-388.
• 12 Haverkate F, Samama M. Familial dysfibrinogenemia and thrombophilia. Report on a study of the SSC Subcommittee on Fibrinogen. Thromb Haemost 1995; 73: 151-161.
• 13 Gris JC, Schved JF, Neveu S, Mares P, Aguilar-Martinez P, Dupaigne D. Impaired fibrinolytic capacity and early recurrent spontaneous abortions. BMJ 1990; 300: 1500.
• 14 Gris JC, Neveu S, Mares P, Biron C, Hedon B, Schved JF. Plasma fibrinolytic activators and their inhibitors in women suffering from early recurrent abortions of unknown etiology. J Lab Clin Med 1993; 122: 606-615.
• 15 Hellgren M, Svensson PJ, Dahlback B. Resistance to activated protein C as a basis for venous thromboembolism associated with pregnancy and oral contraceptives. Am J Obstet Gynecol 1995; 173: 210-213.
• 16 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.
• 17 Zivelin A, Griffin JH, Xu X, Pabinger I, Samama M, Conard J, Brenner B, Eldor A, Seligsohn U. A single genetic origin for a common Caucasian risk factor for venous thrombosis. Blood 1997; 89: 397-402.
• 18 Zivelin A, Rosenberg N, Faier S, Kornbrot N, Peretz H, Mannhalter C, Horellou MH, Seligsohn U. A single genetic origin for the common prothrombotic G20210A polymorphism in the prothrombin gene. Blood 1998; 92: 1119-1124.
• 19 Kluijtmans LAJ, van den Heuvel LP, Boers GH, Frosst P, Stevens EM, van Oost BA, den Heijer M, Trijbels FJ, Rozen R, Blom HJ. Molecular genetic analysis in mild hyperhomocysteinemia: A common mutation in the methylenetetrahydrofolate reductase gene is a genetic risk factor for cardiovascular disease. Am J Hum Genet 1996; 58: 35-41.
• 20 Franco RF, Araujo AG, Guerreiro JF, Elion J, Zago MA. Analysis of the 677C®T mutation of the methylenetetrahydrofolate reductase gene in different ethnic groups. Thromb Haemost 1998; 79: 119-121.
• 21 Clark P, Brennand J, Conkie JA, McCall D, Greer IA, Walker ID. Activated protein C sensitivity, protein C, protein S and coagulation in normal pregnancy. Thromb Haemost 1998; 79: 1166-1170.
• 22 Rai R, Regan L, Hadley E, Dave M, Cohen H. Second trimester pregnancy loss is associated with activated protein C resistance. Br J Haematol 1996; 92: 489-490.
• 23 Younis JS, Brenner B, Ohel G, Lanir N, Rothbart M, Ben-Ami M. Factor V Leiden Mutation is associated with first as well as second trimester recurrent fetal loss. Fertil Steril 1998; 70 (Suppl. 03) S-55.
• 24 Brenner B, Mandel H, Lanir N, Younis J, Rothbart H, Ohel G, Blumenfeld Z. Activated protein C resistance can be associated with recurrent fetal loss. Brit J Haematol 1997; 97: 51-54.
• 25 Rotmensch S, Liberati M, Mittlemann M, Ben-Rafael Z. Activated protein C resistance and adverse pregnancy outcome. Am J Obstet Gynecol 1997; 177: 170-173.
• 26 Dizon-Townson DS, Kinney S, Branch DW, Ward K. The factor V Leiden mutation is not a common cause of recurrent miscarriage. J Reprod Immunol 1997; 34: 217-223.
• 27 Preston FE, Rosendaal FR, Walker ID, Briet E, Berntorp E, Conard J, Fontcuberta J, Makris M, Mariani G, Noteboom W, Pabinger I, Legnani C, Scharrer I, Schulman S, van der Meer FJ. Increased fetal loss in women with heritable thrombophilia. Lancet 1996; 348: 913-916.
• 28 Ridker PM, Miletich JP, Buring JE, Ariyo AA, Price DT, Manson JE, Hill JA. Factor V Leiden mutation as a risk factor for recurrent pregnancy loss. Ann Intern Med 1998; 128: 1000-1003.
• 29 Grandone E, Margaglione M, Colaizzo D, d’Addedda M, Cappucci G, Vecchione G, Scianname N, Pavone G, Di Minno G. Factor V Leiden is associated with repeated and recurrent unexplained fetal losses. Thromb Haemost 1997; 77: 822-824.
• 30 Brenner B, Sarig G, Weiner Z, Younis J, Blumenfeld Z, Lanir N. Thrombophilic polymorphisms in women with fetal loss. Blood 1998; 92 (Suppl. 01) 558a.
• 31 Pickering W, Holmes Z, Regan L, Cohen H. Normal prevalence of the G20210A prothrombin gene mutation in women with recurrent miscarriage. Br J Haematol 1998; 102 (01) 250.
• 32 Deitcher SR, Park VM, Kutteh WH. Prothrombin 20210 G®A mutation analysis in Caucasian women with early first trimester recurrent pregnancy loss. Blood 1998; 92 (Suppl. 01) 118b.
• 33 Deitcher SR, Park VM, Kutteh WH. Methylene tetrahydrofolate reductase 677C®T mutation analysis in Caucasian women with early first trimester recurrent pregnancy loss. Blood 1998; 92 (Suppl. 01) 117b.
• 34 Kornberg A, Raziel A, Rahimini-Levene N, Yona R, Sela BA, Ron-El R. Hypercoagulability and recurrent abortions. Blood 1998; 92 (Suppl. 01) 121b.
• 35 Nelen WL, Blom HJ, Thomas CM, Steegers EA, Boers CH, Eskes TK. Methylenetetrahydrofolate reductase polymorphism affects the change in homocysteine and folate concentrations resulting from low dose folic acid supplementation in women with unexplained recurrent miscarriages. J Nutr 1998; 128: 1336-1341.
• 36 Zöller B, Berntsdotter A, Garcia de Frutos P, Dahlback B. Resistance to activated protein C as an additional genetic risk factor in hereditary deficiency of protein S. Blood 1995; 85: 3518-3523.
• 37 Brenner B, Zivelin A, Lanir N, Greengard JS, Griffin JH, Seligsohn U. Venous thromboembolism associated with double heterozygosity for R506Q mutation of factor V and for T298M mutation of protein C in a large family of a previously described homozygous protein C deficient newborn with massive thrombosis. Blood 1996; 88: 877-880.
• 38 Mandel H, Brenner B, Berant M, Rosenberg N, Lanir N, Jakobs C, Fowler B, Seligsohn U. Coexistence of hereditary homocysteinuria and factor V Leiden—effect on thrombosis. N Engl J Med 1996; 334: 763-768.
• 39 Brenner B, Vulfsons SL, Lanir N, Nahir M. Coexistence of familial antiphospholipid syndrome and factor V Leiden-impact on thrombotic diathesis. Br J Haematol 1996; 94: 166-167.
• 40 Brenner B, Zwang E, Bronshtein M, Seligsohn U. Von Willebrand factor multimer patterns in pregnancy-induced hypertension. Thromb Haemost 1989; 62: 715-717.
• 41 Cadroy Y, Grandjean H, Pichon J, Desprats R, Berrebi A, Boneu B. Evaluation of six markers of haemostatic system in normal pregnancy and pregnancy complicated by hypertension or preeclampsia. Br J Obstet Gynecol 1993; 100: 416-420.
• 42 Higgins JR, Walshe JJ, Darling MR, Norris L, Bonnar J. Hemostasis in the uteroplacental and peripheral circulations in normotensive and pre-eclamptic pregnancies. Am J Obstet Gynecol 1998; 179: 520-526.
• 43 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: 902-905.
• 44 Nagy B, Toth T, Rigo Jr J, Karadi I, Romics L, Papp Z. Detection of factor V Leiden mutation in severe pre-eclamptic Hungarian women. Clin Genet 1998; 53: 478-481.
• 45 Brenner B, Lanir N, Thaler I. HELLP syndrome associated with factor V R506Q mutation. Br J Haematol 1996; 92: 999-1001.
• 46 Krauss T, Augustin HG, Osmers R, Meden H, Unterhalt M, Kuhn W. Activated protein C resistance and factor V Leiden in patients with hemolysis, elevated liver enzymes, low platelets syndrome. Obstet Gynecol 1998; 92: 457-460.
• 47 Dekker GA, de Vries JI, Doelitzsch PM, Huijgens PC, von Blomberg BM, Jakobs C, van Geijn HP. Underlying disorders associated with severe early onset preeclampsia. Am J Obstet Gynecol 1995; 173: 1042-1048.
• 48 Grandone E, Margaglione M, Colaizzo D, Cappucci G, Paladini D, Martinelli P, Montanaro S, Pavone G, Di Minno G. Factor V Leiden, C®T MTHFR polymorphism and genetic susceptibility to preeclampsia. Thromb Haemost 1997; 77: 1052-1054.
• 49 de Vries JIP, 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: 1248-1254.
• 50 Goddijn-Wessel TA, Wouters MG, van der Molen EF, Spuijbrock MD, Steegers-Theunissen RP, Blom HJ, Boers GH, Eskes TK. Hyperhomocysteinemia: a risk factor for placental abruption or infarction. Eur J Obstet Gynecol Reprod Biol 1996; 66: 23-29.
• 51 Vollset SE, Bjorke-Monsen AAL, Irgens LM. Plasma total homocysteine and previous pregnancies: The Hordaland Homocysteine Study. Proceedings of the 2^nd International Symposium on Homocysteine. Netherlands J Med 1998; 52: S54.
• 52 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. J Obstet Gynecol 1998; 179: 1565-1567.
• 53 Kupferminc MJ, Eldor A, Steinman N, Many A, Bar-Am A, Jaffa A, Fait G, Lessing JB. Increased frequency of genetic thrombophilias in women with complications of pregnancy. N Engl J Med 1999; 340: 9-13.
• 54 Grandone E, Margaglione M, Colaizzo D, D’Andrea G, Cappucci G, Brancaccio V, Di Minno G. Genetic susceptibility to pregnancy-related venous thromboembolism: roles of factor V Leiden, prothrombin G20210A, and methylenetetrahydrofolate reductase C677T mutations. Am J Obstet Gynecol 1998; 179: 1324-1328.
• 55 Kutteh WH. Antiphospholipid antibody-associated recurrent pregnancy loss: Treatment with heparin and low-dose aspirin is superior to low-dose aspirin alone. Am J Obstet Gynecol 1996; 174: 1584-1589.
• 56 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 antiphospholipid antibodies. BMJ 1997; 314: 253-257.
• 57 Sanson BJ, Lensing AWA, Prins MH, Ginsberg JS, Barkagen ZS, Lavenne-Pardonge E, Brenner B, Dulitzky M, Nielsen JD, Boda Z, Turi S, MacGillavry M, Hamulyak K, Theunissen IM, Hunt BJ, Buller HR. Safety of low molecular weight heparin in pregnancy. A systematic review. Thromb Haemostes 1999; 81: 668-72.
• 58 Gris JC, Neveu S, Tailland ML, Courtieu C, Mares P, Schved JF. Use of low-molecular weight heparin (Enoxaparin) or of a phenformin-like substance (Moroxydine chloride) in primary early recurrent aborters with an impaired fibrinolytic capacity. Thromb Haemost 1995; 73: 362-367.
• 59 Benigni A, Gregorini G, Frusca T, Chiabrando C, Ballerini S, Valcamonico A, Orisio S, Piccinelli A, Pinciroli V, Fanelli R. Effect of low dose aspirin on fetal and maternal generation of thromboxane by platelets in women at risk for pregnancy induced hypertension. N Engl J Med 1989; 321: 357-362.
• 60 Caritis S, Sibai B, Hauth J, Lindheimer MD, Klebanoff M, Thom E, Van Dorsten P, Landon M, Paul R, Miodovnik M, Meis P, Thurnau G. Low-dose aspirin to prevent preeclampsia in women at high risk. National Institute of Child Health and Human Development Network of Maternal-Fetal Medicine Units. N Engl J Med 1998; 38: 701-705.
• 61 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 Reprod Biol 1998; 80: 49-54.
• 62 Eldor A, Kupferminc MJ, Steinman N, Many A, Bar-Am A, Jaffa A, Fait G, Lessing JB. High incidence of thrombophilia in women with obstetric complications and the beneficial effects of LMW heparin and aspirin in subsequent pregnancies. Blood 1998; 92 (Suppl. 01) 556a.
• 63 Roussev RG, Stern JJ, Kaider BD, Thaler CJ. Anti-endothelial cell antibodies: another cause for pregnency loss?. Am J Reprod Immunol 1998; 39: 89-95.
• 64 Tedesco F, Pausa M, Nardon E, Narchi G, Bulla R, Livi C, Guaschino S, Meroni PL. Prevalence and biological effects of anti-trophoblast and anti-endothelial cell antibodies in patients with recurrent spontaneous abortions. Am J Reprod Immunol 1997; 38: 205-211.
• 65 Rand JH, Wu X-X, Andree HAM, Lockwood CJ, Guller S, Scher J, Harpel PC. Pregnancy loss in the antiphospholipid-antibody syndrome—a possible thrombogenic mechanism. N Engl J Med 1997; 337: 154-160.
• 66 Mercier E, Quere I, Mares P, Gris JC. Primary recurrent miscarriages: anti-b2 glycoprotein I IgG antibodies induce an acquired activated protein C resistance that can be detected by the modified activated protein C resistance test. Blood 1998; 92: 2993-2994.