Abstract
During pregnancy there are hemostatic changes that result in a hypercoagulable state and can have thrombotic consequences. This condition can be aggravated in women who are carriers of congenital thrombophilic factors. This thrombotic tendency can manifest as thrombotic lesions in the placenta with compromise of utero-placental circulation, which are common characteristics present in obstetric complications, such as preeclampsia/eclampsia, miscarriage, fetal loss, intrauterine growth retardation, and abruptio placentae. In this paper we review data concerning about the association of congenital thrombophilia in pregnancy with obstetric complications, mainly preeclampsia and fetal loss, focusing in factor V Leiden and its related activated protein C resistance, prothrombin mutation G20210A and hyperhomocysteinemia related with C677T mutation of methylenetetrahydrofolate reductase. Although factor V Leiden has been the thrombophilic factor most studied, all three thrombophilic mutations have been related with obstetric complications; however, contradictory results about the specific association of each mutation with each type of obstetric complication are described. These discrepancies could obey to the ethnic difference of the studied groups, or to the fact that some studies were performed in closed populations with few migratory movement, where the genetic pool is relatively homogeneous, as well as the different inclusion and exclusion criteria. Even though this variability is present, the significance of recognizing true associations between these thrombophilic mutations and obstetric complications is essential in order to determine the likelihood of routinely screening for these conditions in pregnant women with risk factors for thrombosis and for carrying out specific prophylactic measures.
Similar content being viewed by others
References
Bauer KM. Hypercoagulable states. In: Hoffman R, Benz EJ Jr, Shattil SJ, Furie B, Cohen HJ, Silberstein LE, McGlave P (Eds.). Hematology: Basic principles and practice. Churchill Livingstone, Philadelphia, 2000:2009-2039.
Bick R, Kaplan H. Current concepts of thrombosis: Prevalent trends for diagnosis and management. Med Clin North Am 1998;82:410–458.
Hemker HC, Lévy-Toledano S. Pathophysiological and clinical aspects of venous and arterial thrombosis. Haemostasis 1999;29:76–99.
Egeberg O. Proceedings: Inherited antithrombin III deficiency and thromboembolism. Thromb Diath Haemorrh 1975;34:366.
Middeldorp S, Büller HR, Prins MH, Hirsh J. Approach to the thrombophilic patient. In: Colman RW, Hirsh J, Marder VJ, Clowes AW, George JN (Eds.). Hemostasis and Throm-bosis. Basic principles and clinical practice. Philadelphia, Lippincott Williams & Wilkins, 2001:1085–1100.
Páramo JA, Rocha E. Hipercoagulabilidad y estados trombofilicos. Sangre 1991;36:477–486.
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 USA 1993;90:1004–1008.
Dahlback B. Resistance to activated protein C caused by the factor V R506Q mutation is a common risk factor for venous thrombosis. Thromb Haemostas 1997;78:483–489.
Frosst P, Blom HJ, Milos R, et al. A candidate genetic risk factor for vascular disease: A common mutation in methylenetetrahydrofolate reductase. Nat Genet 1995;10:111–113.
Poort SR, Rosendaal FR, Reitsma PH, Bertina RM. A common genetic variation in the 3-untraslated region of the prothrombin gene is associated with elevated plasma prothrombin levels and an increase in venous thrombosis. Blood 1996;88:3698–3703.
Lane DA, Grant PJ. Role of hemostatic gene polymorphisms in venous and arterial thrombotic disease. Blood 2000;95:1517–1532.
Vandenbroucke J, Koster T, Briet E, Reitsma PH, Bertina RM, Rosendaal FR. Increased risk of venous thrombosis in oral-contraceptive users who are carriers of factor V Leiden mutation. Lancet 1994;344:1453–1457.
Thomas DP, Roberts HR. Hypercoagulability in venous and arterial thrombosis. Ann Intern Med 1997;126:638–644.
Rosendaal FR. Venous thrombosis: A multicausal disease. Lancet 1999;353:1167–1173.
Bonnar J, Green R, Norris L. Perinatal aspects of inherited thrombophilia. Seminars Thromb Hemostas 1999;25:481–485.
Walker ID. Thrombophilia in pregnancy. J Clin Pathol 2000;53:573–580.
Bonnar J, Green R, Norris L. Inherited thrombophilia and pregnancy: The obstetric perspective. Seminars Thromb Hemostas 1998;24:49–53.
Ballem P. Acquired thrombophilia in pregnancy. Seminars Thromb Hemostas 1998;24:41–47.
Lindqvisst PG, Svensson PJ, Dahlbäck B, Marsal K. Factor V Q506 mutation (activated protein C resistance) associated with reduced intrapartum blood loss-A possible evolutionary selection mechanism. Thromb Haemost 1998;79:69–73.
Roberts JM, Taylor RN, Musici TJ, Rodgers GM, Hubel CA, McLaughlin MK. Preeclampsia: An endothelial cell disorder. Am J Obstet Gynecol 1989;161:1200–1204.
Salafia CM, Pezzulo JC, López-Zeno JA, Minior VK, Vintzileos AM. Placental pathologic features of preterm preeclampsia. Am J Obstet Gynecol 1995;173:1079–1105.
Grandone E, Margaglione M, Calaizzo D, et al. Factor V Leiden, C-T MTHFR polymorphism and genetic susceptibility to preeclampsia. Thromb Haemost 1997;77:1052–1054.
Mousa HA, Alfiveric Z. Do placental lesions reflect thrombophilia state in women with adverse pregnancy outcome? Hum Reprod 2000;15:1830–1833.
Alfirevic Z, Mousa HA, Martlew V, Briscoe L, Pérez-Casal M, Toh CH. Postnatal screening for thrombophilia in women with severe pregnancy complications. Obstet Gynecol 2001;97:753–759.
Blumenfeld Z, Brenner B. Thrombophilia-associated pregnancy wastage. Fertil Steril 1999;353:1258–1265.
Huisjes AJ, Franx A, Bruinse HW. High prevalence of hemostatic abnormalities in women with a history of severe preeclampsia. Am J Obstet Gynecol 2000;182:989–990.
Kupferminc MJ, Eldor A, Steinman N, et al. Increased frequency of genetic thrombophilia in women with complications of pregnancy. N Eng J Med 1999;340:9–13.
Kupferminc MJ, Fait G, Many A, Gordon D, Eldor A, Lessing JB. Severe preeclampsia and high frequency of genetic thrombophilic mutations. Obstet Gynecol 2000;96:45–49.
Von Tempelhoff GF, Heilmann L, Spanuth E, Kunzmann E, Hommel G. Incidence of the factor V Leiden-mutation, coagulation inhibitor deficiency, and elevated antiphospholipid-antibodies in patients with preeclamsia or HELLP-syndrome. Thromb Res 2000;100:363–365.
Rigo J Jr, Nagy B, Fintor L, et al. Maternal and neonatal outcome of preeclampsia pregnancies: The potential roles of factor V Leiden mutation and 5,10 methylenetetrahydrofolate reductase. Hypertens Pregnancy 2000;19:163–172.
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.
Van Pampus MG, Dekker GA, Wolf H, et al. High prevalence of hemostatic abnormalities in women wiht a history of severe preeclampsia. Am J Obstet Gynecol 1999;180:989–990.
O'shaughnessy KM, Fu B, Ferraro F, Lewis I, Downing S, Morris NH. Factor V Leiden and thermolabile methylenetetrahydrofolate reductase gene variants in an east anglian preeclampsia cohort. Hypertension 1999;33:1338–1341.
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;185:153–157.
Kobashi G, Yamada H, Asano T, et al. The factor V Leiden mutation is not a common cause of pregnancy-induced hypertension in Japan. Sem Thromb Hemost 1999;25:487–489.
Clark P, Sattar N, Walker ID, Greer IA. The Glasgow Outcome, APCR and Lipid (GOAL) pregnancy study: Significance of pregnancy associated activated protein C resistance. Thromb Haemost 2001;85:30–35.
Dilley A, Benito C, Hooper WC, et al. Mutations in the factor V, prothrombin and MTHFR genes are nor risk factors for recurrent fetal loss. J Matern Fetal Neonatal Med 2002;11:176–182.
Rai R, Regan L, Hadely E, Dave M, Cohen H. Second-trimester pregnancy loss is associated with activated protein C resistance. Br J Haematol 1996;92:489–490.
Preston FE, Rosendaal FR, Walker ID, et al. Increased fetal loss in women with heritable thrombophilia. Lancet 1996;75:387–390.
Younis JS, Brenner B, Ohel G, Tal J, Lanir N, Ben-Ami M. Activated protein C resistance and factor V Leiden mutation can be associated with first-as well as second trimester recurrent pregnancy loss. AmJ Reprod Immunol 2000;43:31–35.
Grandone E, Margagliane M, Calazzio D, et al. Factor V Leiden is associated with repeated and recurrent unexplained fetal losses. Thromb Haemost 1997;77:822–824.
Ridker PM, Miletich JP, Buring JE, et al. Factor V Leiden mutation as a risk factor for recurrent pregnancy loss. Ann Intern Med 1998;128:1000–1003.
Wilcken DEL, Wilcken B. The pathogenesis of coronary artery disease. A possible role for methionine metabolism. J Clin Invest 1976;57:1079–1082.
Steegers-Theunissen RP, Boers GH, Blom HJ, Trijbels FJ, Eskes TK. Hyperhomocysteinaemia and recurrent spontaneous abortion or abruptio placentae. Lancet 1992;339:1122–1123.
D'Angelo A, Selhub J. Homocysteine and thrombotic disease. Blood 1997;90:1–11.
Kang SS, Zhou J, Wong PWK, Kowalisyn J, Strokosch G. Intermediate homocysteinemia: A thermolabile variant of methylenetetrahydrofolate reductase. Am J Hum Genet 1988;43:414–421.
Frosst P, Blom HJ, Milos R, et al. A candidate genetic risk factor for vascular disease: A common mutation in methylenetetrahydrofolate reductase. Nat Genet 1995;10:111–113.
Walker MC, Smith GN, Perkins SL, Keely EJ, Garner PR. Changes in homocysteine levels during normal pregnancy. Am J Obstet Gynecol 1999;180:660–664.
Malinow MR, Rajkovic A, Druell PB, Hess DL, Upson BM. The relationship between maternal and neonatal umbilical cord plasma homocysteine suggests a potential role for maternal homocysteine in fetal metabolism. Obstet Gynecol 1998;178:228–233.
Sohda S, Arinami T, Hamada H, Yamada N, Hamaguchi H, Kubo T. Methylenetetrahydrofolate reductase polymorphism and pre-eclampsia. J Med Genet 1997;34:525–526.
Aubard Y, Darodes N, Cantaloube M. Hyperhomocysteinemia and pregnancy-review of our present understanding and therapeutic implications. Eur J Obstet Gynecol Repr Biol 2000;93:157–165.
Leeda M, Riyazi N, De Vries JIP, Jacobs C, Van Geijn HP, Dekker GA. Effects of folic acid and vitamin B6 supplementation on women with hyperhomocysteinemia and a history of preeclampsia or fetal growth restriction. Am J Obstet Gynecol 1998;179:135–139.
Dekker GA, De Vries JIP, Doelitzch PM, Von Blomberg BME, Jakob C. Underlying disorders associated with severe early onset preeclampsia. Am J Obstet Gynecol 1995;173:1042–1048.
Powers RW, Evans RW, Majors AK, et al. Plasma homocysteine concentration is increased in preeclampsia and is associated with severe early onset preeclampsia. Am J Obstet Gynecol 1998;179:1605–1611.
Wouters MG, Boers GH, Blom HJ, et al. Hyperhomocysteinemia: A risk factor in women with unexpected recurrent early pregnancy loss. Fertil Steril 1993;60:820–825.
Brenner B, Sarig G, Weiner Z, Younis J, Blumenfeld Z, Lanir N. Thrombophilic polymorphisms are common in women with fetal loss without apparent cause. Thromb Haemost 1999;82:6–9.
Quere I, Bellet H, Hoffet M, Janbon C, Mares P, Gris JC. A woman with five consecutive fetal deaths: Case report and retrospective analysis of hyperhomocysteinemia prevalence in 100 consecutive women with recurrent miscarriages. Fertil Steril 1998;69:152–154.
Nelen W, Steegers E, Eskes T, Blom H. Genetic risk factor for unexplained recurrent early pregnancy loss. Lancet 1997;350:861.
Steegers-Theunissen RP, Wathen NC, Eskes TK, Van Raaij-Selten B, Chard T. Maternal and fetal levels of methionine and homocysteine in early human pregnancy. Br J Obstet Gynaecol 1997;104:20–24.
Nelen WL, Blom H, Steegers E, Den Heijer M, Eskes T. Hyperhomocysteinemia and recurrent early pregnancy loss: A meta analysis. Fertil Steril 2000;74:1196–1199.
Holmes ZR, Regan L, Chilcott I, Cohen H. The C677T MTHFR gene mutation is not predictive of risk for recurrent fetal loss. Br J Haematol 1999;105:98–101.
Goddijn-Wessel T, Wouters M, Molen E, et al. Hyperhomocysteinemia: A risk factor for placental abruption or infarction. Eur J Obstet Gynecol Repr Biol 1996;66:23–29.
Martinelli I, Sacchi E, Landi G, Taioli E, Duca F, Mannucci PM. High risk of cerebral-vein thrombosis in carriers of a prothrombin-gene mutation and in users of oral contraceptives. N Engl J Med 1998;338:1793–1797.
Ridker PM, Hennekens CH, Miletich JP. G20210A mutation in prothrombin gene and risk of myocardial infarction, stroke, and venous thrombosis in a large cohort of US men. Circulation 1999;99:999–1004.
Souto JC, Coll I, Llobert D, et al. The prothrombin G20210A allele is the most prevalent genetic risk factor for venous thromboembolism in the Spanish population. Thromb Haemostas 1998;80:366–369.
Martinelli I, Taioli E, Bucciarelli P, Akhavan S, Mannucci M. Interaction between the G20210A mutation of the prothrombin gene and oral contraceptive use in deep vein thrombosis. Arterioscler Thromb Vasc Biol 1999;19:700–703.
Grandone E, Margaglione M, Colaizzo D, et al. 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.
Kupferminc MJ, Peri H, Zwang E, Yaron Y, Wolman I, Eldor A. High prevalence of the prothrombin gene mutation in women with intrauterine growht retardation, abruptio placentae and second trimester loss. Acta Obstet Gynecol Scand 2000;79:963–967.
Grandone E, Margaglione M, Colaizzo D, et al. Prothrombotic genetic risk factors and the occurrence of gestational hypertension with or without proteinuria. Thromb Haemost 1999;81:349–352.
De Groot CJM, Bloemenkamp KWM, Duvekot EJ, et al. Preeclampsia and genetic risk factors for thrombosis: A case-control study. Am J Obstet Gynaecol 1999;181:975–980.
Higgins JR, Kaiser T, Moses EK, North R, Brennecke SP. Prothrombin G20210A mutation: Is it associated with preeclampsia? Gynecol Obstet Invest 2000;50:254–257.
Pihusch R, Buchholz T, Lohse P, et al. Thrombophilic gene mutations and recurrent spontaneous abortion: Prothrombin mutation increases the risk in the first trimester. Am J Reprod Immunol 2001;46:124–131.
Pickering W, Marriott K, Regan L. G20210A prothrombin gene mutation: Prevalence in a recurrent miscarriage population. Clin Appl Thromb Hemost 2001;7:25–28.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Villarreal, C., García-Aguirre, G., Hernández, C. et al. Congenital Thrombophilia Associated to Obstetric Complications. J Thromb Thrombolysis 14, 163–169 (2002). https://doi.org/10.1023/A:1023293114529
Issue Date:
DOI: https://doi.org/10.1023/A:1023293114529