Skip to main content
SpringerLink
Log in

Hereditary thrombophilic risk factors for recurrent pregnancy loss

  • Review
  • Published:
Journal of Community Genetics Aims and scope Submit manuscript

Abstract

This review summarizes current knowledge about the role of hereditary hypercoagulation factors predisposing to thrombophilia-associated recurrent fetal loss. Thrombophilias are a major cause of adverse pregnancy outcome, playing a role in the etiology of up to 40% of cases worldwide. Hereditary thrombophilic predispositions to recurrent pregnancy wastage include genetic lesions in blood coagulation factors II and V as well as natural anticoagulants antithrombin, protein C, and protein S. Furthermore, methylenetetrahydrofolate reductase gene variants conferring higher thrombophilia risk in combination with these mutations and the newly described annexin A5 gene M2 promoter allele are associated with repeated fetal loss. The review gives a concise description of the molecular defects arising from the genetic changes, of the role these factors play in the timing and definition of fetal loss, and risk estimates from available studies and meta-analysis. This knowledge is instrumental for a more precise assessment of individual risks for repeated fetal loss and should guide therapeutic strategies, where relevant. Since the average childbearing age increases in Western societies, the importance of a timely diagnosis of fetal loss predisposition is increasing.

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

  • Alfirevic Z, Kurjak A (1990) Transvaginal colour Doppler ultrasound in normal and abnormal early pregnancy. J Perinat Med 18:173–180

    Article  CAS  PubMed  Google Scholar 

  • Bates SM, Greer IA, Pabinger I, Sofaer S, Hirsh J (2008) Venous thromboembolism, thrombophilia, antithrombotic therapy, and pregnancy: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th edn). Chest 133:844S–886S

    Article  CAS  PubMed  Google Scholar 

  • Bertina RM, Koeleman BP, Koster T, Rosendaal FR, Dirven RJ, de Ronde H, van der Velden PA, Reitsma PH (1994) Mutation in blood coagulation factor V associated with resistance to activated protein C. Nature 369:64–67

    Article  CAS  PubMed  Google Scholar 

  • Bick RL, DRW Metroplex Recurrent Miscarriage Syndrome Cooperative Group (2000) Recurrent miscarriage syndrome due to blood coagulation protein/platelet defects: prevalence, treatment and outcome results. Clin Appl Thromb Hemost 6:115–125

    Article  CAS  PubMed  Google Scholar 

  • Bogdanova N, Horst J, Chlystun M, Croucher PJ, Nebel A, Bohring A, Todorova A, Schreiber S, Gerke V, Krawczak M, Markoff A (2007) A common haplotype of the annexin A5 (ANXA5) gene promoter is associated with recurrent pregnancy loss. Hum Mol Genet 16:573–578

    Article  CAS  PubMed  Google Scholar 

  • Bosler D, Mattson J, Crisan D (2006) Phenotypic heterogeneity in patients with homozygous prothrombin 20210AA genotype. J Mol Diagn 4:420–425

    Article  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  • Brenner B, Sarig G, Weiner Z, Younis J, Blumenfeld Z, Lanir N (1999) Thrombophilic polymorphisms are common in women with fetal loss without apparent cause. Thromb Haemost 82:6–9

    CAS  PubMed  Google Scholar 

  • Cattaneo M (1999) Hyperhomocysteinemia, atherosclerosis and thrombosis. Thromb Haemost 81:165–176

    CAS  PubMed  Google Scholar 

  • Cattaneo M, Tsai MY, Bucciarelli P, Taioli E, Zighetti ML, Bignell M, Mannucci PM (1997) A common mutation in the methylenetetrahydrofolate reductase gene (C677T) increases the risk for deep-vein thrombosis in patients with mutant factor V (factor V:Q506). Arterioscler Thromb Vasc Biol 17:1662–1666

    CAS  PubMed  Google Scholar 

  • Chan WP, Lee CK, Kwong YL, Lam CK, Liang R (1998) A novel mutation of Arg 506 of factor V gene in Hong Kong Chinese. Blood 91:1135

    CAS  PubMed  Google Scholar 

  • Chinni E, Tiscia GL, Colaizzo D, Vergura P, Margaglione M, Grandone E (2009) Annexin V expression in human placenta is influenced by the carriership of the common haplotype M2. Fertil Steril 91:940–942

    Article  CAS  PubMed  Google Scholar 

  • Coulam CB, Jeyendran RS, Fishel LA, Roussev R (2006) Multiple thrombophilic gene mutations rather than specific gene mutations are risk factors for recurrent miscarriage. Am J Reprod Immunol 55:360–368

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • de Visser MC, Rosendaal FR, Bertina RM (1999) A reduced sensitivity for activated protein C in the absence of factor V Leiden increases the risk of venous thrombosis. Blood 93:1271–1276

    PubMed  Google Scholar 

  • Eldibany MM, Caprini JA (2007) Hyperhomocysteinemia and thrombosis: an overview. Arch Pathol Lab Med 131:872–884

    CAS  PubMed  Google Scholar 

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

    Article  PubMed  Google Scholar 

  • Finan RR, Tamim H, Ameen G, Sharida HE, Rashid M, Almawi WY (2002) Prevalence of factor V G1691A (factor V-Leiden) and prothrombin G20210A gene mutations in a recurrent miscarriage population. Am J Hematol 71:300–305

    Article  CAS  PubMed  Google Scholar 

  • Florell SR, Rodgers GM 3rd (1996) Utilization of testing for activated protein C resistance in a reference laboratory. Am J Clin Pathol 106:248–252

    CAS  PubMed  Google Scholar 

  • Foka ZJ, Lambropoulos AF, Saravelos H, Karas GB, Karavida A, Agorastos T, Zournatzi V, Makris PE, Bontis J, Kotsis A (2000) Factor V Leiden and prothrombin G20210A mutations, but not methylenetetrahydrofolate reductase C677T, are associated with recurrent miscarriages. Hum Reprod 15:458–462

    Article  CAS  PubMed  Google Scholar 

  • Gehring NH, Frede U, Neu-Yilik G, Hundsdoerfer P, Vetter B, Hentze MW, Kulozik AE (2001) Increased efficiency of mRNA 3′ end formation: a new genetic mechanism contributing to hereditary thrombophilia. Nat Genet 28:389–392

    Article  CAS  PubMed  Google Scholar 

  • Goodman CS, Coulam CB, Jeyendran RS, Acosta VA, Roussev R (2006) Which thrombophilic gene mutations are risk factors for recurrent pregnancy loss? Am J Reprod Immunol 56:230–236

    Article  CAS  PubMed  Google Scholar 

  • Greengard JS, Sun X, Xu X, Fernandez JA, Griffin JH, Evatt B (1994) Activated protein C resistance caused by Arg506Gln mutation in factor Va. Lancet 343:1361–1362

    Article  CAS  PubMed  Google Scholar 

  • Griffin JH, Evatt B, Wideman C, Fernández JA (1993) Anticoagulant protein C pathway defective in majority of thrombophilic patients. Blood 82:1989–1993

    CAS  PubMed  Google Scholar 

  • Hanson NQ, Aras O, Yang F, Tsai MY (2001) C677T and A1298C polymorphisms of the methylenetetrahydrofolate reductase gene: incidence and effect of combined genotypes on plasma fasting and post-methionine load homocysteine in vascular disease. Clin Chem 47:661–666

    CAS  PubMed  Google Scholar 

  • Koster T, Rosendaal FR, de Ronde H, Briet E, Vandenvroucke JP, Bertina RM (1993) Venous thrombosis due to poor anticoagulant response to activated protein C: Leiden Thrombophilia Study. Lancet 342:1503–1506

    Article  CAS  PubMed  Google Scholar 

  • Kovalevsky G, Gracia CR, Berlin JA, Sammel MD, Barnhart KT (2004) Evaluation of the association between hereditary thrombophilias and recurrent pregnancy loss: a meta-analysis. Arch Intern Med 164:558–563

    Article  PubMed  Google Scholar 

  • Kupferminc MJ (2003) Thrombophilia and pregnancy. Reprod Biol Endocrinol 1:111

    Article  PubMed  Google Scholar 

  • Kupferminc MJ, Eldor A, Steinman N, Many A, Bar-Am A, Jaffa A, Fait G, Lessing JB (1999) Increased frequency of genetic thrombophilia in women with complications of pregnancy. N Engl J Med 340:50–52

    Article  Google Scholar 

  • Lussana F, Dentali F, Abbate R, d’Aloja E, D’Angelo A, De Stefano V, Faioni EM, Grandone E, Legnani C, Martinelli I, Simioni P, Tormene D (2009) Screening for thrombophilia and antithrombotic prophylaxis in pregnancy: guidelines of the Italian Society for Haemostasis and Thrombosis (SISET). Thromb Res 124:e19–e25

    Article  CAS  PubMed  Google Scholar 

  • McGlennen RC, Key NS (2002) Clinical and laboratory management of the prothrombin G20210A mutation. Arch Pathol Lab Med 126:1319–1325

    CAS  PubMed  Google Scholar 

  • Nelen WL, Blom HJ, Steegers EA, den Heijer M, Eskes TK (2000) Hyperhomocysteinemia and recurrent early pregnancy loss: a meta-analysis. Fertil Steril 74:1196–1199

    Article  CAS  PubMed  Google Scholar 

  • Nilsson I, Astedt B, Hedner U, Berezin D (1975) Intrauterine death and circulating anticoagulant (“antithromboplastin”). Acta Med Scand 197:153–159

    Article  CAS  PubMed  Google Scholar 

  • Olivieri O, Friso S, Manzato F, Guella A, Bernardi F, Lunghi B, Girelli D, Azzini M, Brocco G, Russo C, Corrocher R (1995) Resistance to activated protein C in healthy women taking oral contraceptives. Br J Haematol 91:465–470

    Article  CAS  PubMed  Google Scholar 

  • Out HJ, Kooijman CD, Bruinse HW, Derksen RH (1991) Histopathological findings in placentae from patients with intra-uterine fetal death and anti-phospholipid antibodies. Eur J Obstet Gynecol Reprod Biol 41:179–186

    Article  CAS  PubMed  Google Scholar 

  • Pihusch R, Buchholz T, Lohse P, Rübsamen H, Rogenhofer N, Hasbargen U, Hiller E, Thaler CJ (2001) Thrombophilic gene mutations and recurrent spontaneous abortion: prothrombin mutation increases the risk in the first trimester. Am J Reprod Immunol 46:124–131

    Article  CAS  PubMed  Google Scholar 

  • Poort SR, Rosendaal FR, Reitsma PH, Bertina RM (1996) 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 88:3698–36703

    CAS  PubMed  Google Scholar 

  • Press RD, Bauer KA, Kujovich JL, Heit JA (2002) Clinical utility of factor V leiden (R506Q) testing for the diagnosis and management of thromboembolic disorders. Arch Pathol Lab Med 126:1304–1318

    PubMed  Google Scholar 

  • Rai R, Regan L, Hadley E, Dave M, Cohen H (1996) Second-trimester pregnancy loss is associated with activated protein C resistance. Br J Haematol 92:489–490

    CAS  PubMed  Google Scholar 

  • Rand JH, Wu XX (1999) Antibody-mediated disruption of the annexin-V antithrombotic shield: a new mechanism for thrombosis in the antiphospholipid syndrome. Thromb Haemost 82:649–655

    CAS  PubMed  Google Scholar 

  • Rand JH, Wu XX, Guller S, Gil J, Guha A, Scher J, Lockwood CJ (1994) Reduction of annexin-V (placental anticoagulant protein-I) on placental villi of women with antiphospholipid antibodies and recurrent spontaneous abortion. Am J Obstet Gynecol 171:1566–1572

    CAS  PubMed  Google Scholar 

  • Rand JH, Wu XX, Quinn AS, Chen PP, McCrae KR, Bovill EG, Taatjes DJ (2003) Human monoclonal antiphospholipid antibodies disrupt the annexin A5 anticoagulant crystal shield on phospholipid bilayers: evidence from atomic force microscopy and functional assay. Am J Pathol 163:1193–2000

    CAS  PubMed  Google Scholar 

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

    Article  PubMed  Google Scholar 

  • Reznikoff-Etiévan MF, Cayol V, Carbonne B, Robert A, Coulet F, Milliez J (2001) Factor V Leiden and G20210A prothrombin mutations are risk factors for very early recurrent miscarriage. Br J Obstet Gynecol 108:1251–1254

    Article  Google Scholar 

  • Ridker PM, Hennekens CH, Selhub J, Miletich JP, Malinow MR, Stampfer MJ (1997) Interrelation of hyperhomocyst(e)inemia, factor V Leiden, and risk of future venous thromboembolism. Circulation 95:1777–1782

    CAS  PubMed  Google Scholar 

  • Ridker PM, Miletich JP, Buring JE, Ariyo AA, Price DT, Manson JE, Hill JA (1998) Factor V Leiden mutation as a risk factor for recurrent pregnancy loss. Ann Intern Med 128:1000–1003

    CAS  PubMed  Google Scholar 

  • Romisch J, Seiffge D, Reiner G, Paques EP, Heimburger N (1991) In-vivo antithrombotic potency of placenta protein 4 (annexin V). Thromb Res 61:93–104

    Article  CAS  PubMed  Google Scholar 

  • Rosendaal FR, Doggen CJ, Zivelin A, Arruda VR, Aiach M, Siscovick DS, Hillarp A, Watzke HH, Bernardi F, Cumming AM, Preston FE, Reitsma PH (1998) Geographic distribution of the 20210 G to A prothrombin variant. Thromb Haemost 79:706–708

    CAS  PubMed  Google Scholar 

  • Royal College of Obstetricians and Gynecologists RCOG (2009) RCOG Statement on later maternal age. http://www.rcog.org.uk/what-we-do/campaigning-and-opinions/statement/rcog-statement-later-maternal-age, accessed 10 Sep 2009

  • Salafia CM, Cowchock FS (1997) Placental pathology and antiphospholipid antibodies: a descriptive study. Am J Perinat 14:435–441

    Article  CAS  Google Scholar 

  • Sanson BJ, Simioni P, Tormene D, Moia M, Friederich PW, Huisman MV, Prandoni P, Bura A, Rejto L, Wells P, Mannucci PM, Girolami A, Büller HR, Prins MH (1999) The incidence of venous thromboembolism in asymptomatic carriers of a deficiency of antithrombin, protein C, or protein S: a prospective cohort study. Blood 94:3702–3706

    CAS  PubMed  Google Scholar 

  • Sarig G, Younis JS, Hoffman R, Lanir N, Blumenfeld Z, Brenner B (2002) Thrombophilia is common in women with idiopathic pregnancy loss and is associated with late pregnancy wastage. Fertil Steril 77:342–347

    Article  PubMed  Google Scholar 

  • Seligsohn U, Lubetsky A (2001) Genetic susceptibility to venous thrombosis. N Engl J Med 344:1222–1231

    Article  CAS  PubMed  Google Scholar 

  • Shu F, Sugimura M, Kanayama N, Kobayashi H, Kobayashi T, Terao T (2000) Immunohistochemical study of annexin V expression in placentae of preeclampsia. Gynecol Obstet Invest 49:17–23

    Article  CAS  PubMed  Google Scholar 

  • Simioni P, Sanson BJ, Prandoni P, Tormene D, Friederich PW, Girolami B, Gavasso S, Huisman MV, Büller HR, Wouter ten Cate J, Girolami A, Prins MH (1999) Incidence of venous thromboembolism in families with inherited thrombophilia. Thromb Haemost 81:198–202

    CAS  PubMed  Google Scholar 

  • Subrt I, Ulvova-Gallova Z, Bibkova K, Micanova Z, Hejnalova M, Cerna M, Hradecky L, Novotny Z (2008) Recurrent pregnancy loss and frequency of eight antiphospholipid antibodies and genetic thrombophilic factors in Czech women. Am J Reprod Immunol 59:193–200

    Article  CAS  PubMed  Google Scholar 

  • Tiscia G, Colaizzo D, Chinni E, Pisanelli D, Sciannamè N, Favuzzi G, Margaglione M, Grandone E (2009) Haplotype M2 in the annexin A5 (ANXA5) gene and the occurrence of obstetric complications. Thromb Haemost 102:309–313

    CAS  PubMed  Google Scholar 

  • Tranquilli AL, Giannubilo SR, Dell'Uomo B, Grandone E (2004) Adverse pregnancy outcomes are associated with multiple maternal thrombophilic factors. Eur J Obstet Gynecol Reprod Biol 117:144–147

    Article  PubMed  Google Scholar 

  • Tsai AW, Cushman M, Tsai MY (2001) Serum homocysteine, MTHFR C677T genotype and risk of venous thromboembolism: the LITE Study. Thromb Haemost 85(suppl):324a

    Google Scholar 

  • van der Put NML, Gabreels F, Stevens EMB, Smetink JA, Trijbels FJ, Eskes TK, van den Heuvel LP, Blom HJ (1998) A second common mutation in the methylentetrahydrofolate reductase gene: an additional risk factor for neural-tube defects? Am J Hum Genet 62:1044–1051

    Article  PubMed  Google Scholar 

  • van der Molen EF, Arends GE, Nelen WL, van der Put NJ, Heil SG, Eskes TK, Blom HJ (2000) A common mutation in the 5,10-methylenetetrahydrofolate reductase gene as a new risk factor for placental vasculopathy. Am J Obstet Gynecol 182:1258–1263

    Article  PubMed  Google Scholar 

  • Voorberg J, Roelse J, Koopman R, Büller H, Berends F, ten Cate JW, Mertens K, van Mourik JA (1994) Association of idiopathic venous thromboembolism with single point-mutation at Arg506 of factor V. Lancet 343:1535–1536

    Article  CAS  PubMed  Google Scholar 

  • Williamson D, Brown K, Luddington R, Baglin C, Baglin T, Factor V Cambridge (1998) A new mutation (Arg506→Thr) associated with resistance to activated protein C. Blood 91:1140

    CAS  PubMed  Google Scholar 

  • Wramsby ML, Sten-Linder M, Bremme K (2000) Primary habitual abortions are associated with high frequency of factor V Leiden mutation. Fertil Steril 74:987–991

    Article  CAS  PubMed  Google Scholar 

  • Younis JS, Brenner B, Ohel G, Tal J, Lanir N, Ben-Ami M (2000) Activated protein C resistance and factor V Leiden mutation can be associated with first- as well as second-trimester recurrent pregnancy loss. Am J Reprod Immunol 43:31–35

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

We are grateful to Michael Krawczak for valuable discussions and for proofreading the manuscript.

Author information

Authors and Affiliations

  1. Institute of Human Genetics, Westfalian-Wilhelms University of Muenster, Vesaliusweg 12-14, 48149, Münster, Germany

    Nadja Bogdanova

  2. Institute of Medical Biochemistry, ZMBE, Westfalian-Wilhelms University of Muenster, Von-Esmarch Str. 56, 48149, Münster, Germany

    Arseni Markoff

Authors
  1. Nadja Bogdanova
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Arseni Markoff
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Nadja Bogdanova.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Bogdanova, N., Markoff, A. Hereditary thrombophilic risk factors for recurrent pregnancy loss. J Community Genet 1, 47–53 (2010). https://doi.org/10.1007/s12687-010-0011-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12687-010-0011-3

Keywords

Search

Navigation