Download PDF
Am J Perinatol 2002; 19(1): 037-048
DOI: 10.1055/s-2002-20172
ORIGINAL ARTICLE

Copyright © 2002 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel.: +1(212) 584-4662

Obstetric Implications of The Factor V Leiden Mutation: A Review

Dena Bloomenthal1 , Marie-France Delisle1 , Francine Tessier1 , Peter Tsang2
  • 1Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynaecology, University of British Columbia, Children's and Women's Health Centre of British Columbia, Vancouver, BC, Canada
  • 2Children's and Women's Health Centre of British Columbia, Clinical Instructor, Division of Hematology, Department of Medicine, University of British Columbia, and Ambulatory Care Clinic, Vancouver, BC, Canada
Further Information

Publication History

Publication Date:
18 February 2002 (online)

    Permissions and Reprints

ABSTRACT

Factor V Leiden (FVL) is a newly discovered genetic mutation that impairs one of the body's naturally occurring anticoagulation systems. The result is resistance to activated protein C and a predisposition to thrombosis. FVL is the most common cause of primary and recurrent venous thromboembolism in the pregnant and nonpregnant state. The FVL gene is common in the general population and transmitted in an autosomal dominant fashion. When FVL is combined with the prothrombotic state of pregnancy, the result is an increased propensity to manifest a number of pregnancy complications. These include recurrent pregnancy loss and stillbirth, severe and early-onset preeclampsia, placental abruption and possibly, intrauterine growth restriction. It remains unknown whether thromboprophylaxis is effective in ameliorating these pregnancy complications. The current literature and management recommendations are highlighted in this article.

KEYWORD

Factor V Leiden - thrombophilia - pregnancy complications

REFERENCES

  • 1 Dahlback B, Carlsson M, Svensson P J. Familial thrombophilia due to a previously unrecognized mechanism characterized by poor anticoagulant response to activated protein C.  Proc Natl Acad Sci U S A . 1993;  90 1004-1008
    PubMedGoogle Scholar
  • 2 Zoller B, Svensson P J, He X, Dahlback B. Identification of the same factor V gene mutation in 47 out of 50 thrombosis-prone families with inherited resistance to activated protein C.  J Clin Invest . 1994;  94 2521-2524
    PubMedGoogle Scholar
  • 3 Bertina M R, Koeleman B P, Koster T. Mutation in blood coagulation factor V associated with resistance to activated protein C.  Nature . 1994;  369 64-67
    CrossrefPubMedGoogle Scholar
  • 4 Dahlback B, Stenflo J. The protein C anticoagulant system. In: Stamatoyannopoulos G, Niehuis AW, Majeurs PW, Varmus H, eds. The Molecular Basis of Blood Diseases Philadelphia: Saunders 1994: 599-624
    Google Scholar
  • 5 Girling J, deSwiet M. Inherited thrombophilia and pregnancy.  Curr Opin Obstet Gynecol . 1998;  10 135-144
    CrossrefPubMedGoogle Scholar
  • 6 Miles A M, Monga M. Factor V Leiden mutation: the most commonly inherited risk factor for venous thrombosis.  Prim Care Update Ob/Gyn . 1999;  6 141-146
    PubMedGoogle Scholar
  • 7 Cavenagh J D, Colvin B T. Guidelines for the management of thrombophilia.  Postgrad Med J . 1996;  72 87-94
    PubMedGoogle Scholar
  • 8 Gherman R B, Goodwin T M. Obstetric implications of activated protein C resistance and factor V Leiden mutation.  Obstet Gynecol Surv . 2000;  55 117-122
    CrossrefPubMedGoogle Scholar
  • 9 Dahlback B. Inherited resistance to activated protein C, a major cause of venous thrombosis, is due to a mutation in the factor V gene.  Haemostasis . 1994;  24 139-151
    PubMedGoogle Scholar
  • 10 Walker M C, Garner P R, Erin J K, Gail A R, Marchiano D R. Changes in activated protein C resistance in normal pregnancy.  Am J Obstet Gynecol . 1997;  177 162-169
    CrossrefPubMedGoogle Scholar
  • 11 Lockwood C J. Heritable coagulopathies in pregnancy.  Obstet Gynecol Surv . 1999;  54 754-765
    CrossrefPubMedGoogle Scholar
  • 12 Dahlback B. Resistance to activated protein C, the Arg 506 to Gln mutation in the factor V gene, and venous thrombosis.  Thromb Haemosost . 1995;  73 739-742
    PubMedGoogle Scholar
  • 13 Kupferminc M J, Eldor A, Steinman N. Increased frequency of genetic thrombophilia in women with complications of pregnancy.  N Engl J Med . 1999;  340 9-13
    CrossrefPubMedGoogle Scholar
  • 14 Ridker P M, Miletich J P, Hennekens C J, Buring J E. Ethnic distribution of factor V Leiden in 4,047 men and women.  JAMA . 1997;  277 1305-1307
    CrossrefPubMedGoogle Scholar
  • 15 Dizon-Townson D, Nelson L M, Jang H, Varner M W, Ward K. The incidence of the factor V Leiden mutation in an obstetric population and its relationship to deep vein thrombosis.  Am J Obstet Gynecol . 1997;  176 883-886
    PubMedGoogle Scholar
  • 16 Miletich J, Sherman L, Broze Jr G. Absence of thrombosis in subjects with heterozygous protein C deficiency.  N Engl J Med . 1987;  317 991-996
    CrossrefPubMedGoogle Scholar
  • 17 Hallak M, Senderowicz J, Cassel A. Activated protein C resistance (factor V Leiden) associated with thrombosis in pregnancy.  Am J Obstet Gynecol . 1997;  176 889-893
    PubMedGoogle Scholar
  • 18 Grandone E, Margaglione M, Colaizzo D. Genetic susceptibility to pregnancy-related venous thromboembolism: roles of factor V Leiden, prothrombin G20219A and methylenetetrahydrofolate reductase C677T mutations.  Am J Obstet Gynecol . 1998;  179 1324-1328
    CrossrefPubMedGoogle Scholar
  • 19 Bonnar J, Green R, Norris L. Perinatal aspects of inherited thrombophilia.  Semin Thromb Hemost . 1999;  25 481-485
    PubMedGoogle Scholar
  • 20 Lindqvist P. Thrombotic risk during pregnancy: a population study.  Obstet Gynecol . 1999;  94 595-599
    CrossrefPubMedGoogle Scholar
  • 21 Gerhardt A, Scharf R E, Beckmann M W. Prothrombin and factor V mutations in women with a history of thrombosis during pregnancy and the puerperium.  N Engl J Med . 2000;  342 374-380
    CrossrefPubMedGoogle Scholar
  • 22 Sachs B P, Brown D AJ, Driscoll S G. Maternal mortality in Massachusetts: trends and prevention.  New Engl J Med . 1987;  316 667-672
    PubMedGoogle Scholar
  • 23 Hellgren M, Svensson P J, 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
    CrossrefPubMedGoogle Scholar
  • 24 Svensson P J, Dahlback B. Resistance to activated protein C as a basis for venous thrombosis.  N Engl J Med . 1994;  330 517-522
    CrossrefPubMedGoogle Scholar
  • 25 Griffin J H, Evatt B, Widerman C, Fernandez J A. Anticoagulant protein C pathway defective in majority of thrombophilic patients.  Blood . 1993;  82 1989-1993
    PubMedGoogle Scholar
  • 26 Koster T, Rosendaal F R, de Ronde H, Briet E, Vandenbroucke J P, Bertina R. Venous thrombosis due to poor anticoagulant response to activated protein C: Leiden thrombophilia study.  Lancet . 1994;  342 1503-1506
    PubMedGoogle Scholar
  • 27 Bokarewa M I, Bremme K, Blomback M. Arg506-Gln mutation in factor V and risk of thrombosis during pregnancy.  Br J Haematol . 1996;  92 473-478
    CrossrefPubMedGoogle Scholar
  • 28 Koeleman B P, Reitsma P H, Allaart C F, Bertina R M. Activated protein C resistance as an additional risk factor for thrombosis in protein C-deficient families.  Blood . 1994;  84 1031-1035
    PubMedGoogle Scholar
  • 29 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
    PubMedGoogle Scholar
  • 30 Arias F, Romero R, Joist H, Kraus F T. Thrombophilia: a mechanism of disease in women with adverse pregnancy outcome and thrombotic lesions of the placenta.  J Matern Fetal Med . 1998;  7 277-286
    CrossrefPubMedGoogle Scholar
  • 31 Rai R S, Regan L, Hadley E. Second trimester pregnancy loss is associated with activated protein C resistance.  Br J Haematol . 1996;  92 489-490
    PubMedGoogle Scholar
  • 32 Brenner B, Mandel H, Lanir N. Activated protein C resistance can be associated with recurrent fetal loss.  Br J Haematol . 1997;  97 551-554
    CrossrefPubMedGoogle Scholar
  • 33 Grandone E, Margaglione M, Colaizzo S. Factor V Leiden is associated with repeated and recurrent unexplained fetal losses.  Thromb Haemost . 1997;  77 822-824
    PubMedGoogle Scholar
  • 34 Meinardi J R, Middeldorp S, de Kam J P. Increased risk for fetal loss in carriers of the factor V Leiden mutation.  Ann Intern Med . 1999;  130 736-739
    PubMedGoogle Scholar
  • 35 Nemes L, Pajor A, Cegled A. Comparison of the risk of fetal loss between homozygous and heterozygous patients with factor V Leiden mutation.  Thromb Haemost . 1999;  534(suppl) 534-536
    PubMedGoogle Scholar
  • 36 Preston F E, Rosendaal F R, Walker I D. Increased fetal loss in women with heritable thrombophilia.  Lancet . 1996;  348 913-916
    CrossrefPubMedGoogle Scholar
  • 37 Rai R S, Regan L, Chitolie A. Placental thrombosis and second trimester miscarriage associated with activated protein C resistance.  Br J Obstet Gynecol . 1996;  103 842-844
    PubMedGoogle Scholar
  • 38 Dizon-Towson D S, Meline L, Nelson L M. Fetal carriers of the factor V Leiden mutation are prone to miscarriage and placental infarction.  Am J Obstet Gynecol . 1997;  177 402-405
    CrossrefPubMedGoogle Scholar
  • 39 Weiner-Megnagi Z, Ben-Shlomo I, Goldberg Y, Shalev E. Resistance to activated protein C and the Leiden mutation: high prevalence with abruptio placentae.  Am J Obstet Gynecol . 1998;  179 1565-1567
    CrossrefPubMedGoogle Scholar
  • 40 Grisaru D, Fait G, Eldor A. Activated protein C resistance and pregnancy complications.  Am J Obstet Gynecol . 1996;  174 801-802
    PubMedGoogle Scholar
  • 41 Dizon-Townson D S, Nelson L M, Easton K, Ward K. The factor V Leiden mutation may predispose women to severe preeclampsia.  Am J Obstet Gynecol . 1996;  175 902-905
    CrossrefPubMedGoogle Scholar
  • 42 Lindoff C, Ingemarsson I, Martinsson G, Segelmark M, Thysell H, Astedt B. Preeclampsia is associated with a reduced response to activated protein C.  Am J Obstet Gynecol . 1997;  176 457-460
    PubMedGoogle Scholar
  • 43 Grandone E, Margaglione M, Colaizzo D. Factor V Leiden, C>T MTHFR polymorphism and genetic susceptibility to preeclampsia.  Thromb Haemost . 1997;  77 1052-1054
    PubMedGoogle Scholar
  • 44 Hastings S, Knowlton J, Nelson L. Obstetrical and medical complications in women with the factor V Leiden mutation.  Am J Obstet Gynecol . 1998;  178 S104
    PubMedGoogle Scholar
  • 45 van Pampus G M, Dekker G A, Wolf H. High prevalence of hemostatic abnormalities in women with a history of severe preeclampsia.  Am J Obstet Gynecol . 1999;  180 1146-1150
    CrossrefPubMedGoogle Scholar
  • 46 Rigo J, Nagy B, Fintor L. Maternal and neonatal outcome of preeclamptic pregnancies: the potential roles of Factor V Leiden mutation and 5,10 methylenetetradydrofolate reductase.  Hypert Preg . 2000;  19 163-172
    PubMedGoogle Scholar
  • 47 Dekker G A, de Vries I J, Doelitzsch P M. Underlying disorders associated with severe early-onset preeclampsia.  Am J Obstet Gynecol . 1995;  173 1042-1048
    CrossrefPubMedGoogle Scholar
  • 48 Krauss T, Augustin H G, Osmers R. Activated protein C resistance and Factor V Leiden in patients with hemolysis, elevated liver enzymes, low platelets syndrome.  Obstet Gynecol . 1998;  92 457-460
    CrossrefPubMedGoogle Scholar
  • 49 Erhardt E, Stankovics J, Molnar D, Adamovich K, Melegh G. High prevalence of Factor V Leiden mutation in mothers of premature neonates.  Biol Neonate . 2000;  78 145-146
    CrossrefPubMedGoogle Scholar
  • 50 Wisotzkey J D, Bayliss P, Rutherford E, Bell T. Placental genotyping of the factor V Leiden, Prothrombin 20210A and the methylenetetrahydrofolate reductase (MTHFR) C677T alleles in IUGR pregnancies.  Thromb Haemost . 1999;  81 844-845
    PubMedGoogle Scholar
  • 51 SOGC Clinical Practice Guidelines. Prevention and treatment of venous thromboembolism in obstetrics.  September, 2000; 
    PubMedGoogle Scholar
  • 52 Barbour L A. Current concepts of anticoagulant therapy in pregnancy.  Obstet Gynecol Clin . 1997;  24 499-521
    CrossrefPubMedGoogle Scholar
  • 53 Ginsberg J S, Hirsh J. Fifth ACCP Consensus Conference on Antithrombotic therapy.  Chest . 1998;  114 524-530
    PubMedGoogle Scholar
  • 54 Lensing A W, Prins M H, Davidson B L. Treatment of deep venous thrombosis with low molecular weight heparins: a meta-analysis.  Arch Intern Med . 1995;  155 601-607
    CrossrefPubMedGoogle Scholar
  • 55 ACOG Practice Bulletin. Thromboembolism in pregnancy. Number 19, August, 2000
  • 56 Rao A K, Kaplan R, Sheth S. Inherited thrombophilic states.  Semin Thromb Hemost . 1998;  24 (suppl 1) 3-12
    Article in Thieme ConnectPubMedGoogle Scholar
  • 57 Heilmann L, Schneider D M, von Tempelhoff G. Antithrombotic therapy in high-risk pregnancy.  Hematol Oncol Clin North Am . 2000;  13 1133-1150
    PubMedGoogle Scholar
  • 58 Brill-Edwards P, Ginsberg J S, Gent M. Safety of withholding heparin in pregnant women with a history of venous thromboembolism.  N Engl J Med . 2000;  343 1439-1444
    CrossrefPubMedGoogle Scholar
  • 59 Nelson-Piercy C, Letsky E A, de Swiet M. Low molecular weight heparin for obstetric thromboprophylaxis: experience of sixty-nine pregnancies in sixty-one women of high risk.  Am J Obstet Gynecol . 1997;  176 1062-1068
    CrossrefPubMedGoogle Scholar
  • 60 Sanson B J, Lensing A WA, Prins M H. Safety of low molecular weight heparin in pregnancy: a systematic review.  Thromb Haemost . 1999;  81 668-672
    PubMedGoogle Scholar
  • 61 Riyazi N. 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 49-54
    CrossrefPubMedGoogle Scholar
  • 62 Preston F E, Rosendaal F R, Walker I D. Thromboprophylaxis in pregnancy reduces fetal loss in women with heritable thrombophilia: a prospective EPCOT study.  Thromb Haemost . 1999;  227 (suppl 1) 227-231
    PubMedGoogle Scholar
  • 63 Hoffmann R, Younis J, Blumenfeld Z. Enoxoparin is effective in prevention of pregnancy loss in women with thrombophilia.  Thromb Haemost . 1999;  531(suppl) 531-534
    PubMedGoogle Scholar
  • 64 De Stefano V, Mastrangelo S, Paciaroni K. Thrombotic risk during pregnancy and puerperium in women with APC resistance: effective subcutaneous heparin prophylaxis in pregnant patients.  Thromb Haemost . 1995;  74 793-794
    PubMedGoogle Scholar
      >