Factor V Leiden in Women: A Thrombotic Risk Factor or an Evolutionary Advantage?

 

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ABSTRACT

Factor V Leiden is a common gain-of-function gene mutation resulting in a genetic predisposition to thromboembolic complications. Growing evidence in the literature indicates an interaction between factor V Leiden thrombophilia and acquired prothrombotic conditions such as contraceptive use or hormone replacement therapy, resulting in an increased risk of venous thromboembolism (VTE). Similarly, when combined with the prothrombotic influence of pregnancy, women who are carriers of factor V Leiden are faced with an increased risk of adverse pregnancy outcomes, including VTE, pre-eclampsia, fetal loss, placental abruption, and fetal growth restriction. The results of the most important meta-analyses on the relationship between inherited (factor V Leiden) and acquired thrombophilia in women are analyzed in this review, along with the possible evolutionary role of this mutation.

REFERENCES

• 1 Dahlbäck B. Advances in understanding pathogenic mechanisms of thrombophilic disorders.  Blood. 2008;  112 (1) 19-27
  CrossrefPubMedGoogle Scholar
• 2 Nicolaes G AF, Dahlbäck B. Factor V and thrombotic disease: description of a janus-faced protein.  Arterioscler Thromb Vasc Biol. 2002;  22 (4) 530-538
  CrossrefPubMedGoogle Scholar
• 3 Franchini M, Veneri D, Salvagno G L, Manzato F, Lippi G. Inherited thrombophilia.  Crit Rev Clin Lab Sci. 2006;  43 (3) 249-290
  CrossrefPubMedGoogle Scholar
• 4 Segers K, Dahlbäck B, Nicolaes G AF. Coagulation factor V and thrombophilia: background and mechanisms.  Thromb Haemost. 2007;  98 (3) 530-542
  PubMedGoogle Scholar
• 5 Bertina R M, Koeleman B P, Koster T et al.. Mutation in blood coagulation factor V associated with resistance to activated protein C.  Nature. 1994;  369 (6475) 64-67
  CrossrefPubMedGoogle Scholar
• 6 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
  CrossrefPubMedGoogle Scholar
• 7 Ridker P M, Miletich J P, Hennekens C H, Buring J E. Ethnic distribution of factor V Leiden in 4047 men and women. Implications for venous thromboembolism screening.  JAMA. 1997;  277 (16) 1305-1307
  CrossrefPubMedGoogle Scholar
• 8 Rees D C, Cox M, Clegg J B. World distribution of factor V Leiden.  Lancet. 1995;  346 (8983) 1133-1134
  CrossrefPubMedGoogle Scholar
• 9 Rees D C. The population genetics of factor V Leiden (Arg506Gln).  Br J Haematol. 1996;  95 (4) 579-586
  CrossrefPubMedGoogle Scholar
• 10 Zivelin A, Griffin J H, Xu X et al.. A single genetic origin for a common Caucasian risk factor for venous thrombosis.  Blood. 1997;  89 (2) 397-402
  PubMedGoogle Scholar
• 11 Lindqvist P G, Dahlbäck B. Carriership of Factor V Leiden and evolutionary selection advantage.  Curr Med Chem. 2008;  15 (15) 1541-1544
  CrossrefPubMedGoogle Scholar
• 12 Franchini M, Mannucci P M. The hemostatic balance revisited through the lessons of mankind evolution.  Intern Emerg Med. 2008;  3 (1) 3-8
  PubMedGoogle Scholar
• 13 Franchini M, Mannucci P M. Multiple gene interaction and modulation of hemostatic balance.  Clin Chem Lab Med. 2009;  47 (12) 1455-1460
  CrossrefPubMedGoogle Scholar
• 14 Pabinger I. Thrombophilia and its impact on pregnancy.  Thromb Res. 2009;  123 (Suppl 3) S16-S21
  PubMedGoogle Scholar
• 15 Pabinger I, Vormittag R. Thrombophilia and pregnancy outcomes.  J Thromb Haemost. 2005;  3 (8) 1603-1610
  CrossrefPubMedGoogle Scholar
• 16 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
  CrossrefPubMedGoogle Scholar
• 17 Morrison E R, Miedzybrodzka Z H, Campbell D M et al.. Prothrombotic genotypes are not associated with pre-eclampsia and gestational hypertension: results from a large population-based study and systematic review.  Thromb Haemost. 2002;  87 (5) 779-785
  PubMedGoogle Scholar
• 18 Rey E, Kahn S R, David M, Shrier I. Thrombophilic disorders and fetal loss: a meta-analysis.  Lancet. 2003;  361 (9361) 901-908
  CrossrefPubMedGoogle Scholar
• 19 Kosmas I P, Tatsioni A, Ioannidis J P. Association of Leiden mutation in factor V gene with hypertension in pregnancy and pre-eclampsia: a meta-analysis.  J Hypertens. 2003;  21 (7) 1221-1228
  CrossrefPubMedGoogle Scholar
• 20 Kovalevsky G, Gracia C R, Berlin J A, Sammel M D, Barnhart K T. Evaluation of the association between hereditary thrombophilias and recurrent pregnancy loss: a meta-analysis.  Arch Intern Med. 2004;  164 (5) 558-563
  CrossrefPubMedGoogle Scholar
• 21 Dudding T E, Attia J. The association between adverse pregnancy outcomes and maternal factor V Leiden genotype: a meta-analysis.  Thromb Haemost. 2004;  91 (4) 700-711
  PubMedGoogle Scholar
• 22 Lin J, August P. Genetic thrombophilias and preeclampsia: a meta-analysis.  Obstet Gynecol. 2005;  105 (1) 182-192
  CrossrefPubMedGoogle Scholar
• 23 Wu O, Robertson L, Langhorne P et al.. Oral contraceptives, hormone replacement therapy, thrombophilias and risk of venous thromboembolism: a systematic review. The Thrombosis: Risk and Economic Assessment of Thrombophilia Screening (TREATS) Study.  Thromb Haemost. 2005;  94 (1) 17-25
  PubMedGoogle Scholar
• 24 Robertson L, Wu O, Langhorne P Thrombosis: Risk and Economic Assessment of Thrombophilia Screening (TREATS) Study et al. Thrombophilia in pregnancy: a systematic review.  Br J Haematol. 2006;  132 (2) 171-196
  CrossrefPubMedGoogle Scholar
• 25 Biron-Andreani C, Schved J F, Daures J P. Factor V Leiden mutation and pregnancy-related venous thromboembolism: what is the exact risk? Results from a meta-analysis.  Thromb Haemost. 2006;  96 (1) 14-18
  PubMedGoogle Scholar
• 26 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
  PubMedGoogle Scholar
• 27 Kist W J, Janssen N G, Kalk J J, Hague W M, Dekker G A, de Vries J I. Thrombophilias and adverse pregnancy outcome—a confounded problem!.  Thromb Haemost. 2008;  99 (1) 77-85
  PubMedGoogle Scholar
• 28 Wu O, Robertson L, Twaddle S et al.. Screening for thrombophilia in high-risk situations: systematic review and cost-effectiveness analysis. The Thrombosis: Risk and Economic Assessment of Thrombophilia Screening (TREATS) study.  Health Technol Assess. 2006;  10 (11) 1-110
  PubMedGoogle Scholar
• 29 Martinelli I, Battaglioli T, Pedotti P, Cattaneo M, Mannucci P M. Hyperhomocysteinemia in cerebral vein thrombosis.  Blood. 2003;  102 (4) 1363-1366
  CrossrefPubMedGoogle Scholar
• 30 Gerhardt A, Scharf R E, Beckmann M W 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
  CrossrefPubMedGoogle Scholar
• 31 Bloomenthal D, von Dadelszen P, Liston R, Magee L, Tsang P. The effect of factor V Leiden carriage on maternal and fetal health.  CMAJ. 2002;  167 (1) 48-54
  PubMedGoogle Scholar
• 32 Bates S M, Greer I A, Pabinger I, Sofaer S, Hirsh J. American College of Chest Physicians . Venous thromboembolism, thrombophilia, antithrombotic therapy, and pregnancy: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition).  Chest. 2008;  133 (6, Suppl) 844S-886S
  CrossrefPubMedGoogle Scholar
• 33 Kutteh W H, Triplett D A. Thrombophilias and recurrent pregnancy loss.  Semin Reprod Med. 2006;  24 (1) 54-66
  Article in Thieme ConnectPubMedGoogle Scholar
• 34 Lindqvist P G, Svensson P J, Dahlbäck B, Marsál K. Factor V Q506 mutation (activated protein C resistance) associated with reduced intrapartum blood loss—a possible evolutionary selection mechanism.  Thromb Haemost. 1998;  79 (1) 69-73
  PubMedGoogle Scholar
• 35 Lindqvist P G, Zöller B, Dahlbäck B. Improved hemoglobin status and reduced menstrual blood loss among female carriers of factor V Leiden—an evolutionary advantage?.  Thromb Haemost. 2001;  86 (4) 1122-1123
  PubMedGoogle Scholar
• 36 Isma N, Breslin T, Lindblad B, Svensson P J. The Factor V Leiden mutation is associated with a higher blood haemoglobin concentration in women below 50 of the Malmö Thrombophilia Study (MATS).  J Thromb Thrombolysis. 2009;  28 (3) 255-258
  CrossrefPubMedGoogle Scholar
• 37 Clark P, Walker I D, Govan L, Wu O, Greer I A. The GOAL study: a prospective examination of the impact of factor V Leiden and ABO(H) blood groups on haemorrhagic and thrombotic pregnancy outcomes.  Br J Haematol. 2008;  140 (2) 236-240
  PubMedGoogle Scholar
• 38 Göpel W, Ludwig M, Junge A K, Kohlmann T, Diedrich K, Möller J. Selection pressure for the factor-V-Leiden mutation and embryo implantation.  Lancet. 2001;  358 (9289) 1238-1239
  CrossrefPubMedGoogle Scholar

Massimo FranchiniM.D. 

Immunohematology and Transfusion Center, Department of Pathology and Laboratory Medicine

University Hospital of Parma, Parma, Italy

Email: mfranchini@ao.pr.it