Evolution of Factor V Leiden
11 February 2013
Accepted after major revision: 13 April 2013
30 November 2017 (online)
Factor V Leiden is a procoagulant mutation associated with venous and arterial thrombosis and pregnancy complications. Its high prevalence of 5% in Caucasians suggests that there are evolutionary benefits as well. Carriers are indeed reported to have various advantageous phenotypes related to haemostasis, inflammation and fertility: less acute blood loss; less menstrual blood loss; decreased risk of intracranial haemorrhage; milder phenotypes of haemophilia; higher survival in and lower susceptibility to severe sepsis; higher survival in acute respiratory distress syndrome; less severe diabetic nephropathy and higher fecundity in both men and women. Not all these associations come from high quality adequately powered studies and many have not been confirmed by further research. The evolutionary influence of the alleged associations varies and is difficult to establish, partly due to a shift over time in risk factors of the diseases concerned. For most of the phenotypes possible mechanistic explanations can be provided. The procoagulant phenotype and perhaps also certain pregnancy complications follow from activated protein C (APC) resistance. Elevated APC levels possibly mediate anti-inflammatory effects. Higher sperm counts and more successful embryo implantation seem to play a role in the increased fecundity.
- 1 Emmerich J, Rosendaal FR, Cattaneo M. et al. Combined effect of factor V Leiden and prothrombin 20210A on the risk of venous thromboembolism--pooled analysis of 8 case-control studies including 2310 cases and 3204 controls. Study Group for Pooled-Analysis in Venous Thromboembolism. Thromb Haemost 2001; 86: 809-816.
- 2 Middeldorp S. Thrombophilia and pregnancy complications: cause or association?. J Thromb Haemost 2007; 05 (Suppl. 01) 276-282.
- 3 Robertson L, Wu O, Langhorne P. et al. Thrombophilia in pregnancy: a systematic review. Br J Haematol 2006; 132: 171-196.
- 4 Boekholdt SM, Bijsterveld NR, Moons AH. et al. Genetic variation in coagulation and fibrinolytic proteins and their relation with acute myocardial infarction: a systematic review. Circulation 2001; 104: 3063-3068.
- 5 Ye Z, Liu EH, Higgins JP. et al. Seven haemostatic gene polymorphisms in coronary disease: meta-analysis of 66,155 cases and 91,307 controls. Lancet 2006; 367: 651-658.
- 6 Rees DC, Cox M, Clegg JB. World distribution of factor V Leiden. Lancet 1995; 346: 1133-1134.
- 7 Stern C. The Hardy-Weinberg law. Science 1943; 97: 137-138.
- 8 Hille ET, Westendorp RG, Vandenbroucke JP. et al. Mortality and causes of death in families with the factor V Leiden mutation (resistance to activated protein C). Blood 1997; 89: 1963-1967.
- 9 Heijmans BT, Westendorp RG, Knook DL. et al. The risk of mortality and the factor V Leiden mutation in a population-based cohort. Thromb Haemost 1998; 80: 607-609.
- 10 Gopel W, Ludwig M, Junge AK. et al. Selection pressure for the factor-V-Leiden mutation and embryo implantation. Lancet 2001; 358: 1238-1239.
- 11 Cohn DM, Repping S, Buller HR. et al. Increased sperm count may account for high population frequency of factor V Leiden. J Thromb Haemost 2010; 08: 513-516.
- 12 Yan SB, Nelson DR. Effect of factor V Leiden polymorphism in severe sepsis and on treatment with recombinant human activated protein C. Crit Care Med 2004; 32: S239-S246.
- 13 Lindqvist PG, Svensson PJ, Dahlback B. et al. 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.
- 14 Lindqvist PG, Svensson PJ, Marsaal K. et al. Activated protein C resistance (FV:Q506) and pregnancy. Thromb Haemost 1999; 81: 532-537.
- 15 Donahue BS, Gailani D, Higgins MS. et al. Factor V Leiden protects against blood loss and transfusion after cardiac surgery. Circulation 2003; 107: 1003-1008.
- 16 Lindqvist PG, Zoller B, Dahlback B. Improved hemoglobin status and reduced menstrual blood loss among female carriers of factor V Leiden--an evolutionary advantage?. Thromb Haemost 2001; 86: 1122-1123.
- 17 Isma N, Breslin T, Lindblad B. et al. The Factor V Leiden mutation is associated with a higher blood haemoglobin concentration in women below 50 of the Malmo Thrombophilia Study (MATS). J Thromb Thrombolysis 2009; 28: 255-258.
- 18 Corral J, Iniesta JA, Gonzalez-Conejero R. et al. Polymorphisms of clotting factors modify the risk for primary intracranial hemorrhage. Blood 2001; 97: 2979-2982.
- 19 Franchini M, Mannucci PM. The hemostatic balance revisited through the lessons of mankind evolution. Intern Emerg Med 2008; 03: 3-8.
- 20 Kerlin BA, Yan SB, Isermann BH. et al. Survival advantage associated with heterozygous factor V Leiden mutation in patients with severe sepsis and in mouse endotoxemia. Blood 2003; 102: 3085-3092.
- 21 Adamzik M, Frey UH, Riemann K. et al. Factor V Leiden mutation is associated with improved 30-day survival in patients with acute respiratory distress syndrome. Crit Care Med 2008; 36: 1776-1779.
- 22 Wang H, Madhusudhan T, He T. et al. Low but sustained coagulation activation ameliorates glucose-induced podocyte apoptosis: protective effect of factor V Leiden in diabetic nephropathy. Blood 2011; 117: 5231-5242.
- 23 Gopel W, Ludwig M, Junge AK. et al. Selection pressure for the factor-V-Leiden mutation and embryo implantation. Lancet 2001; 358: 1238-1239.
- 24 van Dunne FM, de Craen AJ, Heijmans BT. et al. Gender-specific association of the factor V Leiden mutation with fertility and fecundity in a historic cohort. The Leiden 85-Plus Study. Human Reprod 2006; 21: 967-971.
- 25 van Mens TE, Kaandorp SP, Goddijn M. et al. Factor V Leiden and time to pregnancy; an evolutionary advantage?. J Thromb Haemost. 2011 09. Abstract O-TH-093.
- 26 Segers K, Dahlback B, Nicolaes GA. Coagulation factor V and thrombophilia: background and mechanisms. Thromb Haemost 2007; 98: 530-542.
- 27 Nicolaes GA, Dahlback B. Factor V and thrombotic disease: description of a janus-faced protein. Arterioscler Thromb Vasc Biol 2002; 22: 530-538.
- 28 Zivelin A, Griffin JH, Xu X. et al. A single genetic origin for a common Caucasian risk factor for venous thrombosis. Blood 1997; 89: 397-402.
- 29 Cox MJ, Rees DC, Martinson JJ. et al. Evidence for a single origin of factor V Leiden. Br J Haematol 1996; 92: 1022-1025.
- 30 Cavalli-Sforza LL, Piazza A, Menozzi P. et al. Reconstruction of human evolution: bringing together genetic, archaeological, and linguistic data. Proc Natl Acad Sci USA 1988; 85: 6002-6006.
- 31 Zoller B, Norlund L, Leksell H. et al. High prevalence of the FVR506Q mutation causing APC resistance in a region of southern Sweden with a high incidence of venous thrombosis. Thromb Res 1996; 83: 475-477.
- 32 Beauchamp NJ, Daly ME, Hampton KK. et al. High prevalence of a mutation in the factor V gene within the U.K. population: relationship to activated protein C resistance and familial thrombosis. Br J Haematol 1994; 88: 219-222.
- 33 de Maat MP, Kluft C, Jespersen J. et al. World distribution of factor V Leiden mutation. Lancet 1996; 347: 58.
- 34 Bertina RM, Koeleman BP, Koster T. et al. Mutation in blood coagulation factor V associated with resistance to activated protein C. Nature 1994; 369: 64-67.
- 35 Svensson PJ, Dahlback B. Resistance to activated protein C as a basis for venous thrombosis. N Engl J Med 1994; 330: 517-522.
- 36 Weih M, Junge-Hulsing J, Mehraein S. et al. Hereditary thrombophilia with ischemic stroke and sinus thrombosis. Diagnosis, therapy and meta-analysis. Nervenarzt 2000; 71: 936-945.
- 37 Dentali F, Galli M, Gianni M. et al. Inherited thrombophilic abnormalities and risk of portal vein thrombosis. a meta-analysis. Thromb Haemost 2008; 99: 675-682.
- 38 Rehak M, Rehak J, Muller M. et al. The prevalence of activated protein C (APC) resistance and factor V Leiden is significantly higher in patients with retinal vein occlusion without general risk factors. Case-control study and meta-analysis. Thromb Haemost 2008; 99: 925-929.
- 39 Manten B, Westendorp RG, Koster T. et al. Risk factor profiles in patients with different clinical manifestations of venous thromboembolism: a focus on the factor V Leiden mutation. Thromb Haemost 1996; 76: 510-513.
- 40 Martinelli I, Cattaneo M, Panzeri D. et al. Low prevalence of factor V:Q506 in 41 patients with isolated pulmonary embolism. Thromb Haemost 1997; 77: 440-443.
- 41 Vandenbroucke JP, Bertina RM, Holmes ZR. et al. Factor V Leiden and fatal pulmonary embolism. Thromb Haemost 1998; 79: 511-516.
- 42 Rosendaal FR. Venous thrombosis: a multicausal disease. Lancet 1999; 353: 1167-1173.
- 43 Vandenbroucke J P, Koster T, Briet E. et al. Increased risk of venous thrombosis in oral-contraceptive users who are carriers of factor V Leiden mutation. Lancet 1994; 344: 1453-1457.
- 44 Theodoropoulou A, Sfiridaki A, Oustamanolakis P. et al. Genetic risk factors in young patients with ischemic colitis. Clin Gastroenterol Hepatol 2008; 06: 907-911.
- 45 Higgins PD, Davis KJ, Laine L. Systematic review: the epidemiology of is-chaemic colitis. Aliment Pharmacol Ther 2004; 19: 729-738.
- 46 Hamedani AG, Cole JW, Cheng Y. et al. Factor V Leiden and Ischemic Stroke Risk: The Genetics of Early Onset Stroke (GEOS) Study. J Stroke Cerebrovasc Dis. 2011 Epub ahead of print.
- 47 Kim RJ, Becker RC. Association between factor V Leiden, prothrombin G20210A, and methylenetetrahydrofolate reductase C677T mutations and events of the arterial circulatory system: a meta-analysis of published studies. Am Heart J 2003; 146: 948-957.
- 48 Seehaus S, Shahzad K, Kashif M. et al. Hypercoagulability inhibits monocyte transendothelial migration through protease-activated receptor-1-, phospholi-pase-Cbeta-, phosphoinositide 3-kinase-, and nitric oxide-dependent signaling in monocytes and promotes plaque stability. Circulation 2009; 120: 774-784.
- 49 Lawson SE, Butler D, Enayat MS. et al. Congenital thrombophilia and thrombosis: a study in a single centre. Arch Dis Child 1999; 81: 176-178.
- 50 Nowak-Gottl U, Strater R, Heinecke A. et al. Lipoprotein (a) and genetic polymorphisms of clotting factor V, prothrombin, and methylenetetrahydrofolate re-ductase are risk factors of spontaneous ischemic stroke in childhood. Blood 1999; 94: 3678-3682.
- 51 Debus O, Koch HG, Kurlemann G. et al. Factor V Leiden and genetic defects of thrombophilia in childhood porencephaly. Arch Dis Child Fetal Neonatal Ed 1998; 78: F121-F124.
- 52 Kenet G, Ezra E, Wientroub S. et al. Perthes’ disease and the search for genetic associations: collagen mutations, Gaucher’s disease and thrombophilia. J Bone Joint Surg Br 2008; 90: 1507-1511.
- 53 Clark P, Walker ID, Govan L. et al. 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: 236-240.
- 54 Hogberg U, Brostrom G. The demography of maternal mortality--seven Swedish parishes in the 19th century. Int J Gynaecol Obstet 1985; 23: 489-497.
- 55 Khan KS, Wojdyla D, Say L. et al. WHO analysis of causes of maternal death: a systematic review. Lancet 2006; 367: 1066-1074.
- 56 Gopel W, Gortner L, Kohlmann T. et al. Low prevalence of large intraventricular haemorrhage in very low birthweight infants carrying the factor V Leiden or prothrombin G20210A mutation. Acta Paediatr 2001; 90: 1021-1024.
- 57 Petaja J, Hiltunen L, Fellman V. Increased risk of intraventricular hemorrhage in preterm infants with thrombophilia. Pediatr Res 2001; 49: 643-646.
- 58 Hartel C, Konig I, Koster S. et al. Genetic polymorphisms of hemostasis genes and primary outcome of very low birth weight infants. Pediatrics 2006; 118: 683-689.
- 59 Hagstrom JN. Factor V Leiden and intracranial hemorrhage. Blood 2001; 98: 2875.
- 60 Fijnvandraat K, Derkx B, Peters M. et al. Coagulation activation and tissue necrosis in meningococcal septic shock: severely reduced protein C levels predict a high mortality. Thromb Haemost 1995; 73: 15-20.
- 61 Brandtzaeg P, Sandset PM, Joo GB. et al. The quantitative association of plasma endotoxin, antithrombin, protein C, extrinsic pathway inhibitor and fibrinopep-tide A in systemic meningococcal disease. Thromb Res 1989; 55: 459-470.
- 62 Leclerc F, Hazelzet J, Jude B. et al. Protein C and S deficiency in severe infectious purpura of children: a collaborative study of 40 cases. Intensive Care Med 1992; 18: 202-205.
- 63 Levi M, Dorffler-Melly J, Reitsma P. et al. Aggravation of endotoxin-induced disseminated intravascular coagulation and cytokine activation in heterozygous protein-C-deficient mice. Blood 2003; 101: 4823-4827.
- 64 Garcia de FP, Alim RI, Hardig Y. et al. Differential regulation of alpha and beta chains of C4b-binding protein during acute-phase response resulting in stable plasma levels of free anticoagulant protein S. Blood 1994; 84: 815-822.
- 65 Taylor F, Chang A, Ferrell G. et al. C4b-binding protein exacerbates the host response to Escherichia coli. Blood 1991; 78: 357-363.
- 66 Taylor Jr. FB, Dahlback B, Chang AC. et al. Role of free protein S and C4b binding protein in regulating the coagulant response to Escherichia coli. Blood 1995; 86: 2642-2652.
- 67 Bernard GR, Vincent JL, Laterre P F. et al. Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med 2001; 344: 699-709.
- 68 Bruggemann LW, Schoenmakers SH, Groot AP. et al. Role of the factor V Leiden mutation in septic peritonitis assessed in factor V Leiden transgenic mice. Crit Care Med 2006; 34: 2201-2206.
- 69 Schouten M, van der Sluijs KF, Roelofs JJ. et al. Factor V Leiden mutation does not affect coagulopathy or outcome in lethal H1N1 influenza. Eur Respir J 2010; 36: 1346-1354.
- 70 Schouten M, van’t Veer C, Roelofs JJ. et al. Impact of the factor V Leiden mutation on the outcome of pneumococcal pneumonia: a controlled laboratory study. Crit Care 2010; 14: R145.
- 71 Sun H, Wang X, Degen JL. et al. Reduced thrombin generation increases host susceptibility to group A streptococcal infection. Blood 2009; 113: 1358-1364.
- 72 Yan SB, Nelson DR. Effect of factor V Leiden polymorphism in severe sepsis and on treatment with recombinant human activated protein C. Crit Care Med 2004; 32: S239-S246.
- 73 Sipahi T, Pocan H, Akar N. Effect of various genetic polymorphisms on the incidence and outcome of severe sepsis. Clin Appl Thromb Hemost 2006; 12: 47-54.
- 74 Tsantes A, Tsangaris I, Nikolopoulos G. et al. The effect of homocysteine on the clinical outcomes of ventilated patients with severe sepsis. Minerva Anestesiol 2010; 76: 787-794.
- 75 Benfield TL, Dahl M, Nordestgaard BG. et al. Influence of the factor V Leiden mutation on infectious disease susceptibility and outcome: a population-based study. J Infect Dis 2005; 192: 1851-1857.
- 76 Benfield T, Ejrnaes K, Juul K. et al. Influence of Factor V Leiden on susceptibility to and outcome from critical illness: a genetic association study. Crit Care 2010; 14: R28.
- 77 Kondaveeti S, Hibberd ML, Booy R. et al. Effect of the Factor V Leiden mutation on the severity of meningococcal disease. Pediatr Infect Dis J 1999; 18: 893-896.
- 78 Strandberg K, Stenflo J, Nilsson C. et al. APC-PCI complex concentration is higher in patients with previous venous thromboembolism with Factor V Leiden. J Thromb Haemost 2005; 03: 2578-2580.
- 79 Petaja J, Hakala L, Rasi V. et al. Circulating activated protein C in subjects with heterozygous Gln506-factor V. Haemostasis 1998; 28: 31-36.
- 80 Levi M, van der Poll T, Buller HR. Bidirectional relation between inflammation and coagulation. Circulation 2004; 109: 2698-2704.
- 81 Griffin JH, Zlokovic BV, Mosnier LO. Protein C anticoagulant and cytoprotec-tive pathways. Int J Hematol 2012; 95: 333-345.
- 82 Kerlin BA, Yan SB, Isermann BH. et al. Survival advantage associated with heterozygous factor V Leiden mutation in patients with severe sepsis and in mouse endotoxemia. Blood 2003; 102: 3085-3092.
- 83 Taylor Jr. FB, Chang A, Esmon CT. et al. Protein C prevents the coagulopathic and lethal effects of Escherichia coli infusion in the baboon. J Clin Invest 1987; 79: 918-925.
- 84 Brunkhorst F, Sakr Y, Hagel S. et al. Protein C concentrations correlate with organ dysfunction and predict outcome independent of the presence of sepsis. Anesthesiology 2007; 107: 15-23.
- 85 Yan SB, Helterbrand JD, Hartman DL. et al. Low levels of protein C are associated with poor outcome in severe sepsis. Chest 2001; 120: 915-922.
- 86 Shorr AF, Bernard GR, Dhainaut JF. et al. Protein C concentrations in severe sepsis: an early directional change in plasma levels predicts outcome. Crit Care 2006; 10: R92.
- 87 Marti-Carvajal AJ, Sola I, Lathyris D. et al. Human recombinant activated protein C for severe sepsis. Cochrane Database Syst Rev 2012; 03: CD004388.
- 88 Ranieri VM, Thompson BT, Barie PS. et al. Drotrecogin alfa (activated) in adults with septic shock. N Engl J Med 2012; 366: 2055-2064.
- 89 Schouten M, van’t Veer C, van der Poll T. et al. Effect of the factor V Leiden mutation on the incidence and outcome of severe infection and sepsis. Neth J Med 2012; 70: 309-310.
- 90 De Groot CJ, Bloemenkamp KW, Duvekot EJ. et al. Preeclampsia and genetic risk factors for thrombosis: a case-control study. Am J Obstet Gynecol 1999; 181: 975-980.
- 91 Rudick B, Su HI, Sammel MD. et al. Is factor V Leiden mutation a cause of in vitro fertilization failure?. Fertil Steril 2009; 92: 1256-1259.
- 92 Lussana F, de Rooij SR, Veenendaal M. et al. Prevalence of factor V Leiden and G20210A prothrombin mutation in the Dutch Famine Birth Cohort: a possible survival advantage?. Thromb Haemost 2012; 108: 399-401.