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Factor V Leiden and activated protein C resistance

Author
Kenneth A Bauer, MD
Section Editor
Lawrence LK Leung, MD
Deputy Editor
Jennifer S Tirnauer, MD

INTRODUCTION

Factor V Leiden (FVL) is a mutant form of coagulation factor V. The FVL mutation renders factor V (both the activated and inactive forms) insensitive to the actions of activated protein C (aPC), a natural anticoagulant. As a result, individuals who inherit the FVL mutation are at increased risk of venous thromboembolism (VTE). However, FVL is extremely common in the population, and many individuals with the mutation will never have a VTE. For these reasons, VTE risk reduction (both primary prevention and prevention of recurrence) may involve some challenging decisions.

This topic review discusses the diagnosis of FVL and the management of individuals who carry this mutation.

Separate topic reviews discuss other thrombophilias and the role of thrombophilia screening in various populations:

Other thrombophilias:

Prothrombin G20210A mutation – (See "Prothrombin G20210A mutation".)

                              

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Literature review current through: Nov 2016. | This topic last updated: Tue Aug 09 00:00:00 GMT+00:00 2016.
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References
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  1. Thorelli E, Kaufman RJ, Dahlbäck B. Cleavage of factor V at Arg 506 by activated protein C and the expression of anticoagulant activity of factor V. Blood 1999; 93:2552.
  2. Castoldi E, Brugge JM, Nicolaes GA, et al. Impaired APC cofactor activity of factor V plays a major role in the APC resistance associated with the factor V Leiden (R506Q) and R2 (H1299R) mutations. Blood 2004; 103:4173.
  3. Cramer TJ, Gale AJ. The anticoagulant function of coagulation factor V. Thromb Haemost 2012; 107:15.
  4. Dahlback B. Anticoagulant factor V and thrombosis risk (editorial). Blood 2004; 103:3995.
  5. Simioni P, Castoldi E, Lunghi B, et al. An underestimated combination of opposites resulting in enhanced thrombotic tendency. Blood 2005; 106:2363.
  6. Reitsma PH, Bernardi F, Doig RG, et al. Protein C deficiency: a database of mutations, 1995 update. On behalf of the Subcommittee on Plasma Coagulation Inhibitors of the Scientific and Standardization Committee of the ISTH. Thromb Haemost 1995; 73:876.
  7. Simioni P, Scudeller A, Radossi P, et al. "Pseudo homozygous" activated protein C resistance due to double heterozygous factor V defects (factor V Leiden mutation and type I quantitative factor V defect) associated with thrombosis: report of two cases belonging to two unrelated kindreds. Thromb Haemost 1996; 75:422.
  8. Zehnder JL, Jain M. Recurrent thrombosis due to compound heterozygosity for factor V Leiden and factor V deficiency. Blood Coagul Fibrinolysis 1996; 7:361.
  9. Guasch JF, Lensen RP, Bertina RM. Molecular characterization of a type I quantitative factor V deficiency in a thrombosis patient that is "pseudo homozygous" for activated protein C resistance. Thromb Haemost 1997; 77:252.
  10. Brugge JM, Simioni P, Bernardi F, et al. Expression of the normal factor V allele modulates the APC resistance phenotype in heterozygous carriers of the factor V Leiden mutation. J Thromb Haemost 2005; 3:2695.
  11. Duckers C, Simioni P, Tormene D, et al. Factor V Leiden pseudo-homozygotes have a more pronounced hypercoagulable state than factor V Leiden homozygotes. J Thromb Haemost 2011; 9:864.
  12. Williamson D, Brown K, Luddington R, et al. Factor V Cambridge: a new mutation (Arg306-->Thr) associated with resistance to activated protein C. Blood 1998; 91:1140.
  13. Nogami K, Shinozawa K, Ogiwara K, et al. Novel FV mutation (W1920R, FVNara) associated with serious deep vein thrombosis and more potent APC resistance relative to FVLeiden. Blood 2014; 123:2420.
  14. Steen M, Norstrøm EA, Tholander AL, et al. Functional characterization of factor V-Ile359Thr: a novel mutation associated with thrombosis. Blood 2004; 103:3381.
  15. Mumford AD, McVey JH, Morse CV, et al. Factor V I359T: a novel mutation associated with thrombosis and resistance to activated protein C. Br J Haematol 2003; 123:496.
  16. Pezeshkpoor B, Castoldi E, Mahler A, et al. Identification and functional characterization of a novel F5 mutation (Ala512Val, FVB onn ) associated with activated protein C resistance. J Thromb Haemost 2016; 14:1353.
  17. Bernardi F, Faioni EM, Castoldi E, et al. A factor V genetic component differing from factor V R506Q contributes to the activated protein C resistance phenotype. Blood 1997; 90:1552.
  18. Segers O, Simioni P, Tormene D, et al. Genetic modulation of the FV(Leiden)/normal FV ratio and risk of venous thrombosis in factor V Leiden heterozygotes. J Thromb Haemost 2012; 10:73.
  19. Alhenc-Gelas M, Nicaud V, Gandrille S, et al. The factor V gene A4070G mutation and the risk of venous thrombosis. Thromb Haemost 1999; 81:193.
  20. Margaglione M, Bossone A, Coalizzo D, et al. FV HR2 haplotype as additional inherited risk factor for deep vein thrombosis in individuals with a high-risk profile. Thromb Haemost 2002; 87:32.
  21. Luddington R, Jackson A, Pannerselvam S, et al. The factor V R2 allele: risk of venous thromboembolism, factor V levels and resistance to activated protein C. Thromb Haemost 2000; 83:204.
  22. Benson JM, Ellingsen D, El-Jamil M, et al. Factor V Leiden and factor V R2 allele: high-throughput analysis and association with venous thromboembolism. Thromb Haemost 2001; 86:1188.
  23. Faioni EM, Franchi F, Bucciarelli P, et al. Coinheritance of the HR2 haplotype in the factor V gene confers an increased risk of venous thromboembolism to carriers of factor V R506Q (factor V Leiden). Blood 1999; 94:3062.
  24. Folsom AR, Cushman M, Tsai MY, et al. A prospective study of venous thromboembolism in relation to factor V Leiden and related factors. Blood 2002; 99:2720.
  25. Tormene D, Fortuna S, Tognin G, et al. The incidence of venous thromboembolism in carriers of antithrombin, protein C or protein S deficiency associated with the HR2 haplotype of factor V: a family cohort study. J Thromb Haemost 2005; 3:1414.
  26. Liang R, Lee CK, Wat MS, et al. Clinical significance of Arg306 mutations of factor V gene. Blood 1998; 92:2599.
  27. Chan WP, Lee CK, Kwong YL, et al. A novel mutation of Arg306 of factor V gene in Hong Kong Chinese. Blood 1998; 91:1135.
  28. Zöller B, Berntsdotter A, García de Frutos P, Dahlbäck B. Resistance to activated protein C as an additional genetic risk factor in hereditary deficiency of protein S. Blood 1995; 85:3518.
  29. Procare-GEHT Group. ABO blood group but not haemostasis genetic polymorphisms significantly influence thrombotic risk: a study of 180 homozygotes for the Factor V Leiden mutation. Br J Haematol 2006; 135:697.
  30. Lensen R, Bertina RM, Vandenbroucke JP, Rosendaal FR. High factor VIII levels contribute to the thrombotic risk in families with factor V Leiden. Br J Haematol 2001; 114:380.
  31. Morange PE, Tregouet DA, Frere C, et al. Biological and genetic factors influencing plasma factor VIII levels in a healthy family population: results from the Stanislas cohort. Br J Haematol 2005; 128:91.
  32. Robert A, Aillaud MF, Eschwège V, et al. ABO blood group and risk of venous thrombosis in heterozygous carriers of factor V Leiden. Thromb Haemost 2000; 83:630.
  33. Morelli VM, De Visser MC, Vos HL, et al. ABO blood group genotypes and the risk of venous thrombosis: effect of factor V Leiden. J Thromb Haemost 2005; 3:183.
  34. Castoldi E, Rosing J. APC resistance: biological basis and acquired influences. J Thromb Haemost 2010; 8:445.
  35. Post MS, Rosing J, Van Der Mooren MJ, et al. Increased resistance to activated protein C after short-term oral hormone replacement therapy in healthy post-menopausal women. Br J Haematol 2002; 119:1017.
  36. Juul K, Tybjaerg-Hansen A, Schnohr P, Nordestgaard BG. Factor V Leiden and the risk for venous thromboembolism in the adult Danish population. Ann Intern Med 2004; 140:330.
  37. Christiansen SC, Lijfering WM, Naess IA, et al. The relationship between body mass index, activated protein C resistance and risk of venous thrombosis. J Thromb Haemost 2012; 10:1761.
  38. Kafkas S, Kalkan U, Bolaman Z, et al. Evaluation of smoking as a risk factor for activated protein C resistance during pregnancy. Gynecol Obstet Invest 2007; 64:89.
  39. Zöller B, Svensson PJ, He X, Dahlbäck 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.
  40. de Visser MC, Rosendaal FR, Bertina RM. A reduced sensitivity for activated protein C in the absence of factor V Leiden increases the risk of venous thrombosis. Blood 1999; 93:1271.
  41. Rees DC, Cox M, Clegg JB. World distribution of factor V Leiden. Lancet 1995; 346:1133.
  42. Lee DH, Henderson PA, Blajchman MA. Prevalence of factor V Leiden in a Canadian blood donor population. CMAJ 1996; 155:285.
  43. Ridker PM, Miletich JP, Hennekens CH, Buring JE. Ethnic distribution of factor V Leiden in 4047 men and women. Implications for venous thromboembolism screening. JAMA 1997; 277:1305.
  44. Awidi A, Shannak M, Bseiso A, et al. High prevalence of factor V Leiden in healthy Jordanian Arabs. Thromb Haemost 1999; 81:582.
  45. Irani-Hakime N, Tamim H, Kreidy R, Almawi WY. The prevalence of factor V R506Q mutation-Leiden among apparently healthy Lebanese. Am J Hematol 2000; 65:45.
  46. Taher A, Khalil I, Shamseddine A, et al. High prevalence of Factor V Leiden mutation among healthy individuals and patients with deep venous thrombosis in Lebanon: is the eastern Mediterranean region the area of origin of this mutation? Thromb Haemost 2001; 86:723.
  47. Ridker PM, Hennekens CH, Lindpaintner K, et al. Mutation in the gene coding for coagulation factor V and the risk of myocardial infarction, stroke, and venous thrombosis in apparently healthy men. N Engl J Med 1995; 332:912.
  48. Koster T, Rosendaal FR, de Ronde H, et al. Venous thrombosis due to poor anticoagulant response to activated protein C: Leiden Thrombophilia Study. Lancet 1993; 342:1503.
  49. Rosendaal FR, Koster T, Vandenbroucke JP, Reitsma PH. High risk of thrombosis in patients homozygous for factor V Leiden (activated protein C resistance). Blood 1995; 85:1504.
  50. 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.
  51. Preston FE, Rosendaal FR, Walker ID, et al. Increased fetal loss in women with heritable thrombophilia. Lancet 1996; 348:913.
  52. Tormene D, Simioni P, Prandoni P, et al. The risk of fetal loss in family members of probands with factor V Leiden mutation. Thromb Haemost 1999; 82:1237.
  53. Martinelli I, Taioli E, Cetin I, et al. Mutations in coagulation factors in women with unexplained late fetal loss. N Engl J Med 2000; 343:1015.
  54. 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.
  55. Hille ET, Westendorp RG, Vandenbroucke JP, Rosendaal FR. Mortality and causes of death in families with the factor V Leiden mutation (resistance to activated protein C). Blood 1997; 89:1963.
  56. Middeldorp S, Meinardi JR, Koopman MM, et al. A prospective study of asymptomatic carriers of the factor V Leiden mutation to determine the incidence of venous thromboembolism. Ann Intern Med 2001; 135:322.
  57. Svensson PJ, Dahlbäck B. Resistance to activated protein C as a basis for venous thrombosis. N Engl J Med 1994; 330:517.
  58. Price DT, Ridker PM. Factor V Leiden mutation and the risks for thromboembolic disease: a clinical perspective. Ann Intern Med 1997; 127:895.
  59. Simioni P, Prandoni P, Lensing AW, et al. The risk of recurrent venous thromboembolism in patients with an Arg506-->Gln mutation in the gene for factor V (factor V Leiden). N Engl J Med 1997; 336:399.
  60. Simone B, De Stefano V, Leoncini E, et al. Risk of venous thromboembolism associated with single and combined effects of Factor V Leiden, Prothrombin 20210A and Methylenetethraydrofolate reductase C677T: a meta-analysis involving over 11,000 cases and 21,000 controls. Eur J Epidemiol 2013; 28:621.
  61. Dentali F, Ageno W, Bozzato S, et al. Role of factor V Leiden or G20210A prothrombin mutation in patients with symptomatic pulmonary embolism and deep vein thrombosis: a meta-analysis of the literature. J Thromb Haemost 2012; 10:732.
  62. Bauer KA. The thrombophilias: well-defined risk factors with uncertain therapeutic implications. Ann Intern Med 2001; 135:367.
  63. Martinelli I, Mannucci PM, De Stefano V, et al. Different risks of thrombosis in four coagulation defects associated with inherited thrombophilia: a study of 150 families. Blood 1998; 92:2353.
  64. 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.
  65. Ho WK, Hankey GJ, Quinlan DJ, Eikelboom JW. Risk of recurrent venous thromboembolism in patients with common thrombophilia: a systematic review. Arch Intern Med 2006; 166:729.
  66. Segal JB, Brotman DJ, Necochea AJ, et al. Predictive value of factor V Leiden and prothrombin G20210A in adults with venous thromboembolism and in family members of those with a mutation: a systematic review. JAMA 2009; 301:2472.
  67. Ridker PM, Miletich JP, Stampfer MJ, et al. Factor V Leiden and risks of recurrent idiopathic venous thromboembolism. Circulation 1995; 92:2800.
  68. Eichinger S, Pabinger I, Stümpflen A, et al. The risk of recurrent venous thromboembolism in patients with and without factor V Leiden. Thromb Haemost 1997; 77:624.
  69. Keijzer MB, den Heijer M, Blom HJ, et al. Interaction between hyperhomocysteinemia, mutated methylenetetrahydrofolatereductase (MTHFR) and inherited thrombophilic factors in recurrent venous thrombosis. Thromb Haemost 2002; 88:723.
  70. Simioni P, Prandoni P, Lensing AW, et al. Risk for subsequent venous thromboembolic complications in carriers of the prothrombin or the factor V gene mutation with a first episode of deep-vein thrombosis. Blood 2000; 96:3329.
  71. De Stefano V, Martinelli I, Mannucci PM, et al. The risk of recurrent deep venous thrombosis among heterozygous carriers of both factor V Leiden and the G20210A prothrombin mutation. N Engl J Med 1999; 341:801.
  72. Lindmarker P, Schulman S, Sten-Linder M, et al. The risk of recurrent venous thromboembolism in carriers and non-carriers of the G1691A allele in the coagulation factor V gene and the G20210A allele in the prothrombin gene. DURAC Trial Study Group. Duration of Anticoagulation. Thromb Haemost 1999; 81:684.
  73. Kearon C, Gent M, Hirsh J, et al. A comparison of three months of anticoagulation with extended anticoagulation for a first episode of idiopathic venous thromboembolism. N Engl J Med 1999; 340:901.
  74. Margaglione M, D'Andrea G, Colaizzo D, et al. Coexistence of factor V Leiden and Factor II A20210 mutations and recurrent venous thromboembolism. Thromb Haemost 1999; 82:1583.
  75. Eichinger S, Weltermann A, Mannhalter C, et al. The risk of recurrent venous thromboembolism in heterozygous carriers of factor V Leiden and a first spontaneous venous thromboembolism. Arch Intern Med 2002; 162:2357.
  76. Marchiori A, Mosena L, Prins MH, Prandoni P. The risk of recurrent venous thromboembolism among heterozygous carriers of factor V Leiden or prothrombin G20210A mutation. A systematic review of prospective studies. Haematologica 2007; 92:1107.
  77. Baglin C, Brown K, Luddington R, Baglin T. Risk of recurrent venous thromboembolism in patients with the factor V Leiden (FVR506Q) mutation: effect of warfarin and prediction by precipitating factors. East Anglian Thrombophilia Study Group. Br J Haematol 1998; 100:764.
  78. Sarasin FP, Bounameaux H. Decision analysis model of prolonged oral anticoagulant treatment in factor V Leiden carriers with first episode of deep vein thrombosis. BMJ 1998; 316:95.
  79. Stolz E, Kemkes-Matthes B, Pötzsch B, et al. Screening for thrombophilic risk factors among 25 German patients with cerebral venous thrombosis. Acta Neurol Scand 2000; 102:31.
  80. Ağaoğlu N, Mustafa NA, Türkyilmaz S. Prothrombotic disorders in patients with mesenteric vein thrombosis. J Invest Surg 2003; 16:299.
  81. El-Karaksy H, El-Koofy N, El-Hawary M, et al. Prevalence of factor V Leiden mutation and other hereditary thrombophilic factors in Egyptian children with portal vein thrombosis: results of a single-center case-control study. Ann Hematol 2004; 83:712.
  82. Martinelli I, Cattaneo M, Taioli E, et al. Genetic risk factors for superficial vein thrombosis. Thromb Haemost 1999; 82:1215.
  83. Gillet JL, Allaert FA, Perrin M. [Superficial thrombophlebitis in non varicose veins of the lower limbs. A prospective analysis in 42 patients]. J Mal Vasc 2004; 29:263.
  84. Milio G, Siragusa S, Minà C, et al. Superficial venous thrombosis: prevalence of common genetic risk factors and their role on spreading to deep veins. Thromb Res 2008; 123:194.
  85. de Moerloose P, Reber G, Perrier A, et al. Prevalence of factor V Leiden and prothrombin G20210A mutations in unselected patients with venous thromboembolism. Br J Haematol 2000; 110:125.
  86. Bounameaux H. Factor V Leiden paradox: risk of deep-vein thrombosis but not of pulmonary embolism. Lancet 2000; 356:182.
  87. Meyer G, Emmerich J, Helley D, et al. Factors V leiden and II 20210A in patients with symptomatic pulmonary embolism and deep vein thrombosis. Am J Med 2001; 110:12.
  88. Mäkelburg AB, Veeger NJ, Middeldorp S, et al. Different risk of deep vein thrombosis and pulmonary embolism in carriers with factor V Leiden compared with non-carriers, but not in other thrombophilic defects. Results from a large retrospective family cohort study. Haematologica 2010; 95:1030.
  89. Björgell O, Nilsson PE, Nilsson JA, Svensson PJ. Location and extent of deep vein thrombosis in patients with and without FV:R 506Q mutation. Thromb Haemost 2000; 83:648.
  90. van Langevelde K, Flinterman LE, van Hylckama Vlieg A, et al. Broadening the factor V Leiden paradox: pulmonary embolism and deep-vein thrombosis as 2 sides of the spectrum. Blood 2012; 120:933.
  91. Juul K, Tybjaerg-Hansen A, Mortensen J, et al. Factor V leiden homozygosity, dyspnea, and reduced pulmonary function. Arch Intern Med 2005; 165:2032.
  92. de Bruijn SF, Stam J, Koopman MM, Vandenbroucke JP. Case-control study of risk of cerebral sinus thrombosis in oral contraceptive users and in [correction of who are] carriers of hereditary prothrombotic conditions. The Cerebral Venous Sinus Thrombosis Study Group. BMJ 1998; 316:589.
  93. Zuber M, Toulon P, Marnet L, Mas JL. Factor V Leiden mutation in cerebral venous thrombosis. Stroke 1996; 27:1721.
  94. Lüdemann P, Nabavi DG, Junker R, et al. Factor V Leiden mutation is a risk factor for cerebral venous thrombosis: a case-control study of 55 patients. Stroke 1998; 29:2507.
  95. Deschiens MA, Conard J, Horellou MH, et al. Coagulation studies, factor V Leiden, and anticardiolipin antibodies in 40 cases of cerebral venous thrombosis. Stroke 1996; 27:1724.
  96. Zhang P, Zhang J, Sun G, et al. Risk of Budd-Chiari syndrome associated with factor V Leiden and G20210A prothrombin mutation: a meta-analysis. PLoS One 2014; 9:e95719.
  97. Demarmels Biasiutti F, Merlo C, Furlan M, et al. No association of APC resistance with myocardial infarction. Blood Coagul Fibrinolysis 1995; 6:456.
  98. Kontula K, Ylikorkala A, Miettinen H, et al. Arg506Gln factor V mutation (factor V Leiden) in patients with ischaemic cerebrovascular disease and survivors of myocardial infarction. Thromb Haemost 1995; 73:558.
  99. Longstreth WT Jr, Rosendaal FR, Siscovick DS, et al. Risk of stroke in young women and two prothrombotic mutations: factor V Leiden and prothrombin gene variant (G20210A). Stroke 1998; 29:577.
  100. Cushman M, Rosendaal FR, Psaty BM, et al. Factor V Leiden is not a risk factor for arterial vascular disease in the elderly: results from the Cardiovascular Health Study. Thromb Haemost 1998; 79:912.
  101. Dunn ST, Roberts CR, Schechter E, et al. Role of factor V Leiden mutation in patients with angiographically demonstrated coronary artery disease. Thromb Res 1998; 91:91.
  102. Juul K, Tybjaerg-Hansen A, Steffensen R, et al. Factor V Leiden: The Copenhagen City Heart Study and 2 meta-analyses. Blood 2002; 100:3.
  103. 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.
  104. Mannucci PM, Asselta R, Duga S, et al. The association of factor V Leiden with myocardial infarction is replicated in 1880 patients with premature disease. J Thromb Haemost 2010; 8:2116.
  105. Lalouschek W, Schillinger M, Hsieh K, et al. Matched case-control study on factor V Leiden and the prothrombin G20210A mutation in patients with ischemic stroke/transient ischemic attack up to the age of 60 years. Stroke 2005; 36:1405.
  106. Rosendaal FR, Siscovick DS, Schwartz SM, et al. Factor V Leiden (resistance to activated protein C) increases the risk of myocardial infarction in young women. Blood 1997; 89:2817.
  107. Becker S, Heller C, Gropp F, et al. Thrombophilic disorders in children with cerebral infarction. Lancet 1998; 352:1756.
  108. 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.
  109. Jorquera JI, Montoro JM, Fernández MA, et al. Modified test for activated protein C resistance. Lancet 1994; 344:1162.
  110. Trossaërt M, Conard J, Horellou MH, et al. The modified APC resistance test in the presence of factor V deficient plasma can be used in patients without oral anticoagulant. Thromb Haemost 1996; 75:521.
  111. Pandit TN, Sarode R. Blood component support in acquired coagulopathic conditions: is there a method to the madness? Am J Hematol 2012; 87 Suppl 1:S56.