Do incident and recurrent venous thromboembolism risks truly differ between heterozygous and homozygous Factor V Leiden carriers? A retrospective cohort study

Published:March 09, 2016DOI:


      • Homozygotes studied had higher VTE prevalence and modestly lower VTE-free survival.
      • VTE penetrance and phenotype severity, however, did not differ between both genotypes.
      • Our findings suggest VTE management should not differ by Factor V Leiden genotype.



      While Factor V Leiden (F5 rs6025 A allele) is a known venous thromboembolism (VTE) risk factor, VTE risk among heterozygous vs. homozygous carriers is uncertain.

      Materials and methods

      In a retrospective cohort study of Mayo Clinic patients referred for genotyping between 1996 and 2013, we tested Factor V Leiden genotype as a risk factor for incident and recurrent VTE.


      Among heterozygous (n = 268) and homozygous (n = 111) carriers, the prevalence of VTE was 54% and 68%, respectively (p = 0.016). While mean patient age at first VTE event (43.9 vs. 42.9 years; p = 0.70) did not differ significantly, median VTE-free survival was modestly shorter for homozygous carriers (56.8 vs 59.5 years; p = 0.04). Sixty-nine (48%) and 31 (42%) heterozygous and homozygous carriers had ≥1 VTE recurrence (p = 0.42). In a multivariable model, idiopathic incident VTE and a second thrombophilia were associated with increased and anticoagulation duration >6 months with reduced hazards of VTE recurrence; Factor V Leiden genotype was not an independent predictor of recurrence.


      Aside from a higher VTE prevalence and modestly reduced VTE-free survival, VTE penetrance and phenotype severity did not differ significantly among homozygous vs. heterozygous carriers, suggesting that VTE prophylaxis and management should not differ by Factor V Leiden genotype.


      APC (Activated protein C), FVa (Factor FVa), PCR (Polymerase chain reaction), PE (Pulmonary embolism), VTE (Venous thromboembolism)


      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to European Journal of Internal Medicine
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Dahlback B.
        • Hildebrand B.
        Inherited resistance to activated protein C is corrected by anticoagulant cofactor activity found to be a property of factor V.
        Proc Natl Acad Sci U S A. 1994; 91: 1396-1400
        • Svensson P.J.
        • Dahlback B.
        Resistance to activated protein C as a basis for venous thrombosis.
        N Engl J Med. 1994; 330: 517-522
        • Sun X.
        • Evatt B.
        • Griffin J.H.
        Blood coagulation factor Va abnormality associated with resistance to activated protein C in venous thrombophilia.
        Blood. 1994; 83: 3120-3125
        • Camire R.M.
        • Kalafatis M.
        • Cushman M.
        • Tracy R.P.
        • Mann K.G.
        • Tracy P.B.
        The mechanism of inactivation of human platelet factor Va from normal and activated protein C-resistant individuals.
        J Biol Chem. 1995; 270: 20794-20800
        • Kalafatis M.
        • Bertina R.M.
        • Rand M.D.
        • Mann K.G.
        Characterization of the molecular defect in factor VR506Q.
        J Biol Chem. 1995; 270: 4053-4057
        • Zivelin A.
        • Griffin J.H.
        • Xu X.
        • Pabinger I.
        • Samama M.
        • Conard J.
        • et al.
        A single genetic origin for a common Caucasian risk factor for venous thrombosis.
        Blood. 1997; 89: 397-402
        • The International HapMap Project
        Nature. 2003; 426: 789-796
        • Rees D.C.
        • Cox M.
        • Clegg J.B.
        World distribution of factor V Leiden.
        Lancet. 1995; 346: 1133-1134
        • Ridker P.M.
        • Hennekens C.H.
        • Lindpaintner K.
        • Stampfer M.J.
        • Eisenberg P.R.
        • Miletich J.P.
        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: 912-917
        • Press R.D.
        • Bauer K.A.
        • Kujovich J.L.
        • Heit J.A.
        Clinical utility of factor V leiden (R506Q) testing for the diagnosis and management of thromboembolic disorders.
        Arch Pathol Lab Med. 2002; 126: 1304-1318<1304:CUOFVL>2.0.CO;2
        • Koster T.
        • Rosendaal F.R.
        • Deronde H.
        • Briet E.
        • Vandenbroucke J.P.
        • Bertina R.M.
        Venous thrombosis due to poor anticoagulant response to activated protein-C - Leiden thrombophilia study.
        Lancet. 1993; 342: 1503-1506–9
        • Rosendaal F.R.
        • Koster T.
        • Vandenbroucke J.P.
        • Reitsma P.H.
        High risk of thrombosis in patients homozygous for factor V Leiden (activated protein C resistance).
        Blood. 1995; 85: 1504-1508
        • Folsom A.R.
        • Cushman M.
        • Tsai M.Y.
        • Aleksic N.
        • Heckbert S.R.
        • Boland L.L.
        • et al.
        A prospective study of venous thromboembolism in relation to factor V Leiden and related factors.
        Blood. 2002; 99: 2720-2725
        • Juul K.
        • Tybjaerg-Hansen A.
        • Schnohr P.
        • Nordestgaard B.G.
        Factor V Leiden and the risk for venous thromboembolism in the adult Danish population.
        Ann Intern Med. 2004; 140: 330-337
        • Heit J.A.
        • Sobell J.L.
        • Li H.
        • Sommer S.S.
        The incidence of venous thromboembolism among factor V Leiden carriers: a community-based cohort study.
        J Thromb Haemost. 2005; 3: 305-311
        • Ridker P.M.
        • Glynn R.J.
        • Miletich J.P.
        • Goldhaber S.Z.
        • Stampfer M.J.
        • Hennekens C.H.
        Age-specific incidence rates of venous thromboembolism among heterozygous carriers of factor V Leiden mutation.
        Ann Intern Med. 1997; 126: 528-531
        • Group T.P.
        Comparison of thrombotic risk between 85 homozygotes and 481 heterozygotes carriers of the factor V Leiden mutation: retrospective analysis from the Procare Study.
        Blood Coagul Fibrinolysis. 2000; 11: 511-518
        • Group T.P.
        Is recurrent venous thromboembolism more frequent in homozygous patients for the factor V Leiden mutation than in heterozygous patients?.
        Blood Coagul Fibrinolysis. 2003; 14: 523-529
        • Harris P.A.
        • Taylor R.
        • Thielke R.
        • Payne J.
        • Gonzalez N.
        • Conde J.G.
        Research electronic data capture (REDCap)–a metadata-driven methodology and workflow process for providing translational research informatics support.
        J Biomed Inform. 2009; 42: 377-381
        • Vossen C.Y.
        • Conard J.
        • Fontcuberta J.
        • Makris M.
        • VDM F.J.
        • Pabinger I.
        • et al.
        Risk of a first venous thrombotic event in carriers of a familial thrombophilic defect. The European Prospective Cohort on Thrombophilia (EPCOT).
        J Thromb Haemost. 2005; 3: 459-464
        • Middeldorp S.
        • Meinardi J.R.
        • Koopman M.M.
        • van Pampus E.C.
        • Hamulyak K.
        • van Der Meer J.
        • 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: 322-327
        • Beretta A.L.
        • Bianchi M.
        • Norchi S.
        • Martinelli I.
        Pregnancy-associated deep vein thrombosis in a double homozygous carrier of factor V Leiden and prothrombin G20210A.
        Thromb Haemost. 2005; 94: 1329-1330
        • Ho W.K.
        • Hankey G.J.
        • Quinlan D.J.
        • Eikelboom J.W.
        Risk of recurrent venous thromboembolism in patients with common thrombophilia: a systematic review.
        Arch Intern Med. 2006; 166: 729-736
        • Kearon C.
        • Akl E.A.
        • Comerota A.J.
        • Prandoni P.
        • Bounameaux H.
        • Goldhaber S.Z.
        • et al.
        Antithrombotic therapy for VTE disease: Antithrombotic Therapy and Prevention of Thrombosis.
        in: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. 9th ed. Chest. 141(2 Suppl). 2012: e419S-e494S
        • Bucciarelli P.
        • De Stefano V.
        • Passamonti S.M.
        • Tormene D.
        • Legnani C.
        • Rossi E.
        • et al.
        Influence of proband's characteristics on the risk for venous thromboembolism in relatives with factor V Leiden or prothrombin G20210A polymorphisms.
        Blood. 2013; 122: 2555-2561
        • Dizon-Townson D.
        • Miller C.
        • Sibai B.
        • Spong C.Y.
        • Thom E.
        • Wendel Jr, G.
        • et al.
        The relationship of the factor V Leiden mutation and pregnancy outcomes for mother and fetus.
        Obstet Gynecol. 2005; 106: 517-524
        • Samama M.M.
        • Conard J.
        • Nassiri S.
        • Horellou M.H.
        • Arkam R.
        • Elalamy I.
        Comparison of two groups of 22 women homozygous or heterozygous for factor V Leiden mutation.
        Bull Acad Natl Med. 1997; 181: 919-935