title: Risk of venous thromboembolism in carriers of factor V Leiden with a concomitant inherited thrombophilic defect: a retrospective analysis.
abstract: Factor V Leiden is the most common genetic defect associated with venous thromboembolism. Its clinical expression is limited and shows a wide intrafamilial and interfamilial variation, which might be explained by the influence of other genetic risk factors. We retrospectively studied 226 patients with factor V Leiden and documented venous thromboembolism (probands) and 400 first-degree carrier relatives to assess the contribution of concomitant genetic risk factors to the occurrence of venous thromboembolism. The prothrombin G20210A mutation was found in 8.3%, homozygosity of factor V Leiden in 7.2%, and inherited deficiencies of antithrombin, protein C or protein S in 4.7% of symptomatic carriers (probands and relatives), as compared with 6.0, 3.4 and 0.9% of asymptomatic carriers, respectively. The total follow-up time in relatives was 11 049 years. Prevalences of venous thromboembolism were 10.8% in single heterozygous factor V Leiden carrier relatives, 16.0% in double-heterozygotes for factor V Leiden and the prothrombin mutation, 36.8% in homozygotes for factor V Leiden, and 40.0% in double-heterozygotes for factor V Leiden and an inherited deficiency of protein C or protein S. Annual incidences in these groups were 0.39, 0.57, 1.41, and 4.76%, respectively. Multivariate analysis showed a small, non-significant additional effect of the prothrombin mutation on the risk of venous thromboembolism in heterozygotes for factor V Leiden [adjusted hazard ratio, 1.3; 95% confidence interval (CI), 0.5-3.8]. This effect was more pronounced for homozygosity of factor V Leiden (adjusted hazard ratio, 3.9; 95% CI, 1.7-9.0) and inherited protein C or protein S deficiencies (adjusted hazard ratio, 17.5; 95% CI, 3.8-81.2). Our data provide evidence of clustering of the evaluated genetic thrombophilic defects in symptomatic factor V Leiden carriers and support the assumption that the clinical expression of factor V Leiden depends on clustering in a part of carriers.
authors.affiliation: Division of Haemostasis, Thrombosis and Rheology, University Hospital, Groningen, The Netherlands. j.r.meinardi@mzh.nl
authors.forename: J R
authors.initials: JR
authors.lastname: Meinardi
authors.forename: S
authors.initials: S
authors.lastname: Middeldorp
authors.forename: P J
authors.initials: PJ
authors.lastname: de Kam
authors.forename: M M
authors.initials: MM
authors.lastname: Koopman
authors.forename: E C
authors.initials: EC
authors.lastname: van Pampus
authors.forename: K
authors.initials: K
authors.lastname: Hamulyák
authors.forename: M H
authors.initials: MH
authors.lastname: Prins
authors.forename: H R
authors.initials: HR
authors.lastname: Büller
authors.forename: J
authors.initials: J
authors.lastname: van der Meer
mesh_terms: D000328:Adult; D005165:Factor V / Q000235:genetics*; D005192:Family Health; D005260:Female; D006579:Heterozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D011247:Pregnancy; D015995:Prevalence; D012044:Regression Analysis; D012189:Retrospective Studies; D012307:Risk Factors; D013923:Thromboembolism / Q000209:etiology / Q000235:genetics*; D019851:Thrombophilia / Q000150:complications / Q000235:genetics*; D020246:Venous Thrombosis / Q000209:etiology / Q000235:genetics
chemical_list: C095381:factor V Leiden; D005165:Factor V