Co-segregation of thrombophilic disorders in factor V Leiden carriers; the contributions of factor VIII, factor XI, thrombin activatable fibrinolysis inhibitor and lipoprotein(a) to the absolute risk of venous thromboembolism

Abstract

Background and objectives: The clinical expression of factor V Leiden varies widely within and between families and only a minority of carriers will ever develop venous thromboembolism. Co-segregation of thrombophilic disorders is a possible explanation. Our aim was to assess the contributions of high levels of factor VIII:C, factor XI:C, thrombin activatable fibrinolysis inhibitor (TAFI) and lipoprotein (a) (Lp(a)) to the risk of venous thromboembolism in factor V Leiden carriers.

Design and methods: Levels of the four proteins were measured, in addition to tests of deficiencies for antithrombin, protein C and protein S, and the prothrombin G20210A mutation, in 153 factor V Leiden carriers, derived from a family cohort study. The (adjusted) relative risk and absolute risk of venous thromboembolism for high levels of each protein were calculated.

Results: Of carriers, 60% had one or more concomitant thrombophilic disorders. Crude odds ratios (95% CI) of venous thromboembolism for high protein levels were: 3.2 (1.1-9.3) (factor VIII:C); 1.7 (0.6-4.9) (factor XI:C); 3.0 (1.1-8.2) (TAFI); and 1.9 (0.7-5.7) (Lp(a)). Adjusted for age, sex, other concomitant thrombophilic disorders and exogenous risk factors, the odds ratio for venous thromboembolism were 2.7 (0.8-8.7) for high factor VIII:C levels and 1.8 (0.6-5.3) for high TAFI levels. Annual incidences in subgroups of carriers were 0.35% (0.09-0.89), 0.44% (0.05-1.57) and 0.94% (0.35-2.05) for concomitance of high levels of factor VIII:C, TAFI and both, respectively, as compared to 0.09% (0.00-0.48) in single factor V Leiden carriers and 1.11% (0.30-2.82) for other concomitant disorders.

Interpretation and conclusions: High levels of factor VIII:C and TAFI, in contrast with factor XI:C and Lp(a), are mild risk factors for venous thromboembolism, and substantially contribute to the risk of venous thromboembolism in factor V Leiden carriers. Our data support the hypothesis that the clinical expression of factor V Leiden depends on co-segregation of thrombophilic disorders.