Predicting Thrombosis in Factor V^Leiden Heterozygotes.

Factor V^Leiden (G1691A;R506Q) is an autosomal dominant allele displaying high prevalence (3–7%) in the United States Caucasian population and a high incidence of venous thrombosis in homozygotes (50% lifetime risk) but reduced penetrance in heterozygote carriers (<10% lifetime risk). Factors that precipitate or suppress the expression of the thrombotic phenotype in factor V^Leiden heterozygotes are not well defined except for relatively infrequent instances of coexpression of other thrombophilic risk factors, e.g. the prothrombin G20210A mutant. Our goal is to mathematically evaluate the effect of factor V^Leiden on tissue factor-initiated thrombin generation and determine whether concentration variations within the normal range of antithrombin (86–128%), prothrombin (60–140%) or protein C (77–183%) modulate the factor V^Leiden effect when all other factor levels are at mean physiologic concentrations. Our mathematical model (Hockin et al. (2002) JBC 277:18322) was extended to incorporate the protein C pathway by including descriptions of thrombin binding to thrombomodulin, activation of protein C and factor Va inactivation by activated protein C. Simulations were conducted with 100% factor V, 50% factor V/50% factor V^Leiden (heterozygote), and 100% factor V^Leiden (homozygote). Heterozygous expression of factor V^Leiden increases the maximum level of thrombin by 25% and the maximum rate of thrombin generation by a factor of 1.6 over that seen with 100% factor V. Homozygous factor V^Leiden yields a 2.6-fold increase in maximum rate and a 60% increase in maximum thrombin level compared to 100% factor V. Decreasing the protein C concentration to 77% in a factor V^Leiden heterozygote results in a thrombin generation profile with maximum levels and rates comparable to the factor V^Leiden homozygote. At 150% protein C, thrombin generation is suppressed to levels similar to those seen with 100% factor V. When the effect of variable prothrombin levels in a factor V^Leiden heterozygote is examined, a 60% level of prothrombin decreases the maximum level of thrombin generation below that seen with 100% factor V. When prothrombin levels are at 140% in the factor V^Leiden heterozygote, the thrombin generation profile is similar to that observed with 100% factor V^Leiden . When the effect of variable antithrombin levels was tested in a factor V^Leiden heterozygote, a 14% decrease in antithrombin resulted in maximum thrombin levels approaching those of the factor V^Leiden homozygote. In contrast, 128% antithrombin in a factor V^Leiden heterozygote resulted in the suppression of thrombin generation to levels consistent with those seen with 100% factor V. Our results predict that the thrombotic effect of heterogenous expression of factor V^Leiden can be reduced when prothrombin levels are at the low extreme of the normal range or when antithrombin or protein C levels are at the high extreme of the normal range. Conversely, the thrombotic effect of the heterozygous expression of factor V^Leiden is intensified when prothrombin levels are at the high extreme of normal values or when antithrombin or protein C levels at the low extreme of normal. These results may contribute to the understanding of phenotypic variation within factor V^Leiden heterozygotes.