Carriership of the
factor V (
FV) Leiden mutation increases the risk of
venous thromboembolism (VTE) ~4-fold, but the individual risk of each
FV Leiden carrier depends on several co-inherited risk and protective factors. Under the hypothesis that
thrombin generation might serve as an intermediate phenotype to identify genetic modulators of VTE risk, we enrolled 188
FV Leiden heterozygotes (11 with VTE) and determined the following parameters:
thrombin generation in the absence and presence of activated
protein C (APC); plasma levels of
prothrombin,
factor X,
antithrombin,
protein S and
tissue factor pathway inhibitor; and the genotypes of 24 SNPs located in the genes encoding these
coagulation factors and inhibitors. Multiple regression analysis was subsequently applied to identify the (genetic) determinants of
thrombin generation. The endogenous
thrombin potential (ETP) showed a striking inter-individual variability among different
FV Leiden carriers and, especially when measured in the presence of APC, correlated with VTE risk. Several SNPs in the F2 (rs1799963, rs3136516), F10 (rs693335), SERPINC1 (rs2227589), PROS1 (Heerlen polymorphism) and
TFPI (rs5940) genes significantly affected the ETP-APC and/or the ETP+APC in
FV Leiden carriers. Most of these SNPs have shown an association with VTE risk in conventional epidemiological studies, suggesting that the genetic dissection of
thrombin generation leads to the detection of clinically relevant SNPs. In conclusion, we have identified several SNPs that modulate
thrombin generation in
FV Leiden heterozygotes. These SNPs may help explain the large variability in VTE risk observed among different
FV Leiden carriers.