Influence of single nucleotide polymorphisms on thrombin generation in factor V Leiden heterozygotes

Olivier Segers; Paolo Simioni; Daniela Tormene; Elisabetta Castoldi

doi:10.1160/TH13-05-0360

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2014; 111(03): 438-446
DOI: 10.1160/TH13-05-0360

Blood Coagulation, Fibrinolysis and Cellular Haemostasis

Schattauer GmbH

Influence of single nucleotide polymorphisms on thrombin generation in factor V Leiden heterozygotes

Olivier Segers

¹Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Centre, Maastricht, the Netherlands

,

Paolo Simioni

²Department of Cardiologic, Thoracic and Vascular Sciences, 2nd Chair of Internal Medicine, University of Padua Medical School, Padua, Italy

,

Daniela Tormene

²Department of Cardiologic, Thoracic and Vascular Sciences, 2nd Chair of Internal Medicine, University of Padua Medical School, Padua, Italy

,

Elisabetta Castoldi

¹Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Centre, Maastricht, the Netherlands

› Author Affiliations

Abstract

Summary

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.

Keywords

Factor V Leiden - intermediate phenotype - single nucleotide polymorphism - thrombin generation - venous thromboembolism

Full Text

References

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