Thrombin generation as an intermediate phenotype for venous thrombosis

Olivier Segers; René van Oerle; Hugo ten Cate; Jan Rosing; Elisabetta Castoldi

doi:10.1160/TH09-06-0356

Thrombosis and Haemostasis, Inhaltsverzeichnis

Thromb Haemost 2010; 103(01): 114-122
DOI: 10.1160/TH09-06-0356

Blood Coagulation, Fibrinolysis and Cellular Haemostasis

Schattauer GmbH

Thrombin generation as an intermediate phenotype for venous thrombosis

A proof-of-concept study

Olivier Segers

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

,

René van Oerle

²Department of Internal Medicine, Laboratory for Clinical Thrombosis and Haemostasis, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Centre, Maastricht, the Netherlands

,

Hugo ten Cate

²Department of Internal Medicine, Laboratory for Clinical Thrombosis and Haemostasis, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Centre, Maastricht, the Netherlands

,

Jan Rosing

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

,

Elisabetta Castoldi

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

› Institutsangaben

Abstract

Summary

In vitro thrombin generation, which reflects an individual’s plasma coagulation potential and has been shown to correlate with the risk of venous thromboembolism (VTE), might represent a useful intermediate phenotype for the genetic dissection of VTE. As a proof of principle, we have investigated whether the thrombin generation assay can detect changes in the haemostatic balance associated with common genetic variation affecting the level or function of coagulation factors and inhibitors. The study population consisted of 140 healthy individuals. Plasma levels of coagulation factors and inhibitors and thrombin generation parameters determined at low tissue factor (TF) ± thrombomodulin (TM) and at high TF ± activated protein C (APC) were available from a previous study. All individuals were genotyped for F5 Leiden, F2 G20210A and 19 additional single nucleotide polymorphisms (SNPs) in haemostasis-related genes. The association of each SNP with plasma levels of the corresponding proteins and with thrombin generation parameters (lag time, peak height and endogenous thrombin potential [ETP]) was evaluated by statistical analysis. Not only F5 Leiden and F2 G20210A, but also several other common SNPs, significantly affected thrombin generation parameters. In particular, FGA A1069G (Thr312Ala) decreased the ETP_-APC, F2 A19911G increased the ETP_-APC, F10 IVS2 C+517G decreased the ETP_+APC, F12 C-46T decreased peak height at low TF, and TFPI T-287C and TFPI IVS7 T-33C decreased the ETP_+APC. These results indicate that the thrombin generation assay is sensitive to genetic variation in haemostasis-related genes, which makes it a promising tool to identify novel genetic risk factors of VTE.

Keywords

VTE - thrombin generation - SNP - intermediate phenotype

Volltext

Referenzen

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