Thrombin generation in cardiovascular disease and mortality – results from the Gutenberg Health Study

Thrombin generation may be a potential tool to improve risk stratification for cardiovascular diseases. The aim of this study was to explore the relation between thrombin generation and cardiovascular risk factors, cardiovascular diseases, and total mortality. For this study, 5,000 subjects from the population-based Gutenberg Health Study were analyzed in a highly standardized setting. Thrombin generation was assessed by the Calibrated Automated Thrombogram method at 1 and 5 pM tissue factor triggers in platelet-poor plasma. Lag time, endogenous thrombin potential, and peak height were derived from the thrombin generation curve. Sex-specific multivariable linear regression analysis adjusted for age, cardiovascular risk factors, cardiovascular diseases and therapy, was used to assess clinical determinants of thrombin generation. Cox regression models adjusted for age, sex, cardiovascular risk factors and vitamin K antagonists investigated the association between thrombin generation parameters and total mortality. Lag time was positively associated with obesity and dyslipidaemia for both sexes (P<0.0001). Obesity was also positively associated with endogenous thrombin potential in both sexes (P<0.0001) and peak height in males (1 pM tissue factor, P=0.0048) and females (P<0.0001). Cox regression models showed an increased mortality in individuals with lag time (1 pM tissue factor, hazard ratio=1.46, 95% confidence interval: 1.07-2.00; P=0.018) and endogenous thrombin potential (5 pM tissue factor, hazard ratio=1.50, 95% confidence interval: 1.06-2.13; P=0.023) above the 95th percentile of the reference group, independently of the cardiovascular risk profile. This large-scale study demonstrates that traditional cardiovascular risk factors, particularly obesity, are relevant determinants of thrombin generation. Lag time and endogenous thrombin potential were found to be potentially relevant predictors of increased total mortality, observations which deserve further investigation.