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

Abstract

Thrombin generation may be a potential tool to improve risk stratification for cardiovascular diseases. This study aims to explore the relation between thrombin generation and cardiovascular risk factors, cardiovascular diseases, and total mortality. For this study, N=5000 subjects from the population-based Gutenberg Health Study were analysed in a highly standardized setting. Thrombin generation was assessed by the Calibrated Automated Thrombogram method at 1 and 5 pM tissue factors trigger 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% CI: 1.07; 2.00], p=0.018) and endogenous thrombin potential (5 pM tissue factor, hazard ratio = 1.50, [1.06; 2.13], p=0.023) above the 95th percentile of the reference group, independent of the cardiovascular risk profile. This large-scale study demonstrates traditional cardiovascular risk factors, particularly obesity, as relevant determinants of thrombin generation. Lag time and endogenous thrombin potential were found as potentially relevant predictors of increased total mortality, which deserves further investigation.

Figure 1.

Survival over 10 years for markers of thrombin generation above and below reference limits. Kaplan-Meier survival curves of the overall study sample demonstrating the 10-year survival of individuals with the thrombin generation parameters lag time (left panels), endogenous thrombin potential (ETP) (middle panels), and peak height (right panels) within the range of the reference group (green line), individuals above the 90^th percentile of the reference group (blue line), and individuals above the 97.5^th percentile of the reference group (red line), at 1 (upper panels) and 5 pM (lower panels) tissue factor (TF). For the lag times at both 1 and 5 pM TF, P<0.001 for the difference between the reference and the 90^th percentile, as well as for the reference and the 97.5^th percentile. For the ETP at 5 pM TF, P=0.034 for the difference between the reference and the 90^th percentile and P=0.00097 for the difference between the reference and the 97.5^th percentile.