Abstract
Background: Thrombin formation is one of the key enzymatic processes that direct the activity of the hemostatic system. Thrombin generation (TG), a method addressing the overall potential of a given plasma sample to form thrombin, may be a potential tool to improve risk stratification for cardiovascular diseases (CVD). This study aims to explore the relation between TG and cardiovascular risk factors (CVRFs), CVD, and total mortality. Methods: For this study, N=5000 subjects from the population-based Gutenberg Health Study were analyzed in a highly standardized setting. TG was measured by the Calibrated Automated Thrombogram method at 1 and 5 pM tissue factor (TF) trigger in platelet poor plasma. Lag time, endogenous thrombin potential (ETP), and peak height were derived from the TG curve. Sex-specific multivariable linear regression analysis adjusted for age, CVRFs, CVD and therapy (vitamin K antagonists, oral contraceptives and hormonal replacement therapy), was used to analyze the determinants of TG. Cox regression models adjusted for age, sex, CVRFs and vitamin K antagonists investigated the association between TG parameters and total mortality. Results: Lag time (at 1 and 5 pM TF) was positively associated with obesity and dyslipidemia for both sexes (p<0.0001). Additionally, obesity was a positive determinant of ETP (at 1pM and 5 pM TF) in both sexes (p<0.0001) and peak height in males (1 pM TF, p=0.0048) and females (1 pM TF and 5 pM TF, p<0.0001). Cox regression models showed an increased mortality in individuals with a lag time (1 pM TF, HR=1.46, [95% CI: 1.07; 2.00], p=0.018) and ETP (5 pM TF, HR = 1.50, [1.06; 2.13], p=0.023) above the 95th percentile of the reference group, independent of the cardiovascular risk profile. Kaplan Meier survival curves showed a decreased survival in individuals with a lag time above the 90th percentile of the reference (1 and 5 pM TF, p<0.0001) and ETP above the 97.5th percentile of the reference (1 pM TF, p=0.00097). Conclusion: This large-scale study provides important insights in the effects of traditional CVRFs, particularly obesity, on TG in males and females. Lag time and ETP were found as potentially relevant predictors of increased mortality in the general population, which deserves further investigation.
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