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.

Thrombin generation: a global coagulation procedure to investigate hypo- and hyper-coagulability

“…In this issue of the Journal van Paridon et al add more evidence on the mechanisms of hypercoagulability and clinically relevant outcomes. 1 They evaluated TG in a large population of subjects (n=5,000) enrolled in a prospective study with a relatively long follow-up (up to 9.65 years). The authors found that some TG parameters were independently associated with overall mortality.…”

“…The study by van Paridon et al is the first to investigate the association of hypercoagulability (as measured by TG) and the risk of mortality in a large population. 1 However, some issues emerge from the study that warrant consideration. While it is plausible that high ETP is directly associated with overall mortality, it is less plausible that the prolonged (not shortened) lagtime is associated with mortality.…”

“…Notwithstanding these limitations, the study by van Paridon et al should be considered an important step forward for the development of TG as a global procedure to assess the hemostatic system and its relationship with overall mortality. 1 …”

“…The article by van Paridon et al . 1 published in this issue of Haematologica on results of thrombin generation (TG) in cardiovascular disease and mortality, stemming from the Gutenberg Health Study, provides an opportunity to comment on TG as a global laboratory procedure to investigate hypo- and hyper-coagulability.…”

Prospective Assessment of Biomarkers of Hypercoagulability for the Identification of Patients With Severe Coronary Artery Disease. The ROADMAP-CAD Study

“…[25][26][27] Moreover our findings are further supported by the results of the population based Gutenberg Health Study which included 5000 subjects and showed that in patients with cardiovascular disease or cardiovascular risk factors the prolongation of the lag-time of thrombin generation is associated with mortality. 28 Based on the analysis of the previously published studies a methodological approach is required for the interpretation of this finding. Thrombogram-Thrombinoscope ® assay is performed with exogenously added PPP-reagent ® which contains optimal concentrations of TF and procoagulant phospholipids (5pM and 4 mM respectively).…”