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Clinical determinants of thrombin generation
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 pan- els), and peak height (right panels) within the range of the reference group (green line), individuals above the 90th percentile of the reference group (blue line), and individuals above the 97.5th 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 90th percentile, as well as for the reference and the 97.5th percentile. For the ETP at 5 pM TF, P=0.034 for the difference between the reference and the 90th percentile and P=0.00097 for the difference between the reference and the 97.5th percentile.
relation between higher ETP (above the 95th percentile of the reference group) at 5 pM TF, as a global measure of both procoagulant and anticoagulant forces in the plasma, and increased risk of death, independently of CVRF and CVD. These findings indicate that both lag time and ETP are potential biomarkers for increased mortality risk, beyond the traditional CVRF. As discussed for the previ- ous published PROSPER study, the association between a prolonged lag time and total mortality is not only a sur- prising and counterintuitive observation, but also one that is difficult to explain. With a risk of being too speculative, potential mechanisms might include consumption of ini- tiators of coagulation before the system overshoots to start actual thrombosis. In other words, a constant (weak) prothrombotic trigger activates the coagulation system which is subsequently downregulated by the natural anti- coagulants antithrombin and TFPI until, at a certain moment, the prothrombotic trigger increases and the sys- tem becomes overactivated and anticoagulants can no longer prevent thrombosis. In such a scenario, consump- tion of factor VII or XII, for example, could lead to a pro- longed lag time in a sensitive in vitro assay. Another poten- tial contributor to the prolonged lag time could be altered TFPI levels between subjects. However, assessing the TFPI levels in the presented cohort is part of another study and beyond the scope of the current study.
Limitations of our study are that we measured TG in platelet-poor plasma after one-step centrifugation of whole blood (10 min at 2,000 x g) in contrast to recommendations (two-step centrifugation, 2000 x g for 5 min, 10,000 x g for 10 minutes). A previous small-scale analysis by Loeffen and colleagues16 showed that in order to eliminate residual platelets and microparticles, which may contribute to vari- ability in TG results, double-centrifuged samples are prefer- able. We cannot, therefore, exclude that residual platelets and microparticles contributed to the observed associations between CVRF and TG parameters. Next, we had only cumulative mortality data available, so conclusions could not be made regarding associations between TG variables and specific causes of mortality. However, the standardized clinical investigation of the cardiovascular profile, standard- ized laboratory measurements of the large Gutenberg Health Study sample and availability of prospective mortal- ity data are essential strenghts of our study, which delivers important evidence on the TG assay as a potential tool for improving risk stratification for CVD.
In conclusion, this is the first, large, population-based study demonstrating an important relation between TG parameters, such as the time to minimum thrombin formed or the amount of thrombin formed, and total mor- tality. Further research is required on the underlying mechanism as well as to explore the potential role of the
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