Intermediate Thrombin Activation Is Associated with Reduced Cardiovascular Death Independently of Markers of Lipid Metabolism and Inflammation

Abstract 31

Clinical trials showed an increased frequency of cardiovascular death (CVD) in patients receiving direct thrombin inhibitors. Considering the detrimental effect of local coagulation activation during an acute cardiovascular event these observations are deemed unexpected. These observations raise the question whether enhanced thrombin generation may convey protective effects during non-acute disease stages of cardiovascular disease.

To address the question whether increased endogenous thrombin generation may convey beneficial effects in regard to cardiovascular disease we evaluated the association of the ETP and prothrombin fragment 1+2 (F1+2) with cardiovascular death (CVD) in a large prospective study (3156 individuals, median follow up ten years, Ludwigshafen RIsk and Cardiovascular Health (LURIC)-study). Furthermore, we explored the association of ETP with markers of inflammation (CRP, SAA), endothelial dysfunction (sICAM-1, sVCAM-1), and inflammatory cell activation (PAFAH).

An inverse association between ETP and CVD was observed, with the lowest hazard ratio (HR) in the 3^rd ETP quartile. This effect remained significant after adjusting for age, gender, DM, BMI, smoking, hypertension, hsCRP, LDL, HDL and triglycerides and after excluding patients receiving anticoagulants (HR for MOR 0.675, CI 0.531–0.858, P=0.001, and HR for CVD 0.667, CI 0.493–0.903, P=0.009). The nadir of sICAM-1 or sVCAM-1 was observed in the 3^rd, for PAFAH in the 4^th ETP quartile. When stratifying patients according to F1+2 we observed a similar U-shaped association with CVD (lowest HR in the 2^nd quartile: 0.718, CI 0,524–0.983, P=0.039). In contrast, the HR for CVD according to fibrinogen strata increased continuously across the quartiles (highest HR in the 4^th quartile: 1.828, CI 1.318–2.536, P<0.001).

These results establish that intermediate levels of ETP or PTF1+2 are associated with a reduced HR for CVD and with lower plasma levels of markers of endothelial dysfunction or inflammatory cell activation. Based on these data we propose that low but sustained levels of thrombin generation mediate vasculo-protective effects translating long term into a reduced risk of CVD. These data may provide a rationale for the observed increased frequency of myocardial infarction in clinical studies evaluating direct thrombin inhibitors.