Associations Between Thrombin Generation and the Risk of Cardiovascular Disease in Elderly Patients: Results From the PROSPER Study

Background. Hypercoagulability may be an important contributor to the pathophysiology of atherosclerosis and atherothrombosis. As thrombin fulfills a central role in coagulation and links to several cellular mechanisms involved in arterial disease, we hypothesized that thrombin generation is associated with cardiovascular events in elderly patients. Methods. We studied the relationship between plasma thrombin generation and incident coronary heart disease (CHD) and stroke in the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER). From this multicenter prospective cohort, 4,932 samples of subjects (7082 years) with pre-existing vascular disease or risk factors were available for thrombin generation measurements. Results. Within the 3.2 years of follow-up incident stroke and CHD was observed in 227 and 545 subjects, respectively. Baseline thrombin generation was significantly decreased in subjects with incident stroke compared with subjects without: normalized peak height 71.1 +/- 40.8% versus 82.3 +/- 44.9%, p = .0002, and normalized endogenous thrombin potential 79.1 +/- 23.3% versus 87.0 +/- 24.8%, p <.0001 (mean and SDs). Thrombin generation was independently and inversely associated with stroke risk: hazard ratio 0.71 (95% CI: 0.60-0.85), 0.68 (95% CI: 0.58-0.79), for normalized peak height and normalized endogenous thrombin potential, respectively (all p <.001). In subjects with incident CHD, thrombin generation was comparable to subjects without a coronary event. Only an increased normalized peak height was significantly associated with incident CHD (hazard ratio 1.17 [95% CI: 1.06-1.28], p = .002). Conclusions. We demonstrate that a delayed and decreased thrombin generation is a strong and independent predictor for stroke in elderly people at increased risk of vascular disease. However, no convincing consistent association could be demonstrated between thrombin generation and incident CHD.