Endogenous fibrinolytic function and risks of future myocardial infarction and stroke: observations from the Physicians' Health Study

Abstract

Summary Employing plasma and DNA samples collected at baseline among 14,916 participants in the Physicians' Health Study who were free of reported vascular disease at study initiation and were then followed prospectively for the occurrence of myocardial infarction, stroke, and venous thrombosis, we have found that baseline evaluations of endogenous tissue-type plasminogen activator (tPA:ag) as well as cross linked fibrin degradation products (D-dimer) are highly predictive of risk of future coronary and cerebral thrombosis, but not venous thrombosis. We have also found that levels of tPA:ag directly correlate with body mass index and cigarette consumption and inversely correlate with alcohol consumption and HDL cholesterol. In contrast, we have found no association between Lp(a) and risk of future myocardial infarction or stroke. Despite strong associations between plasma levels of tPA:ag and thrombotic risk, we have not found significant relationships between specific genetic polymorphisms associated with PAI-1 or tPA production to be predictive of risk. Thus, environmental and behavioural factors are likely to be critical in determining the net fibrinolytic balance on a systemic and local basis. Data from the Physicians' Health Study, taken in context with other important prospective evaluations of fibrinolytic potential, strongly support the hypothesis that hemostatic and thrombotic risk factors for vascular disease can be detected reliably on a population basis, and raise the possibility that assessment of novel risk factors may prove valuable in the detection and prevention of cardiovascular disease.