Background. Increased levels of certain hemostatic factors may play a part in the development of acute coronary syndromes and may be associated with an increased risk of coronary events in patients with angina pectoris. Methods. We conducted a prospective multicenter study of 3043 patients with angina pectoris who underwent coronary angiography and were followed for two years. Base-line measurements included the concentrations of selected hemostatic factors indicative of a thrombophilic state or endothelial injury. The results were analyzed in relation to the subsequent incidence of myocardial infarction or sudden coronary death. Results. After adjustment for the extent of coronary artery disease and other risk factors, an increased incidence of myocardial infarction or sudden death was associated with higher base-line concentrations of fibrinogen (mean SD, 3.28 0.74 g per liter in patients who subsequently had coronary events, as compared with 3.00 0.71 g per liter in those who did not; P 0.01), von Willebrand factor antigen (138 49 percent vs. 125 49 percent, P 0.05), and tissue plasminogen activator (t-PA) antigen (11.9 4.7 ng per milliliter vs. 10.0 4.2 ng per milliliter, P 0.02). The concentration of C-reactive protein was also directly correlated with the incidence of coronary events (P 0.05), except when we adjusted for the fibrinogen concentration. In patients with high serum cholesterol levels, the risk of coronary events rose with increasing levels of fibrinogen and C-reactive protein, but the risk remained low even given high serum cholesterol levels in the presence of low fibrinogen concentrations. Conclusions. In patients with angina pectoris, the levels of fibrinogen, von Willebrand factor antigen, and t-PA antigen are independent predictors of subsequent acute coronary syndromes. In addition, low fibrinogen concentrations characterize patients at low risk for coronary events despite increased serum cholesterol levels. Our data are consistent with a pathogenetic role of impaired fibrinolysis, endothelial-cell injury, and inflammatory activity in the progression of coronary artery disease. (N Engl J Med 1995;332:635-41.) From the Medical Statistics Unit, London School of Hygiene and Tropical Medicine, London (S.G.T., S.D.M.P.); the Department of Internal Medicine, University of Münster, Münster, Germany (J.K., J.C.W.L.); and the Gaubius Laboratory, Leiden, the Netherlands (F.H.). Address reprint requests to Dr. van de Loo at the Department of Internal Medicine, University of Münster, AlbertSchweitzer-Str. 33, D-48129 Münster, Germany. Supported by a grant from the European Community. *The investigators and institutions participating in the European Concerted Action on Thrombosis and Disabilities (ECAT) Angina Pectoris Study are listed in the Appendix. C ORONARY thrombosis is now generally recognized as the precipitating event in the transition from stable to acute ischemic heart disease, manifested by unstable angina, 1 acute myocardial infarction, 2 and sudden death from coronary causes. 3 Besides local stimuli such as disruption of plaques, systemic thrombogenic factors may contribute to the occurrence, extent, and persistence of coronary thrombosis and its clinical sequelae. 4 These factors include abnormalities of blood flow, 5 platelet hyperreactivity, 6,7 defective fibrinolysis, 8,9 and increased concentrations of hemostatic proteins, specifically fibrinogen and factor VII. 10 Thus, with the use of appropriate laboratory tests, it may be possible to detect a thrombogenic state and thus identify patients at increased risk for cardiovascular disease. Support for this hypothesis comes mainly from prospective studies of healthy subjects, which have demonstrated a direct and independent association between plasma fibrinogen concentrations and the risk of coronary events. 5,10-14 However, data on patients with known coronary artery disease are sparse and come from small cohort studies of patients with angina pectoris 15,16 or those who have had a first myocardial infarction. 8,9,17-19 In the European Concerted Action on Thrombosis and Disabilities (ECAT) Angina Pectoris Study, 20 we recruited more than 3000 patients with angina pectoris and used angiography to determine the extent of coronary artery disease. Our principal objective was to investigate the associations between base-line measurements of hemostatic factors that indicate the existence of a thrombophilic state or an alteration in the vascular endothelium, on the one hand, and the occurrence of coronary events during a two-year follow-up period, on the other.
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