Hemostatic factors, atherogenesis and atherosclerosis

A number of reports have documented during the last two decades the relationship between some components of the coagulation system (fibrinogen, factor VII, von Willebrand factor) and fibrinolytic factors (tissue-type plasminogen activator (TPA) and plasminogen activator inhibitor-1 (PAI-1)] and the clinical manifestations of atherosclerosis. The role of fibrinogen as cardiovascular risk factor was pointed out in the seventies and eighties, when several perspective studies showed the existence of a gradual and continuous correlation between baseline levels of fibrinogen and the incidence of subsequent ischemic cardiovascular events. In the Northwick Park Heart Study a fibrinogen level in the upper tertile of the population increased the risk of CHD threefold over those in the lower third of population, and a fibrinogen level of just one standard deviation (0.6 mg/ml) above the mean (2.9 mg/ml), increased by 84% the risk of a first CHD event within the next 5 years. Fibrinogen levels are related with the presence and severity of CAD, and a strong predictive power of fibrinogen levels for outcome of patients after acute myocardial infarction has been documented. Moreover, in patients with stable intermittent claudication followed up to six years, fibrinogen represented the main independent predictor of death. In a review on the epidemiologic evidence relating fibrinogen to CHD, high fibrinogen levels resulted an independent predictor of cardiovascular disease, with a 2.3-fold increase in risk, and markedly enhanced the cholesterol-related risk. Data in this direction has been confirmed by the recent ECAT study, which showed that in patients with angina pectoris the levels of fibrinogen, von Willebrand factor antigen, and TPA antigen are independent predictors of subsequent coronary syndromes. In the presence of cholesterol elevations, high fibrinogen levels increases CHD more than sixfold, while patients with low fibrinogen concentration are at low risk of events despite increased cholesterol levels. Elevated triglycerides, smoking and physical inactivity all are associated with elevated fibrinogen levels. Cigarette smoking has a strong influence on fibrinogen concentrations, with higher levels in smokers and ex-smokers than in non-smokers. Smoking cessation and intense physical activity reduce fibrinogen levels. Menopausal state is associated with a significant increase in fibrinogen levels (+ 10%) and hormone replacement therapy may have a positive effect. During the last years, some evidence of a predictive power of platelet aggregation for further cardiovascular events was provided by small-scale studies in healty subjects and in patients with previous myocardial infarction. The evidence of a relationship between factor VII plasma concentration and risk for cardiovascular events is weaker than for fibrinogen. Evidence of high levels of factor VII activity in patients with high risk for coronary artery disease and in survivors of myocardial infarction has been provided. Reduced fibrinolytic activity seems to be associated with an increased risk of cardiovascular disease. Some reports have documented the relationship between the levels of PAI-1 or TPA and cardiovascular diseases, CHD, carotid atherosclerosis, stroke, thrombotic events, and long term mortality. However, the real predictive power of these factors has still to be precisely assessed. Present evidence of a predictive power of blood clotting factors level for ischemic cardiovascular events adds further relevance to the long-standing theories hypothesizing the involvement of blood platelets and coagulation factors in atherogenesis, and stresses the importance of hemostasis in the genesis of clinical events and the possibility of preventing cardiovascular events by interfering with hemostatic system.