Postprandial lipid metabolism and thrombosis

The atherosclerotic basis of CHD and the pathogenic roles in this condition played by disturbances of lipoprotein metabolism, high blood pressure and cigarette smoking are well known (Grundy et al. 1987). In addition, the major cause of sudden cardiac death (Davies & Thomas, 1984), acute myocardial infarction (De Wood et al. 1980), unstable angina pectoris (Fuster & Chesebro, 1986) and silent myocardial ischaemia (Gurfmkel et al. 1994) is recognized to be the formation of thrombus at sites where the endothelium overlying atheromatous plaques has sloughed or fissured (Davies, 1996). The resultant contact of circulating blood with atheromatous material permits the formation of complexes of the plasma protein factor VII with its co-factor, tissue factor, present in abundance in the core of the plaque (Wilcox et al. 1989). These complexes are powerfully pro-coagulant, and their rapid formation in high local concentration overwhelms the inhibitory mechanisms which normally maintain the coagulant pathway at a basal level of activity (Bauer & Rosenberg, 1987). An amplifying cascade of linked proteolytic reactions is triggered, culminating in the generation of thrombin in sufficient quantity to produce the haemostatic mass of fibrin and aggregated platelets which is the thrombus (Macfarlane, 1964). Factor VII exists in plasma mainly as a single-chain zymogen (FVII) but also in trace quantity as the derivative two-chain enzyme, activated factor VII (FVIIa; Wildgoose et al. 1992; Morrissey et al. 1993). It is the FVIIa-tissue factor complex that is responsible for the initiation of coagulation and, a priori, the magnitude of the thrombotic response to plaque disruption is likely to depend in part on the concentration of circulating FVIIa at that instant. This is the rationale of warfarin anticoagulant therapy which is known to reduce the risk of thrombosis in CHD (International Anticoagulant Review Group, 1970; Chalmers et al. 1977). Warfarin acts by suppressing the activity level of factor VII and other vitamin K-dependent clotting factors. On this account, the discovery of a high factor VII coagulant activity (FVIIc) in men at high risk for fatal CHD is of particular relevance (Heinrich et al. 1994; Ruddock & Meade, 1994). Plasma FVIIc is a function of the concentrations of FVIIa and FVII (Miller et al. 1994), and the question immediately arises as to the causes of an elevated factor VII, months or even years before the onset of an acute coronary event.