Fibrinogen--marker or mediator of vascular disease?

Fibrinogen plays a key role in platelet aggregation, the final step of the coagulation cascade, i.e. the formation of fibrin, and it is a major determinant of plasma viscosity and erythrocyte aggregation. It is both constitutively expressed and inducible during an acute phase reaction. Increased plasma fibrinogen levels are associated with an increased risk of coronary heart disease and myocardial infarction. The question as to whether fibrinogen is only a marker of the inflammatory process involved in atherosclerosis or a mediator, i.e. a pathogenic factor, has not yet been answered. Human in vivo studies do not permit a conclusive answer to this question. If it is a pathogenic factor, fibrinogen lowering would be a therapeutic option. Selective fibrinogen-lowering agents do not exist however. All agents that lower fibrinogen also have other cardiovascular effects such as a decrease in cholesterol or inflammation. Newer information stems from molecular biology. Polymorphisms in the human fibrinogen gene with higher fibrinogen levels do not increase the risk for myocardial infarction. Fibrinogen knockout mice crossed with an atherosclerosis-susceptible strain (apoprotein E null mice) did not show a decreased extent of atherosclerosis despite the absence of fibrinogen, and a mouse strain over-expressing fibrinogen did not show an increased degree of atherosclerosis. Thus, fibrinogen seems to be a marker rather than a mediator of vascular disease, which would make selective fibrinogen lowering a useless preventive or therapeutic strategy.