The Northwick Park Heart Study: evidence from the laboratory

The Northwick Park Heart Study (NPHS) has shown associations of high plasma fibrinogen and factor VII (FVIIc) levels with the risk of death from coronary heart disease (CHD). The finding for fibrinogen has been confirmed in many other studies. Whereas one further study has found a similar prospective association for FVIIc, several have not. Experimental studies have demonstrated the impact that the coagulation activity of fibrinogen and FVIIc have on the progression and phenotype of atherosclerotic lesions. FVIIc-driven thrombin generation and fibrin formation within the vessel wall are important determinants of both plaque (in)stability and atherothrombosis. In blood, local concentrations of FVIIc and thrombin may be sufficient to allow interactions between these serine proteases and protease-activated receptors, to drive cellular inflammatory reactions that further promote these processes. Local fibrinogen concentrations dictate fibrin clot structure and resistance to fibrinolysis. Within the atherosclerotic plaque, coagulation reactions driven by proinflammatory stimuli may initially support lesion stability (as part of wound healing), but, with advanced inflammation, thrombin and fibrin generation diminish because of proteolytic activity contributing to plaque instability. The NPHS findings have proved controversial, but, in the light of current knowledge, a reappraisal of the importance of FVIIc and fibrinogen in atherosclerosis, atherothrombosis and CHD is justified. Hypercoagulability, reflected in turn by thrombin generation capacity, and local concentrations of coagulation proteins, including FVIIc and fibrinogen, is linked to plaque phenotype, and even minute local concentrations of fibrinogen and proteases such as FVIIc may affect thrombin generation capacity.