Recent large clinical trials have demonstrated that
HMG-CoA reductase inhibitors, or
statins, markedly reduce morbidity and mortality when used in the primary and
secondary prevention of
cardiovascular disease. It has been established that the benefits of
statin therapy in
cardiovascular disease can be explained not only by the
lipid-lowering potential of
statins but also by nonlipid-related mechanisms (so-called "pleiotropic effects") that contribute to the positive effect of
statins on the incidence of cardiovascular events. The coagulation and fibrinolytic systems are two separate but reciprocally linked
enzyme cascades that regulate the formation and breakdown of
fibrin. Numerous studies have demonstrated that disturbances of coagulation and fibrinolysis contribute to the development and progression of
atherosclerosis, and that they affect the incidence of
atherosclerosis-related clinical events. High plasma levels or activities of
fibrinogen,
factor VII,
factor VIII, von Willebrand factor (vWF), soluble
thrombomodulin,
tissue plasminogen activator (tPA) and
plasminogen activator inhibitor-1 (PAI-1) are thought to be associated with increased morbidity and mortality related to
cardiovascular disease. Experimental studies and many clinical studies have recently shown that
statins produce favourable effects on haemostatic parameters, including those that are risk factors for cardiovascular disease.
Statins diminish procoagulant activity, which is observed at different stages of the coagulation cascade, including
tissue factor (TF) activity, conversion of
prothrombin to
thrombin and
thrombin activity. In some studies,
statins also reduced
fibrinogen levels. By altering the levels and activities of tPA and
PAI-1,
statins seem to stimulate fibrinolysis. The data on the effects of combined treatment with
statins and other drugs on haemostasis are rather limited. They suggest that
statins combined with
fibric acid derivatives,
omega-3 fatty acids and 17beta-estradiol are superior to
statins alone. The only two clinical studies performed in patients with
acute coronary syndromes showed a relatively weak effect of
statins on haemostasis in those patients. Although various
statins may produce different effects on individual variables, there are no convincing data showing that differences in their physicochemical and pharmacokinetic properties significantly alter their net effect on excessive procoagulant activity. Apart from the
lipid-lowering effect,
statins suppress the synthesis of several important nonsterol
isoprenoids derived from the
mevalonate pathway, especially farnesyl and geranylgeranyl
pyrophosphates, which via enhanced protein prenylation, are involved in the regulation of many cellular processes. It is presumed that the inhibitory effect of
statins on the
mevalonate pathway is involved in the regulation of some key steps of coagulation and fibrinolysis processes. In this way they probably regulate the synthesis of TF, tPA and
PAI-1, and perhaps they also control the generation and activity of
thrombin. The beneficial effects of
statins on coagulation and fibrinolysis may be responsible for their ability to decrease the number of cardiovascular events. The
lipid-independent effects of
statins on haemostasis may contribute to the marked decrease in the incidence rates of mortality, hospitalisation and revascularisation in patients treated with these drugs.