Statins as Antithrombotic Drugs

Abstract

Statins are powerful lipid-lowering drugs that inhibit cholesterol biosynthesis via downregulation of hydroxymethylglutaryl coenzyme-A reductase.1 They are largely used in patients with or at risk of cardiovascular disease inasmuch as randomized trials have consistently shown that statins lower the rate of myocardial infarction, stroke, and cardiovascular death.2 The majority of trials with statins investigated patients with stable atherosclerotic disease, in whom the reduction in cardiovascular events appeared to be related to the cholesterol-lowering effect of statins and ultimately to plaque stabilization.3 However, experimental data demonstrated that statins may also exert a direct antithrombotic effect in models of arterial and venous thrombosis via a mechanism unrelated to the cholesterol-lowering activity4,5; this may suggest that statins inhibit several pathways of hemostasis, including platelet activation and coagulation cascade. Consistent with these observations are the potential negative properties that have been observed, including the association between statin therapy and cerebral hemorrhage. In this review, we present experimental data in support of the ability of statins to interfere directly with the clotting system and platelet activation, as well as the clinical settings that suggest that statins exert beneficial effects related to their antithrombotic properties. Colli et al6 were the first to show that statins interfere with activation of the clotting system and the coagulation cascade. Specifically, they demonstrated that fluvastatin dose-dependently inhibits activity of tissue factor (TF), a glycoprotein that converts factor X to factor Xa,7 and suggested that downexpression of geranylgeranylated protein is implicated in TF lowering. These data were confirmed in patients affected by polygenic hypercholesterolemia8 in whom simvastatin 20 mg/d for 8 weeks resulted in downregulation of TF antigen and activity and thrombin generation. Of note, inhibition of clotting activation, as assessed by plasma values of prothrombin fragment F1+2, a marker of …