Simvastatin depresses blood clotting by inhibiting activation of prothrombin, factor V, and factor XIII and by enhancing factor Va inactivation

Background-The mechanism of the antithrombotic action of statins is unclear . The aim of this study was to evaluate the effects of simvastatin on the c oagulation process at sites of microvascular injury. Methods and Results-Tissue factor-initiated coagulation was assessed in blo od samples collected every 30 seconds from bleeding-time wounds of 17 patie nts who had advanced coronary artery disease and total cholesterol levels o f 224.6+/-11.8 mg/dL (mean+/-SEM). Quantitative Western blotting for time c ourses of fibrinogen depletion and activation of prothrombin, factor V, and factor XIII was performed before and after 3 months of simvastatin treatme nt (20 mg/d). Simvastatin induced reductions in total cholesterol (23%) and LDL-cholesterol (36%), which were accompanied by significant decreases in the rates of prothrombin activation (16.2+/-2.1%; P=0.004), formation of al pha -thrombin B-chain (27.4+/-1.8%: P=0.001), generation of factor Va heavy chain (29.7+/-3.1%; P=0.007) and factor Va light chain (18.9+/-1.2%; P=0.0 2), factor XIII activation (19.8+/-1.3%; P=0.001), and fibrinogen conversio n to fibrin (72.2+/-3%; P=0.002). Posttreatment fibrinopeptides A and B con centrations, determined by using high-performance liquid chromatography, we re reduced within the last 30 seconds of bleeding. The 30-kDa fragment of t he factor Va heavy chain (residues 307 to 506), produced by activated prote in C, and the 97-kDa fragment of the factor Va heavy chain (residues 1 to 6 43) were released more rapidly after simvastatin treatment. The antithrombo tic actions of simvastatin showed no relationship to its cholesterol-loweri ng action. Conclusions-Simvastatin treatment depresses blood clotting, which leads to reduced rates of prothrombin activation, factor Va generation, fibrinogen c leavage, factor XIII activation, and an increased rate of factor Va inactiv ation. These effects are not related to cholesterol reduction.