INHIBITION OF THROMBOXANE BIOSYNTHESIS AND PLATELET-FUNCTION BY SIMVASTATIN IN TYPE IIA HYPERCHOLESTEROLEMIA

Thromboxane A(2) (TXA(2)) biosynthesis is enhanced in the majority of patients with type IIa hypercholesterolemia. Because simvastatin (a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor) was previously shown to reduce platelet aggregation and TXB(2) production ex vivo, we investigated TXA(2) biosynthesis and platelet function in 24 patients with type IIa hypercholesterolemia randomized to receive in a double-blind fashion simvastatin (20 mg/d) or placebo for 3 months. The urinary excretion of 11-dehydro-TXB(2), largely a reflection of platelet TXA(2) production in vivo, was measured by a previously validated radioimmunoassay technique. Blood lipid levels and urinary 11-dehydro-TXB(2) excretion were significantly (P<.001) reduced by simvastatin. In contrast, placebo-treated patients did not show any statistically significant changes in either blood lipids or 11-dehydro-TXB(2) excretion. The reduction in 11-dehydro-TXB(2) associated with simvastatin was correlated with the reduction in total cholesterol (r=.81, P<.0001), LDL cholesterol (r=.79, P<.0001), and apolipoprotein B (r=.76, P<.0001) levels. Platelets from patients with type IIa hypercholesterolemia required significantly (P<.01) more collagen and ADP to aggregate and synthesized less TXB(2) in response to both agonists after simvastatin therapy. Bleeding time, platelet sensitivity to Iloprost, and blood lipoprotein(a) and HDL cholesterol levels were not significantly affected by either treatment. We conclude that enhanced TXA(2) biosynthesis in type IIa hypercholesterolemia is, at least in part, dependent on abnormal cholesterol levels and/or other simvastatin-sensitive mechanisms affecting platelet function.