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 previousl y shown to reduce platelet aggregation and TXB(2) production ex vivo, we investigated TXA(2) biosynthesis and platelet function in 24 patien ts with type IIa hypercholesterolemia randomized to receive in a doubl e-blind fashion simvastatin (20 mg/d) or placebo for 3 months. The uri nary excretion of 11-dehydro-TXB(2), largely a reflection of platelet TXA(2) production in vivo, was measured by a previously validated radi oimmunoassay technique. Blood lipid levels and urinary 11-dehydro-TXB( 2) excretion were significantly (P<.001) reduced by simvastatin. In co ntrast, placebo-treated patients did not show any statistically signif icant changes in either blood lipids or 11-dehydro-TXB(2) excretion. T he reduction in 11-dehydro-TXB(2) associated with simvastatin was corr elated with the reduction in total cholesterol (r=.81, P<.0001), LDL c holesterol (r=.79, P<.0001), and apolipoprotein B (r=.76, P<.0001) lev els. Platelets from patients with type IIa hypercholesterolemia requir ed significantly (P<.01) more collagen and ADP to aggregate and synthe sized less TXB(2) in response to both agonists after simvastatin thera py. Bleeding time, platelet sensitivity to Iloprost, and blood lipopro tein(a) and HDL cholesterol levels were not significantly affected by either treatment. We conclude that enhanced TXA(2) biosynthesis in typ e IIa hypercholesterolemia is, at least in part, dependent on abnormal cholesterol levels and/or other simvastatin-sensitive mechanisms affe cting platelet function.