Increased Thromboxane Biosynthesis in Type lla Hypercholesterolemia

Background. Increased platelet thromboxane (TX)A2 production has been described in type IIa hypercholesterolemia. To verify the relevance of these capacity-related measurements to the actual rate of TXA2 biosynthesis in vivo, we studied the urinary excretion of its major enzymatic metabolites in 46 patients with type hIa hypercholesterolemia and 20 age-matched controls. Methods and Results. Urinary ll-dehydro-TXB2 and 2,3-dinor-TXB2 were measured by previously validated radioimmunoassays. The excretion rate of ll-dehydro-TXB2 was significantly (p<0.001) higher in patients (68.7±35.1 ng/hr, mean±SD) than in controls (22.4±9.4 ng/hr), with metabolite excretion >2 SD of the normal mean in 74% of the patients. Urinary ll-dehydro-TXB2 was significantly (p<0.01) correlated with the threshold aggregating concentration of collagen (r= -0.641) and arachidonate (r= -0.734) and with agonist-induced platelet TXB2 production in vitro (r=0.647 and 0.748, respectively). Moreover, a statistically significant correlation (r=0.673,p<0.001, n=66) was found between ll-dehydroTXB2 excretion and total plasma cholesterol. The enzyme 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor simvastatin (20 mg/day for 6 months) significantly reduced cholesterol levels by 22-28% and urinary ll-dehydro-TXB2 excretion by 32-42% in 10 patients. However, the reduction in the latter did not correlate with the reduction in the former and may have resulted from a nonspecific effect of simvastatin. Moreover, selective inhibition of platelet cyclooxygenase activity by low-dose aspirin (50 mg/day for 7 days) was associated with cumulative inhibition of ll-dehydro-TXB2 excretion by approximately 70%v in six patients. Conclusions. TXA2 biosynthesis is enhanced in the majority of patients with type lla hypercholesterolemia; this is, at least in part, a consequence of abnormal cholesterol levels, as suggested by the correlation between the two. Low-dose aspirin can largely suppress increased metabolite excretion, thus suggesting that it reflects TXA2-dependent platelet activation in vivo. (Circulation 1992;85:1792-1798)