Selective cumulative inhibition of platelet thromboxane production by low-dose aspirin in healthy subjects

Abstract

Acetylation of platelet cyclooxygenase by oral aspirin is dose-dependent and cumulative with repeated administration. However, no single dose of aspirin has been found to be completely selective of platelet thromboxane (TX) synthesis inhibition in man. We determined the dose dependence, cumulative nature and selectivity of aspirin effects on platelet TXB2 and renal prostaglandin (PG) and prostacyclin (PGI2) production. We measured, by radioimmunoassay, serum TXB2 levels after whole blood clotting and urinary excretion of PGE2, PGF(2α), and 6-keto-PGF(1α), before and after single or repeated oral aspirin doses given to 46 healthy subjects. Single doses of 6-100 mg aspirin resulted in a linear (r = 0.92, P < 0.01) inhibition of platelet TXB2 production, ranging from 12 to 95% after 24 h. A daily dose of 0.45 mg/kg given for 7 d produced a cumulative and virtually complete inhibition of platelet TXB2 production, without significantly reducing the urinary excretion of PGE2, PGF(2α), and 6-keto-PGF(1α) in both healthy men and women. The platelet inhibitory effect of this regimen was maintained unaltered throughout 1 mo of therapy, with no evidence of cumulative inhibition of renal PG-synthesis. Moreover, furosemide-induced renal PGI2 synthesis and renin release were unaffected by chronic low-dose aspirin. Following cessation of aspirin therapy, platelet TXB2 production returned toward control values at a similar rate as after a single higher dose. We conclude that in healthy subjects: (a) aspirin causes a dose-dependent inhibition of platelet TXA2 production, with no obvious sex-related difference; (b) the inhibitory effect of daily low-dose aspirin is cumulative on platelet TXA2 but not on renal PG-synthesis; (c) during chronic low-dose aspirin therapy, renal PGI2-producing cells are readily activable by furosemide at a time of virtually complete suppression of platelet cyclooxygenase activity.