Selective Cumulative Inhibition of Platelet Thromboxane Production by Low-dose Aspirin in Healthy Subjects

Paola Patrignani; Paola Filabozzi; Carlo Patrono

doi:10.1172/JCI110576

Selective Cumulative Inhibition of Platelet Thromboxane Production by Low-dose Aspirin in Healthy Subjects

Paola Patrignani, Paola Filabozzi, and Carlo Patrono

Published June 1, 1982 - More info

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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.