Low dose aspirin and inhibition of thromboxane B2 production in healthy subjects

doi:10.1016/0049-3848(80)90066-3

Thrombosis Research

Volume 17, Issues 3–4, 1–15 February 1980, Pages 317-327

https://doi.org/10.1016/0049-3848(80)90066-3 Get rights and content

Abstract

We studied the time- and dose-dependence of the inhibitory effect of oral aspirin on platelet production of thromboxane (TX) B₂ in response to endogenously formed thrombin, by allowing the whole blood to clot at 37°C for 30 min and measuring TXB₂ concentrations by radioimmunoassay in the separated serum. The concentrations of generated TXB₂ averaged 222.4 ± 81.3 (SD) ng/ml of serum in 45 healthy subjects, and were highly reproducible in the same subject upon repeated sampling. A single 100-mg aspirin dose reduced serum TXB₂ by 98% during the 1^st hour. Single doses of 100–400 mg aspirin resulted in 94–98% inhibition after 24 and 48 h, and 90–92% after 72h. Thereafter, serum TXB₂ returned to control levels with a time course consistent with platelet turnover. More than 90% inhibition could be maintained, over one month, by giving a 200-mg aspirin dose every 72h. Thus, aspirin can achieve a ceiling effect on TXB₂ production in healthy subjects at a considerably lower dosage than currently employed regimens for antithrombotic therapy.

References (31)

M.A. Packham et al.
Clinical pharmacology of platelets
Blood
(1977)
J.R. O'Brien
Effects of salicylates on human platelets
Lancet
(1968)
S. Villa et al.
Normal prostacyclin-like activity in vascular tissue from thrombocytopenic rats
Thromb.Res.
(1977)
N.L. Baenziger et al.
Cultured human skin fibroblasts and arterial cells produce a labile platelet-inhibitory prostaglandin
Biochem.Biophys.Res.Commun.
(1977)
H. Anhut et al.
Radioimmunological determination of Thromboxane release in cardiac anaphylaxis
Eur.J.Pharmacol.
(1977)
C. Patrono et al.
Aspirin intolerance: unaltered susceptibility of platelet cyclooxygenase to inhibition by aspirin $in vitro$
J.Allergy Clin.Immunol.
(1978)
M.J. Silver et al.
Human blood Prostaglandins: formation during clotting
Prostaglandins
(1972)
A randomized trial of Aspirin and Sulfinpyrazone in threatened stroke
N.Engl.J.Med.
(1978)
H.J. Weiss et al.
The effect of salicylates on the hemostatic properties of platelets in man
J.Clin.Invest.
(1968)
G.J. Roth et al.
Acetylation of prostaglandin synthetase by aspirin

G.J. Roth et al.

Modification by aspirin of the amino terminal serine of Prostaglandin synthetase

Clin. Res.

(1978)

J.B. Smith et al.

Aspirin selectively inhibits prostaglandin production in human platelets

Nature (New Biol.)

(1971)

M. Hamberg et al.

Isolation and structure of two prostaglandin endoperoxides that cause platelet aggregation

M. Hamberg et al.

Thromboxanes: a new group of biologically active compounds derived from prostaglandin endoperoxides

P.W. Majerus

Why aspirin?

Circulation

(1976)

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Citation Excerpt :
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Secondary analysis of multi-centered randomized controlled trial investigating effects of daily LDA (60 mg) in high-risk pregnancies. Maternal samples were drawn at three points: before LDA initiation (13–26 weeks’ gestation), 24–28 weeks’ gestation (at least two weeks after LDA) and 34–36 weeks’ gestation. 15-epi-LXA₄ levels were measured by ELISA.
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PaperLow dose aspirin and inhibition of thromboxane B2 production in healthy subjects

Abstract

Blood

Lancet

Thromb.Res.

Biochem.Biophys.Res.Commun.

Eur.J.Pharmacol.

J.Allergy Clin.Immunol.

Prostaglandins

A randomized trial of Aspirin and Sulfinpyrazone in threatened stroke

N.Engl.J.Med.

The effect of salicylates on the hemostatic properties of platelets in man

J.Clin.Invest.

Acetylation of prostaglandin synthetase by aspirin