An overview of antithrombotic therapy

Aspirin and agents acting on the cyclo-oxygenase pathway

Aspirin irreversibly inhibits cyclo-oxygenase by acetylation of amino acids that are next to the active site. In platelets, this is the rate limiting step in synthesis of thromboxane A₂, and inhibition occurs in the megakaryocyte so that all budding platelets are dysfunctional. Because platelets are unable to regenerate fresh cyclo-oxygenase in response, the effect of aspirin remains as long as the lifespan of the platelet (generally about 10 days). A severe weakness of aspirin is that its specificity for cyclo-oxygenase means it has little effect on other pathways of platelet activation. Thus aspirin fails to prevent aggregation induced by thrombin and only partially inhibits that induced by ADP and high dose collagen. Antithrombotic doses used in clinical trials have varied widely from less than 50 mg to over 1200 mg/day, with no evidence of any difference in clinical efficacy. Absorption is over 80% with extensive presystemic metabolism to salicylic acid. Only the parent acetylsalicylic acid has any significant effect on platelet function.