Thrombogenic effect of high-dose aspirin in rabbits. Relationship to inhibition of vessel wall synthesis of prostaglandin I2-like activity.
Aspirin is a promising antithrombogenic agent. It inhibits the generation of thromboxane A(2) by acetylating platelet cyclo-oxygenase. Aspirin also inhibits vessel wall production of PGI(2) which is an inhibitor of platelet aggregation, and therefore is potentially thrombotic. To investigate these two opposing effects we studied the effects of aspirin upon fibrin accretion onto experimentally induced venous thrombi in rabbits and on the PGI(2)-like activity of vessel wall using the thrombin-induced [(14)C]serotonin release assay. A 200-mg/kg dose of aspirin significantly augmented thrombus size when compared to (a) sodium salicylate administered in equal doses, (b) aspirin in a 10-mg/kg dose or (c) controls (P < 0.001). A 200-mg/kg dose of aspirin totally inhibited vessel wall PGI(2)-like activity whereas aspirin in a 10-mg/kg dose produced less inhibition, and 200 mg/kg sodium salicylate had no effect. Local instillation of tranylcypromine, an inhibitor of PGI(2) formation, also significantly augmented thrombus size compared to saline-treated controls and totally inhibited the production of PGI(2)-like activity. The thrombogenic effect of high dose aspirin was lost if an interval of 2.5 h or longer elapsed between vessel damage and drug administration, indicating that in contrast to the platelet, the effect of aspirin on vessel wall prostaglandin synthesis is relatively short-lived. It is concluded that aspirin, in doses higher than those used clinically, can augment experimental thrombosis, presumably by inhibiting the synthesis of vessel wall PGI(2).
D000818:Animals; D001241:Aspirin / Q000494:pharmacology*; D001777:Blood Coagulation / Q000187:drug effects*; D001808:Blood Vessels / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D011464:Epoprostenol / Q000378:metabolism*; D005337:Fibrin / Q000378:metabolism; D011453:Prostaglandins / Q000378:metabolism*; D011817:Rabbits; D012459:Salicylates / Q000494:pharmacology; D012701:Serotonin / Q000378:metabolism; D014680:Veins
D011453:Prostaglandins; D012459:Salicylates; D012701:Serotonin; D005337:Fibrin; D011464:Epoprostenol; D001241:Aspirin