Ethanol enhances the inhibitory effect of an oral GPIIb/IIIa antagonist on human platelet function

Abstract

Ethanol is a commonly used substance that can significantly influence platelet responses when combined with therapeutic drugs. In in vitro studies, we combined ethanol with LY309562, a novel 2,6-disubstituted isoquinolone RGD mimic that competes for fibrinogen binding to GPIIb/IIIa. Ethanol inhibits aggregation and secretion, partly by inhibiting thromboxane A2 formation. We measured aggregation and secretion of dense granule contents by platelets labeled with [14C] serotonin in plasma from blood anticoagulated with FPRCH2Cl (PPACK). Alone, LY309562 dose-dependently inhibited aggregation induced by 10 μmol/L adenosine diphosphate, 1 μg/mL collagen, 2 μmol/L U46619 (a thromboxane A2 mimetic), or 15 μmol/L SFLLRN (protease-activated receptor-1-activating peptide); inhibition was complete at 1 μmol/L LY309562 and partial at 0.1 μmol/L (50% inhibitory concentration [IC50] 0.19-0.33 μmol/L). Secretion induced by collagen, U46619, and SFLLRN was also inhibited by LY309562 (IC50 0.08-0.31 μmol/L). At inhibitory concentrations of LY309562, ethanol (2 or 4 mg/mL) further inhibited responses to collagen, U46619, and SFLLRN (IC50 for aggregation 0.12-0.16 μmol/L; for secretion 0.04-0.12 μmol/L). Responses of aspirin-treated platelets to U46619 were also inhibited, indicating that ethanol was not acting solely by inhibiting thromboxane A2 formation. Because it is likely that our results with LY309562 are representative of results with other GPIIb/IIIa antagonists, our in vitro data suggest that the concomitant use of GPIIb/IIIa antagonists and consumption of alcoholic beverages may result in further impairment of platelet participation in hemostasis and thrombosis. (J Lab Clin Med 2002;140:391-7)