Abstract 482: Dose Dependent Effect of Aspirin in Platelets: Results from the ADEPT Study
Background: The antiplatelet effect of aspirin is believed to be due to COX-1 inhibition. However, dose dependent inhibition of non-COX-1 mediated pathways in platelets by aspirin may influence overall antithrombotic properties.
Methods: In the ADEPT (Aspirin Dose and Effect on PlaTelets) Study, a prospective, randomized, double-blind, and double crossover investigation, the effect of aspirin dosing on platelet inhibition using multiple assays in patients with stable coronary artery disease was evaluated. Patients (n=110) were randomized to a drug treatment sequence of 81, 162 and 325 mg/day for 4 weeks each over a 12 week period. 2 and 5 mM arachidonic acid (AA)-, ADP- and collagen -induced aggregation by light transmittance aggregometry (LTA); 1mM AA-induced aggregation by thrombelastography (TEG), and collagen/epinephrine-based PFA-100 methods were used to evaluate aspirin response at the end of each treatment period.
Results: Aspirin response measured by collagen-induced platelet aggregation by LTA and PFA-100 exhibited a significant dose related response (81 vs 162mg, p=0.005, and 81mg vs 325 mg, p=0.001) whereas ADP and AA-induced aggregation showed no effect of dose (p >0.05 for all comparisons). However, there was near complete inhibition (~97%) of the platelet COX-1 pathway as indicated by 1,2 and 5 mM AA-induced platelet aggregation by LTA and 1mM induced whole blood aggregation by TEG at all doses of aspirin.
Conclusions: Despite near complete inhibition of COX-1 at all doses of aspirin, a dose-dependent inhibition of collagen-induced platelet aggregation measured by LTA and PFA-100 was observed, indicating a novel non-COX-1 mediated dose dependent inhibition of platelet function by aspirin. These data suggest that aspirin exerts a non-COX-1 dependent effect on pathways at or downstream from the GPVI receptor. Non-COX-1 mediated pathways may affect the overall antithrombotic properties of aspirin and deserve further investigation.