Abstract 1310: Differential Effects of P2Y12 Versus P2Y1 Antagonism on Thrombosis, Bleeding and Ex Vivo Platelet Aggregation in Rabbits
This study investigated the effects of two platelet puringeric receptors, P2Y1 and P2Y12, on arterial thrombosis, provoked bleeding and ex vivo ADP-induced platelet aggregation in rabbits, using the selective P2Y12 antagonist clopidogrel and the selective P2Y1 antagonist MRS-2500. Clopidogrel (0.3 to 30 mg/kg/d, n=6 per group) was dosed orally for 3 days in rabbits, and experiments were conducted at 2 to 3 hr after the last dose. MRS-2500 (0.006+0.009 to 0.6+0.9 mg/kg+mg/kg/hr, n=6 per group) was infused i.v. starting 30 min before and maintained throughout the experiment. Antithrombotic activity was evaluated by thrombus weight reduction in a model of electrically-induced carotid artery thrombosis. Bleeding time (BT) was measured for up to 20 min following cuticle incision. Ex vivo inhibition of peak platelet aggregation (IPA) to 10 μM ADP was determined in citrated platelet-rich plasma by optical aggregometry. In vehicle-treated rabbits, thrombus weight was 10.3±0.6 mg and BT was 3.1±0.1 min (n=6 per group). Both clopidogrel and MRS-2500 strongly decreased thrombus weight at their top dose (by 85±1% and 84±1%, respectively). At this high level of efficacy, BT (ratio = treatment / vehicle) was increased to 6±0.4 for clopidogrel and only 3±0.3 for MRS-2500; IPA was near-maximal at 57±5% for clopidogrel and 91±3% for MRS-2500. MRS-2500 increased IPA proportionately over the full range of thrombus weight reduction, but clopidogrel produced surprisingly little IPA at doses causing significant antithrombotic efficacy. At IPA of only 18±5%, clopidogrel reduced thrombus weight by 55±2% and doubled BT. At high levels of IPA (>55%), clopidogrel increased BT without additional thrombus weight reduction. BT with MRS-2500 was limited even at high levels (>80%) of both IPA and efficacy. In summary, differential effects of P2Y12 versus P2Y1 antagonism on arterial thrombosis, bleeding and ex vivo platelet aggregation were noted in rabbits. Ex vivo IPA to 10 μM ADP in rabbits underestimates efficacy and better predicts BT prolongation for clopidogrel. In contrast, IPA predicts efficacy and overestimates BT effects for MRS-2500.