Soluble CD39 but not Aspirin Decreases Platelet Deposition and Improves Outcome in Reperfused Murine Stroke

P109 Acute ischemic stroke evokes progressive microvascular thrombosis, largely driven by platelet recruitment, at sites distal to the primary site of vascular obstruction. Aspirin (ASA), which blocks thromboxane-mediated platelet aggregation, is of limited efficacy in ischemic stroke and may increase intracerebral hemorrhage. CD39, an integral endothelial protein with enzymatic (apyrase) activity, degrades ADP released by platelets to suppress platelet-mediated platelet recruitment. We recently reported that the CD39 gene is a critical thromboregulator in ischemic cerebral vessels. The current study was designed to determine whether soluble CD39 (solCD39) can limit the accumulation of radiolabeled platelets in stroke and to compare these effects with those of ASA. Twenty C57/BlJ6 mice were used; platelets were isolated from 10 mice and radiolabeled using111 Indium-oxyquinoline. The remaining mice were divided into 2 groups and given 106 cpm platelets and a separate intravenous injection of ASA (5 mg/kg, n=6) or solCD39 (4 mg/kg, n=4) prior to 45 minutes of intraluminal right middle cerebral artery occlusion, followed by suture withdrawal/reperfusion. Ipsilateral/contralateral blood flow, measured by laser doppler at 24 hrs, was significantly greater (44%) in the solCD39- vs the ASA-treated mice (p=0.002). Accumulation of111 Indium-platelets in the ischemic hemispheres, measured as the ipsilateral/contralateral cpm ratio, was 1.02 ± 0.058 for solCD39-treated mice, whereas aspirin failed to limit platelet accumulation and was similar to historic platelet accumulation in untreated murine stroke (2.99 ± 1.88 for ASA, p=0.0002 vs solCD39). Not only was platelet accumulation reduced and cerebral blood flow improved by solCD39, but mortality was significantly reduced by solCD39 vs ASA (0% vs 67%, respectively, p=0.04). CD39-mediated catabolism of ADP in the platelet releasate appears to be a more potent means to reduce postischemic platelet recruitment and improve outcome than ASA-mediated inhibition of the cyclooxygenase pathway.