Original Research: Focus on Platelets Ticagrelor Effectively and Reversibly Blocks Murine Platelet P2Y12-Mediated Thrombosis and Demonstrates a Requirement for Sustained P2Y12 Inhibition to Prevent Subsequent Neointima*

Objective—Our goal was to study the effects of ticagrelor on murine platelet function and thrombosis and characterize the time course of P2Y12 inhibition required to inhibit neointima formation following vascular injury. Methods and Results—Mice were treated with ticagrelor or vehicle. Platelet aggregation and P-selectin expression were assessed over time, and thrombus formation was assessed in laser-injured cremasteric arterioles of P2Y12 / and P2Y12 / mice. Neointima formation in FeCl3-injured carotid artery was assessed in C57BL/6 mice treated with different regimens of ticagrelor. Ticagrelor inhibited platelet aggregation and P-selectin expression in a dose-dependent, reversible manner. Ticagrelor inhibited thrombus formation to the same extent as seen in P2Y12 / mice. Neointima formation was markedly reduced in mice treated with ticagrelor before and 4 hours after injury (neointima area: control, 39 921 22 749 m, versus ticagrelor, 3705 2600 m; P 0.01), whereas administration of ticagrelor either before injury only or from 4 hours postinjury was ineffective. Conclusion—Ticagrelor effectively and reversibly inhibits P2Y12-mediated platelet function and thrombosis in mice. P2Y12 inhibition is required both at the time of and after injury to effectively inhibit neointima formation. Additional studies are warranted to evaluate the role of P2Y12 inhibition in preventing restenosis. (Arterioscler Thromb Vasc Biol. 2010;30:2385-2391.)