Ticagrelor inhibits human platelet aggregation via adenosine in addition to P2Y12 antagonism

Summary Background Ticagrelor, a P2Y12 antagonist, is an antiplatelet agent approved for the treatment of acute coronary syndromes; it also inhibits adenosine uptake by erythrocytes and other cells. Objective To test whether ticagrelor inhibits platelet aggregation (PA) in whole blood (WB) by increasing the extracellular levels of adenosine, which inhibits PA via the A2A receptor. Methods Collagen‐induced PA was measured in WB or platelet‐rich plasma (PRP) from 50 healthy subjects and two patients with inherited P2Y12 deficiency, in presence/absence of adenosine concentrations that by themselves marginally affected PA in WB, and ZM241385 (A2A antagonist). The effects of ticagrelor, the active metabolite of prasugrel (PAM) (P2Y12 antagonist), and dipyridamole (adenosine uptake inhibitor) on PA and on adenosine clearance in WB were compared. Results For PA in WB, adenosine contributed to drug‐induced inhibition of PA; the adenosine contribution was similar for dipyridamole and ticagrelor but was significantly greater for ticagrelor than for PAM (P 60 min in the presence of dipyridamole. Conclusion This study provides the first evidence of an additional antiplatelet mechanism by ticagrelor, mediated by the induced increase of adenosine levels.