P2Y12 antagonist ticagrelor inhibits the release of procoagulant extracellular vesicles from activated platelets

Abstract

Inhibition of P2Y1 and P2Y12 receptors reduces platelet aggregation and affects the release of distinct subpopulations of PEVs. Ticagrelor decreases the release of procoagulant PEVs from activated platelets, which may contribute to the observed clinical benefits in patients treated with ticagrelor.

Ticagrelor attenuates the increase of extracellular vesicle concentrations in plasma after acute myocardial infarction compared to clopidogrel

“…AFFECT EV is the first clinical study which directly compared the long‐term effects of P2Y12 antagonists ticagrelor and clopidogrel on the concentrations and procoagulant activity of plasma EVs in a randomized and investigator‐blinded way. Different P2Y12 antagonists added to whole blood or platelet‐rich plasma were shown to decrease the agonist‐induced release of platelet EVs . However, the previous evidence was derived from experimental studies and one uncontrolled cohort study, whereas our study compared the effects of ticagrelor and clopidogrel on EV release head‐to‐head, in a randomized and investigator‐blinded way.…”

“…Different P2Y12 antagonists added to whole blood or platelet-rich plasma were shown to decrease the agonist-induced release of platelet EVs. 28,[32][33][34][35][36] However, the previous evidence was derived from experimental studies 28,34 and one uncontrolled cohort study, 37 whereas our study compared the effects of ticagrelor and clopidogrel on EV release head-to-head, in a randomized and investigator-blinded way. Thus, our study increased the level of evidence of this finding from level C (data derived from small, observational studies) to level B (data derived from a single randomized controlled trial).…”

Randomized controlled trial protocol to investigate the antiplatelet therapy effect on extracellular vesicles (AFFECT EV) in acute myocardial infarction

“…The procoagulant activity of EVs will be determined as the ability of EVs in plateletfree plasma to generate fibrin, as described previously [30]. Briefly, after pre-incubation for min at 37°C, clotting will be initiated by addition of CaCl2.…”

“…Both ticagrelor and clopidogrel inhibit the release of platelet EVs [30,31], but the effects of ticagrelor and clopidogrel on EVs have never been compared in a randomized clinical study.…”

Role of P2Y Receptors in Platelet Extracellular Vesicle Release

“…Whereas the release of CD61+ PEV requires inhibition of both ADP receptors, the release of CD61+/CD62P+/PS+ PEV is sensitive to inhibition of the P2Y12 receptor alone. Because CD62P+/PS+ PEVs are involved in inflammation and thrombosis, the anti-inflammatory effects of the P2Y12 antagonist ticagrelor may in part be due to inhibition of this PEV subpopulation [ 31 ]. However, in another study, inhibition of P2Y12 receptor inhibited the release of PEV in response to ADP and other agonists whereas inhibition of the P2Y1 receptor inhibited the release of PEVs only upon activation by ADP [ 32 ].…”