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Incomplete reversibility of platelet inhibition following prolonged exposure to ticagrelor
Author(s) -
Gerrits A. J.,
Jakubowski J. A.,
Sugidachi A.,
Michelson A. D.,
Frelinger A. L.
Publication year - 2017
Publication title -
journal of thrombosis and haemostasis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.947
H-Index - 178
eISSN - 1538-7836
pISSN - 1538-7933
DOI - 10.1111/jth.13627
Subject(s) - ticagrelor , platelet , pharmacology , p2y12 , medicine , platelet inhibition , platelet aggregation , chemistry , aspirin , clopidogrel
Essentials Irreversible platelet inhibition persists after reversibly‐binding ticagrelor is discontinued. Reversibility of platelet inhibition by ticagrelor and its active metabolite was assessed. Incomplete recovery was observed after prolonged exposure to ticagrelor. Activated GPIIb‐IIIa and P‐selectin, not platelet reactivity index, showed irreversibility.Summary Introduction Ticagrelor is described as a reversible P2Y 12 antagonist. However, residual platelet inhibition persists after discontinuation of ticagrelor when plasma levels are undetectable. We assessed the reversibility of platelet inhibition by ticagrelor and its active metabolite (T‐ AM ) in comparison with cangrelor and prasugrel's active metabolite (P‐ AM ). Methods Whole blood was treated in vitro with ~ 50% inhibitory concentrations of ticagrelor, T‐ AM , cangrelor, P‐ AM and assessed for ADP ‐stimulated activated GPII b‐ III a and P‐selectin and vasodilator‐stimulated phosphoprotein ( VASP ) platelet reactivity index ( PRI ) before and after 100‐fold dilution. Results Platelets exposed for 30 min to ticagrelor, T‐ AM or cangrelor showed full recovery of activated GPII b‐ III a but only partial recovery of P‐selectin. Longer exposure (24 h) to the drug decreased reversibility of activated GPII b‐ III a by ticagrelor (65.1% [49.5–80.6], % of vehicle with 95% confidence interval [ CI ]) and T‐ AM (88.8% [79.2–98.3]), but not by cangrelor (101.4% [96.4–106.4]). Compared with 30 min exposure, the reversibility of P‐selectin further decreased after 24 h exposure to ticagrelor (from 91.8% [82.1–101.5] to 51.8% [45.5–85.0]), but not T‐ AM (from 79.0% [67.8–90.3] to 77.4% [61.8–93.1]) or cangrelor (from 76.0% [67.6–84.4] to 76.2% [70.6–81.8]). In contrast, 24 h exposure to ticagrelor, T‐ AM and cangrelor resulted in full recovery of platelet reactivity as measured by PRI . Platelets exposed to P‐ AM showed no recovery of ADP reactivity. Conclusions Incomplete recovery after prolonged exposure to ticagrelor, observed by activated GPII b‐ III a and P‐selectin but not upstream VASP signaling, suggests that P2Y 12 regains functionality and irreversible changes occur independent of VASP signaling.