title: Incomplete reversibility of platelet inhibition following prolonged exposure to ticagrelor.
abstract: 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.
  
  
  
  Introduction Ticagrelor is described as a reversible P2Y12antagonist. 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 GPIIb-IIIa 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 GPIIb-IIIa but only partial recovery of P-selectin. Longer exposure (24 h) to the drug decreased reversibility of activated GPIIb-IIIa 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 GPIIb-IIIa and P-selectin but not upstream VASP signaling, suggests that P2Y12regains functionality and irreversible changes occur independent of VASP signaling.
authors.affiliation: Center for Platelet Research Studies, Division of Hematology/Oncology, Boston Children's Hospital, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
authors.forename: A J
authors.initials: AJ
authors.lastname: Gerrits
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, USA.
authors.forename: J A
authors.initials: JA
authors.lastname: Jakubowski
authors.affiliation: Biological Research Laboratories, Daiichi Sankyo Co., Ltd., Tokyo, Japan.
authors.forename: A
authors.initials: A
authors.lastname: Sugidachi
authors.affiliation: Center for Platelet Research Studies, Division of Hematology/Oncology, Boston Children's Hospital, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
authors.forename: A D
authors.initials: AD
authors.lastname: Michelson
authors.affiliation: Center for Platelet Research Studies, Division of Hematology/Oncology, Boston Children's Hospital, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
authors.forename: A L
authors.initials: AL
authors.lastname: Frelinger
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000249:Adenosine Monophosphate / Q000031:analogs & derivatives / Q000494:pharmacology; D001792:Blood Platelets / Q000187:drug effects* / Q000378:metabolism; D015815:Cell Adhesion Molecules / Q000097:blood; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007700:Kinetics; D008840:Microfilament Proteins / Q000097:blood; D019007:P-Selectin / Q000097:blood; D010750:Phosphoproteins / Q000097:blood; D010974:Platelet Aggregation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D010979:Platelet Function Tests; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000378:metabolism; D000068799:Prasugrel Hydrochloride / Q000494:pharmacology; D058921:Purinergic P2Y Receptor Antagonists / Q000494:pharmacology*; D058925:Receptors, Purinergic P2Y12 / Q000097:blood / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D000077486:Ticagrelor; D000098662:Vasodilator-Stimulated Phosphoprotein
chemical_list: D015815:Cell Adhesion Molecules; D008840:Microfilament Proteins; D019007:P-Selectin; C548576:P2RY12 protein, human; D010750:Phosphoproteins; D010975:Platelet Aggregation Inhibitors; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D058921:Purinergic P2Y Receptor Antagonists; D058925:Receptors, Purinergic P2Y12; C546937:SELP protein, human; D000098662:Vasodilator-Stimulated Phosphoprotein; D000249:Adenosine Monophosphate; C117446:cangrelor; D000068799:Prasugrel Hydrochloride; D000077486:Ticagrelor; D000241:Adenosine
keywords: acute coronary syndrome; antiplatelet drugs; blood platelets; drug kinetics; ticagrelor