Incomplete reversibility of platelet inhibition following prolonged exposure to ticagrelor

J Thromb Haemost. 2017 May;15(5):858-867. doi: 10.1111/jth.13627. Epub 2017 Feb 18.


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 P2Y12 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 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 P2Y12 regains functionality and irreversible changes occur independent of VASP signaling.

Keywords: acute coronary syndrome; antiplatelet drugs; blood platelets; drug kinetics; ticagrelor.

Publication types

  • Comparative Study

MeSH terms

  • Adenosine / analogs & derivatives*
  • Adenosine / pharmacology
  • Adenosine Monophosphate / analogs & derivatives
  • Adenosine Monophosphate / pharmacology
  • Blood Platelets / drug effects*
  • Blood Platelets / metabolism
  • Cell Adhesion Molecules / blood
  • Dose-Response Relationship, Drug
  • Humans
  • Kinetics
  • Microfilament Proteins / blood
  • P-Selectin / blood
  • Phosphoproteins / blood
  • Platelet Aggregation / drug effects*
  • Platelet Aggregation Inhibitors / pharmacology*
  • Platelet Function Tests
  • Platelet Glycoprotein GPIIb-IIIa Complex / metabolism
  • Prasugrel Hydrochloride / pharmacology
  • Purinergic P2Y Receptor Antagonists / pharmacology*
  • Receptors, Purinergic P2Y12 / blood
  • Receptors, Purinergic P2Y12 / drug effects
  • Signal Transduction / drug effects
  • Ticagrelor


  • Cell Adhesion Molecules
  • Microfilament Proteins
  • P-Selectin
  • P2RY12 protein, human
  • Phosphoproteins
  • Platelet Aggregation Inhibitors
  • Platelet Glycoprotein GPIIb-IIIa Complex
  • Purinergic P2Y Receptor Antagonists
  • Receptors, Purinergic P2Y12
  • SELP protein, human
  • vasodilator-stimulated phosphoprotein
  • Adenosine Monophosphate
  • cangrelor
  • Prasugrel Hydrochloride
  • Ticagrelor
  • Adenosine