Ticagrelor Inhibits Toll-Like and Protease-Activated Receptor Mediated Platelet Activation in Acute Coronary Syndromes

Cardiovasc Drugs Ther. 2020 Feb;34(1):53-63. doi: 10.1007/s10557-019-06932-7.

Abstract

Purpose: Since ticagrelor inhibits the cellular uptake of adenosine, thereby increasing extracellular adenosine concentration and biological activity, we hypothesized that ticagrelor has adenosine-dependent antiplatelet properties. In the current study, we compared the effects of ticagrelor and prasugrel on platelet activation in acute coronary syndrome (ACS).

Methods: Platelet surface expression of P-selectin and activated glycoprotein (GP) IIb/IIIa in response to adenosine diphosphate (ADP), the toll-like receptor (TLR)-1/2 agonist Pam3CSK4, the TLR-4 agonist lipopolysaccharide (LPS), the protease-activated receptor (PAR)-1 agonist SFLLRN, and the PAR-4 agonist AYPGKF were measured by flow cytometry in blood from 80 ticagrelor- and 80 prasugrel-treated ACS patients on day 3 after percutaneous coronary intervention. Residual platelet aggregation to arachidonic acid (AA) and ADP were assessed by multiple electrode aggregometry and light transmission aggregometry.

Results: ADP-induced platelet activation and aggregation, and AA-induced platelet aggregation were similar in patients on ticagrelor and prasugrel, respectively (all p ≥ 0.3). Further, LPS-induced platelet surface expression of P-selectin and activated GPIIb/IIIa did not differ significantly between ticagrelor- and prasugrel-treated patients (both p > 0.4). In contrast, Pam3CSK4-induced platelet surface expression of P-selectin and activated GPIIb/IIIa were significantly lower in ticagrelor-treated patients (both p ≤ 0.005). Moreover, SFLLRN-induced platelet surface expression of P-selectin and activated GPIIb/IIIa were significantly less pronounced in patients on ticagrelor therapy compared to prasugrel-treated patients (both p < 0.03). Finally, PAR-4 mediated platelet activation as assessed by platelet surface expression of activated GPIIb/IIIa following stimulation with AYPGKF was significantly lower in patients receiving ticagrelor (p = 0.02).

Conclusion: Ticagrelor inhibits TLR-1/2 and PAR mediated platelet activation in ACS patients more strongly than prasugrel.

Keywords: Antiplatelet therapy; Cardiovascular disease; P2Y12 antagonists; Protease-activated receptors; Toll-like receptors.

Publication types

  • Comparative Study
  • Observational Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acute Coronary Syndrome / blood
  • Acute Coronary Syndrome / diagnosis
  • Acute Coronary Syndrome / therapy*
  • Aged
  • Blood Platelets / drug effects*
  • Blood Platelets / metabolism
  • Female
  • Humans
  • Male
  • Middle Aged
  • P-Selectin / metabolism
  • Percutaneous Coronary Intervention* / adverse effects
  • Platelet Aggregation / drug effects*
  • Platelet Aggregation Inhibitors / therapeutic use*
  • Platelet Glycoprotein GPIIb-IIIa Complex / metabolism
  • Prasugrel Hydrochloride / therapeutic use*
  • Purinergic P2Y Receptor Antagonists / therapeutic use*
  • Receptors, Proteinase-Activated / metabolism*
  • Signal Transduction
  • Ticagrelor / therapeutic use*
  • Toll-Like Receptors / metabolism*
  • Treatment Outcome

Substances

  • P-Selectin
  • Platelet Aggregation Inhibitors
  • Platelet Glycoprotein GPIIb-IIIa Complex
  • Purinergic P2Y Receptor Antagonists
  • Receptors, Proteinase-Activated
  • SELP protein, human
  • Toll-Like Receptors
  • Prasugrel Hydrochloride
  • Ticagrelor