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

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.

P2Y12 Inhibitor Monotherapy with Clopidogrel versus Ticagrelor in Patients with Acute Coronary Syndrome Undergoing Percutaneous Coronary Intervention

“…Besides, ticagrelor strongly inhibits toll-like receptor-1/2 and protease-activated receptor mediated platelet activation in patients with ACS. Off-target effects of ticagrelor might be one of potential mechanism for the reduction of adverse ischemic outcomes compared to clopidogrel [29].…”

High Mobility Group Box 1 enhances ADP-mediated platelet activation by increasing platelet surface P2Y12localization

“…These data put HMGB1 in the ranks of other platelet agonists such as thrombin and collagen, which stimulate release of endogenous platelet-derived ADP to fuel feed-forward platelet activation and aggregation through P2Y12 46,47 . Although ADP is considered a relatively weak physiologic agonist, it is essential for recruiting and cross-linking additional platelets 45,48,49 and stabilizing the outer shell of the platelet plug 50 . While prior studies have shown that lipopolysaccharide (LPS), a strong TLR4 agonist, induces platelet dense and α-granule release 51 , P2Y12 inhibition has shown mixed results on LPS-induced platelet activation and coagulation [52][53][54][55] . Our data showing an approximately 50% decrease in HMGB1induced platelet activation in the presence of P2Y12 inhibition may serve as a new foundation for studies investigating differences in LPS and HMGB1-mediated platelet signaling.…”

Comparison of Light Transmission Aggregometry With Impedance Aggregometry in Patients on Potent P2Y12 Inhibitors

“…47,48 Further pointing at in vitro differences between prasugrel and ticagrelor-inhibited platelets are our previous findings that ticagrelor exerts a significantly stronger inhibitory effect on TLR-1/2 and PAR mediated platelet activation in ACS patients than prasugrel. 49 On the contrary, the thienopyridines clopidogrel and prasugrel are converted into active metabolites in the liver and intestines and bind covalently to the P2Y 12 receptor. 50 The P2Y 12 receptor enables full and stable platelet aggregation in response to ADP after initiation of platelet aggregation via P2Y 1 .…”