Protease‐activated receptor‐mediated platelet aggregation in acute coronary syndrome patients on potent P2Y12 inhibitors

Abstract

Background Despite the increasing use of potent P2Y12 inhibitors, further atherothrombotic events still impair the prognosis of many acute coronary syndrome (ACS) patients. This may in part be attributable to intact platelet aggregation via the human thrombin receptors protease‐activated receptor (PAR)‐1 and PAR‐4. Objective We studied PAR mediated platelet aggregation in ACS patients following percutaneous coronary intervention (PCI) with stent implantation in a cross‐sectional study. Methods Platelet aggregation to ADP as well as to the PAR‐1 agonist SFLLRN and the PAR‐4 agonist AYPGKF was assessed by multiple electrode aggregometry in 194 ACS patients on dual antiplatelet therapy with aspirin and either prasugrel (n = 114) or ticagrelor (n = 80) 3 days after PCI. Results Based on the consensus cutoff value, high on‐treatment residual platelet reactivity to ADP (HRPR ADP) was observed in only 2 prasugrel‐treated patients. Both patients with HRPR ADP had also a normal response to SFLLRN and AYPGKF. Among the 112 prasugrel‐treated patients with adequate P2Y12 inhibition, 50 patients (45%) still had a normal response to SFLLRN, and 70 patients (63%) still had a normal response to AYPGKF. Among the 80 ticagrelor‐treated patients with adequate P2Y12 inhibition, 25 patients (31%) still had a normal response to SFLLRN, and 50 (63%) still had a normal response to AYPGKF. Conclusion Normal platelet aggregation via PAR‐1 and PAR‐4 is preserved in many patients with adequate P2Y12 inhibition by prasugrel and ticagrelor. The present findings may at least in part explain adverse ischemic events despite potent P2Y12 inhibition.

Angiotensin-Converting Enzyme Inhibitors and Angiotensin Receptor Blockers in Acute Coronary Syndrome: Implications for Platelet Reactivity?

“…On-treatment residual AA-and ADP-inducible platelet reactivity was significantly higher in patients with ACE inhibitors as compared to patients with ARBs (AA: 17 AU [12][13][14][15][16][17][18][19][20][21][22] vs. 13 AU [7][8][9][10][11][12][13][14][15][16][17][18], p = 0.006; ADP: 20 AU (16-24) vs. 16 AU (11)(12)(13)(14)(15)(16)(17)(18)(19)(20), p < 0.001; Table 2, Fig. 1).…”

“…However, atherothrombotic events still impair the prognosis of many patients with ACS despite state-of-the-art antiplatelet therapy [6]. While high on-treatment residual platelet reactivity (HRPR) to ADP is a rare phenomenon in patients treated with prasugrel or ticagrelor [7], subsequent ischemic events in patients receiving the novel P2Y12 antagonists may in part be attributable to platelet activation via other, non-inhibited pathways [8][9][10]. In addition, previous studies have identified several concomitant pharmacological therapies potentially attenuating the antiplatelet effects of clopidogrel [11][12][13][14].…”

Platelet-to-lymphocyte and Neutrophil-to-lymphocyte Ratios Predict Target Vessel Restenosis after Infrainguinal Angioplasty with Stent Implantation

“…NPA are a sensitive marker of platelet activation and reflect the extent of neutrophil-platelet interaction [ 18 , 41 ]. TRAP is a strong protease activated receptor−1 agonist leading to pronounced platelet activation despite dual antiplatelet therapy [ 42 , 43 ]. Moreover, we have previously shown that TRAP inducible platelet surface expression of P-selectin and activated glycoprotein IIb/IIIa are associated with ischemic events after peripheral angioplasty and stenting [ 3 ].…”

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

“…Furthermore, in previous studies we have shown that alternative platelet activation pathways, i.e. toll- like (TLR) and protease- activated receptor (PAR) signaling, remain active despite P2Y 12 inhibition with prasugrel or ticagrelor, 33 , 49 pointing at the possibility that even these potent drugs are associated with HRPR.…”

“…Whole blood impedance aggregometry was performed with the Multiplate analyzer (Roche Diagnostics, Mannheim, Germany) as previously described. 29 , 33 One Multiplate test cell contains 2 independent sensor units and 1 unit consists of 2 silver-coated highly conductive copper wires with a length of 3.2 mm. After dilution (1:2 with 0.9% NaCl solution) of hirudin-anticoagulated whole blood and stirring in the test cuvettes for 3 minutes at 37°C, ADP (6.4 μM, Roche Diagnostics, Mannheim, Germany) or arachidonic acid (AA; final concentration of 0.5 mM; Roche Diagnostics, Mannheim, Germany), was added and aggregation was continuously recorded for 6 minutes.…”