Article Text

PDF
22 Inhibition Of ADP- and thromboxane-dependent pathways of platelet aggregation by The P2Y12 antagonists, ticagrelor and prasugrel
  1. N S Kirkby1,2,
  2. P D M Leadbeater2,
  3. M V Chan1,
  4. S Nylander3,
  5. J A Mitchell2,
  6. T D Warner1
  1. 1William Harvey Research Institute, Barts and the London School of Medicine, London, UK
  2. 2National Heart and Lung Institute, Imperial College London, London, UK
  3. 3Bioscience Department, AstraZeneca R&D Mölndal, Sweden

Abstract

Increasing evidence suggests that strong P2Y12 receptor blockade may attenuate both ADP- and thromboxane (TX) A2-dependent pathways of platelet aggregation. To explore this, we compared the potency of two structurally distinct P2Y12 receptor antagonists for (i) inhibition of ADP-dependent aggregation, and (ii) inhibition of TXA2-dependent aggregation and TXA2-synthesis. Platelet-rich plasma from healthy human volunteers was treated with (i) ticagrelor (0.1–10 μM), (ii) prasugrel-active-metabolite (PAM; 0.1–10 μM) or (iii) vehicle. Aggregations to ADP, the TXA2 mimetic U46619 and arachidonic acid (AA) were recorded using 96-well plate light transmission aggregometry. TXA2 synthesis was measured by ELISA for TXB2. Ticagrelor and PAM produced concentration-dependent inhibitions of aggregation to ADP. Ticagrelor was more potent than PAM (−logIC50 against 20 μM ADP: 6.5±0.1 vs 5.6±0.1; p<0.01). As has been reported previously, the potency of ticagrelor, but not PAM, was greater at lower agonist concentration (eg, −logIC50 against 2.5 μM ADP: 7.1±0.3). Both drugs inhibited U46619-induced aggregation (logIC50 against 3 μM U46619, 6.5±0.3 and 5.6±0.1, respectively for ticagrelor and PAM), AA-induced aggregation (−logIC50 against 1 mM AA, 6.8±0.1 and 5.9±0.1) and AA-induced TXA2 formation −logIC50 against 1 mM AA, 6.9±0.9 and 5.9±0.3) with similar potencies as against ADP. P2Y12 antagonists inhibit TXA2 receptor (TP)-dependent platelet aggregation and TXA2 synthesis with similar potencies to those inhibiting ADP-induced aggregation. This is consistent with the idea that the ADP-P2Y12 interaction is crucial in supporting the activation mechanisms downstream of the TXA2 receptor, TP, and those driving TXA2 synthesis. These results question the necessity of anti-thrombotic aspirin therapy when used in combination with strong P2Y12 inhibition.

Statistics from Altmetric.com

Request permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.