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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


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.

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