Abstract 18581: The Effectiveness of P2Y12 Receptor Antagonist Therapy is Strongly Determined by Endothelial Mediators of Platelet Function
Background: In vivo platelet function is a product of intrinsic platelet reactivity, modifiable by dual antiplatelet therapy (DAPT), and the extrinsic inhibitory endothelial mediators NO and PGI2 whose actions are increasingly understood to be potentiated by P2Y12 receptor antagonists. Thus, the in vivo synergy between NO and PGI2 may amplify the anti-thrombotic effects of P2Y12 inhibitors suggesting that at the level of individual patients, endothelial function could influence therapeutic potential. Here, we investigate this by characterising the interplay of PGI2, NO and P2Y12 blockade on platelet function.
Methods: 8 healthy male volunteers received aspirin (75mg) and prasugrel (10mg) for 7 days. Platelet responses to TRAP-6 (25μM) or collagen (4 or 10μg/ml) in the presence of PGI2 (1nM), NO (100nM), PGI2+NO or vehicle were assessed by LTA. Experiments were replicated in vitro (n=4) utilizing aspirin (30μM) and prasugrel active metabolite (PAM; 6, 3 or 1.5μM) to represent maximal and partial P2Y12 blockade.
Results: Ex vivo, prior to DAPT, PGI2, NO, or PGI2+NO had little effect upon platelet aggregation. TRAP-6 (25μM): vehicle, 74±3%; PGI2+NO, 66±3%. Following DAPT, PGI2 or NO alone caused minor inhibition. TRAP-6: vehicle, 57±4%; PGI2, 47±6%; NO 49±6%. Conversely, the combination of PGI2+NO produced strong inhibitory effects, 19±6% (p<0.05).
In vitro, with maximal P2Y12 inhibition (PAM, 6μM) aggregation to TRAP-6 (25μM) was reduced: vehicle, 56±5%; PGI2, 30±12%; NO, 46±7%; PGI2+NO, 15±8% (p<0.05). However, with partial inhibition (PAM, 3μM) only PGI2+NO inhibited aggregation: vehicle, 67±6%; PGI2, 56±9%; NO, 62±5%; PGI2+NO, 33±15% (p<0.05).
Conclusion: Our studies demonstrate that PGI2 and NO synergise with P2Y12 blockade to produce the greatest inhibition of platelet activation. This has important therapeutic and diagnostic implications. For instance, should aspirin be prescribed alongside potent P2Y12 inhibitors, potentially compromising production of PGI2 and consequently, its role in this key synergistic interaction? Additionally, our findings support the concept that assessment of endothelial function be incorporated into ex vivo platelet testing to allow better correlation between platelet testing and at risk patient outcomes.
Author Disclosures: R.B. Knowles: None. M.V. Chan: None. P.C. Armstrong: None. C. Shih: None. M.A. Hayman: None. I. Vojnovic: None. A.T. Tucker: None. A.D. Timmis: None. T.D. Warner: None.
- © 2014 by American Heart Association, Inc.