P2Y12 receptor blockade synergises strongly with nitric oxide and prostacyclin to inhibit platelet activation.
File(s)
Accepted version
Author(s)
Type
Journal Article
Abstract
AIMS: In vivo platelet function is a product of intrinsic platelet reactivity, modifiable by dual antiplatelet therapy (DAPT), and the extrinsic inhibitory endothelial mediators, nitric oxide (NO) and prostacyclin (PGI2 ), that are powerfully potentiated by P2Y12 receptor blockade. This implies that for individual patients endothelial mediator production is an important determinant of DAPT effectiveness. Here, we have investigated this idea using platelets taken from healthy volunteers treated with anti-platelet drugs. METHODS: Three groups of male volunteers (n = 8) received either prasugrel (10 mg), aspirin (75 mg) or DAPT (prasugrel + aspirin) once daily for 7 days. Platelet reactivity in the presence of DEA/NONOate and PGI2 was studied before and following treatment. RESULTS: Ex vivo, PGI2 and/or DEA/NONOate had little inhibitory effect on TRAP-6-induced platelet reactivity in control conditions. However, in the presence of DAPT, combination of DEA/NONOate + PGI2 reduced platelet aggregation (74 ± 3% to 19 ± 6%, p < 0.05). In vitro studies showed even partial (25%) P2Y12 receptor blockade produced a significant (67 ± 2% to 39 ± 10%, p < 0.05) inhibition when DEA/NONOate + PGI2 was present. CONCLUSIONS: We demonstrate that PGI2 and NO synergise with P2Y12 receptor antagonists to produce powerful platelet inhibition. Furthermore, even with submaximal P2Y12 blockade the presence of PGI2 and NO greatly enhances platelet inhibition. Our findings highlight the importance of endothelial mediator in vivo modulation of P2Y12 inhibition and introduces the concept of refining ex vivo platelet function testing by incorporating an assessment of endothelial function to better predict thrombotic outcomes and adjust therapy to prevent adverse outcomes in individual patients.
Date Issued
2015-11-11
Date Acceptance
2015-11-05
Citation
British Journal of Clinical Pharmacology, 2015, 81 (4), pp.621-633
ISSN
1365-2125
Publisher
Wiley
Start Page
621
End Page
633
Journal / Book Title
British Journal of Clinical Pharmacology
Volume
81
Issue
4
Copyright Statement
© 2015 The Authors. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
License URL
Subjects
blood platelets
endothelium
epoprostenol
nitric oxide
purinergic P2Y receptor antagonists
Publication Status
Published