Imperial College London
Alternate

ProfessorJaneMitchell

Faculty of Medicine, National Heart & Lung Institute

Professor of Pharmacology in Critical Care Medicine
 
 
 
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Contact

 

+44 (0)20 7351 8137j.a.mitchell

 
 
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Assistant

 

Ms Lisa Quinn +44 (0)20 7594 1345

 
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Location

 

Sir Alexander Fleming BuildingSouth Kensington Campus

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Summary

 

Publications

Citation

BibTex format

@article{Chan:2015:10.1111/bcp.12826,
author = {Chan, MV and Knowles, RB and Lundberg, MH and Tucker, AT and Mohamed, NA and Kirkby, NS and Armstrong, PC and Mitchell, JA and Warner, TD},
doi = {10.1111/bcp.12826},
journal = {British Journal of Clinical Pharmacology},
pages = {621--633},
title = {P2Y12 receptor blockade synergises strongly with nitric oxide and prostacyclin to inhibit platelet activation.},
url = {http://dx.doi.org/10.1111/bcp.12826},
volume = {81},
year = {2015}
}
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RIS format (EndNote, RefMan)

TY  - JOUR
AB  - 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.
AU  - Chan,MV
AU  - Knowles,RB
AU  - Lundberg,MH
AU  - Tucker,AT
AU  - Mohamed,NA
AU  - Kirkby,NS
AU  - Armstrong,PC
AU  - Mitchell,JA
AU  - Warner,TD
DO  - 10.1111/bcp.12826
EP  - 633
PY  - 2015///
SN  - 1365-2125
SP  - 621
TI  - P2Y12 receptor blockade synergises strongly with nitric oxide and prostacyclin to inhibit platelet activation.
T2  - British Journal of Clinical Pharmacology
UR  - http://dx.doi.org/10.1111/bcp.12826
UR  - http://hdl.handle.net/10044/1/28327
VL  - 81
ER  -
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