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@article{Taylor:2019:10.1111/bph.14589,
author = {Taylor, KA and Smyth, E and Rauzi, F and Cerrone, M and Khawaja, AA and Gazzard, B and Nelson, M and Boffito, M and Emerson, M},
doi = {10.1111/bph.14589},
journal = {British Journal of Pharmacology},
pages = {879--889},
title = {Pharmacological impact of antiretroviral therapy on platelet function to investigate HIV-associated cardiovascular risk},
url = {http://dx.doi.org/10.1111/bph.14589},
volume = {176},
year = {2019}
}

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TY  - JOUR
AB  - Background and purposeSome clinical studies have reported increased myocardial infarction in people living with HIV taking the antiretroviral abacavir sulphate (ABC). Given that clinical studies contain confounding variables (e.g. HIV status), we investigated the pharmacological impact of antiretrovirals on platelet function in HIVnegative volunteers in order to identify mechanisms of increased cardiovascular risk.Experimental approachPlatelets were isolated from healthy volunteers and HIVnegative subjects enrolled on a Phase I clinical trial and platelet function evaluated using aggregometry and flow cytometry. In vivo platelet thromboembolism was monitored in anaesthetised mice.Key resultsHuman platelet aggregation was unaffected by all antiretrovirals tested but ABC treatment led uniquely to increased platelet granule release. ABC also interrupted nitric oxide (NO)mediated inhibition of platelet aggregation and increased in vivo aggregation in mice. An alternative antiretroviral, tenofovir, did not affect platelet function. Furthermore, aggregation and activation of platelets isolated from twenty subjects taking clinicallyrelevant doses of tenofovir were comparable to baseline samples.Conclusions and implicationsABC can enhance platelet activation, independently of HIV status suggesting a potential pharmacological effect that is absent with tenofovir. Mechanistically, we propose that ABC enhances platelet degranulation and interrupts NOmediated platelet inhibition. The interaction of ABC with NO signalling is supported by data demonstrating ABCmediated enhancement of aggregation in vivo and in vitro responses that persist in the presence of NO. Although an association between ABC and platelet activation has not been confirmed in patients, these findings provide evidence of a mechanistic link between platelet activation and antiretroviral therapy.
AU  - Taylor,KA
AU  - Smyth,E
AU  - Rauzi,F
AU  - Cerrone,M
AU  - Khawaja,AA
AU  - Gazzard,B
AU  - Nelson,M
AU  - Boffito,M
AU  - Emerson,M
DO  - 10.1111/bph.14589
EP  - 889
PY  - 2019///
SN  - 0007-1188
SP  - 879
TI  - Pharmacological impact of antiretroviral therapy on platelet function to investigate HIV-associated cardiovascular risk
T2  - British Journal of Pharmacology
UR  - http://dx.doi.org/10.1111/bph.14589
UR  - https://bpspubs.onlinelibrary.wiley.com/doi/full/10.1111/bph.14589
UR  - http://hdl.handle.net/10044/1/66716
VL  - 176
ER  -

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