Drug-Free Platelets Can Act as Seeds for Aggregate Formation During Antiplatelet Therapy.
2122 - 2133
Arterioscler Thromb Vasc Biol
MetadataShow full item record
OBJECTIVE: Reduced antiplatelet drug efficacy occurs in conditions of increased platelet turnover, associated with increased proportions of drug-free, that is, uninhibited, platelets. Here, we detail mechanisms by which drug-free platelets promote platelet aggregation in the face of standard antiplatelet therapy. APPROACH AND RESULTS: To model standard antiplatelet therapy, platelets were treated in vitro with aspirin, the P2Y12 receptor blocker prasugrel active metabolite, or aspirin plus prasugrel active metabolite. Different proportions of uninhibited platelets were then introduced. Light transmission aggregometry analysis demonstrated clear positive associations between proportions of drug-free platelets and percentage platelet aggregation in response to a range of platelet agonists. Using differential platelet labeling coupled with advanced flow cytometry and confocal imaging we found aggregates formed in mixtures of aspirin-inhibited platelets together with drug-free platelets were characterized by intermingled platelet populations. This distribution is in accordance with the ability of drug-free platelets to generate thromboxane A2 and so drive secondary platelet activation. Conversely, aggregates formed in mixtures of prasugrel active metabolite-inhibited or aspirin plus prasugrel active metabolite-inhibited platelets together with drug-free platelets were characterized by distinct cores of drug-free platelets. This distribution is consistent with the ability of drug-free platelets to respond to the secondary activator ADP. CONCLUSIONS: These experiments are the first to image the interactions of inhibited and uninhibited platelets in the formation of platelet aggregates. They demonstrate that a general population of platelets can contain subpopulations that respond strikingly differently to overall stimulation of the population and so act as the seed for platelet aggregation.
AuthorsHoefer, T; Armstrong, PC; Finsterbusch, M; Chan, MV; Kirkby, NS; Warner, TD
- College Publications 
Showing items related by title, author, creator and subject.
Investigation of the role of platelet turnover on platelet inhibition and thrombus formation with regard to antiplatelet therapy Hofer, Thomas (Queen Mary University of London, 2014-05-27)Aspirin is often prescribed in patients with acute coronary syndromes together with an ADP-P2Y12 inhibitor such as clopidogrel or prasugrel, an established treatment protocol called dual antiplatelet therapy. Although short ...
Novel whole blood assay for phenotyping platelet reactivity in mice identifies ICAM-1 as a mediator of platelet-monocyte interaction. Armstrong, PC; Kirkby, NS; Chan, MV; Finsterbusch, M; Hogg, N; Nourshargh, S; Warner, TD (2015-09-03)Testing of platelet function is central to the cardiovascular phenotyping of genetically modified mice. Traditional platelet function tests have been developed primarily for testing human samples and the volumes required ...
Platelet responses to agonists in a cohort of highly characterised platelet donors are consistent over time. Garner, SF; Furnell, A; Kahan, BC; Jones, CI; Attwood, A; Harrison, P; Kelly, AM; Goodall, AH; Cardigan, R; Ouwehand, WH (2016-12-21)BACKGROUND AND OBJECTIVES: Platelet function shows significant inheritance that is at least partially genetically controlled. There is also evidence that the platelet response is stable over time, but there are few studies ...