Circulating primers enhance platelet function and induce resistance to antiplatelet therapy. (25th June 2015)

• Record Type: Journal Article
• Authors: Blair, T. A.; Moore, S. F.; Hers, I.
• Is Part Of: Journal of thrombosis and haemostasis. Volume 13:Number 8(2015:Aug.)
• Page Start: 1479
• Page End: 1493
• Publication Date: 2015-06-25
• Subjects: Thrombosis -- Periodicals; Hemostasis -- Periodicals; Blood coagulation disorders -- Periodicals; 616.1
• DOI: 10.1111/jth.13022
• Languages: English
• ISSNs: 1538-7933

Abstract

<abstract abstract-type="main" id="jth13022-abs-0001"> <title>Summary</title> <sec id="jth13022-sec-0001" sec-type="section"> <title>Background</title> <p>Aspirin and P2Y<sub>12</sub> antagonists are antiplatelet compounds that are used clinically in patients with thrombosis. However, some patients are 'resistant' to antiplatelet therapy, which increases their risk of developing acute coronary syndromes. These patients often present with an underlying condition that is associated with altered levels of circulating platelet primers and platelet hyperactivity. Platelet primers cannot stimulate platelet activation, but, in combination with physiologic stimuli, significantly enhance platelet function.</p> </sec> <sec id="jth13022-sec-0002" sec-type="section"> <title>Objectives</title> <p>To explore the role of platelet primers in resistance to antiplatelet therapy, and to evaluate whether phosphoinositide 3‐kinase (PI3K) contributes to this process.</p> </sec> <sec id="jth13022-sec-0003" sec-type="section"> <title>Methods and Results</title> <p>We used platelet aggregation, thromboxane A<sub>2</sub> production and <italic>ex vivo</italic> thrombus formation as functional readouts of platelet activity. Platelets were treated with the potent P2Y<sub>12</sub> inhibitor AR‐C66096, aspirin, or a combination of both, in the presence or absence of the platelet primers insulin‐like growth factor‐1 (IGF‐1) and thrombopoietin (TPO), or the Gz‐coupled receptor ligand epinephrine. We found that platelet primers largely overcame the inhibitory effects of antiplatelet compounds on platelet functional responses. IGF‐1‐mediated and TPO‐mediated, but not epinephrine‐mediated, enhancements in the presence of antiplatelet drugs were blocked by the PI3K inhibitors wortmannin and LY294002.</p> </sec> <sec id="jth13022-sec-0004" sec-type="section"> <title>Conclusions</title> <p>These results demonstrate that platelet primers can contribute to antiplatelet resistance. Furthermore, our data demonstrate that there are PI3K‐dependent and PI3K‐independent mechanisms driving primer‐mediated resistance to antiplatelet therapy.</p> </sec> </abstract>