Abstract
BackgroundAspirin and P2Y12 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.ObjectivesTo explore the role of platelet primers in resistance to antiplatelet therapy, and to evaluate whether phosphoinositide 3-kinase (PI3K) contributes to this process.Methods and ResultsWe used platelet aggregation, thromboxane A2 production and ex vivo thrombus formation as functional readouts of platelet activity. Platelets were treated with the potent P2Y12 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.ConclusionsThese 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.
Highlights
Platelet hemostasis is a tightly regulated process mediated by various feedback control mechanisms and key signaling receptors
ASA irreversibly inhibits the conversion of arachidonic acid (AA) to thromboxane A2 (TxA2), an important positive feedback mediator involved in platelet activation
Our results demonstrate that: (i) platelet primers can rescue the inhibitory effects induced by P2Y12 blockade and ASA treatment; and (ii) phosphoinositide 3-kinase (PI3K) plays a critical role in insulin-like growth factor1 (IGF-1)-mediated and TPO-mediated resistance, whereas there are PI3K-independent mechanisms driving epinephrine-mediated resistance
Summary
Platelet hemostasis is a tightly regulated process mediated by various feedback control mechanisms and key signaling receptors. Disruption of these regulatory controls leads to thrombosis, which, in turn, can trigger the development of an occlusive clot and subsequent cardiovascular complications. The current ‘gold standard’ preventive measure employed by clinics to treat thrombosis involves the administration of antiplatelet drugs that target cyclooxygenase-1 (COX-1) (e.g. acetylsalicylic acid [ASA]; aspirin) and the platelet P2Y12 receptor (e.g. clopidogrel, prasugrel, or ticagrelor). ASA and platelet P2Y12 receptor antagonists may be prescribed to patients as monotherapy; they are administered via a dual antiplatelet regimen as a preventive measure against thrombotic vascular events [5,6]. As the PCI-CURE and CARESS trials have demonstrated major improvements in the clinical outcomes of patients receiving combined treatment [7,8], whereas other studies have shown no additional benefit of ASA treatment in the presence of strong P2Y12 receptor blockade [9]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
