Accéder au contenu
Merck

Circulating primers enhance platelet function and induce resistance to antiplatelet therapy.

Journal of thrombosis and haemostasis : JTH (2015-06-04)
T A Blair, S F Moore, I Hers
RÉSUMÉ

Aspirin 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. To explore the role of platelet primers in resistance to antiplatelet therapy, and to evaluate whether phosphoinositide 3-kinase (PI3K) contributes to this process. We 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. 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.

MATÉRIAUX
Référence du produit
Marque
Description du produit

Sigma-Aldrich
HEPES, ≥99.5% (titration)
Sigma-Aldrich
HEPES, BioPerformance Certified, ≥99.5% (titration), suitable for cell culture
Sigma-Aldrich
Chlorure de sodium, for molecular biology, DNase, RNase, and protease, none detected, ≥99% (titration)
Sigma-Aldrich
Acide chlorhydrique solution, 1.0 N, BioReagent, suitable for cell culture
Sigma-Aldrich
Chlorure de sodium solution, 5 M in H2O, BioReagent, for molecular biology, suitable for cell culture
Sigma-Aldrich
Chlorure de sodium solution, 0.9% in water, BioXtra, suitable for cell culture
Sigma-Aldrich
Chlorure de sodium, BioReagent, suitable for cell culture, suitable for insect cell culture, suitable for plant cell culture, ≥99%
Sigma-Aldrich
Acide chlorhydrique, 36.5-38.0%, BioReagent, for molecular biology
Sigma-Aldrich
HEPES, BioUltra, for molecular biology, ≥99.5% (T)
Supelco
Acide chlorhydrique solution, volumetric, 0.1 M HCl (0.1N), endotoxin free
SAFC
Chlorure de sodium solution, 5 M
Sigma-Aldrich
HEPES solution, 1 M in H2O
Sigma-Aldrich
Acetylsalicylic acid, ≥99.0%
SAFC
HEPES
Sigma-Aldrich
Chlorure de sodium solution, BioUltra, for molecular biology, ~5 M in H2O
Sigma-Aldrich
Chlorure de sodium, BioXtra, ≥99.5% (AT)
Sigma-Aldrich
Chlorure de sodium, 99.999% trace metals basis
Sigma-Aldrich
Chlorure de sodium, BioUltra, for molecular biology, ≥99.5% (AT)
Sigma-Aldrich
Hydrogen chloride, ReagentPlus®, ≥99%
Sigma-Aldrich
Aspirin, meets USP testing specifications
Sigma-Aldrich
HEPES, BioXtra, suitable for mouse embryo cell culture, ≥99.5% (titration)
SAFC
HEPES
Sigma-Aldrich
Acide chlorhydrique solution, ~6 M in H2O, for amino acid analysis
Sigma-Aldrich
Chlorure d'hydrogène solution, 3 M in cyclopentyl methyl ether (CPME)
Sigma-Aldrich
Acide chlorhydrique solution, 32 wt. % in H2O, FCC
Sigma-Aldrich
Chlorure de sodium, meets analytical specification of Ph. Eur., BP, USP, 99.0-100.5%
Sigma-Aldrich
HEPES, BioXtra, pH 5.0-6.5 (1 M in H2O), ≥99.5% (titration)
Sigma-Aldrich
Acetylsalicylic acid, analytical standard
Sigma-Aldrich
Chlorure de sodium solution, 5 M
Sigma-Aldrich
Wortmannin, from Penicillium funiculosum, ≥98% (HPLC and TLC)