Decreased platelet miR-223 expression is associated with high on-clopidogrel platelet reactivity

Shi, Rui; Ge, Lan; Zhou, Xin; Ji, Wenjie; Lu, Rui-Yi; Zhang, Yingying; Zeng, Shan; Liu, Xing; Zhao, Jianhua; Zhang, Wencheng; Jiang, Tiemin; Li, Yuming

doi:10.1016/j.thromres.2013.02.015

Cited by 99 publications

(106 citation statements)

References 35 publications

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“…Plasma levels of this miRNA have been reported to change after treatment with aspirin (de Boer et al 2013) or aspirin and prasugrel (Zampetaki et al 2012). Similar observations have also been made for miR-223 (Shi et al 2013(Shi et al , 2015, while low miR-19b-1-5p expression was linked to aspirin insensitivity in platelets (Kok et al 2015).…”

Section: Next Stop: Epigeneticssupporting

confidence: 82%

Pharmacogenomics of Antiplatelet Drugs

Cerletti

Izzi

Iacoviello

et al. 2017

Platelets in Thrombotic and Non-Thrombotic Disorders

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Pharmacogenomics might contribute to the individual response variability to antiplatelet drugs (particularly aspirin and clopidogrel) in patients with ischemic coronary or cerebral vascular disease in terms of both therapeutic and adverse effects. Over the last two decades, a large number of studies and several meta-analyses on the possible genomic regulation of common "polygenic" ischemic cardio-and cerebrovascular diseases have been published. These studies have identified numerous DNA variants as disease or antiplatelet drug susceptibility markers. Some of these DNA variants confer a variable increase in risk for disease, while loss-of-function variants in the hepatic CYP2C19 system have been reported to be the predominant genetic mediators of clopidogrel and other thienopyridine drug antiplatelet response. However, the overall available data are still somewhat contradictory and do not yet allow to define a clear role for pharmacogenomics in providing effective, reliable, personalized antiplatelet therapy: neither clear conclusions nor definite guidelines are available on the clinical advantages of pharmacogenetic testing before prescribing antiplatelet drugs. In the near future, the relative role of additional rare polymorphisms, structural variants and tissue-specific epigenetic features of the human genome will hopefully be defined as significant contributors to the pathogenesis of cardio-and cerebrovascular disease and of individual patient's response to antiplatelet drugs.

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Section: Next Stop: Epigeneticssupporting

confidence: 82%

Pharmacogenomics of Antiplatelet Drugs

Cerletti

Izzi

Iacoviello

et al. 2017

Platelets in Thrombotic and Non-Thrombotic Disorders

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“…Second, decreased plasma miR-223 accompanied type 2 diabetes [10,11] and smoking habit [12], and antedated diabetes onset [10]. Third, HTPR on clopidogrel and aspirin associated with lower miR-223 in platelets [7] and plasma [8]. On the other hand, miR-223 was unrelated to a 12-month prognosis after coronary angioplasty [19] and platelet function was independent of miR-223 in mice [20].…”

Section: Discussionmentioning

confidence: 99%

“…Landry et al [5] validated the predicted binding site for platelet Ago2-miR-223 within the 3 0 untranslated region of the mRNA encoding P2Y 12 adenosine diphosphate (ADP) receptor, which may reflect a continuous miR-223-mediated repression of P2Y 12 expression in platelets that are capable of protein synthesis [6]. In keeping with this concept, in patients with troponin-negative non-ST-elevation acute coronary syndromes (ACS) on a dual antiplatelet therapy (DAPT) with aspirin and clopidogrel, depressed miR-223 in both platelets [7] and plasma [8] accompanied high on-treatment plasma reactivity (HTPR), a recognized adverse outcome predictor [9]. Additionally, low miR-223 was associated with adverse cardiovascular (CV) outcome [2] and some of traditional CV risk factors [10][11][12].…”

Section: Introductionmentioning

confidence: 99%

Association of plasma miR-223 and platelet reactivity in patients with coronary artery disease on dual antiplatelet therapy: A preliminary report

et al. 2014

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Decreased plasma levels of microRNA-223 (miR-223), predominantly of platelet origin, were proposed as a surrogate marker of efficacy of antiplatelet therapy. However, higher on-treatment platelet reactivity was associated with lower plasma miR-223 in patients with coronary artery disease (CAD) on dual antiplatelet therapy (DAPT) including clopidogrel and aspirin. Our aim was to compare plasma miR-223 and platelet reactivity in CAD patients on DAPT with newer P2Y12 antagonists vs. clopidogrel. We studied 21 men with CAD admitted to our centre owing to a non-ST-elevation acute coronary syndrome, and with an uncomplicated hospital course. From the day of admission, the patients were receiving either clopidogrel (n = 11) or prasugrel/ticagrelor (n = 10) in addition to aspirin. Before discharge, miR-223 expression in plasma was estimated by quantitative polymerase chain reaction using the comparative Ct method relative to miR-16 as an endogenous control. Multiple electrode aggregometry was used to assess platelet aggregation in response to adenosine diphosphate (ADP). ADP-induced platelet reactivity was decreased in the patients treated with prasugrel or ticagrelor compared with those on clopidogrel (mean ± SD: 139 ± 71 vs. 313 ± 162 arbitrary units [AU]*min, p = 0.006), due to a more potent antiplatelet activity of the novel P2Y12 antagonists. Consequently, six out of seven patients in the lower tertile of the ADP-induced platelet aggregation were treated with the newer P2Y12 blockers, whereas six out of seven patients in the upper tertile were on clopidogrel. Plasma miR-223 was elevated with decreasing platelet reactivity (Spearman's rho = -0.52; p = 0.015 for trend), being significantly higher in the lower tertile of the ADP-induced platelet aggregation (median [range]: 1.06 [0.25-2.31]) vs. the upper tertile (0.20 [0.13-2.30]) (p = 0.04). In conclusion, our preliminary results argue against the notion of low plasma miR-223 as a marker of platelet responsiveness to DAPT. On the contrary, more potent platelet inhibition associated mainly with newer P2Y12 antagonists appears to coincide with higher miR-223 relative to the subjects with attenuated responsiveness to DAPT.

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“…To explore the functional consequences of reduced miR-NA expression in platelets, the authors focused on miR-223, an abundant platelet miRNA. Decreased levels of miR-223 have previously been associated with increased platelet reactivity in patients on clopidogrel 11 and with a higher incidence of cardiovascular events in the general population. 3 In male miR-223 knockout mice (miR-223 y/− ), there was no difference in the tail bleeding time, but the in vivo formation of neutrophil-platelet aggregates was increased, the thrombus formation after FeCl 3 injury was exaggerated, and more emboli were detected in the microcirculation on laser-induced endothelial injury.…”

Section: Article See P 157mentioning

confidence: 98%