Newly Formed Reticulated Platelets Undermine Pharmacokinetically Short-Lived Antiplatelet Therapies

Armstrong, Paul C; Hoefer, Thomas; Knowles, Rebecca; Tucker, A.; Hayman, Margaret; Ferreira, Plinio; Chan, Melissa; Warner, Timothy D.

doi:10.1161/atvbaha.116.308763

Cited by 63 publications

(61 citation statements)

References 41 publications

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“…One explanation for high on-treatment platelet reactivity during sepsis is the dysregulation of hepatic cytochrome P450 enzymes upon endotoxemia [43], which are responsible for activation of the prodrug clopidogrel. Another possibility is that high on-treatment platelet reactivity is mediated by platelets that escape pharmacological therapy when they are formed at the nadir of drug bioavailability [44]. However, both mechanisms are unlikely since clopidogrel and ticagrelor showed indistinguishable effects on circulating miRNAs; despite ticagrelor being an allosteric antagonist that does not require enzymatic activation and is present continuously in the plasma at therapeutic concentrations during treatment [45].…”

Section: Discussionmentioning

confidence: 99%

Circulating MicroRNA Levels Indicate Platelet and Leukocyte Activation in Endotoxemia Despite Platelet P2Y12 Inhibition

Braza-Boïls

Barwari

Gutmann

et al. 2020

IJMS

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There is evidence for the effects of platelet inhibition on innate immune activation. Circulating microRNAs (miRNAs) have been implicated as markers of platelet and leukocyte activation. In the present study, we assessed the effects of P2Y 12 inhibitors on platelet and leukocyte miRNAs during endotoxemia. Healthy volunteers were randomly assigned to receive oral ticagrelor (n = 10), clopidogrel (n = 8) or no drug (n = 8) for one week, followed by an intravenous bolus of 2 ng/kg endotoxin. Serum was collected at baseline, after one week of antiplatelet treatment and 6 and 24 h after endotoxin administration. MiRNAs were screened using LNA-based qPCR, followed by TaqMan-qPCR validation of candidates. Clinical validation was performed in 41 sepsis patients. Platelet-enriched miR-197, miR-223 and miR-223* were decreased in volunteers following antiplatelet therapy. Endotoxin increased platelet miRNAs, whilst the opposite effect was seen for leukocyte-enriched miR-150. Neither of these endotoxin-mediated effects were altered by P2Y 12 inhibitors. Sepsis patients with fatal outcomes (n = 12) had reduced miR-150 levels compared with survivors (n = 29). In conclusion, we show that miR-150 is downregulated in experimental endotoxemia and can predict survival in sepsis but is unaffected by P2Y 12 inhibition. While P2Y 12 inhibition reduces platelet-associated miRNAs in healthy volunteers, it fails to attenuate the response of platelet miRNAs to endotoxemia.

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Section: Discussionmentioning

confidence: 99%

Circulating MicroRNA Levels Indicate Platelet and Leukocyte Activation in Endotoxemia Despite Platelet P2Y12 Inhibition

Braza-Boïls

Barwari

Gutmann

et al. 2020

IJMS

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“…Platelet RNA content represents a surrogate marker for newly formed immature platelets which are also called reticulated platelets due to the presence of residual cytosolic mRNA [19]. Reticulated platelets are known to be more reactive than older platelets and promote platelet aggregate formation [20] and are indicative for a higher platelet turnover. However, no impact of subgingival debridement on platelet RNA content could be observed in our study.…”

Section: Discussionmentioning

confidence: 99%

Periodontal treatment does not result in detectable platelet activation in vivo

et al. 2019

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Objectives Periodontitis is associated with systemic inflammation, elevated platelet activation and enhanced risk for cardiovascular diseases, while periodontal treatment reduces tissue inflammation and shows desirable effects on the oral biofilm and dental health. However, subgingival debridement during conservative treatment can lead to local trauma and transient bacteraemia, which might affect cardiovascular risk in these patients. Therefore, we investigated the effect of periodontal treatment on systemic platelet activation. Materials and methods In a prospective therapeutic trial, 26 patients underwent periodontal treatment and patient blood was analysed immediately before and immediately after intervention for platelet activation markers (flow cytometric analysis of Pselectin, CD63 and CD40L surface expression, integrin αIIbβ3 activation and fibrinogen binding, intra-platelet reactive oxygen species production, platelet-leukocyte aggregate formation and intra-platelet vasodilator-stimulated phosphoprotein phosphorylation) in response to adenosine diphosphate (ADP). Results The present study shows that basal platelet activation levels remain largely unaltered in response to periodontal treatment. We also did not observe significant changes in platelet reactivity in response to different concentrations of platelet agonist ADP. Conclusion Subgingival debridement does not result in relevantly elevated platelet activation. Thus, augmented platelet activation seems unlikely to be a causative triggering factor that increases the short-term risk for platelet-mediated thrombotic events in response to subgingival debridement. Clinical relevance Subgingival debridement is a safe procedure and does not increase the short-term risk for platelet-mediated thrombotic events.

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“…Reticulated platelet count has been strongly associated with aspirin resistance, especially with short-lived antiplatelet therapies as they can re-synthesize COX-1/2 (Guthikonda et al 2007, Armstrong et al 2017. However, IPC has emerged as the strongest independent platelet count-derived predictor of antiplatelet response (Stratz et al 2016).…”

Section: Reticulated Platelets and Aspirin Resistancementioning

confidence: 99%

It's reticulated: the liver at the heart of atherosclerosis

Nagareddy

Noothi

Flynn

et al. 2018

Journal of Endocrinology

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Platelets play a critical role in both the initiation and progression of atherosclerosis, and even more so in the ensuing atherothrombotic complications. Low-dose aspirin remains the mainstay of antiplatelet therapy in high-risk patients by reducing the risk of myocardial ischemia, stroke or death due to cardiovascular disease. However, antiplatelet therapies lose their efficacy in people with diabetes mellitus, increasing the risk of future atherothrombotic events. The molecular mechanisms that promote platelet hyperactivity remain unclear but could be due to glycation-induced conformational changes of platelet membranes resulting in impaired aspirin entry or less-efficient acetylation/compensatory increase in COX-2 expression in newborn platelets. Emerging evidence from our laboratory and elsewhere suggest that enhanced platelet turnover (thrombopoiesis), particularly the production of immature reticulated platelets from the bone marrow, could contribute to atherosclerotic complications. We have identified a major role for neutrophil-derived S100A8/A9, a damage-associated molecular pattern, in driving reticulated thrombopoiesis by directly interacting with its receptors on Kupffer cells in the liver. In this review, we discuss the role of hepatic inflammation in driving reticulated platelet production and suggest potential targets to control their production, improve efficacy of current antiplatelet therapies and reduce the risk of atherothrombotic complications.

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Newly Formed Reticulated Platelets Undermine Pharmacokinetically Short-Lived Antiplatelet Therapies

Abstract: Supplemental Digital Content is available in the text.

Cited by 63 publications

References 41 publications

Circulating MicroRNA Levels Indicate Platelet and Leukocyte Activation in Endotoxemia Despite Platelet P2Y12 Inhibition

Circulating MicroRNA Levels Indicate Platelet and Leukocyte Activation in Endotoxemia Despite Platelet P2Y12 Inhibition

Periodontal treatment does not result in detectable platelet activation in vivo

It's reticulated: the liver at the heart of atherosclerosis

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