Proteome and functional decline as platelets age in the circulation

Allan, Harriet E; Hayman, Margaret; Marcone, Simone; Chan, Melissa; Edin, Matthew L.; Maffucci, Tania; Joshi, Abhishek; Menke, Laura; Crescente, Marilena; Mayr, Manuel; Zeldin, Darryl C.; Armstrong, Paul C; Warner, Timothy D.

doi:10.1101/2021.06.02.446106

Cited by 3 publications

(1 citation statement)

References 73 publications

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“…16 Interestingly, a recent proteomic study provided the first insights on RPs proteome: it was found that platelet aging leads to a relevant reduction in cytoskeletal protein, a reduction in mitochondria number, lower calcium dynamics and granule secretion, and it has been suggested that old platelets have blunted hemostatic responses and accumulate circulating proteins. 54 Other preclinical studies concerning RPs' biology are summarized in Figure 1 and Table 1. 49,[55][56][57]…”

Section: Insights On Rps Biologymentioning

confidence: 99%

Role of Reticulated Platelets in Cardiovascular Disease

Bongiovanni

Han

Klug

et al. 2022

ATVB

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Human platelets differ considerably with regard to their size, RNA content and thrombogenicity. Reticulated platelets (RPs) are young, hyper-reactive platelets that are newly released from the bone marrow. They are larger and contain more RNA compared to older platelets. In comparison to more mature platelets, they exhibit a significantly higher thrombogenicity and are known to be elevated in patients with an increased platelet turnover such as, diabetics and after acute myocardial infarction. Several studies have shown that RPs correlate with an insufficient antiplatelet response to aspirin and specific P2Y 12 receptor inhibitors. In addition, RPs are promising novel biomarkers for the prediction of adverse cardiovascular events in cardiovascular disease. However, the reason for RPs intrinsic hyper-reactivity and their association with ischemic events is not completely understood and the biology of RPs is still under investigation. We here present a structured review of preclinical and clinical findings concerning the role of RPs in cardiovascular disease.

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Section: Insights On Rps Biologymentioning

confidence: 99%

Role of Reticulated Platelets in Cardiovascular Disease

Bongiovanni

Han

Klug

et al. 2022

ATVB

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Temporal in vivo platelet labelling in mice reveals age-dependent receptor expression and conservation of specific mRNAs

Armstrong

Allan

Kirkby

et al. 2021

Preprint

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The proportion of young platelets, also known as newly formed or reticulated, within the overall platelet population has been clinically correlated with adverse cardiovascular outcomes. Our understanding of this is incomplete, however, because of limitations in the technical approaches available to study platelets of different ages. In this study we have developed and validated an in vivo ′temporal labelling′ approach using injectable fluorescent anti-platelet antibodies to sub-divide platelets by age and assess differences in functional and molecular characteristics. With this approach we found that young platelets (<24h old) in comparison to older platelets, respond to stimuli with greater calcium flux and degranulation, and contribute more to the formation of thrombi in vitro and in vivo. Sequential sampling confirmed this altered functionality to be independent of platelet size with no size differences or changes relative to the global population seen at any age. The age associated decrease in thrombotic function was accompanied by significant decreases in the surface expression of GPVI and CD31 (PECAM-1) and an increase in CD9. Platelet mRNA content also decreased with age but at different rates for individual mRNAs indicating apparent conservation of those encoding granule proteins. Our pulse-chase type approach to define circulating platelet age has allowed timely re-examination of commonly held beliefs regarding size and reactivity of young platelets whilst providing novel insights into the temporal regulation of receptor and protein expression. Overall, future application of this validated tool will inform on age-based platelet heterogeneity in physiology and disease.

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Neutrophil-Derived Protein S100A8/A9 Alters the Platelet Proteome in Acute Myocardial Infarction and Is Associated With Changes in Platelet Reactivity

Joshi

Schmidt

Burnap

et al. 2022

ATVB

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Objective: Platelets are central to acute myocardial infarction (MI). How the platelet proteome is altered during MI is unknown. We sought to describe changes in the platelet proteome during MI and identify corresponding functional consequences. Approach and Results: Platelets from patients experiencing ST-segment–elevation MI (STEMI) before and 3 days after treatment (n=30) and matched patients with severe stable coronary artery disease before and 3 days after coronary artery bypass grafting (n=25) underwent quantitative proteomic analysis. Elevations in the proteins S100A8 and S100A9 were detected at the time of STEMI compared with stable coronary artery disease (S100A8: FC, 2.00; false discovery rate, 0.05; S100A9: FC, 2.28; false discovery rate, 0.005). During STEMI, only S100A8 mRNA and protein levels were correlated in platelets ( R =0.46, P =0.012). To determine whether de novo protein synthesis occurs, activated platelets were incubated with 13C-labeled amino acids for 24 hours and analyzed by mass spectrometry. No incorporation was confidently detected. Platelet S100A8 and S100A9 was strongly correlated with neutrophil abundance at the time of STEMI. When isolated platelets and neutrophils were coincubated under quiescent and activated conditions, release of S100A8 from neutrophils resulted in uptake of S100A8 by platelets. Neutrophils released S100A8/A9 as free heterodimer, rather than in vesicles or extracellular traps. In the community-based Bruneck study (n=338), plasma S100A8/A9 was inversely associated with platelet reactivity—an effect abrogated by aspirin. Conclusions: Leukocyte-to-platelet protein transfer may occur in a thromboinflammatory environment such as STEMI. Plasma S100A8/A9 was negatively associated with platelet reactivity. These findings highlight neutrophils as potential modifiers for thrombotic therapies in coronary artery disease.

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Proteome and functional decline as platelets age in the circulation

Cited by 3 publications

References 73 publications

Role of Reticulated Platelets in Cardiovascular Disease

Role of Reticulated Platelets in Cardiovascular Disease

Temporal in vivo platelet labelling in mice reveals age-dependent receptor expression and conservation of specific mRNAs

Neutrophil-Derived Protein S100A8/A9 Alters the Platelet Proteome in Acute Myocardial Infarction and Is Associated With Changes in Platelet Reactivity

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