Megakaryocytes contain extranuclear histones and may be a source of platelet-associated histones during sepsis

Frydman, Galit H.; Tessier, Shannon N.; Wong, Keith H.K.; Vanderburg, Charles; Fox, James G.; Toner, Mehmet; Tompkins, Ronald G.; Irimia, Daniel

doi:10.1038/s41598-020-61309-3

Cited by 22 publications

(18 citation statements)

References 58 publications

(78 reference statements)

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“…A prothrombotic state was also described in COVID-19, with pulmonary embolism, venous thromboembolism, and disseminated intravascular coagulation (DIC) commonly observed as complications in critically ill patients [3]. In one COVID-19 autopsy series, platelet and megakaryocyterich thrombi were found in multiple organs including the heart, kidney and lungs, in some cases despite full anticoagulation [21]. This can result from increased tissue factor, a potent procoagulant from activated macrophages, increased fibrinogen and factor VIII levels and/or from direct endothelial damage that could be caused by SARS-CoV-2 infection [22].…”

Section: Pathophysiologymentioning

confidence: 99%

Cardiac complications during the active phase of COVID-19: review of the current evidence

et al. 2021

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Growing reports since the beginning of the pandemic and till date describe increased rates of cardiac complications (CC) in the active phase of coronavirus disease 2019 (COVID-19). CC commonly observed include myocarditis/myocardial injury, arrhythmias and heart failure, with an incidence reaching about a quarter of hospitalized patients in some reports. The increased incidence of CC raise questions about the possible heightened susceptibility of patients with cardiac disease to develop severe COVID-19, and whether the virus itself is involved in the pathogenesis of CC. The wide array of CC seems to stem from multiple mechanisms, including the ability of the virus to directly enter cardiomyocytes, and to indirectly damage the heart through systemic hyperinflammatory and hypercoagulable states, endothelial injury of the coronary arteries and hypoxemia. The induced CC seem to dramatically impact the prognosis of COVID-19, with some studies suggesting over 50% mortality rates with myocardial damage, up from ~ 5% overall mortality of COVID-19 alone. Thus, it is particularly important to investigate the relation between COVID-19 and heart disease, given the major effect on morbidity and mortality, aiming at early detection and improving patient care and outcomes. In this article, we review the growing body of published data on the topic to provide the reader with a comprehensive and robust description of the available evidence and its implication for clinical practice.

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Section: Pathophysiologymentioning

confidence: 99%

Cardiac complications during the active phase of COVID-19: review of the current evidence

et al. 2021

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“…Recently released report confirmed the presence of membrane and cellular histone in platelets and megakaryocytes during sepsis 102 . Though emperipolesis may explain this observation, this needs further validation especially in COVID-19.…”

Section: Emperipolesismentioning

confidence: 85%

<strong></strong><strong>COVID-19 Clot: What Is It? Why in the Lungs? Extracellular Histone, “Auto-Activation” of Prothrombin, Emperipolesis, Megakaryocytes, “Self-Association” of Von Willebrand Factor and Beyond</strong>

Varatharajah¹

2020

Preprint

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COVID-19 thromboembolic disease has brought all of us back to the drawing board. In COVID-19, pre-existing activated endothelium with increased Von Willebrand factor (VWF), low density lipoprotein (LDL) promoting “self-association” and “sticking” of long VWF strings to the vascular endothelial wall, suppressed ADAMTS13 cleavage of VWF, hypoxia induced upregulation and activation of VWF, fibrous network from neutrophil extracellular traps (NETs) with free DNA and histone, all appear to be initiating the thrombogenesis. Worsening complement activation, cytokine storm and resulting endothelial destruction, unregulated thrombogenesis leads to vascular occlusions and hypoxia. At this stage, the presence of abundant extracellular DNA, histone and -defensins appears worse than the SARS-CoV-2 itself. Previously observed in vitro mechanisms like histone “auto-activating” prothrombin, histone activated platelets generating thrombin without FXII, thrombin and plasmin cleaving complement C5 appears highly likely in COVID-19. Megakaryocytes are actively producing platelets in the lungs and appear to play a major role in thrombogenesis of COVID-19 raising suspicion of emperipolesis. This focused review is a compilation of my observations in relation to the pathophysiology of the intravascular environment, mainly in COVID-19 lungs. Pathophysiology based clinical trials are paramount in reducing morbidity and mortality in COVID-19.

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“…Recurrent top 4 genes from our progressive transcriptome Lasso are visualized as a heatmap in Figure 5F clearly capturing the incremental gradient in gene expression between controls, ET, PV and MF. These include ADAMTS3 (ADAM metallopeptidase protease (Mead and Apte, 2018) with likely roles in VEGF signaling, tissue remodeling and expression of related collagens through profibrotic PAR1 and TGF-b signaling), PSMB5 (implicated in proteasomal degradation/UPR activation (Wang et al, 2017) and identified previously in MPNs (Skov et al, 2010)), NT5C related to PI3K signaling (Fruman et al, 2017;Moniz et al, 2017) and SUPT6H/SPT6 (Bres et al, 2008;Frydman et al, 2020), a tumor-initiating histone chaperone associated with chromatin remodeling. Lassoselected candidate markers capture the underlying MPN pathology and offer potential therapeutic targets.…”

Section: Prediction Of Mf Based On Shared Unique and Progressive Mpn Platelet Transcriptomementioning

confidence: 99%

Platelet transcriptome yields progressive markers in chronic myeloproliferative neoplasms and identifies putative targets of therapy

Shen

Perkins

et al. 2021

Preprint

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Predicting disease natural history remains a particularly challenging endeavor in chronic degenerative disorders and cancer, thus limiting early detection, risk stratification, and preventive interventions. Here, profiling the spectrum of chronic myeloproliferative neoplasms (MPNs), as a model, we identify the blood platelet transcriptome as a generalizable strategy for highly sensitive progression biomarkers that also enable prediction via machine learning algorithms. Using RNA sequencing (RNA seq), we derive disease relevant gene expression and alternative splicing in purified platelets from 120 peripheral blood samples constituting two independently collected and mutually validating patient cohorts of the three MPN subtypes: essential thrombocythemia, ET (n=24), polycythemia vera, PV (n=33), and primary or post ET/PV secondary myelofibrosis, MF (n=42), as well as healthy donors (n=21). The MPN platelet transcriptome discriminates each clinical phenotype and reveals an incremental molecular reprogramming that is independent of patient driver mutation status or therapy. Leveraging this dataset, in particular the progressive expression gradient noted across MPN, we develop a machine learning model (Lasso-penalized regression) predictive of the advanced subtype MF at high accuracy (AUC-ROC of 0.95-0.96) with validation under two conditions: i) temporal, with training on the first cohort (n=71) and independent testing on the second (n=49) and ii) 10 fold cross validation on the entire dataset. Lasso-derived signatures offer a robust core set of < 10 MPN progression markers. Mechanistic insights from our data highlight impaired protein homeostasis as a prominent driver of MPN evolution, with persistent integrated stress response. We also identify JAK inhibitor-specific signatures and other interferon, proliferation, and proteostasis associated markers as putative targets for MPN-directed therapy. Our platelet transcriptome snapshot of chronic MPNs establishes a methodological foundation for deciphering disease risk stratification and progression beyond genetic data alone, thus presenting a promising avenue toward potential utility in a wide range of age-related disorders.

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Megakaryocytes contain extranuclear histones and may be a source of platelet-associated histones during sepsis

Cited by 22 publications

References 58 publications

Cardiac complications during the active phase of COVID-19: review of the current evidence

Cardiac complications during the active phase of COVID-19: review of the current evidence

<strong></strong><strong>COVID-19 Clot: What Is It? Why in the Lungs? Extracellular Histone, “Auto-Activation” of Prothrombin, Emperipolesis, Megakaryocytes, “Self-Association” of Von Willebrand Factor and Beyond</strong>

Platelet transcriptome yields progressive markers in chronic myeloproliferative neoplasms and identifies putative targets of therapy

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