Platelets amplify endotheliopathy in COVID-19

Barrett, Tessa; Cornwell, MacIntosh; Myndzar, Khrystyna; Rolling, Christina C.; Xia, Yuhe; Drenkova, Kamelia; Biebuyck, Antoine; Fields, Alexander T.; Tawil, Michael; Luttrell‐Williams, Elliot; Yuriditsky, Eugene; Smith, Grace; Cotzia, Paolo; Neal, Matthew D.; Kornblith, Lucy Z.; Pittaluga, Stefania; Rapkiewicz, Amy; Burgess, Hannah M.; Mohr, Ian; Stapleford, Kenneth A.; Voora, Deepak; Ruggles, Kelly V.; Hochman, Judith S.; Berger, Jeffrey S.

doi:10.1126/sciadv.abh2434

Cited by 96 publications

(104 citation statements)

References 63 publications

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“…Recent evidence points towards a role for platelets in endotheliopathy. Barrett et al [ 42 ] demonstrated the presence of two main RNA transcripts, S100A8 and S100A9, expressed in platelets from COVID-19 patients that lead to the release of myeloid-related protein (MRP) 8/14. This was shown to activate endothelial cells and promote an inflammatory hypercoagulable phenotype.…”

Section: Proposed Mechanisms Of Hypercoagulability In Covid-19mentioning

confidence: 99%

The Pathobiological Basis for Thrombotic Complications in COVID-19: a Review of the Literature

et al. 2021

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Purpose of Review COVID-19 has rapidly evolved into a global pandemic infecting over two hundred and forty-four million individuals to date. In addition to the respiratory sequelae and systemic infection that ensues, an alarming number of micro and macrovascular thrombotic complications have been observed. This review examines the current understanding of COVID-19-associated thrombotic complications, potential mechanisms, and pathobiological basis for thromboses development. Recent Findings The endothelium plays a major role in the process due to direct and indirect injury. The immune system also contributes to a pro-thrombotic environment with immune cell dysregulation leading to excessive formation of cytokines, also called cytokine storm, and an eventual promotion of a hypercoagulable environment, known as immunothrombosis. Additionally, neutrophils play an important role by forming neutrophil extracellular traps, which are shown to be pro-thrombotic and further enhanced in COVID-19 patients. A disruption of the fibrinolysis system has also been observed. Summary Multiple pathways likely contribute synergistically to form a pro-thrombotic milieu. A better understanding of these factors and the complex interplay between them will lead to the improvement of diagnostic and therapeutic interventions.

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Section: Proposed Mechanisms Of Hypercoagulability In Covid-19mentioning

confidence: 99%

The Pathobiological Basis for Thrombotic Complications in COVID-19: a Review of the Literature

et al. 2021

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“…In addition to the direct proinflammatory/prothrombotic and cytotoxic effects of the SARS-Cov-2 S protein on vascular endothelium, as well as impairment of the renin-angiotensinaldosterone system (83), prolonged platelet activation in severe COVID-19 infection also amplifies endotheliopathy (89) In this context, a very recent study by Barrett et al described potential mechanisms by which activated platelets exacerbate endothelial activation and damage (90). Using a strategy based on integration of endothelial cells and platelets isolated from patients hospitalized with COVID-19, transcriptomic analysis of mRNA expression extracted from endothelial cells exposed to platelet releasate revealed alterations in processes involved in maintenance of tight junction barrier integrity, coagulation and inflammation, characteristic of an "inflammatory, hypercoaguable phenotype" (90).…”

Section: Platelet-mediated Endothelial Damage and Dysfunctionmentioning

confidence: 99%

“…These proteins are stored in platelet granules and dimerize to form the potent, proinflammatory protein, calprotectin (MRP8/14). Interacting with CD36 on vascular endothelium, calprotectin weakens cellcell interactions and initiates release of the proinflammatory cytokines, IL-6, and IL-8 (90)(91)(92).…”

Section: Platelet-mediated Endothelial Damage and Dysfunctionmentioning

confidence: 99%

Emerging Role of Platelet-Endothelium Interactions in the Pathogenesis of Severe SARS-CoV-2 Infection-Associated Myocardial Injury

et al. 2022

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Cardiovascular dysfunction and disease are common and frequently fatal complications of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Indeed, from early on during the SARS-CoV-2 virus pandemic it was recognized that cardiac complications may occur, even in patients with no underlying cardiac disorders, as part of the acute infection, and that these were associated with more severe disease and increased morbidity and mortality. The most common cardiac complication is acute cardiac injury, defined by significant elevation of cardiac troponins. The potential mechanisms of cardiovascular complications include direct viral myocardial injury, systemic inflammation induced by the virus, sepsis, arrhythmia, myocardial oxygen supply-demand mismatch, electrolyte abnormalities, and hypercoagulability. This review is focused on the prevalence, risk factors and clinical course of COVID-19-related myocardial injury, as well as on current data with regard to disease pathogenesis, specifically the interaction of platelets with the vascular endothelium. The latter section includes consideration of the role of SARS-CoV-2 proteins in triggering development of a generalized endotheliitis that, in turn, drives intense activation of platelets. Most prominently, SARS-CoV-2–induced endotheliitis involves interaction of the viral spike protein with endothelial angiotensin-converting enzyme 2 (ACE2) together with alternative mechanisms that involve the nucleocapsid and viroporin. In addition, the mechanisms by which activated platelets intensify endothelial activation and dysfunction, seemingly driven by release of the platelet-derived calcium-binding proteins, SA100A8 and SA100A9, are described. These events create a SARS-CoV-2–driven cycle of intravascular inflammation and coagulation, which contributes significantly to a poor clinical outcome in patients with severe disease.

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“…Consequently, this finding might partially explain the presence of the long COVID syndrome, which is also characterized by an increased burden of thromboembolic events [135]. Moreover, the interaction of platelets with the vascular endothelium in the setting of COVID-19 seems bidirectional, since platelet-derived myeloid-related protein 8/14 was overexpressed in SARS-CoV-2 infection and induced microvascular endothelial cell activation and dysfunction, leading to a procoagulant phenotype [136].…”

Section: Inflammation and Platelet Activation In Coronavirus Disease-19mentioning

confidence: 99%

Inflammatory Mediators of Platelet Activation: Focus on Atherosclerosis and COVID-19

Theofilis

Sagris

Antonopoulos

et al. 2021

IJMS

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Background: Atherosclerotic cardiovascular diseases are characterized by a dysregulated inflammatory and thrombotic state, leading to devastating complications with increased morbidity and mortality rates. Summary: In this review article, we present the available evidence regarding the impact of inflammation on platelet activation in atherosclerosis. Key messages: In the context of a dysfunctional vascular endothelium, structural alterations by means of endothelial glycocalyx thinning or functional modifications through impaired NO bioavailability and increased levels of von Willebrand factor result in platelet activation. Moreover, neutrophil-derived mediators, as well as neutrophil extracellular traps formation, have been implicated in the process of platelet activation and platelet-leukocyte aggregation. The role of pro-inflammatory cytokines is also critical since their receptors are also situated in platelets while TNF-α has also been found to induce inflammatory, metabolic, and bone marrow changes. Additionally, important progress has been made towards novel concepts of the interaction between inflammation and platelet activation, such as the toll-like receptors, myeloperoxidase, and platelet factor-4. The accumulating evidence is especially important in the era of the coronavirus disease-19 pandemic, characterized by an excessive inflammatory burden leading to thrombotic complications, partially mediated by platelet activation. Lastly, recent advances in anti-inflammatory therapies point towards an anti-thrombotic effect secondary to diminished platelet activation.

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Platelets amplify endotheliopathy in COVID-19

Cited by 96 publications

References 63 publications

The Pathobiological Basis for Thrombotic Complications in COVID-19: a Review of the Literature

The Pathobiological Basis for Thrombotic Complications in COVID-19: a Review of the Literature

Emerging Role of Platelet-Endothelium Interactions in the Pathogenesis of Severe SARS-CoV-2 Infection-Associated Myocardial Injury

Inflammatory Mediators of Platelet Activation: Focus on Atherosclerosis and COVID-19

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