Platelets amplify endotheliopathy in COVID-19, 2021, Barrett et al.

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Platelets amplify endotheliopathy in COVID-19
Tessa J. Barrett, MacIntosh Cornwell, Khrystyna Myndzar, Christina C. Rolling, Yuhe Xia, Kamelia Drenkova1, Antoine Biebuyck, Alexander T. Fields, Michael Tawil, Elliot Luttrell-Williams, Eugene Yuriditsky, Grace Smith, Paolo Cotzia, Matthew D. Neal, Lucy Z. Kornblith, Stefania Pittaluga, Amy V. Rapkiewicz, Hannah M. Burgess, Ian Mohr, Kenneth A. Stapleford, Deepak Voora, Kelly Ruggles, Judith Hochman, Jeffrey S. Berger

Abstract
Given the evidence for a hyperactive platelet phenotype in COVID-19, we investigated effector cell properties of COVID-19 platelets on endothelial cells (ECs). Integration of EC and platelet RNA sequencing revealed that platelet-released factors in COVID-19 promote an inflammatory hypercoagulable endotheliopathy. We identified S100A8 and S100A9 as transcripts enriched in COVID-19 platelets and were induced by megakaryocyte infection with SARS-CoV-2.

Consistent with increased gene expression, the heterodimer protein product of S100A8/A9, myeloid-related protein (MRP) 8/14, was released to a greater extent by platelets from COVID-19 patients relative to controls.

We demonstrate that platelet-derived MRP8/14 activates ECs, promotes an inflammatory hypercoagulable phenotype, and is a significant contributor to poor clinical outcomes in COVID-19 patients.

Last, we present evidence that targeting platelet P2Y12 represents a promising candidate to reduce proinflammatory platelet-endothelial interactions. Together, these findings demonstrate a previously unappreciated role for platelets and their activation-induced endotheliopathy in COVID-19.

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Platelets also maintain vascular function and integrity by bidirectional interactions with ECs and leukocytes. Under inflammatory conditions, the cross-talk between platelets, coagulation, and the endothelium exacerbates local and systemic inflammation

Herein we demonstrate that platelets from COVID-19 patients are hyperactive and that platelet-released factors activate microvascular ECs, promoting an inflammatory hypercoagulable phenotype.

An investigation into platelet candidate genes that code for abundantly released proteins found up-regulation of S100A8 and S100A9 in platelets from COVID-19 patients. In vitro, we confirmed that SARS-CoV-2 could alter megakaryocyte gene expression and up-regulate S100A8 and S100A9. Consistent with an increase in transcription, the heterodimer protein product of S100A8/A9, myeloid-related protein 8 (MRP8)/MRP14, is released to a greater extent by platelets from COVID-19 patients relative to controls. MRP8/14 activates microvascular ECs and weakens EC cell-cell contacts resulting in increased permeability of the endothelium

Severe COVID-19 is associated with a hypercoagulable state and robust inflammatory response that predisposes patients to macro- and microthrombotic events. The coordinated activation of the inflammatory and thrombotic response has been termed thrombo-inflammation. Levels of prothrombotic acute phase mediators, including fibrinogen, vWF, and D-dimer, are increased in COVID-19 patients, implicating the endothelium, platelets, and the coagulation system as likely mediators of thromboinflammation in COVID-19. The resulting endotheliopathy is thought to link inflammation, immune dysregulation, and thrombosis, and be a driver of poor clinical outcomes in COVID-19 patients (39, 40). Despite suggestions that SARS-CoV-2 triggers endotheliopathy, recent experimental evidence supports indirect activating mechanisms driving EC injury in COVID-19.

Platelets are first responders to vascular injury and act to bridge the immune system and thrombosis via activation and release of hemostatic and inflammatory mediators. Activated platelets secrete a host of proinflammatory mediators in the local microenvironment, altering the endothelium's inflammatory and adhesive properties. Activated platelets isolated from patients with inflammatory disease, such as systemic lupus erythematosus (SLE), HIV, and psoriasis, induce a proinflammatory EC phenotype

In conclusion, we define a novel role for platelet-induced endotheliopathy in COVID-19. The activated platelet phenotype observed in COVID-19 consistently induces a proinflammatory and dysfunctional endothelium. Platelet-derived MRP8/14 is increased in COVID-19 and induces endothelial injury. Circulating MRP8/14 has the potential to serve as a useful biomarker of thrombosis and severity of disease in patients infected with SARS-CoV-2. Platelet-directed therapy, specifically P2Y12 inhibitors, may represent a particularly attractive therapy because of its effect on platelet S100A8/A9 and platelet-induced endotheliopathy.