Signaling through FcγRIIA and the C5a-C5aR pathway mediates platelet hyperactivation in COVID-19

• Published in: bioRxiv
• Main Authors: Apostolidis, Sokratis A, Sarkar, Amrita, Giannini, Heather M, Goel, Rishi R, Mathew, Divij, Suzuki, Aae, Baxter, Amy E, Greenplate, Allison R, Alanio, Cécile, Abdel-Hakeem, Mohamed, Oldridge, Derek A, Giles, Josephine, Wu, Jennifer E, Chen, Zeyu, Huang, Yinghui Jane, Pattekar, Ajinkya, Manne, Sasikanth, Kuthuru, Oliva, Dougherty, Jeanette, Weiderhold, Brittany, Weisman, Ariel R, Ittner, Caroline A G, Gouma, Sigrid, Dunbar, Debora, Frank, Ian, Huang, Alexander C, Vella, Laura A, Reilly, John P, Hensley, Scott E, Rauova, Lubica, Zhao, Liang, Meyer, Nuala J, Poncz, Mortimer, Abrams, Charles S, Wherry, E John
• Format: Journal Article Paper
• Language: English
• Published: United States Cold Spring Harbor Laboratory Press 03.05.2021
• Subjects: Cardiovascular disease; Cardiovascular diseases; Coronaviruses; COVID-19; Ferritin; Hyperactivity; Immunoglobulin G; Inflammation; Microfluidics; Morbidity; Oncology; P-selectin; PD-1 protein; Plasma; Platelet aggregation; Severe acute respiratory syndrome coronavirus 2; Signal transduction; Syk protein; Thromboembolism
• ISSN: 2692-8205
• DOI: 10.1101/2021.05.01.442279

Patients with COVID-19 present with a wide variety of clinical manifestations. Thromboembolic events constitute a significant cause of morbidity and mortality in patients infected with SARS-CoV-2. Severe COVID-19 has been associated with hyperinflammation and pre-existing cardiovascular disease. Platelets are important mediators and sensors of inflammation and are directly affected by cardiovascular stressors. In this report, we found that platelets from severely ill, hospitalized COVID-19 patients exhibit higher basal levels of activation measured by P-selectin surface expression, and have a poor functional reserve upon stimulation. Correlating clinical features to the ability of plasma from COVID-19 patients to stimulate control platelets identified ferritin as a pivotal clinical marker associated with platelet hyperactivation. The COVID-19 plasma-mediated effect on control platelets was highest for patients that subsequently developed inpatient thrombotic events. Proteomic analysis of plasma from COVID-19 patients identified key mediators of inflammation and cardiovascular disease that positively correlated with platelet activation. Mechanistically, blocking the signaling of the FcγRIIa-Syk and C5a-C5aR pathways on platelets, using antibody-mediated neutralization, IgG depletion or the Syk inhibitor fostamatinib, reversed this hyperactivity driven by COVID-19 plasma and prevented platelet aggregation in endothelial microfluidic chamber conditions, thus identifying these potentially actionable pathways as central for platelet activation and/or vascular complications in COVID-19 patients. In conclusion, we reveal a key role of platelet-mediated immunothrombosis in COVID-19 and identify distinct, clinically relevant, targetable signaling pathways that mediate this effect. These studies have implications for the role of platelet hyperactivation in complications associated with SARS-CoV-2 infection. The FcγRIIA and C5a-C5aR pathways mediate platelet hyperactivation in COVID-19.