AUTHOR=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 R. , Wu Jennifer E. , Chen Zeyu , Huang Yinghui Jane , Belman Jonathan , 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. , The UPenn COVID Processing Unit , Reilly John P. , Hensley Scott E. , Rauova Lubica , Zhao Liang , Meyer Nuala J. , Poncz Mortimer , Abrams Charles S. , Wherry E. John , Adamski Sharon , Alam Zahidul , Addison Mary M. , Byrne Katelyn T. , Chandra Aditi , Descamps Hélène C. , Han Nicholas , Kaminskiy Yaroslav , Kammerman Shane C. , Kim Justin , Hamilton Jacob T. , Markosyan Nune , Noll Julia Han , Omran Dalia K. , Perkey Eric , Prager Elizabeth M. , Pueschl Dana , Rennels Austin , Shah Jennifer B. , Shilan Jake S. , Wilhausen Nils , Vanderbeck Ashley N. TITLE=Signaling Through FcγRIIA and the C5a-C5aR Pathway Mediate Platelet Hyperactivation in COVID-19 JOURNAL=Frontiers in Immunology VOLUME=13 YEAR=2022 URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2022.834988 DOI=10.3389/fimmu.2022.834988 ISSN=1664-3224 ABSTRACT=

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 exhibited higher basal levels of activation measured by P-selectin surface expression and had poor functional reserve upon in vitro stimulation. To investigate this question in more detail, we developed an assay to assess the capacity of plasma from COVID-19 patients to activate platelets from healthy donors. Platelet activation was a common feature of plasma from COVID-19 patients and correlated with key measures of clinical outcome including kidney and liver injury, and APACHEIII scores. Further, we 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 in vitro 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. These data identified these potentially actionable pathways as central for platelet activation and/or vascular complications and clinical outcomes 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.