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bioRxiv · 10.1101/2021.05.01.442279

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

Apostolidis, S. A.·Sarkar, A.·Giannini, H. M.·Goel, R. R.·Mathew, D.·Suzuki, A.·Baxter, A. E.·Greenplate, A. R.·Alanio, C.·Abdel-Hakeem, M.·Oldridge, D. A.·Giles, J. R.·Wu, J. E.·Chen, Z.·Huang, Y. J.·Pattekar, A.·Manne, S.·Kuthuru, O.·Dougherty, J.·Weiderhold, B.·Weisman, A. R.·Ittner, C. A. G.·Gouma, S.·Dunbar, D.·Frank, I.·Huang, A. C.·Vella, L. A.·The UPenn COVID Processing Unit,·Reilly, J. P.·Hensley, S. E.·Rauova, L.·Zhao, L.·Meyer, N. J.·Poncz, M.·Abrams, C. S.·Wherry, E. J.
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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 exhibit higher basal levels of activation measured by P-selectin surface expression, and have a poor functional reserve upon in vitro 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 in vitro platelet activation. Mechanistically, blocking the signaling of the Fc{gamma}RIIa-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. Cover illustration O_FIG_DISPLAY_L [Figure 1] M_FIG_DISPLAY C_FIG_DISPLAY One-sentence summaryThe Fc{gamma}RIIA and C5a-C5aR pathways mediate platelet hyperactivation in COVID-19

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Apostolidis, S. A., Sarkar, A., Giannini, H. M., Goel, R. R., Mathew, D., Suzuki, A., Baxter, A. E., Greenplate, A. R., Alanio, C., Abdel-Hakeem, M., Oldridge, D. A., Giles, J. R., Wu, J. E., Chen, Z., Huang, Y. J., Pattekar, A., Manne, S., Kuthuru, O., Dougherty, J., Weiderhold, B., Weisman, A. R., Ittner, C. A. G., Gouma, S., Dunbar, D., Frank, I., Huang, A. C., Vella, L. A., The UPenn COVID Processing Unit,, Reilly, J. P., Hensley, S. E., Rauova, L., Zhao, L., Meyer, N. J., Poncz, M., Abrams, C. S., Wherry, E. J.. 2021-05-03. Signaling through FcγRIIA and the C5a-C5aR pathway mediates platelet hyperactivation in COVID-19. https://doi.org/10.1101/2021.05.01.442279

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