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Lipid-binding Antiphospholipid Antibodies Trigger Autoimmune Signaling in Severe COVID-19

A. Hollerbach1, N. Müller-Calleja1, D. Pedrosa2, M.F. Sprinzl3, P.R. Galle3, L. Teyton4, W. Ruf2,4, K.J. Lackner1

1Johannes Gutenberg University Medical Center Mainz / Institute for Clinical Chemistry and Laboratory Medicine, Mainz, Germany, 2Johannes Gutenberg University Medical Center Mainz / Center for Thrombosis and Hemostasis (CTH), Mainz, Germany, 3Johannes Gutenberg University Medical Center Mainz / Department of Medicine I, Mainz, Germany, 4Scripps Research / Department of Immunology and Microbiology, La Jolla, United States

Abstract Number: OC 03.4

Meeting: ISTH 2021 Congress

Theme: COVID and Coagulation » COVID and Coagulation, Basic Science

Background: Antiphospholipid antibodies (aPL) are causally involved in the pathogenesis of the antiphospholipid syndrome (APS), but lipid-binding aPL are also frequently found in acute infections. While lipid-binding aPL are considered irrelevant for APS we have shown that they are prothrombotic in vivo and have delineated the underlying signaling pathway. COVID-19 associated coagulopathy has many similarities to severe and catastrophic APS e.g. stroke, venous and pulmonary clots, as well as microvascular thrombosis and aPL have been described in COVID-19. However, their role in COVID-19 is still poorly understood.

Aims: In this study, we aimed to elucidate the role of lipid-binding aPL in severe COVID-19.

Methods: B cells were analyzed using flow cytometry. aPL were measured by immunoassays including a home-made ELISA for lipid-binding aPL. Cultured cells were stimulated with immunoglobulins isolated from COVID-19 patients. Gene expression was measured by qRT-PCR, cellular procoagulant activity was determined by a clotting assay. In vivo thrombus formation was determined in the flow-restricted inferior vena cava mouse model.

Results: We identified a distinct population of circulating B1a cells producing lipid-reactive aPL of the IgG isotype in COVID-19 patients. 43 of 53 COVID-19 patients tested positive for lipid-binding aPL. Positive patients had more often a critical clinical course and a higher mortality. In vitro, COVID-19 aPL induced inflammatory and prothrombotic pathways in monocytes and endothelial cells and rapidly decrypted cell surface tissue factor. These effects were dependent on a recently described signaling pathway involving lysobisphosphatidic acid (LBPA) presented by the endothelial protein C receptor (EPCR) on the cell surface. In vivo, COVID-19 aPL induced thrombus formation by this EPCR-LBPA-dependent signaling pathway.

Conclusions: COVID-19 patients develop lipid-binding aPL produced by circulating B1a cells. These aPL are associated with a more severe course and mortality and show prothrombotic and inflammatory properties by targeting the previously delineated aPL autoimmune signaling pathway dependent on EPCR-LBPA.

To cite this abstract in AMA style:

Hollerbach A, Müller-Calleja N, Pedrosa D, Sprinzl MF, Galle PR, Teyton L, Ruf W, Lackner KJ. Lipid-binding Antiphospholipid Antibodies Trigger Autoimmune Signaling in Severe COVID-19 [abstract]. Res Pract Thromb Haemost. 2021; 5 (Suppl 2). https://abstracts.isth.org/abstract/lipid-binding-antiphospholipid-antibodies-trigger-autoimmune-signaling-in-severe-covid-19/. Accessed September 29, 2023.

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