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Aberrant glycosylation of anti-SARS-CoV-2 IgG is a pro-thrombotic stimulus for platelets

Alexander P Bye, Willianne Hoepel, Joanne L Mitchell, Sophie Jégouic, Silvia Loureiro, Tanya Sage, Steven de Taeye, View ORCID ProfileMarit van Gils, Neline Kriek, Nichola Cooper, Ian Jones, Jeroen den Dunnen, Jonathan M Gibbins
doi: https://doi.org/10.1101/2021.03.26.437014
Alexander P Bye
1Institute for Cardiovascular and Metabolic Research, University of Reading, Reading, United Kingdom
2School of Biological Sciences, University of Reading, UK
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Willianne Hoepel
3Department of Rheumatology and Clinical Immunology, Amsterdam UMC, Amsterdam Rheumatology and Immunology Center, Amsterdam, Netherlands
4Department of Experimental Immunology, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands
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Joanne L Mitchell
1Institute for Cardiovascular and Metabolic Research, University of Reading, Reading, United Kingdom
5Institute of Cardiovascular Sciences, College of Medical and Dental Sciences, University of Birmingham
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Sophie Jégouic
2School of Biological Sciences, University of Reading, UK
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Silvia Loureiro
2School of Biological Sciences, University of Reading, UK
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Tanya Sage
1Institute for Cardiovascular and Metabolic Research, University of Reading, Reading, United Kingdom
2School of Biological Sciences, University of Reading, UK
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Steven de Taeye
6Department of Medical Microbiology, Amsterdam UMC, University of Amsterdam, Amsterdam Infection and Immunity Institute, Amsterdam, Netherlands
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Marit van Gils
6Department of Medical Microbiology, Amsterdam UMC, University of Amsterdam, Amsterdam Infection and Immunity Institute, Amsterdam, Netherlands
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  • ORCID record for Marit van Gils
Neline Kriek
1Institute for Cardiovascular and Metabolic Research, University of Reading, Reading, United Kingdom
2School of Biological Sciences, University of Reading, UK
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Nichola Cooper
7Hammersmith Hospital, Imperial College London, London, UK
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Ian Jones
2School of Biological Sciences, University of Reading, UK
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Jeroen den Dunnen
3Department of Rheumatology and Clinical Immunology, Amsterdam UMC, Amsterdam Rheumatology and Immunology Center, Amsterdam, Netherlands
4Department of Experimental Immunology, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands
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Jonathan M Gibbins
1Institute for Cardiovascular and Metabolic Research, University of Reading, Reading, United Kingdom
2School of Biological Sciences, University of Reading, UK
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  • For correspondence: j.m.gibbins@reading.ac.uk
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Abstract

A subset of patients with COVID-19 become critically ill, suffering from severe respiratory problems and also increased rates of thrombosis. The causes of thrombosis in severely ill COVID-19 patients are still emerging, but the coincidence of critical illness with the timing of the onset of adaptive immunity could implicate an excessive immune response. We hypothesised that platelets might be susceptible to activation by anti-SARS-CoV-2 antibodies and contribute to thrombosis. We found that immune complexes containing recombinant SARS-CoV-2 spike protein and anti-spike IgG enhanced platelet-mediated thrombosis on von Willebrand Factor in vitro, but only when the glycosylation state of the Fc domain was modified to correspond with the aberrant glycosylation previously identified in patients with severe COVID-19. Furthermore, we found that activation was dependent on FcyRIIA and we provide in vitro evidence that this pathogenic platelet activation can be counteracted by therapeutic small molecules R406 (fostamatinib) and ibrutinib that inhibit tyrosine kinases syk and btk respectively or by the P2Y12 antagonist cangrelor.

Competing Interest Statement

Jonathan Gibbins; Consultancy for Astra Zeneca, Research funding from Celgene/Bristol Myers Squibb, Research funding from Arena Pharmaceuticals Steven de Taeye and Marit van Gils; Amsterdam UMC has filed a patent application concerning the SARS-CoV-2 mAbs described in the manuscript. Nichola Cooper; honoraria and research funding from Rigel, Griffols and Novartis

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted March 26, 2021.
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Aberrant glycosylation of anti-SARS-CoV-2 IgG is a pro-thrombotic stimulus for platelets
Alexander P Bye, Willianne Hoepel, Joanne L Mitchell, Sophie Jégouic, Silvia Loureiro, Tanya Sage, Steven de Taeye, Marit van Gils, Neline Kriek, Nichola Cooper, Ian Jones, Jeroen den Dunnen, Jonathan M Gibbins
bioRxiv 2021.03.26.437014; doi: https://doi.org/10.1101/2021.03.26.437014
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Aberrant glycosylation of anti-SARS-CoV-2 IgG is a pro-thrombotic stimulus for platelets
Alexander P Bye, Willianne Hoepel, Joanne L Mitchell, Sophie Jégouic, Silvia Loureiro, Tanya Sage, Steven de Taeye, Marit van Gils, Neline Kriek, Nichola Cooper, Ian Jones, Jeroen den Dunnen, Jonathan M Gibbins
bioRxiv 2021.03.26.437014; doi: https://doi.org/10.1101/2021.03.26.437014

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