RT Journal Article
SR Electronic
T1 Aberrant glycosylation of anti-SARS-CoV-2 IgG is a pro-thrombotic stimulus for platelets
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2021.03.26.437014
DO 10.1101/2021.03.26.437014
A1 Bye, Alexander P
A1 Hoepel, Willianne
A1 Mitchell, Joanne L
A1 Jégouic, Sophie
A1 Loureiro, Silvia
A1 Sage, Tanya
A1 de Taeye, Steven
A1 van Gils, Marit
A1 Kriek, Neline
A1 Cooper, Nichola
A1 Jones, Ian
A1 den Dunnen, Jeroen
A1 Gibbins, Jonathan M
YR 2021
UL http://biorxiv.org/content/early/2021/03/26/2021.03.26.437014.abstract
AB 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 StatementJonathan 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