Aberrant glycosylation of anti-SARS-CoV-2 spike IgG is a prothrombotic stimulus for platelets

Alexander P. Bye, Willianne Hoepel, Joanne L. Mitchell, Sophie Jégouic, Silvia Loureiro, Tanya Sage, Gestur Vidarsson, Jan Nouta, Manfred Wuhrer, Steven de Taeye, Marit van Gils, Neline Kriek, Nichola Cooper, Ian Jones, Jeroen den Dunnen, Jonathan M. Gibbins

Research output: Contribution to journalArticleAcademicpeer-review

56 Citations (Scopus)

Abstract

A subset of patients with coronavirus disease 2019 (COVID-19) become critically ill, suffering from severe respiratory problems and also increased rates of thrombosis. The causes of thrombosis in severely ill patients with COVID-19 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 hypothesized that platelets might be susceptible to activation by anti–severe acute respiratory syndrome coronavirus 2 (anti-SARS-CoV-2) antibodies and might contribute to thrombosis. We found that immune complexes containing recombinant SARS-CoV-2 spike protein and anti-spike immunoglobulin G 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 FcγRIIA, and we provide in vitro evidence that this pathogenic platelet activation can be counteracted by the therapeutic small molecules R406 (fostamatinib) and ibrutinib, which inhibit tyrosine kinases Syk and Btk, respectively, or by the P2Y12 antagonist cangrelor.
Original languageEnglish
Pages (from-to)1481-1489
Number of pages9
JournalBlood
Volume138
Issue number16
DOIs
Publication statusPublished - 21 Oct 2021

Keywords

  • Antibodies, Viral/blood
  • Antigen-Antibody Complex/immunology
  • Blood Platelets/immunology
  • COVID-19/complications
  • Glycosylation
  • Humans
  • Immunoglobulin G/immunology
  • Platelet Activation/immunology
  • SARS-CoV-2/immunology
  • Spike Glycoprotein, Coronavirus/metabolism
  • Thrombosis/immunology
  • von Willebrand Factor/genetics

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