Aberrant glycosylation of anti-SARS-CoV-2 spike IgG is a prothrombotic stimulus for platelets, Bye et al, 2021

Aberrant glycosylation of anti-SARS-CoV-2 spike IgG is a prothrombotic stimulus for platelets
Alexander P. Bye, Willianne Hoepel, Joanne L. Mitchell, Sophie Jegouic, 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, and Jonathan M. Gibbins
https://doi.org/10.1182/blood.2021011871
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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 FcgRIIA, 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.

Key Points (per paper)

• Aberrant glycosylation of anti-SARS-CoV-2 spike IgG immune complexes increases platelet thrombus formation on VWF.
  
  
• Inhibition of Syk, Btk, P2Y12, or FcgRIIA reverses enhancement of thrombus formation mediated by anti-SARS- CoV-2 spike immune complexes.
  

 

Refers to severe disease progression in acute COVID, but may have relevance to Long COVID and the initiation of micro-thrombi.
Immune complexes forming from IgG and recombinant spike protein, enhance platelet-mediated thrombosis, when there is abnormal glycosylation (of the Fc domain).

 

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