TY - JOUR
T1 - Aberrant glycosylation of anti-SARS-CoV-2 spike IgG is a prothrombotic stimulus for platelets
AU - Bye, Alexander P.
AU - Hoepel, Willianne
AU - Mitchell, Joanne L.
AU - Jégouic, Sophie
AU - Loureiro, Silvia
AU - Sage, Tanya
AU - Vidarsson, Gestur
AU - Nouta, Jan
AU - Wuhrer, Manfred
AU - de Taeye, Steven
AU - van Gils, Marit
AU - Kriek, Neline
AU - Cooper, Nichola
AU - Jones, Ian
AU - den Dunnen, Jeroen
AU - Gibbins, Jonathan M.
N1 - Funding Information: Conflict-of-interest disclosure: J.M.G. has served as a consultant for Astra Zeneca and has received research funding from Celgene/Bristol Myers Squibb and Arena Pharmaceuticals. S.d.T. and M.v.G. have filed a patent application concerning the SARS-CoV-2 mAbs described in the article. N.C. has received honoraria and research funding from Rigel, Grifols, and Novartis. The remaining authors declare no competing financial interests. Funding Information: This work was supported by Imperial College National Institute for Health Research bioresources and grants from the British Heart Foundation (RG/15/2/31224 and RG/20/7/34866), ZonMw (10430 01 201 0008) and by Amsterdam Infection and Immunity COVID-19 grant 24184. Publisher Copyright: © 2021 American Society of Hematology
PY - 2021/10/21
Y1 - 2021/10/21
N2 - 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.
AB - 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.
KW - Antibodies, Viral/blood
KW - Antigen-Antibody Complex/immunology
KW - Blood Platelets/immunology
KW - COVID-19/complications
KW - Glycosylation
KW - Humans
KW - Immunoglobulin G/immunology
KW - Platelet Activation/immunology
KW - SARS-CoV-2/immunology
KW - Spike Glycoprotein, Coronavirus/metabolism
KW - Thrombosis/immunology
KW - von Willebrand Factor/genetics
UR - https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85113184843&origin=inward
UR - https://www.ncbi.nlm.nih.gov/pubmed/34315173
U2 - https://doi.org/10.1182/blood.2021011871
DO - https://doi.org/10.1182/blood.2021011871
M3 - Article
C2 - 34315173
SN - 0006-4971
VL - 138
SP - 1481
EP - 1489
JO - Blood
JF - Blood
IS - 16
ER -