• Andreas Greinacher, Kathleen Selleng, Julia Mayerle, Raghavendra Palankar, Jan Wesche, Sven Reiche, Andrea Aebischer, Theodore E Warkentin, Maximilian Muenchhoff, Johannes C Hellmuth, Oliver T Keppler, Daniel Duerschmied, Achim Lother, Siegbert Rieg, Meinrad Paul Gawaz, Karin Anne Lydia Mueller, Christian S Scheer, Matthias Napp, Klaus Hahnenkamp, Guglielmo Lucchese, Antje Vogelgesang, Agnes Flöel, Piero Lovreglio, Angela Stufano, Rolf Marschalek, Thomas Thiele, and Immune-Response in COVID-19 Vaccination Study Group.
• Institute of Immunology and Transfusion Medicine, Department of Transfusion Medicine, Universitätsmedizin Greifswald, Greifswald, Germany.
• Blood. 2021 Oct 7; 138 (14): 1269-1277.

AbstractVaccine-induced immune thrombotic thrombocytopenia (VITT) is a severe adverse effect of ChAdOx1 nCoV-19 COVID-19 vaccine (Vaxzevria) and Janssen Ad26.COV2.S COVID-19 vaccine, and it is associated with unusual thrombosis. VITT is caused by anti-platelet factor 4 (PF4) antibodies activating platelets through their FcγRIIa receptors. Antibodies that activate platelets through FcγRIIa receptors have also been identified in patients with COVID-19. These findings raise concern that vaccination-induced antibodies against anti-SARS-CoV-2 spike protein cause thrombosis by cross-reacting with PF4. Immunogenic epitopes of PF4 and SARS-CoV-2 spike protein were compared using in silico prediction tools and 3D modeling. The SARS-CoV-2 spike protein and PF4 share at least 1 similar epitope. Reactivity of purified anti-PF4 antibodies from patients with VITT was tested against recombinant SARS-CoV-2 spike protein. However, none of the affinity-purified anti-PF4 antibodies from 14 patients with VITT cross-reacted with SARS-CoV-2 spike protein. Sera from 222 polymerase chain reaction-confirmed patients with COVID-19 from 5 European centers were tested by PF4-heparin enzyme-linked immunosorbent assays and PF4-dependent platelet activation assays. We found anti-PF4 antibodies in sera from 19 (8.6%) of 222 patients with COVID-19. However, only 4 showed weak to moderate platelet activation in the presence of PF4, and none of those patients developed thrombotic complications. Among 10 (4.5%) of 222 patients who had COVID-19 with thrombosis, none showed PF4-dependent platelet-activating antibodies. In conclusion, antibodies against PF4 induced by vaccination do not cross-react with the SARS-CoV-2 spike protein, indicating that the intended vaccine-induced immune response against SARS-CoV-2 spike protein is not the trigger of VITT. PF4-reactive antibodies found in patients with COVID-19 in this study were not associated with thrombotic complications.© 2021 by The American Society of Hematology.

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