Anti–platelet factor 4 antibodies causing VITT do not cross-react with SARS-CoV-2 spike protein Academic Article uri icon

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  • Abstract Vaccine-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.


  • Greinacher, Andreas
  • Selleng, Kathleen
  • Mayerle, Julia
  • Palankar, Raghavendra
  • Wesche, Jan
  • Reiche, Sven
  • Aebischer, Andrea
  • Warkentin, Ted
  • Muenchhoff, Maximilian
  • Hellmuth, Johannes C
  • Keppler, Oliver T
  • Duerschmied, Daniel
  • Lother, Achim
  • Rieg, Siegbert
  • Gawaz, Meinrad Paul
  • Mueller, Karin Anne Lydia
  • Scheer, Christian S
  • Napp, Matthias
  • Hahnenkamp, Klaus
  • Lucchese, Guglielmo
  • Vogelgesang, Antje
  • Flöel, Agnes
  • Lovreglio, Piero
  • Stufano, Angela
  • Marschalek, Rolf
  • Thiele, Thomas

publication date

  • October 7, 2021

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