> Details

Greinacher, Andreas; Selleng, Kathleen; Palankar, Raghavendra; Wesche, Jan; Handtke, Stefan; Wolff, Martina; Aurich, Konstanze; Lalk, Michael; Methling, Karen; Völker, Uwe; Hentschker, Christian; Michalik, Stephan; Steil, Leif; Reder, Alexander; Schönborn, Linda; Beer, Martin; Franzke, Kati; Büttner, Andreas; Fehse, Boris; Stavrou, Evi X.; Rangaswamy, Chandini; Mailer, Reiner K.; Englert, Hanna; Frye, Maike; [...]

Insights in ChAdOx1 nCoV-19 vaccine-induced immune thrombotic thrombocytopenia

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  • Media type: E-Article
  • Title: Insights in ChAdOx1 nCoV-19 vaccine-induced immune thrombotic thrombocytopenia
  • Contributor: Greinacher, Andreas; Selleng, Kathleen; Palankar, Raghavendra; Wesche, Jan; Handtke, Stefan; Wolff, Martina; Aurich, Konstanze; Lalk, Michael; Methling, Karen; Völker, Uwe; Hentschker, Christian; Michalik, Stephan; Steil, Leif; Reder, Alexander; Schönborn, Linda; Beer, Martin; Franzke, Kati; Büttner, Andreas; Fehse, Boris; Stavrou, Evi X.; Rangaswamy, Chandini; Mailer, Reiner K.; Englert, Hanna; Frye, Maike; [...]
  • imprint: American Society of Hematology, 2021
  • Published in: Blood
  • Language: English
  • DOI: 10.1182/blood.2021013231
  • ISSN: 1528-0020; 0006-4971
  • Origination:
  • Footnote:
  • Description: <jats:title>Abstract</jats:title> <jats:p>SARS-CoV-2 vaccine ChAdOx1 nCoV-19 (AstraZeneca) causes a thromboembolic complication termed vaccine-induced immune thrombotic thrombocytopenia (VITT). Using biophysical techniques, mouse models, and analysis of VITT patient samples, we identified determinants of this vaccine-induced adverse reaction. Super-resolution microscopy visualized vaccine components forming antigenic complexes with platelet factor 4 (PF4) on platelet surfaces to which anti-PF4 antibodies obtained from VITT patients bound. PF4/vaccine complex formation was charge-driven and increased by addition of DNA. Proteomics identified substantial amounts of virus production-derived T-REx HEK293 proteins in the ethylenediaminetetraacetic acid (EDTA)-containing vaccine. Injected vaccine increased vascular leakage in mice, leading to systemic dissemination of vaccine components known to stimulate immune responses. Together, PF4/vaccine complex formation and the vaccine-stimulated proinflammatory milieu trigger a pronounced B-cell response that results in the formation of high-avidity anti-PF4 antibodies in VITT patients. The resulting high-titer anti-PF4 antibodies potently activated platelets in the presence of PF4 or DNA and polyphosphate polyanions. Anti-PF4 VITT patient antibodies also stimulated neutrophils to release neutrophil extracellular traps (NETs) in a platelet PF4-dependent manner. Biomarkers of procoagulant NETs were elevated in VITT patient serum, and NETs were visualized in abundance by immunohistochemistry in cerebral vein thrombi obtained from VITT patients. Together, vaccine-induced PF4/adenovirus aggregates and proinflammatory reactions stimulate pathologic anti-PF4 antibody production that drives thrombosis in VITT. The data support a 2-step mechanism underlying VITT that resembles the pathogenesis of (autoimmune) heparin-induced thrombocytopenia.</jats:p>
  • Access State: Open Access