Insights in ChAdOx1 nCoV-19 vaccine-induced immune thrombotic thrombocytopenia Academic Article uri icon

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abstract

  • Abstract 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.

authors

  • 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
  • Thiele, Thomas
  • Kochanek, Stefan
  • Krutzke, Lea
  • Siegerist, Florian
  • Endlich, Nicole
  • Warkentin, Ted
  • Renné, Thomas

publication date

  • December 2, 2021

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