Mary Wilson
Well-known member
DECEMBER 2, 2021
https://doi.org/10.1182/blood.2021013231
Andreas Greinacher, Kathleen Selleng, Raghavendra Palankar, Jan Wesche, Stefan Handtke, Martina Wolff, Konstanze Aurich, Michael Lalk, Karen Methling, Uwe Völker, Christian Hentschker, Stephan Michalik, Leif Steil, Alexander Reder, Linda Schönborn, Martin Beer, Kati Franzke, Andreas Büttner,
Boris Fehse, Evi X. Stavrou, Chandini Rangaswamy, Reiner K. Mailer, Hanna Englert, Maike Frye,
Thomas Thiele, Stefan Kochanek, Lea Krutzke, Florian Siegerist, Nicole Endlich,Theodore E. Warkentin,
Thomas Renné
Key Points
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.
https://ashpublications.org/blood/a...rm=Read+More+»&utm_id=135209&sfmc_id=19282790
https://doi.org/10.1182/blood.2021013231
Andreas Greinacher, Kathleen Selleng, Raghavendra Palankar, Jan Wesche, Stefan Handtke, Martina Wolff, Konstanze Aurich, Michael Lalk, Karen Methling, Uwe Völker, Christian Hentschker, Stephan Michalik, Leif Steil, Alexander Reder, Linda Schönborn, Martin Beer, Kati Franzke, Andreas Büttner,
Boris Fehse, Evi X. Stavrou, Chandini Rangaswamy, Reiner K. Mailer, Hanna Englert, Maike Frye,
Thomas Thiele, Stefan Kochanek, Lea Krutzke, Florian Siegerist, Nicole Endlich,Theodore E. Warkentin,
Thomas Renné
Key Points
- ChAdOx1 nCoV-19 vaccine contains human TRex HEK293 cell-derived proteins and EDTA.
- Vaccine components and PF4 form complexes on platelet surfaces to which VITT patient antibodies bind.
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.
https://ashpublications.org/blood/a...rm=Read+More+»&utm_id=135209&sfmc_id=19282790
