Insights in ChAdOx1 nCoV-19 vaccine-induced immune thrombotic thrombocytopenia.
Blood
; 138(22): 2256-2268, 2021 12 02.
Article
in English
| MEDLINE | ID: covidwho-1443788
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.
Full text:
Available
Collection:
International databases
Database:
MEDLINE
Main subject:
Autoantibodies
/
Immunoglobulin G
/
Platelet Factor 4
/
Drug Contamination
/
Purpura, Thrombocytopenic, Idiopathic
/
Capsid Proteins
/
HEK293 Cells
/
Spike Glycoprotein, Coronavirus
/
Genetic Vectors
/
SARS-CoV-2
Type of study:
Diagnostic study
/
Prognostic study
Topics:
Vaccines
Language:
English
Journal:
Blood
Year:
2021
Document Type:
Article
Affiliation country:
Blood.2021013231
Similar
MEDLINE
...
LILACS
LIS