-
Tytuł:
-
Insights in ChAdOx1 nCoV-19 vaccine-induced immune thrombotic thrombocytopenia.
-
Autorzy:
-
Greinacher A; Institute of Immunology and Transfusion Medicine, Department of Transfusion Medicine, University Medicine Greifswald, Greifswald, Germany.
Selleng K; Institute of Immunology and Transfusion Medicine, Department of Transfusion Medicine, University Medicine Greifswald, Greifswald, Germany.
Palankar R; Institute of Immunology and Transfusion Medicine, Department of Transfusion Medicine, University Medicine Greifswald, Greifswald, Germany.
Wesche J; Institute of Immunology and Transfusion Medicine, Department of Transfusion Medicine, University Medicine Greifswald, Greifswald, Germany.
Handtke S; Institute of Immunology and Transfusion Medicine, Department of Transfusion Medicine, University Medicine Greifswald, Greifswald, Germany.
Wolff M; Institute of Immunology and Transfusion Medicine, Department of Transfusion Medicine, University Medicine Greifswald, Greifswald, Germany.
Aurich K; Institute of Immunology and Transfusion Medicine, Department of Transfusion Medicine, University Medicine Greifswald, Greifswald, Germany.
Lalk M; Institute of Biochemistry, University of Greifswald, Greifswald, Germany.
Methling K; Institute of Biochemistry, University of Greifswald, Greifswald, Germany.
Völker U; Interfaculty Institute of Genetics and Functional Genomics, Department Functional Genomics, University Medicine Greifswald, Greifswald, Germany.; German Centre for Cardiovascular Research (DZHK), Partner Site Greifswald, Greifswald, Germany.
Hentschker C; Interfaculty Institute of Genetics and Functional Genomics, Department Functional Genomics, University Medicine Greifswald, Greifswald, Germany.
Michalik S; Interfaculty Institute of Genetics and Functional Genomics, Department Functional Genomics, University Medicine Greifswald, Greifswald, Germany.
Steil L; Interfaculty Institute of Genetics and Functional Genomics, Department Functional Genomics, University Medicine Greifswald, Greifswald, Germany.
Reder A; Interfaculty Institute of Genetics and Functional Genomics, Department Functional Genomics, University Medicine Greifswald, Greifswald, Germany.
Schönborn L; Institute of Immunology and Transfusion Medicine, Department of Transfusion Medicine, University Medicine Greifswald, Greifswald, Germany.
Beer M; Institute of Diagnostic Virology, Friedrich-Loeffler Institute, Greifswald-Insel Riems, Germany.
Franzke K; Institute of Infectious Diseases, Friedrich-Loeffler Institute, Greifswald-Insel Riems, Germany.
Büttner A; Institute of Forensic Medicine, Rostock University Medical Center, Rostock, Germany.
Fehse B; Research Department Cell & Gene Therapy, Department of Stem Cell Transplantation, University Medical Center Hamburg-Eppendorf, Hamburg Germany.; German Center for Infection Research (DZIF), Partner Site Hamburg-Lübeck-Borstel-Riems, Germany.
Stavrou EX; Department of Medicine, Hematology and Oncology Division, CWRU School of Medicine, Cleveland, OH.; Department of Medicine, Section of Hematology-Oncology, Louis Stokes Veterans Administration Medical Center, Cleveland, OH.
Rangaswamy C; Institute of Clinical Chemistry and Laboratory Medicine, University Medical Center Hamburg-Eppendorf (UKE), Hamburg, Germany.
Mailer RK; Institute of Clinical Chemistry and Laboratory Medicine, University Medical Center Hamburg-Eppendorf (UKE), Hamburg, Germany.
Englert H; Institute of Clinical Chemistry and Laboratory Medicine, University Medical Center Hamburg-Eppendorf (UKE), Hamburg, Germany.
Frye M; Institute of Clinical Chemistry and Laboratory Medicine, University Medical Center Hamburg-Eppendorf (UKE), Hamburg, Germany.
Thiele T; Institute of Immunology and Transfusion Medicine, Department of Transfusion Medicine, University Medicine Greifswald, Greifswald, Germany.
Kochanek S; Department of Gene Therapy, Ulm University, Ulm, Germany.
Krutzke L; Department of Gene Therapy, Ulm University, Ulm, Germany.
Siegerist F; Institute of Anatomy and Cell Biology, University Medicine Greifswald, Greifswald, Germany.
Endlich N; Institute of Anatomy and Cell Biology, University Medicine Greifswald, Greifswald, Germany.; NIPOKA GmbH, Greifswald, Germany.
Warkentin TE; Department of Pathology and Molecular Medicine, and.; Department of Medicine, McMaster University, Hamilton, ON, Canada; and.
Renné T; Institute of Clinical Chemistry and Laboratory Medicine, University Medical Center Hamburg-Eppendorf (UKE), Hamburg, Germany.; Center for Thrombosis and Hemostasis (CTH), Johannes Gutenberg University Medical Center, Mainz, Germany.
-
Źródło:
-
Blood [Blood] 2021 Dec 02; Vol. 138 (22), pp. 2256-2268.
-
Typ publikacji:
-
Journal Article; Research Support, Non-U.S. Gov't
-
Język:
-
English
-
Imprint Name(s):
-
Publication: 2021- : [New York] : Elsevier
Original Publication: New York, Grune & Stratton [etc.]
-
MeSH Terms:
-
Drug Contamination*
SARS-CoV-2*
Antigen-Antibody Complex/*immunology
Autoantibodies/*immunology
COVID-19/*prevention & control
Capsid Proteins/*adverse effects
ChAdOx1 nCoV-19/*adverse effects
Genetic Vectors/*adverse effects
HEK293 Cells/*immunology
Immunoglobulin G/*immunology
Platelet Factor 4/*immunology
Purpura, Thrombocytopenic, Idiopathic/*etiology
Spike Glycoprotein, Coronavirus/*adverse effects
Adenoviridae/immunology ; Animals ; Antigen-Antibody Complex/ultrastructure ; Autoantibodies/biosynthesis ; Capillary Leak Syndrome/etiology ; Capsid Proteins/immunology ; Cell Line, Transformed ; ChAdOx1 nCoV-19/chemistry ; ChAdOx1 nCoV-19/immunology ; ChAdOx1 nCoV-19/toxicity ; Dynamic Light Scattering ; Epitopes/chemistry ; Epitopes/immunology ; Extracellular Traps/immunology ; Extravasation of Diagnostic and Therapeutic Materials/etiology ; Genetic Vectors/immunology ; HEK293 Cells/chemistry ; Humans ; Imaging, Three-Dimensional ; Immunoglobulin G/biosynthesis ; Inflammation ; Mice ; Microscopy/methods ; Platelet Activation ; Proteomics ; Purpura, Thrombocytopenic, Idiopathic/blood ; Purpura, Thrombocytopenic, Idiopathic/immunology ; Sinus Thrombosis, Intracranial/diagnostic imaging ; Sinus Thrombosis, Intracranial/immunology ; Spike Glycoprotein, Coronavirus/immunology ; Virus Cultivation
-
References:
-
Vaccines (Basel). 2021 Apr 16;9(4):. (PMID: 33923530)
Blood. 2022 Aug 4;140(5):478-490. (PMID: 35486845)
JAMA. 2021 Jul 27;326(4):332-338. (PMID: 34213527)
Front Immunol. 2018 Aug 14;9:1902. (PMID: 30154800)
JCI Insight. 2021 Aug 9;6(15):. (PMID: 34166229)
ACS Nano. 2018 Dec 26;12(12):12030-12041. (PMID: 30540167)
Front Immunol. 2021 Feb 05;11:609324. (PMID: 33613531)
Nat Commun. 2017 May 22;8:14945. (PMID: 28530237)
Cell Syst. 2016 Sep 28;3(3):287-301.e3. (PMID: 27641958)
EBioMedicine. 2019 Feb;40:595-604. (PMID: 30711515)
Nat Rev Immunol. 2002 May;2(5):323-35. (PMID: 12033738)
Vaccines (Basel). 2020 Oct 30;8(4):. (PMID: 33142956)
Blood. 2021 Mar 11;137(10):1392-1405. (PMID: 32932519)
Blood. 2018 Dec 6;132(23):2431-2440. (PMID: 30309891)
Nat Rev Immunol. 2020 Feb;20(2):95-112. (PMID: 31558839)
J Thromb Haemost. 2021 May;19(5):1342-1347. (PMID: 33639037)
Int J Mol Sci. 2021 Feb 28;22(5):. (PMID: 33670859)
J Thromb Haemost. 2021 May;19(5):1149-1160. (PMID: 33587783)
Science. 2017 Dec 1;358(6367):1202-1206. (PMID: 29191910)
Blood. 2013 Apr 25;121(17):3484-92. (PMID: 23460609)
Sci Rep. 2017 Sep 13;7(1):11473. (PMID: 28904359)
Blood. 2007 Apr 1;109(7):2832-9. (PMID: 17148587)
Transl Res. 2020 Nov;225:131-140. (PMID: 32417430)
Arterioscler Thromb Vasc Biol. 2006 Oct;26(10):2386-93. (PMID: 16873726)
Nat Methods. 2012 Jun 28;9(7):676-82. (PMID: 22743772)
Thromb Haemost. 2016 Apr;115(4):752-61. (PMID: 26467272)
N Engl J Med. 2021 Jun 10;384(23):2202-2211. (PMID: 33861525)
Arterioscler Thromb Vasc Biol. 2021 Jan;41(1):141-152. (PMID: 33267665)
Sci Rep. 2019 May 1;9(1):6744. (PMID: 31043645)
N Engl J Med. 2015 Nov 5;373(19):1883-4. (PMID: 26535525)
Gene. 2015 Sep 15;569(2):182-90. (PMID: 26026906)
Nat Commun. 2015 Sep 22;6:8277. (PMID: 26391892)
Blood Adv. 2020 Jan 28;4(2):287-295. (PMID: 31968077)
Immunity. 2003 May;18(5):675-85. (PMID: 12753744)
J Thromb Haemost. 2017 Nov;15(11):2099-2114. (PMID: 28846826)
Trends Cell Biol. 2021 Jan;31(1):17-23. (PMID: 33023793)
Nat Commun. 2019 Mar 21;10(1):1322. (PMID: 30899022)
Blood. 2006 Mar 15;107(6):2346-53. (PMID: 16304054)
Eur J Hum Genet. 2001 Oct;9(10):780-6. (PMID: 11781690)
J Immunol. 2019 Oct 1;203(7):1786-1792. (PMID: 31471526)
Blood. 2014 Feb 6;123(6):931-4. (PMID: 24357731)
Nature. 2021 Aug;596(7873):565-569. (PMID: 34233346)
Lancet. 2021 Dec 19;396(10267):1979-1993. (PMID: 33220855)
Sci Transl Med. 2015 Jul 1;7(294):294ra105. (PMID: 26136476)
Blood. 2010 Mar 4;115(9):1797-803. (PMID: 19965682)
Thromb Res. 2021 Aug;204:40-51. (PMID: 34144250)
N Engl J Med. 2021 Jun 3;384(22):2092-2101. (PMID: 33835769)
Front Immunol. 2020 Oct 07;11:568513. (PMID: 33117353)
Blood. 2013 Jul 11;122(2):272-81. (PMID: 23673861)
Am J Physiol Lung Cell Mol Physiol. 2000 Dec;279(6):L1218-25. (PMID: 11076812)
Brain Behav Immun. 2015 Jul;47:44-57. (PMID: 25452148)
N Engl J Med. 2021 Jun 3;384(22):2124-2130. (PMID: 33835768)
Blood. 2011 Jan 27;117(4):1370-8. (PMID: 20959601)
EBioMedicine. 2021 May;67:103382. (PMID: 34000623)
PLoS Biol. 2021 Feb 17;19(2):e3001109. (PMID: 33596198)
JCI Insight. 2018 Sep 20;3(18):. (PMID: 30232279)
Viruses. 2020 Nov 26;12(12):. (PMID: 33255892)
Blood. 2017 May 25;129(21):2864-2872. (PMID: 28416511)
-
Grant Information:
-
I01 BX003851 United States BX BLRD VA; R01 HL137695 United States HL NHLBI NIH HHS
-
Substance Nomenclature:
-
0 (Antigen-Antibody Complex)
0 (Autoantibodies)
0 (Capsid Proteins)
0 (Epitopes)
0 (Immunoglobulin G)
0 (PF4 protein, human)
0 (Spike Glycoprotein, Coronavirus)
0 (spike protein, SARS-CoV-2)
37270-94-3 (Platelet Factor 4)
B5S3K2V0G8 (ChAdOx1 nCoV-19)
-
Entry Date(s):
-
Date Created: 20210929 Date Completed: 20211209 Latest Revision: 20220910
-
Update Code:
-
20240105
-
PubMed Central ID:
-
PMC8483989
-
DOI:
-
10.1182/blood.2021013231
-
PMID:
-
34587242
-
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.
(© 2021 by The American Society of Hematology.)
Comment in: Blood. 2021 Dec 2;138(22):2159-2160. (PMID: 34854882)
