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Thrombotic Thrombocytopenia after ChAdOx1 nCov-19 Vaccination
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Abstract
BACKGROUND: Several cases of unusual thrombotic events and thrombocytopenia have developed after vaccination with the recombinant adenoviral vector encoding the spike protein antigen of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (ChAdOx1 nCov-19, AstraZeneca). More data were needed on the pathogenesis of this unusual clotting disorder. METHODS: We assessed the clinical and laboratory features of 11 patients in Germany and Austria in whom thrombosis or thrombocytopenia had developed after vaccination with ChAdOx1 nCov-19. We used a standard enzyme-linked immunosorbent assay to detect platelet factor 4 (PF4)-heparin antibodies and a modified (PF4-enhanced) platelet-activation test to detect platelet-activating antibodies under various reaction conditions. Included in this testing were samples from patients who had blood samples referred for investigation of vaccine-associated thrombotic events, with 28 testing positive on a screening PF4-heparin immunoassay. RESULTS: Of the 11 original patients, 9 were women, with a median age of 36 years (range, 22 to 49). Beginning 5 to 16 days after vaccination, the patients presented with one or more thrombotic events, with the exception of 1 patient, who presented with fatal intracranial hemorrhage. Of the patients with one or more thrombotic events, 9 had cerebral venous thrombosis, 3 had splanchnic-vein thrombosis, 3 had pulmonary embolism, and 4 had other thromboses; of these patients, 6 died. Five patients had disseminated intravascular coagulation. None of the patients had received heparin before symptom onset. All 28 patients who tested positive for antibodies against PF4-heparin tested positive on the platelet-activation assay in the presence of PF4 independent of heparin. Platelet activation was inhibited by high levels of heparin, Fc receptor-blocking monoclonal antibody, and immune globulin (10 mg per milliliter). Additional studies with PF4 or PF4-heparin affinity purified antibodies in 2 patients confirmed PF4-dependent platelet activation. CONCLUSIONS: Vaccination with ChAdOx1 nCov-19 can result in the rare development of immune thrombotic thrombocytopenia mediated by platelet-activating antibodies against PF4, which clinically mimics autoimmune heparin-induced thrombocytopenia. (Funded by the German Research Foundation.).
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“Thrombocytopenia and immune thrombocytopenia (ITP) were also included due to their association with TTS and reports of ITP as an independent safety signal [7,19,20].”
From COVID-19 vaccines and adverse events of special interest: A multinational Global Vaccine Data Network (GVDN) cohort study of 99 million vaccinated individuals (2024) · cites this paper as [19]
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“These adverse events, which primarily affect young women, have been linked with the ChAdOx1 nCoV-1932 and Ad26.COV2.S (Johnson & Johnson–Janssen) Covid-19 vaccines,33 both of which are adenoviral vector vaccines.”
From Safety of the BNT162b2 mRNA Covid-19 Vaccine in a Nationwide Setting (2021) · cites this paper as [32]
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Metadata
- Authors
- Greinacher, A., Thiele, T., Warkentin, T. E., Weisser, K., Kyrle, P. A., & Eichinger, S.
- Affiliations
- Universitätsmedizin Greifswald (DE)
- Corresponding author
- Greinacher, Andreas
- ORCID
- Venue
- New England Journal of Medicine
- Publisher
- Massachusetts Medical Society
- Published
- 2021-06-03
- Volume
- 384
- Issue
- 22
- Pages
- 2092-2101
- ISSN
- 0028-4793 (ISSN-L)
- 1533-4406
- PMC
- PMC8095372
- OpenAlex
- W3140226555
- Cited by
- 2,259
- References
- 27
- Citations by year
- 2026: 77 · 2025: 139 · 2024: 171 · 2023: 297 · 2022: 725 · 2021: 848
- FWCI
- 479.45
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- New England Journal of Medicine (publishedVersion)
- Research Square (acceptedVersion, cc-by)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Deutsche Forschungsgemeinschaft (Projektnummer 374031971 – TRR 240)
- Topics
- Health Sciences › Medicine › Hematology › Heparin-Induced Thrombocytopenia and Thrombosis
- Life Sciences › Immunology and Microbiology › Immunology › Complement system in diseases
- Health Sciences › Medicine › Hematology › Platelet Disorders and Treatments
- Keywords
- ChAdOx1 nCoV-19 vaccine, AstraZeneca COVID-19 vaccine, vaccine-associated thrombosis, platelet factor 4, PF4/heparin antibodies, platelet-activating antibodies, cerebral venous thrombosis, pulmonary embolism, splanchnic vein thrombosis, disseminated intravascular coagulation, heparin, Fc receptor blockade, gamma globulin
- MeSH terms
- COVID-19 Vaccines, ChAdOx1 nCoV-19, Adult, Autoantibodies, Autoimmune Diseases, Blood Chemical Analysis, Disseminated Intravascular Coagulation, Enzyme-Linked Immunosorbent Assay, Female, Humans, Male, Middle Aged, Platelet Factor 4, Thrombocytopenia, Thrombosis, Platelet Activation, Fatal Outcome, Intracranial Hemorrhages, Young Adult
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