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 ITP were included due to their association with TTS and reports of ITP as an independent safety signal.
“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]
The Discussion describes thrombocytopenia as part of vaccine-induced immune thrombotic thrombocytopenia (VITT), supporting the link between thrombocytopenia and the thrombotic syndrome. It does not identify immune thrombocytopenia (ITP) as a separate condition associated with that syndrome or report ITP as an independent safety signal; those parts are unsupported by this source. (LLM, conf=0.86)
Experimental — accuracy not yet measuredThromboembolic events primarily affect young women and have been linked with the ChAdOx1 nCoV-19 and Ad26.COV2.S Covid-19 vaccines, both of which are adenoviral vector vaccines.
“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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- 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 · 2018: 1
- 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 › Surgery › 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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