Cited by 2,259Heparin-Induced Thrombocytopenia and ThrombosisComplement system in diseasesPlatelet Disorders and Treatments

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Thrombotic Thrombocytopenia after ChAdOx1 nCov-19 Vaccination

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Greinacher, Andreas, Thiele, Thomas, Warkentin, Theodore E., Weisser, Karin, Kyrle, Paul A., Eichinger, Sabine·2021·New England Journal of Medicine

DOI 10.1056/nejmoa2104840PMC PMC8095372

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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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Authors: Greinacher, A., Thiele, T., Warkentin, T. E., Weisser, K., Kyrle, P. A., & Eichinger, S.
Affiliations: Universitätsmedizin Greifswald (DE)
Corresponding author: Greinacher, Andreas
ORCID: Greinacher, Andreas
Thiele, Thomas
Warkentin, Theodore E.
Weisser, Karin
Kyrle, Paul A.
Eichinger, Sabine
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
DOI: 10.1056/nejmoa2104840
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
Licence: www.nejmgroup.org/legal/terms-of-use.htm (vor)
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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Thrombotic Thrombocytopenia after ChAdOx1 nCov-19 Vaccination

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