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Thrombotic Thrombocytopenia after ChAdOx1 nCov-19 Vaccination.
N Engl J Med. 2021 06 03; 384(22):2092-2101.NEJM

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.).

Authors+Show Affiliations

From Institut für Immunologie und Transfusionsmedizin, Universitätsmedizin Greifswald, Greifswald (A.G., T.T.), and the Division of Safety of Medicinal Products and Medical Devices, Paul-Ehrlich-Institut (Federal Institute for Vaccines and Biomedicines), Langen (K.W.) - both in Germany; the Departments of Pathology and Molecular Medicine and of Medicine, McMaster University, Hamilton, ON, Canada (T.E.W.); and the Department of Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, Vienna (P.A.K., S.E.).From Institut für Immunologie und Transfusionsmedizin, Universitätsmedizin Greifswald, Greifswald (A.G., T.T.), and the Division of Safety of Medicinal Products and Medical Devices, Paul-Ehrlich-Institut (Federal Institute for Vaccines and Biomedicines), Langen (K.W.) - both in Germany; the Departments of Pathology and Molecular Medicine and of Medicine, McMaster University, Hamilton, ON, Canada (T.E.W.); and the Department of Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, Vienna (P.A.K., S.E.).From Institut für Immunologie und Transfusionsmedizin, Universitätsmedizin Greifswald, Greifswald (A.G., T.T.), and the Division of Safety of Medicinal Products and Medical Devices, Paul-Ehrlich-Institut (Federal Institute for Vaccines and Biomedicines), Langen (K.W.) - both in Germany; the Departments of Pathology and Molecular Medicine and of Medicine, McMaster University, Hamilton, ON, Canada (T.E.W.); and the Department of Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, Vienna (P.A.K., S.E.).From Institut für Immunologie und Transfusionsmedizin, Universitätsmedizin Greifswald, Greifswald (A.G., T.T.), and the Division of Safety of Medicinal Products and Medical Devices, Paul-Ehrlich-Institut (Federal Institute for Vaccines and Biomedicines), Langen (K.W.) - both in Germany; the Departments of Pathology and Molecular Medicine and of Medicine, McMaster University, Hamilton, ON, Canada (T.E.W.); and the Department of Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, Vienna (P.A.K., S.E.).From Institut für Immunologie und Transfusionsmedizin, Universitätsmedizin Greifswald, Greifswald (A.G., T.T.), and the Division of Safety of Medicinal Products and Medical Devices, Paul-Ehrlich-Institut (Federal Institute for Vaccines and Biomedicines), Langen (K.W.) - both in Germany; the Departments of Pathology and Molecular Medicine and of Medicine, McMaster University, Hamilton, ON, Canada (T.E.W.); and the Department of Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, Vienna (P.A.K., S.E.).From Institut für Immunologie und Transfusionsmedizin, Universitätsmedizin Greifswald, Greifswald (A.G., T.T.), and the Division of Safety of Medicinal Products and Medical Devices, Paul-Ehrlich-Institut (Federal Institute for Vaccines and Biomedicines), Langen (K.W.) - both in Germany; the Departments of Pathology and Molecular Medicine and of Medicine, McMaster University, Hamilton, ON, Canada (T.E.W.); and the Department of Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, Vienna (P.A.K., S.E.).

Pub Type(s)

Case Reports
Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

33835769

Citation

Greinacher, Andreas, et al. "Thrombotic Thrombocytopenia After ChAdOx1 nCov-19 Vaccination." The New England Journal of Medicine, vol. 384, no. 22, 2021, pp. 2092-2101.
Greinacher A, Thiele T, Warkentin TE, et al. Thrombotic Thrombocytopenia after ChAdOx1 nCov-19 Vaccination. N Engl J Med. 2021;384(22):2092-2101.
Greinacher, A., Thiele, T., Warkentin, T. E., Weisser, K., Kyrle, P. A., & Eichinger, S. (2021). Thrombotic Thrombocytopenia after ChAdOx1 nCov-19 Vaccination. The New England Journal of Medicine, 384(22), 2092-2101. https://doi.org/10.1056/NEJMoa2104840
Greinacher A, et al. Thrombotic Thrombocytopenia After ChAdOx1 nCov-19 Vaccination. N Engl J Med. 2021 06 3;384(22):2092-2101. PubMed PMID: 33835769.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Thrombotic Thrombocytopenia after ChAdOx1 nCov-19 Vaccination. AU - Greinacher,Andreas, AU - Thiele,Thomas, AU - Warkentin,Theodore E, AU - Weisser,Karin, AU - Kyrle,Paul A, AU - Eichinger,Sabine, Y1 - 2021/04/09/ PY - 2021/4/10/pubmed PY - 2021/6/16/medline PY - 2021/4/9/entrez SP - 2092 EP - 2101 JF - The New England journal of medicine JO - N Engl J Med VL - 384 IS - 22 N2 - 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.). SN - 1533-4406 UR - https://www.unboundmedicine.com/medline/citation/33835769/Thrombotic_Thrombocytopenia_after_ChAdOx1_nCov_19_Vaccination_ L2 - https://www.nejm.org/doi/10.1056/NEJMoa2104840?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -