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      Vaccine‐induced immune thrombotic thrombocytopenia (VITT) – a novel clinico‐pathological entity with heterogeneous clinical presentations

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          Summary

          Vaccine‐induced immune thrombotic thrombocytopenia (VITT) is a novel entity that emerged in March 2021 following reports of unusual thrombosis after ChAdOx1 nCoV‐19, (AstraZeneca) vaccination. Following the recognition of this syndrome, multiple consensus guidelines have been released to risk stratify patients presenting with possible symptoms after ChAdOx1 nCoV‐19 vaccination. All guidelines rapidly identify VITT in patients with the complete triad of thrombocytopenia, thrombosis and elevated D‐dimers after ChAdOx1 nCoV‐19 vaccination. However, with earlier recognition of the associated symptoms, the clinical manifestations are likely to be more heterogeneous and represent an evolving spectrum of disease. In this setting, current guidelines may lack the sensitivity to detect early cases of VITT and risk missed or delayed diagnoses. The broad clinical phenotype and challenges associated with diagnosis of VITT are highlighted in our present case series of four patients with confirmed VITT. Dependent on the guidance used, each patient could have been classified as a low probability of VITT at presentation. The present study highlights the issues associated with the recognition of VITT, the limitations of current guidance and the need for heightened clinical vigilance as our understanding of the pathophysiology of this novel condition evolves.

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          Thrombotic Thrombocytopenia after ChAdOx1 nCov-19 Vaccination

          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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            Thrombosis and Thrombocytopenia after ChAdOx1 nCoV-19 Vaccination

            We report findings in five patients who presented with venous thrombosis and thrombocytopenia 7 to 10 days after receiving the first dose of the ChAdOx1 nCoV-19 adenoviral vector vaccine against coronavirus disease 2019 (Covid-19). The patients were health care workers who were 32 to 54 years of age. All the patients had high levels of antibodies to platelet factor 4–polyanion complexes; however, they had had no previous exposure to heparin. Because the five cases occurred in a population of more than 130,000 vaccinated persons, we propose that they represent a rare vaccine-related variant of spontaneous heparin-induced thrombocytopenia that we refer to as vaccine-induced immune thrombotic thrombocytopenia.
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              Pathologic Antibodies to Platelet Factor 4 after ChAdOx1 nCoV-19 Vaccination

              Background The mainstay of control of the coronavirus disease 2019 (Covid-19) pandemic is vaccination against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Within a year, several vaccines have been developed and millions of doses delivered. Reporting of adverse events is a critical postmarketing activity. Methods We report findings in 23 patients who presented with thrombosis and thrombocytopenia 6 to 24 days after receiving the first dose of the ChAdOx1 nCoV-19 vaccine (AstraZeneca). On the basis of their clinical and laboratory features, we identify a novel underlying mechanism and address the therapeutic implications. Results In the absence of previous prothrombotic medical conditions, 22 patients presented with acute thrombocytopenia and thrombosis, primarily cerebral venous thrombosis, and 1 patient presented with isolated thrombocytopenia and a hemorrhagic phenotype. All the patients had low or normal fibrinogen levels and elevated d -dimer levels at presentation. No evidence of thrombophilia or causative precipitants was identified. Testing for antibodies to platelet factor 4 (PF4) was positive in 22 patients (with 1 equivocal result) and negative in 1 patient. On the basis of the pathophysiological features observed in these patients, we recommend that treatment with platelet transfusions be avoided because of the risk of progression in thrombotic symptoms and that the administration of a nonheparin anticoagulant agent and intravenous immune globulin be considered for the first occurrence of these symptoms. Conclusions Vaccination against SARS-CoV-2 remains critical for control of the Covid-19 pandemic. A pathogenic PF4-dependent syndrome, unrelated to the use of heparin therapy, can occur after the administration of the ChAdOx1 nCoV-19 vaccine. Rapid identification of this rare syndrome is important because of the therapeutic implications.
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                Author and article information

                Contributors
                michellelavin@rcsi.ie
                Journal
                Br J Haematol
                Br J Haematol
                10.1111/(ISSN)1365-2141
                BJH
                British Journal of Haematology
                John Wiley and Sons Inc. (Hoboken )
                0007-1048
                1365-2141
                22 June 2021
                22 June 2021
                : 10.1111/bjh.17613
                Affiliations
                [ 1 ] National Coagulation Centre St. James’s Hospital Dublin Ireland
                [ 2 ] Irish Centre for Vascular Biology School of Pharmacy and Biomedical Sciences RCSI Dublin Ireland
                [ 3 ] North West Cancer Centre Altnagelvin Area Hospital Derry Northern Ireland
                [ 4 ] Department of Haematology University Hospital Limerick Limerick Ireland
                [ 5 ] Department of Haematology Tallaght University Hospital Dublin Ireland
                [ 6 ] Department of Medicine Wexford General Hospital Wexford Ireland
                [ 7 ] Department of Haematology University Hospital Waterford Waterford Ireland
                [ 8 ] Haemophilia and Thrombosis Centre Belfast City Hospital Belfast Northern Ireland UK
                Author notes
                [*] [* ] Correspondence: Michelle Lavin, National Coagulation Centre, St. James’s Hospital, Dublin 8, Ireland.

                E‐mail: michellelavin@ 123456rcsi.ie

                Author information
                https://orcid.org/0000-0003-2999-4216
                Article
                BJH17613
                10.1111/bjh.17613
                8444927
                34159588
                079b7c15-202d-4126-89ef-4bb39e5293d7
                © 2021 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd

                This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

                History
                : 24 April 2021
                : 11 May 2021
                Page count
                Figures: 1, Tables: 3, Pages: 9, Words: 8201
                Funding
                Funded by: 3M Foundation , doi 10.13039/100015579;
                Funded by: Health Research Board , doi 10.13039/100010414;
                Award ID: COV19‐2020‐086
                Categories
                Research Paper
                Research Papers
                Custom metadata
                2.0
                corrected-proof
                Converter:WILEY_ML3GV2_TO_JATSPMC version:6.0.7 mode:remove_FC converted:16.09.2021

                Hematology
                vaccine,thrombosis,thrombocytopenia,covid‐19,cerebral venous sinus thrombosis,splanchnic vein thrombosis

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