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Biomarkers in long COVID-19: A systematic review
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      Vaccine-induced immune thrombotic thrombocytopenia is mediated by a stereotyped clonotypic antibody

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          Thrombotic Thrombocytopenia after ChAdOx1 nCov-19 Vaccination

          Andreas Greinacher, Thomas Thiele, Theodore Warkentin … (2021)
          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

            Nina Schultz, Ingvild Sørvoll, Annika Michelsen … (2021)
            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

              Marie Scully, Deepak Singh, Robert Lown … (2021)
              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

                Journal
                Journal ID (nlm-ta): Blood
                Journal ID (iso-abbrev): Blood
                Title: Blood
                Publisher: by The American Society of Hematology
                ISSN (Print): 0006-4971
                ISSN (Electronic): 1528-0020
                Publication date PMC-release: 6 June 2022
                Publication date (Print): 13 October 2022
                Publication date (Electronic): 6 June 2022
                Volume: 140
                Issue: 15
                Pages: 1738-1742
                Affiliations
                [1 ]Department of Immunology, College of Medicine and Public Health, Flinders University, Bedford Park, SA, Australia
                [2 ]Department of Immunology, South Australia (SA) Pathology (Flinders Medical Centre), Bedford Park, SA, Australia
                [3 ]Flinders Proteomics Facility, College of Medicine and Public Health, Flinders University, Bedford Park, SA, Australia
                [4 ]SA Pathology, Adelaide, SA, Australia
                [5 ]Intensive Care Unit, Calvary Hospital, Adelaide, SA, Australia
                [6 ]Department of Haematology, Royal Adelaide Hospital, Central Area Local Health Network (CALHN), Adelaide, SA, Australia
                Author notes
                [∗ ]Correspondence: Jing Jing Wang, Department of Immunology, College of Medicine and Public Health, Flinders University, Bedford Park, SA 5042, Australia;
                Article
                Publisher Item ID: S0006-4971(22)00737-6
                DOI: 10.1182/blood.2022016474
                PMC ID: 9906116
                PubMed ID: 35661872
                SO-VID: 9af13eb0-ea62-4237-b508-dbb629945e04
                Copyright © © 2022 by The American Society of Hematology.
                License:

                Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.

                History
                Date received : 28 March 2022
                Date accepted : 31 May 2022
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                Subject: Letter to Blood

                ScienceOpen disciplines: Hematology
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                ScienceOpen disciplines: Hematology

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