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      COVID‐19 vaccine‐associated immune thrombosis and thrombocytopenia (VITT): Diagnostic and therapeutic recommendations for a new syndrome

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          Abstract

          Very rare cases of thrombosis associated with thrombocytopenia have occurred following the vaccination with AstraZeneca COVID‐19 vaccine. The aim of this concise review is to summarize the current knowledge on the epidemiologic and pathogenic mechanisms of this syndrome named vaccine‐associated immune thrombosis and thrombocytopenia (VITT). A practical patient management section will also be dealt with using information available from national and international scientific societies as well as expert panels. A literature search on the VITT syndrome was carried out in PubMed using appropriate MeSH headings. Overall, 40 VITT cases have been reported. Continuous pharmacovigilance monitoring is needed to collect more data on the real incidence and the pathogenesis of VITT syndrome. Such information will also help us to optimize the management this rare but often clinically severe thrombotic condition associated with COVID‐19 vaccination.

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          Most cited references30

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          Association Between Administration of Systemic Corticosteroids and Mortality Among Critically Ill Patients With COVID-19: A Meta-analysis

          Effective therapies for patients with coronavirus disease 2019 (COVID-19) are needed, and clinical trial data have demonstrated that low-dose dexamethasone reduced mortality in hospitalized patients with COVID-19 who required respiratory support.
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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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              REGN-COV2, a Neutralizing Antibody Cocktail, in Outpatients with Covid-19

              Abstract Background Recent data suggest that complications and death from coronavirus disease 2019 (Covid-19) may be related to high viral loads. Methods In this ongoing, double-blind, phase 1–3 trial involving nonhospitalized patients with Covid-19, we investigated two fully human, neutralizing monoclonal antibodies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein, used in a combined cocktail (REGN-COV2) to reduce the risk of the emergence of treatment-resistant mutant virus. Patients were randomly assigned (1:1:1) to receive placebo, 2.4 g of REGN-COV2, or 8.0 g of REGN-COV2 and were prospectively characterized at baseline for endogenous immune response against SARS-CoV-2 (serum antibody–positive or serum antibody–negative). Key end points included the time-weighted average change in viral load from baseline (day 1) through day 7 and the percentage of patients with at least one Covid-19–related medically attended visit through day 29. Safety was assessed in all patients. Results Data from 275 patients are reported. The least-squares mean difference (combined REGN-COV2 dose groups vs. placebo group) in the time-weighted average change in viral load from day 1 through day 7 was −0.56 log10 copies per milliliter (95% confidence interval [CI], −1.02 to −0.11) among patients who were serum antibody–negative at baseline and −0.41 log10 copies per milliliter (95% CI, −0.71 to −0.10) in the overall trial population. In the overall trial population, 6% of the patients in the placebo group and 3% of the patients in the combined REGN-COV2 dose groups reported at least one medically attended visit; among patients who were serum antibody–negative at baseline, the corresponding percentages were 15% and 6% (difference, −9 percentage points; 95% CI, −29 to 11). The percentages of patients with hypersensitivity reactions, infusion-related reactions, and other adverse events were similar in the combined REGN-COV2 dose groups and the placebo group. Conclusions In this interim analysis, the REGN-COV2 antibody cocktail reduced viral load, with a greater effect in patients whose immune response had not yet been initiated or who had a high viral load at baseline. Safety outcomes were similar in the combined REGN-COV2 dose groups and the placebo group. (Funded by Regeneron Pharmaceuticals and the Biomedical and Advanced Research and Development Authority of the Department of Health and Human Services; ClinicalTrials.gov number, NCT04425629.)
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                Author and article information

                Contributors
                massimo.franchini@asst-mantova.it
                Journal
                Eur J Haematol
                Eur J Haematol
                10.1111/(ISSN)1600-0609
                EJH
                European Journal of Haematology
                John Wiley and Sons Inc. (Hoboken )
                0902-4441
                1600-0609
                09 June 2021
                : 10.1111/ejh.13665
                Affiliations
                [ 1 ] Department of Hematology and Transfusion Medicine Carlo Poma Hospital Mantova Italy
                Author notes
                [*] [* ] Correspondence

                Massimo Franchini, Department of Hematology and Transfusion Medicine, Carlo Poma Hospital, Mantova, Italy.

                Email: massimo.franchini@ 123456asst-mantova.it

                Article
                EJH13665
                10.1111/ejh.13665
                8239516
                33987882
                4a1ba0b7-5470-4440-8f88-a2647db0950a
                © 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd

                This article is being made freely available through PubMed Central as part of the COVID-19 public health emergency response. It can be used for unrestricted research re-use and analysis in any form or by any means with acknowledgement of the original source, for the duration of the public health emergency.

                History
                : 10 May 2021
                : 11 May 2021
                Page count
                Figures: 1, Tables: 1, Pages: 8, Words: 11580
                Categories
                Review
                Reviews
                Custom metadata
                2.0
                corrected-proof
                Converter:WILEY_ML3GV2_TO_JATSPMC version:6.0.2 mode:remove_FC converted:29.06.2021

                Hematology
                astrazeneca vaccine,cerebral venous thrombosis,heparin,thrombocytopenia
                Hematology
                astrazeneca vaccine, cerebral venous thrombosis, heparin, thrombocytopenia

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